@article {pmid34871345, year = {2021}, author = {Lozano, CP and Wilkens, LR and Shvetsov, YB and Maskarinec, G and Park, SY and Shepherd, JA and Boushey, CJ and Hebert, JR and Wirth, MD and Ernst, T and Randolph, T and Lim, U and Lampe, JW and Marchand, LL and Hullar, MAJ}, title = {Associations of the Dietary Inflammatory Index with total adiposity and ectopic fat through the gut microbiota, lipopolysaccharides, and C-reactive protein in the Multiethnic Cohort-Adiposity Phenotype Study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqab398}, pmid = {34871345}, issn = {1938-3207}, abstract = {Background Mechanisms linking a pro-inflammatory diet to obesity remain under investigation. The ability of diet to influence the gut microbiome (GM) in creating chronic low-grade systemic inflammation provides a plausible connection to adiposity.<br><br>METHODS: In the cross-sectional Multiethnic Cohort Adiposity Phenotype Study (812 men, 843 women, 60 to 77 years) we tested whether associations between the energy-adjusted Dietary Inflammatory Index (E-DIITM) score and total adiposity, visceral adipose tissue (VAT), and liver fat (% volume) function through the GM, lipopolysaccharides (LPS), and high-sensitivity C-reactive protein (hs-CRP). Dual energy X-ray absorptiometry (DXA)-derived total fat mass, MRI-measured VAT, and MRI-based liver fat were measured. Participants provided stool and fasting blood samples and completed a food frequency questionnaire (FFQ). Stool bacterial DNA was amplified and the 16S rRNA gene was sequenced at the V1-V3 region. E-DII score was computed from FFQ data, with a higher E-DII representing a more pro-inflammatory diet. The associations between E-DII score, GM (10 phyla, 28 genera, alpha diversity), and adiposity phenotypes were examined using linear regression and mediation analyses, adjusting for confounders.<br><br>RESULTS: There were positive total effects (c) between E-DII and total fat mass (c = 0.68; 95% CI = 0.47, 0.90), VAT (c = 4.61; 95% CI = 2.95, 6.27), and liver fat (c = 0.40; 95% CI = 0.27, 0.53). The association between E-DII score and total fat mass was mediated by LPS, Flavonifractor, [Ruminococcus] gnavus group, and Tyzzerella. The association between E-DII score and ectopic fat occurred indirectly through Fusobacteria, Christensenellaceae R-7 group, Coprococcus 2, Escherichia- Shigella, [Eubacterium] xylanophilum group, Flavonifractor, Lachnoclostridium, [Ruminococcus] gnavus group, Tyzzerella, [Ruminococcus] gnavus group (VAT only), and alpha diversity (liver fat only). There was no significant association between E-DII score and adiposity phenotype through hs-CRP.<br><br>CONCLUSION: Associations found between E-DII and adiposity phenotypes occurred through the GM and LPS.}, }
@article {pmid34871308, year = {2021}, author = {Karuna, S and Li, SS and Grant, S and Walsh, SR and Frank, I and Casapia, M and Trahey, M and Hyrien, O and Fisher, L and Miner, MD and Randhawa, AK and Polakowski, L and Kublin, JG and Corey, L and Montefiori, D and , }, title = {Neutralizing antibody responses over time in demographically and clinically diverse individuals recovered from SARS-CoV-2 infection in the United States and Peru: A cohort study.}, journal = {PLoS medicine}, volume = {18}, number = {12}, pages = {e1003868}, doi = {10.1371/journal.pmed.1003868}, pmid = {34871308}, issn = {1549-1676}, abstract = {BACKGROUND: People infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) experience a wide range of clinical manifestations, from asymptomatic and mild illness to severe illness and death, influenced by age and a variety of comorbidities. Neutralizing antibodies (nAbs) are thought to be a primary immune defense against the virus. Large, diverse, well-characterized cohorts of convalescent individuals provide standardized values to benchmark nAb responses to past SARS-CoV-2 infection and define potentially protective levels of immunity.<br><br>METHODS AND FINDINGS: This analysis comprises an observational cohort of 329 HIV-seronegative adults in the United States (n = 167) and Peru (n = 162) convalescing from SARS-CoV-2 infection from May through October 2020. The mean age was 48 years (range 18 to 86), 54% of the cohort overall was Hispanic, and 34% identified as White. nAb titers were measured in serum by SARS-CoV-2.D614G Spike-pseudotyped virus infection of 293T/ACE2 cells. Multiple linear regression was applied to define associations between nAb titers and demographic variables, disease severity and time from infection or disease onset, and comorbidities within and across US and Peruvian cohorts over time. nAb titers peaked 28 to 42 days post-diagnosis and were higher in participants with a history of severe Coronavirus Disease 2019 (COVID-19) illness (p < 0.001). Diabetes, age >55 years, male sex assigned at birth, and, in some cases, body mass index were also independently associated with higher nAb titers, whereas hypertension was independently associated with lower nAb titers. nAb titers did not differ by race, underlying pulmonary disease or smoking. Two months post-enrollment, nAb ID50 (ID80) titers declined 3.5 (2.8)-fold overall. Study limitations in this observational, convalescent cohort include survivorship bias and missing early viral loads and acute immune responses to correlate with the convalescent responses we observed.<br><br>CONCLUSIONS: In summary, in our cohort, nAb titers after SARS-CoV-2 infection peaked approximately 1 month post-diagnosis and varied by age, sex assigned at birth, disease severity, and underlying comorbidities. Our data show great heterogeneity in nAb responses among people with recent COVID-19, highlighting the challenges of interpreting natural history studies and gauging responses to vaccines and therapeutics among people with recent infection. Our observations illuminate potential correlations of demographic and clinical characteristics with nAb responses, a key element for protection from COVID-19, thus informing development and implementation of preventative and therapeutic strategies globally.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04403880.}, }
@article {pmid34868058, year = {2021}, author = {Martin, PJ and Levine, DM and Storer, BE and Zheng, X and Jain, D and Heavner, B and Norris, BM and Geraghty, DE and Spellman, SR and Sather, CL and Wu, F and Hansen, JA}, title = {A Model of Minor Histocompatibility Antigens in Allogeneic Hematopoietic Cell Transplantation.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {782152}, pmid = {34868058}, issn = {1664-3224}, abstract = {Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types.}, }
@article {pmid34865707, year = {2021}, author = {Appelbaum, FR}, title = {Effectiveness of allogeneic hematopoietic cell transplantation for older patients with acute myeloid leukemia.}, journal = {Best practice &amp; research. Clinical haematology}, volume = {34}, number = {4}, pages = {101320}, doi = {10.1016/j.beha.2021.101320}, pmid = {34865707}, issn = {1532-1924}, abstract = {Outcomes with conventional chemotherapy for older patients with acute myeloid leukemia (AML) remain disappointing, with few cures. For younger patients with AML, allogeneic hematopoietic cell transplantation (HCT) offers the best chance for cure, but this strategy is seldomly used for older patients. With recently improved methodologies, transplantation has become increasingly safe, suggesting that its use in older patients be reconsidered. This report will address four issues: the current frequency of transplantation for AML according to patient age; the impact of patient age on transplant outcomes; the comparative outcomes of transplantation versus chemotherapy for older patients with AML; and possible methods to improve the outcome of allogeneic HCT in older patients with AML.}, }
@article {pmid34865071, year = {2021}, author = {Austin, MN and Meyn, LA and Avolia, HA and Petrina, MA and Cosentino, LA and Alphonse, C and Chen, BA and Bunge, K and Noguchi, L and Beigi, R and Squires, K and Hillier, SL}, title = {Impact of Dapivirine and Placebo Vaginal Rings on the Microbiota of Adolescent, Lactating, and Postmenopausal Females.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiab590}, pmid = {34865071}, issn = {1537-6613}, abstract = {BACKGROUND: A 25 mg dapivirine vaginal ring has been demonstrated to reduce risk of HIV acquisition in nonpregnant adult women. In this secondary analysis of studies conducted in US adolescent, lactating, and postmenopausal females, vaginal microbiota was assessed prior to and after ring use, and between dapivirine and placebo ring users.<br><br>METHODS: Vaginal fluid swabs were collected before and after product use for the evaluation of microbiota using Nugent's criteria, quantitative culture, and qPCR.<br><br>RESULTS: Vaginal ring use did not impact bacterial vaginosis prevalence among the three populations and was associated with minimal shifts in microbiota. Adolescents in both arms demonstrated an increased prevalence of Lactobacillus crispatus and a decrease in quantity of Megasphaera lornae. Postmenopausal active and placebo ring users demonstrated an increased prevalence of lactobacilli and non-albicans yeast while dapivirine ring users demonstrated an increased prevalence of Candida albicans, and increased quantity of Group B Streptococcus (GBS) and non-albicans yeasts. Prevotella species were increased in lactating women while P. timonensis increased in prevalence and concentration among adolescent and postmenopausal women and P. bivia increased in prevalence among adolescent dapivirine ring users.<br><br>CONCLUSIONS: Dapivirine vaginal ring use was associated with minimal changes in the vaginal microbiota that are likely not clinically significant.}, }
@article {pmid34864895, year = {2021}, author = {Chaguza, C and Tonkin-Hill, G and Lo, SW and Hadfield, J and Croucher, NJ and Harris, SR and Bentley, SD}, title = {RCandy: an R package for visualising homologous recombinations in bacterial genomes.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btab814}, pmid = {34864895}, issn = {1367-4811}, abstract = {MOTIVATION: Homologous recombination is an important evolutionary process in bacteria and other prokaryotes, which increases genomic sequence diversity and can facilitate adaptation. Several methods and tools have been developed to detect genomic regions recently affected by recombination. Exploration and visualisation of such recombination events can reveal valuable biological insights, but it remains challenging. Here, we present RCandy, a platform-independent R package for rapid, simple, and flexible visualisation of recombination events in bacterial genomes.<br><br>AVAILABILITY: RCandy is an R package freely available for use under the MIT license. It is platform-independent and has been tested on Windows, Linux, and MacOSX. The source code comes together with a detailed vignette available on GitHub at https://github.com/ChrispinChaguza/RCandy.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid34863618, year = {2021}, author = {Rogers, JH and Cox, SN and Hughes, JP and Link, AC and Chow, EJ and Fosse, I and Lukoff, M and Shim, MM and Uyeki, TM and Ogokeh, C and Jackson, ML and Boeckh, M and Englund, JA and Mosites, E and Rolfes, MA and Chu, HY}, title = {Trends in COVID-19 vaccination intent and factors associated with deliberation and reluctance among adult homeless shelter residents and staff, 1 November 2020 to 28 February 2021 - King County, Washington.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2021.11.026}, pmid = {34863618}, issn = {1873-2518}, abstract = {INTRODUCTION: Little is known about COVID-19 vaccination intent among people experiencing homelessness. This study assesses surveyed COVID-19 vaccination intent among adult homeless shelter residents and staff and identifies factors associated with vaccine deliberation (responded "undecided") and reluctance (responded "no"), including time trends.<br><br>METHODS: From 11/1/2020-2/28/21, we conducted repeated cross-sectional surveys at nine shelters in King County, WA as part of ongoing community-based SARS-CoV-2 surveillance. We used a multinomial model to identify characteristics associated with vaccine deliberation and reluctance.<br><br>RESULTS: A total of 969 unique staff (n = 297) and residents (n = 672) participated and provided 3966 survey responses. Among residents, 53.7% (n = 361) were vaccine accepting, 28.1% reluctant, 17.6% deliberative, and 0.6% already vaccinated, whereas among staff 56.2% were vaccine accepting, 14.1% were reluctant, 16.5% were deliberative, and 13.1% already vaccinated at their last survey. We observed higher odds of vaccine deliberation or reluctance among Black/African American individuals, those who did not receive a seasonal influenza vaccine, and those with lower educational attainment. There was no significant trend towards vaccine acceptance.<br><br>CONCLUSIONS: Strong disparities in vaccine intent based on race, education, and prior vaccine history were observed. Increased vaccine intent over the study period was not detected. An intersectional, person-centered approach to addressing health inequities by public health authorities planning vaccination campaigns in shelters is recommended. Clinical Trial Registry Number: NCT04141917.}, }
@article {pmid34863587, year = {2021}, author = {Maxwell, KN and Cheng, HH and Powers, J and Gulati, R and Ledet, EM and Morrison, C and Le, A and Hausler, R and Stopfer, J and Hyman, S and Kohlmann, W and Naumer, A and Vagher, J and Greenberg, SE and Naylor, L and Laurino, M and Konnick, EQ and Shirts, BH and AlDubayan, SH and Van Allen, EM and Nguyen, B and Vijai, J and Abida, W and Carlo, MI and Dubard-Gault, M and Lee, DJ and Maese, LD and Mandelker, D and Montgomery, B and Morris, MJ and Nicolosi, P and Nussbaum, RL and Schwartz, LE and Stadler, Z and Garber, JE and Offit, K and Schiffman, JD and Nelson, PS and Sartor, O and Walsh, MF and Pritchard, CC}, title = {Inherited TP53 Variants and Risk of Prostate Cancer.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2021.10.036}, pmid = {34863587}, issn = {1873-7560}, abstract = {BACKGROUND: Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53.<br><br>OBJECTIVE: To determine whether gTP53 predisposes to prostate cancer.<br><br>This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort.<br><br>We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer.<br><br>RESULTS AND LIMITATIONS: We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3-7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2-55; p < 0.0001). We identified gTP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2-14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available gTP53 prostate tumors had somatic inactivation of the second TP53 allele. Among gTP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51-62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis.<br><br>CONCLUSIONS: Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing.<br><br>PATIENT SUMMARY: Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.}, }
@article {pmid34863298, year = {2021}, author = {Nuechterlein, N and Shapiro, LG and Holland, EC and Cimino, PJ}, title = {Machine learning modeling of genome-wide copy number alteration signatures reliably predicts IDH mutational status in adult diffuse glioma.}, journal = {Acta neuropathologica communications}, volume = {9}, number = {1}, pages = {191}, pmid = {34863298}, issn = {2051-5960}, support = {K08CA245037/MH/NIMH NIH HHS/United States ; DGE-1762114//National Science Foundation/ ; }, abstract = {Knowledge of 1p/19q-codeletion and IDH1/2 mutational status is necessary to interpret any investigational study of diffuse gliomas in the modern era. While DNA sequencing is the gold standard for determining IDH mutational status, genome-wide methylation arrays and gene expression profiling have been used for surrogate mutational determination. Previous studies by our group suggest that 1p/19q-codeletion and IDH mutational status can be predicted by genome-wide somatic copy number alteration (SCNA) data alone, however a rigorous model to accomplish this task has yet to be established. In this study, we used SCNA data from 786 adult diffuse gliomas in The Cancer Genome Atlas (TCGA) to develop a two-stage classification system that identifies 1p/19q-codeleted oligodendrogliomas and predicts the IDH mutational status of astrocytic tumors using a machine-learning model. Cross-validated results on TCGA SCNA data showed near perfect classification results. Furthermore, our astrocytic IDH mutation model validated well on four additional datasets (AUC = 0.97, AUC = 0.99, AUC = 0.95, AUC = 0.96) as did our 1p/19q-codeleted oligodendroglioma screen on the two datasets that contained oligodendrogliomas (MCC = 0.97, MCC = 0.97). We then retrained our system using data from these validation sets and applied our system to a cohort of REMBRANDT study subjects for whom SCNA data, but not IDH mutational status, is available. Overall, using genome-wide SCNAs, we successfully developed a system to robustly predict 1p/19q-codeletion and IDH mutational status in diffuse gliomas. This system can assign molecular subtype labels to tumor samples of retrospective diffuse glioma cohorts that lack 1p/19q-codeletion and IDH mutational status, such as the REMBRANDT study, recasting these datasets as validation cohorts for diffuse glioma research.}, }
@article {pmid34862752, year = {2021}, author = {Bruce, EA and Mills, MG and Sampoleo, R and Perchetti, GA and Huang, ML and Despres, HW and Schmidt, MM and Roychoudhury, P and Shirley, DJ and Jerome, KR and Greninger, AL and Botten, JW}, title = {Predicting Infectivity: Comparing Four PCR-based Assays to Detect Culturable SARS-CoV-2 in Clinical Samples.}, journal = {EMBO molecular medicine}, volume = {}, number = {}, pages = {e15290}, doi = {10.15252/emmm.202115290}, pmid = {34862752}, issn = {1757-4684}, abstract = {With the COVID-19 pandemic caused by SARS-CoV-2 now in its second year, there remains an urgent need for diagnostic testing that can identify infected individuals, particularly those who harbor infectious virus. Various RT-PCR strategies have been proposed to identify specific viral RNA species that may predict the presence of infectious virus, including detection of transcriptional intermediates (e.g. subgenomic RNA [sgRNA]) and replicative intermediates (e.g. negative-strand RNA species). Using a novel primer/probe set for detection of subgenomic (sg)E transcripts, we successfully identified 100% of specimens containing culturable SARS-CoV-2 from a set of 126 clinical samples (total sgE CT values ranging from 12.3-37.5). This assay showed superior performance compared to a previously published sgRNA assay and to a negative-strand RNA assay, both of which failed to detect target RNA in a subset of samples from which we isolated live virus. In addition, total levels of viral RNA (genome, negative-strand, and sgE) detected with the WHO/Charité primer-probe set correlated closely with levels of infectious virus. Specifically, infectious virus was not detected in samples with a CT above 31.0. Clinical samples with higher levels of viral RNA also displayed cytopathic effect (CPE) more quickly than those with lower levels of viral RNA. Finally, we found that the infectivity of SARS-CoV-2 samples is significantly dependent on the cell type used for viral isolation, as Vero E6 cells expressing TMRPSS2 extended the analytical sensitivity of isolation by more than 3 CT compared to parental Vero E6 cells and resulted in faster isolation. Our work shows that using a total viral RNA Ct cut-off of >31 or specifically testing for sgRNA can serve as an effective rule-out test for the presence of culturable virus.}, }
@article {pmid34862099, year = {2021}, author = {Psutka, SP and Gulati, R and Jewett, MAS and Fadaak, K and Finelli, A and Legere, L and Morgan, TM and Pierorazio, PM and Allaf, ME and Herrin, J and Lohse, CM and Houston Thompson, R and Boorjian, SA and Atwell, TD and Schmit, GD and Costello, BA and Shah, ND and Leibovich, BC}, title = {A Clinical Decision Aid to Support Personalized Treatment Selection for Patients with Clinical T1 Renal Masses: Results from a Multi-institutional Competing-risks Analysis.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2021.11.002}, pmid = {34862099}, issn = {1873-7560}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Personalized treatment for clinical T1 renal cortical masses (RCMs) should take into account competing risks related to tumor and patient characteristics.<br><br>OBJECTIVE: To develop treatment-specific prediction models for cancer-specific mortality (CSM), other-cause mortality (OCM), and 90-d Clavien grade ≥3 complications across radical nephrectomy (RN), partial nephrectomy (PN), thermal ablation (TA), and active surveillance (AS).<br><br>Pretreatment clinical and radiological features were collected for consecutive adult patients treated with initial RN, PN, TA, or AS for RCMs at four high-volume referral centers (2000-2019).<br><br>Prediction models used competing-risks regression for CSM and OCM and logistic regression for 90-d Clavien grade ≥3 complications. Performance was assessed using bootstrap validation.<br><br>RESULTS AND LIMITATIONS: The cohort comprised 5300 patients treated with RN (n = 1277), PN (n = 2967), TA (n = 476), or AS (n = 580). Over median follow-up of 5.2 yr (interquartile range 2.5-8.7), there were 117 CSM, 607 OCM, and 198 complication events. The C index for the predictive models was 0.80 for CSM, 0.77 for OCM, and 0.64 for complications. Predictions from the fitted models are provided in an online calculator (https://small-renal-mass-risk-calculator.fredhutch.org). To illustrate, a hypothetical 74-yr-old male with a 4.5-cm RCM, body mass index of 32 kg/m2, estimated glomerular filtration rate of 50 ml/min, Eastern Cooperative Oncology Group performance status of 3, and Charlson comorbidity index of 3 has predicted 5-yr CSM of 2.9-5.6% across treatments, but 5-yr OCM of 29% and risk of 90-d Clavien grade 3-5 complications of 1.9% for RN, 5.8% for PN, and 3.6% for TA. Limitations include selection bias, heterogeneity in practice across treatment sites and the study time period, and lack of control for surgeon/hospital volume.<br><br>CONCLUSIONS: We present a risk calculator incorporating pretreatment features to estimate treatment-specific competing risks of mortality and complications for use during shared decision-making and personalized treatment selection for RCMs.<br><br>PATIENT SUMMARY: We present a risk calculator that generates personalized estimates of the risks of death from cancer or other causes and of complications for surgical, ablation, and surveillance treatment options for patients with stage 1 kidney tumors.}, }
@article {pmid34861680, year = {2021}, author = {Hamadani, M and Ngoya, M and Sureda, A and Bashir, Q and Litovich, CA and Finel, H and Chen, Y and Boumendil, A and Zain, J and Castagna, L and Cashen, AF and Blaise, D and Shadman, M and Pastano, R and Khimani, F and Arat, M and Dietrich, S and Schmitz, N and Glass, B and Kharfan-Dabaja, MA and Corradini, P and Sauter, CS and Montoto, S and Kwon, M and Herrera, AF and Dreger, P}, title = {Outcome of Allogeneic Transplantation for Mature T-cell Lymphomas: Impact of Donor Source and Disease Characteristics.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005899}, pmid = {34861680}, issn = {2473-9537}, abstract = {Mature T-cell lymphomas constitute the most common indication of allogeneic hematopoietic cell transplantation (allo-HCT) in lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas, relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma-NOS (PTCL-NOS) between 2008 and 2018. HCT platforms compared were post-transplant cyclophosphamide-based haploidentical (haplo-) HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in-vivo T-cell depletion (MUD TCD+), and MUD HCT without TCD (MUD TCD-). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included non-relapse mortality (NRM), and relapse/progression incidence (RI). 1942 patients were eligible (haplo-HCT 237; MSD 911; MUD-TCD+ 468; MUD TCD- 326). Cohorts were comparable for baseline characteristics except higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. On univariate and multivariate comparisons, OS and PFS, RI, and NRM were not significantly different between haplo-HCT, MSD, MUD-TCD+, and MUD-TCD- cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%; and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared to PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma. Outcomes of haplo-HCT were comparable to that of matched donor allo-HCT.}, }
@article {pmid34861158, year = {2021}, author = {Grzelak, CA and Goddard, ET and Lederer, EE and Rajaram, K and Dai, J and Shor, RE and Lim, AR and Kim, J and Beronja, S and Funnell, APW and Ghajar, CM}, title = {Elimination of fluorescent protein immunogenicity permits modeling of metastasis in immune-competent settings.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2021.11.004}, pmid = {34861158}, issn = {1878-3686}, }
@article {pmid34861039, year = {2021}, author = {Clough, CA and Pangallo, J and Sarchi, M and Ilagan, JO and North, K and Bergantinos, R and Stolla, MC and Naru, J and Nugent, P and Kim, E and Stirewalt, DL and Subramaniam, AR and Abdel-Wahab, O and Abkowitz, JL and Bradley, RK and Doulatov, S}, title = {Coordinated mis-splicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021012652}, pmid = {34861039}, issn = {1528-0020}, abstract = {SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts, a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause ring sideroblasts (RS) remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell (iPSC) model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces mis-splicing of ~100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All three mis-splicing events reduce protein expression, notably occurring via 5' UTR alteration and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated mis-splicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing ring sideroblast formation.}, }
@article {pmid34861035, year = {2021}, author = {Williams, AM and Mirzaei Salehabadi, S and Xing, M and Phillips, NS and Ehrhardt, M and Howell, R and Yasui, Y and Oeffinger, K and Gibson, TM and Chow, EJ and Leisenring, WM and Srivastava, DS and Hudson, MM and Robison, LL and Armstrong, G and Krull, KR}, title = {Modifiable Risk Factors for Neurocognitive and Psychosocial Problems After Hodgkin Lymphoma.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021013167}, pmid = {34861035}, issn = {1528-0020}, abstract = {Long-term survivors of childhood Hodgkin lymphoma (HL) experience high burden of chronic health morbidities. Correlates of neurocognitive and psychosocial morbidity have not been well established. 1,760 survivors of HL (mean[SD] age 37.5[6.0] years, time since diagnosis 23.6[4.7] years, 52.1% female) and 3,180 siblings (age 33.2[8.5] years, 54.5% female) completed cross-sectional surveys assessing neurocognitive function, emotional distress, quality of life, social attainment, smoking, and physical activity. Treatment exposures were abstracted from medical records. Chronic health conditions were graded according to NCI CTCAE v4.3 (1=mild, 2=moderate, 3=severe/disabling, 4=life-threatening). Multivariable analyses, adjusted for age, sex, and race, estimated relative risk (RR) of impairment in survivors vs. siblings and, among survivors, risk of impairment associated with demographic, clinical, treatment factors and grade 2+ chronic health conditions. Compared with siblings, survivors had significant higher risk (p's<0.05) of neurocognitive impairment (e.g. memory 8.1% vs. 5.7%), anxiety (7.0%%vs. 5.4%),depression (9.1% vs. 7%), unemployment (9.6% vs. 4.4%), and impaired physical/mental quality of life (e.g. physical function 11.2% vs. 3.0%). Smoking was associated with higher risk of impairment in task efficiency (RR=1.56[1.02-2.39]), emotional regulation (RR=1.84[1.35-2.49]), anxiety (RR=2.43[1.51-3.93]), and depression (RR=2.73[1.85-4.04]). Meeting CDC exercise guidelines was associated with lower risk of impairment in task efficiency (RR=0.70[0.52-0.95]), organization (RR=0.60[0.45-0.80]), depression (RR=0.66[0.48-0.92]), and multiple quality of life domains. Cardiovascular and neurologic conditions were associated with impairment in nearly all domains. Survivors of HL are at elevated risk for neurocognitive and psychosocial impairment, and risk is associated with modifiable factors that provide targets for interventions to improve long-term functional outcomes.}, }
@article {pmid34856072, year = {2021}, author = {Ruiz-Rodado, V and Dowdy, T and Lita, A and Kramp, T and Zhang, M and Jung, J and Dios-Esponera, A and Zhang, L and Herold-Mende, CC and Camphausen, K and Gilbert, MR and Larion, M}, title = {Cysteine is a limiting factor for glioma proliferation and survival.}, journal = {Molecular oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/1878-0261.13148}, pmid = {34856072}, issn = {1878-0261}, abstract = {Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that render cancer cells dependent on certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13 C-tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support GSH synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.}, }
@article {pmid34855461, year = {2021}, author = {Lamble, AJ and Eidenschink Brodersen, L and Alonzo, TA and Wang, J and Pardo, L and Sung, L and Cooper, TM and Kolb, EA and Aplenc, R and Tasian, SK and Loken, MR and Meshinchi, S}, title = {CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2101595}, doi = {10.1200/JCO.21.01595}, pmid = {34855461}, issn = {1527-7755}, abstract = {PURPOSE: Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).<br><br>MATERIALS AND METHODS: AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.<br><br>RESULTS: The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations (P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations (P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.<br><br>CONCLUSION: CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.}, }
@article {pmid34854745, year = {2021}, author = {Waisman Malaret, AJ and Chang, P and Zhu, K and Zheng, Y and Newcomb, LF and Liu, M and McKenney, JK and Brooks, JD and Carroll, P and Dash, A and Filson, CP and Gleave, ME and Liss, M and Martin, FM and Morgan, TM and Nelson, PS and Lin, DW and Wagner, AA}, title = {Evaluating the Outcomes of Active Surveillance in Grade Group 2 Prostate Cancer: Prospective Results From the Canary PASS Cohort.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000002354}, doi = {10.1097/JU.0000000000002354}, pmid = {34854745}, issn = {1527-3792}, abstract = {INTRODUCTION: Active Surveillance (AS) for grade group 2 (GG2) patients is not yet well-defined. We sought to compare clinical outcomes of men with GG1 and GG2 prostate cancer undergoing AS in a large prospective North American cohort.<br><br>METHODS: Participants were prospectively enrolled in an AS study with protocol-directed follow up at 10 centers in the US and Canada. We evaluated time from diagnosis to biopsy grade reclassification and time to treatment. In men treated after initial surveillance, adverse pathology (AP) and recurrence were also analyzed.<br><br>RESULTS: At diagnosis, 154 (9%) had GG2 and 1574 (91%) had GG1. Five-year reclassification rates were similar between GG2 or GG1 (30% vs 37%, p=0.11). However, more patients with GG2 were treated at 5 years (58% vs 34%, p <0.001) and GG at diagnosis was associated with time to treatment (HR=1.41; p=0.01). Treatment rates were similar in patients who reclassified during AS, but in patients who did not reclassify, those diagnosed with GG2 underwent definitive treatment more often than GG1 (5-year treatment rates 52% and 12%, p <0.0001). In participants who underwent RP after initial surveillance, the adjusted risk of AP was similar (HR=1.26; p=0.4). Biochemical recurrence (BCR) within 3 years of treatment for GG2 and GG1 patients was 6% for both groups.<br><br>CONCLUSIONS: In patients on active surveillance, the rate of definitive treatment is higher after an initial diagnosis of GG2 than GG1. Adverse pathology after RP and short-term BCR after definitive treatment were similar between GG2 and GG1.}, }
@article {pmid34854708, year = {2021}, author = {Ouellette, M and Bejian, AA and Chen, T and Jones, DS and Johnston, CD and Dewhirst, FE}, title = {Complete Genome Sequence of Arachnia rubra Strain DSM 100122T, a Cultured Member of the Human Oral Microbiome.}, journal = {Microbiology resource announcements}, volume = {10}, number = {48}, pages = {e0095921}, doi = {10.1128/MRA.00959-21}, pmid = {34854708}, issn = {2576-098X}, support = {R01 DE016937/DE/NIDCR NIH HHS/United States ; R01 DE027850/DE/NIDCR NIH HHS/United States ; T32 DE007327/DE/NIDCR NIH HHS/United States ; }, abstract = {We report the complete genome of Arachnia rubra strain DSM 100122T. The genome is 3.32 Mb, with a GC content of 64.2%. The genome contains 3,005 predicted genes, including 2,923 predicted protein-coding genes.}, }
@article {pmid34854279, year = {2021}, author = {Bertrums, EJM and Zwaan, CM and Hasegawa, D and De Haas, V and Reinhardt, DN and Locatelli, F and De Moerloose, B and Dworzak, M and Buijs, A and Smisek, P and Kolenova, A and Pronk, CJ and Klusmann, JH and Carboné, A and Ferster, A and Antoniou, E and Meshinchi, S and Raimondi, SC and Niemeyer, CM and Hasle, H and Van den Heuvel-Eibrink, MM and Goemans, BF}, title = {Guideline for management of non-Down syndrome neonates with a myeloproliferative disease on behalf of the I-BFM AML Study Group and EWOG-MDS.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2021.279507}, pmid = {34854279}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid34853798, year = {2021}, author = {Samuelson, C and Radtke, S and Zhu, H and Llewellyn, M and Fields, E and Cook, S and Huang, MW and Jerome, KR and Kiem, HP and Humbert, O}, title = {Multiplex CRISPR/Cas9 genome editing in hematopoietic stem cells for fetal hemoglobin reinduction generates chromosomal translocations.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {23}, number = {}, pages = {507-523}, doi = {10.1016/j.omtm.2021.10.008}, pmid = {34853798}, issn = {2329-0501}, abstract = {Sickle cell disease and β-thalassemia are common monogenic disorders that cause significant morbidity and mortality globally. The only curative treatment currently is allogeneic hematopoietic stem cell transplantation, which is unavailable to many patients due to a lack of matched donors and carries risks including graft-versus-host disease. Genome editing therapies targeting either the BCL11A erythroid enhancer or the HBG promoter are already demonstrating success in reinducing fetal hemoglobin. However, where a single locus is targeted, reliably achieving levels high enough to deliver an effective cure remains a challenge. We investigated the application of a CRISPR/Cas9 multiplex genome editing approach, in which both the BCL11A erythroid enhancer and HBG promoter are disrupted within human hematopoietic stem cells. We demonstrate superior fetal hemoglobin reinduction with this dual-editing approach without compromising engraftment or lineage differentiation potential of edited cells post-xenotransplantation. However, multiplex editing consistently resulted in the generation of chromosomal rearrangement events that persisted in vivo following transplantation into immunodeficient mice. The risk of oncogenic events resulting from such translocations therefore currently prohibits its clinical translation, but it is anticipated that, in the future, alternative editing platforms will help alleviate this risk.}, }
@article {pmid34850899, year = {2021}, author = {Braun, IM and Abrams, DI and Blansky, SE and Pergam, SA}, title = {Cannabis and the Cancer Patient.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2021}, number = {58}, pages = {68-77}, doi = {10.1093/jncimonographs/lgab012}, pmid = {34850899}, issn = {1745-6614}, abstract = {Session 2 of the National Cancer Institute's Cannabis, Cannabinoids, and Cancer Research Workshop opened with testimony from a lymphoma survivor who detailed medicinal cannabis-related improvements in nausea, low appetite, insomnia, and mental health and the limited clinical counsel she received regarding cannabis use. Discussion next turned to the evolution of the legal landscape of cannabis in the United States, one in which state and federal laws frequently conflict and the Controlled Substance Act renders cannabis Schedule I. This legal climate creates conundrums for US medicinal cannabis researchers who contend with limited funding opportunities, avenues to source trial drug, and procedural red tape and for oncology clinicians who recommend medicinal cannabis to patients with some frequency while perceiving themselves as ill equipped to make such clinical recommendations. Ultimately, it creates challenges for cancer patients who find themselves turning to nonmedical and anecdotal information sources. The risks of cannabis use by the cancer patient were discussed next. These include infection, pharmacodynamic and pharmacokinetic drug-botanical interactions, cyclic nausea and vomiting, e-cigarette or vaping product use-associated illness, legal issues, and high cost. The session concluded with a broad survey of the research supporting oncologic cannabinoid use, conclusive evidence for chemotherapy-induced nausea and vomiting, and suggestive evidence for cancer-related pain.}, }
@article {pmid34850742, year = {2021}, author = {Campion, SL and Brenna, E and Thomson, E and Fischer, W and Ladell, K and McLaren, JE and Price, DA and Frahm, N and McElrath, JM and Cohen, KW and Maenza, JR and Walsh, SR and Baden, LR and Haynes, BF and Korber, B and Borrow, P and McMichael, AJ}, title = {Preexisting memory CD4+ T cells contribute to the primary response in an HIV-1 vaccine trial.}, journal = {The Journal of clinical investigation}, volume = {131}, number = {23}, pages = {}, doi = {10.1172/JCI150823}, pmid = {34850742}, issn = {1558-8238}, abstract = {Naive and memory CD4+ T cells reactive with human immunodeficiency virus type 1 (HIV-1) are detectable in unexposed, unimmunized individuals. The contribution of preexisting CD4+ T cells to a primary immune response was investigated in 20 HIV-1-seronegative volunteers vaccinated with an HIV-1 envelope (Env) plasmid DNA prime and recombinant modified vaccinia virus Ankara (MVA) boost in the HVTN 106 vaccine trial (clinicaltrials.gov NCT02296541). Prevaccination naive or memory CD4+ T cell responses directed against peptide epitopes in Env were identified in 14 individuals. After priming with DNA, 40% (8/20) of the elicited responses matched epitopes detected in the corresponding preimmunization memory repertoires, and clonotypes were shared before and after vaccination in 2 representative volunteers. In contrast, there were no shared epitope specificities between the preimmunization memory compartment and responses detected after boosting with recombinant MVA expressing a heterologous Env. Preexisting memory CD4+ T cells therefore shape the early immune response to vaccination with a previously unencountered HIV-1 antigen.}, }
@article {pmid34849892, year = {2021}, author = {Isabella, AJ and Leyva-Díaz, E and Kaneko, T and Gratz, SJ and Moens, CB and Hobert, O and O'Connor-Giles, K and Thakur, R and Sun, H}, title = {The field of neurogenetics: where it stands and where it is going.}, journal = {Genetics}, volume = {218}, number = {4}, pages = {}, doi = {10.1093/genetics/iyab085}, pmid = {34849892}, issn = {1943-2631}, }
@article {pmid34849828, year = {2021}, author = {Isabella, AJ and Leyva-Díaz, E and Kaneko, T and Gratz, SJ and Moens, CB and Hobert, O and O'Connor-Giles, K and Thakur, R and Sun, H}, title = {The field of neurogenetics: where it stands and where it is going.}, journal = {G3 (Bethesda, Md.)}, volume = {11}, number = {8}, pages = {}, doi = {10.1093/g3journal/jkab239}, pmid = {34849828}, issn = {2160-1836}, }
@article {pmid34849635, year = {2021}, author = {Mitchell, KM and Maheu-Giroux, M and Dimitrov, D and Moore, M and Hughes, JP and Donnell, D and Beyrer, C and El-Sadr, WM and Cohen, MS and Boily, MC}, title = {How can progress towards Ending the HIV Epidemic in the United States be monitored?.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciab976}, pmid = {34849635}, issn = {1537-6591}, abstract = {The plan for Ending the HIV Epidemic (EHE) in the United States aims to reduce new infections by 75% by 2025 and by 90% by 2030. For EHE to be successful, it is important to accurately measure changes in numbers of new HIV infections after 5 and 10 years (to determine whether the EHE goals have been achieved) but also over shorter time-scales (to monitor progress and intensify prevention efforts if required). In this viewpoint, we aim to demonstrate why the method used to monitor progress towards the EHE goals needs to be carefully considered. We briefly describe and discuss different methods to estimate numbers of new HIV infections, based on longitudinal cohort studies, cross-sectional incidence surveys and routine surveillance data. We particularly focus on identifying conditions under which unadjusted and adjusted estimates based on routine surveillance data can be used to estimate changes in new HIV infections.}, }
@article {pmid34849445, year = {2021}, author = {Collier, KA and Asad, S and Tallman, D and Jenison, J and Rajkovic, A and Mardis, ER and Parsons, HA and Tolaney, SM and Winer, EP and Lin, NU and Ha, G and Adalsteinsson, VA and Stover, DG}, title = {Association of 17q22 Amplicon Via Cell-Free DNA With Platinum Chemotherapy Response in Metastatic Triple-Negative Breast Cancer.}, journal = {JCO precision oncology}, volume = {5}, number = {}, pages = {}, doi = {10.1200/PO.21.00104}, pmid = {34849445}, issn = {2473-4284}, abstract = {PURPOSE: To determine whether specific somatic copy-number alterations detectable in circulating tumor DNA (ctDNA) from patients with metastatic triple-negative breast cancer (mTNBC) are associated with sensitivity to platinum chemotherapy.<br><br>MATERIALS AND METHODS: In this secondary analysis of a large cohort of patients with mTNBC whose ctDNA underwent ultralow-pass whole-genome sequencing, tumor fraction and somatic copy-number alterations were derived with the ichorCNA algorithm. Seventy-two patients were identified who had received a platinum-based chemotherapy regimen in the metastatic setting. Gene-level copy-number analyses were performed with GISTIC2.0. Cytobands were associated with progression-free survival (PFS) to platinum chemotherapy using Cox proportional hazards models. The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium data sets were interrogated for frequency of significant cytobands in primary triple-negative breast cancer (pTNBC) tumors.<br><br>RESULTS: Among 71 evaluable patients, 17q21 and 17q22 amplifications were most strongly associated with improved PFS with platinum chemotherapy. There were no significant differences in clinicopathologic features or (neo)adjuvant chemotherapy among patients with 17q22 amplification. Patients with 17q22 amplification (n = 17) had longer median PFS with platinum (7.0 v 3.8 months; log-rank P = .015) than patients without 17q22 amplification (n = 54), an effect that remained significant in multivariable analyses (PFS hazard ratio 0.37; 95% CI, 0.16 to 0.84; P = .02). Among 39 patients who received the nonplatinum chemotherapy agent capecitabine, there was no association between 17q22 amplification and capecitabine PFS (log-rank P = .69). In The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium, 17q22 amplification occurred in more than 20% of both pTNBC and mTNBC tumors, whereas 17q21 was more frequently amplified in mTNBC relative to pTNBC (16% v 8.1%, P = .015).<br><br>CONCLUSION: The 17q22 amplicon, detected by ctDNA, is associated with improved PFS with platinum chemotherapy in patients with mTNBC and warrants further investigation.}, }
@article {pmid34848822, year = {2021}, author = {Penson, DF and Armstrong, AJ and Concepcion, RS and Agarwal, N and Olsson, CA and Karsh, LI and Dunshee, CJ and Duggan, W and Shen, Q and Sugg, J and Haas, GP and Higano, CS}, title = {Correction: Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41391-021-00477-3}, pmid = {34848822}, issn = {1476-5608}, }
@article {pmid34847733, year = {2021}, author = {Chalker, C and Santana-Davila, R and Voutsinas, JM and Wu, QV and Hwang, V and Baik, CS and Lee, S and Barber, B and Futran, ND and Houlton, JJ and Laramore, GE and Liao, JJ and Parvathaneni, U and Martins, RG and Eaton, KD and Rodriguez, CP}, title = {High End-of-Life Health Care Utilization in a Contemporary Cohort of Head and Neck Cancer Patients Treated with Immune Checkpoint Inhibitors.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {}, doi = {10.1089/jpm.2021.0323}, pmid = {34847733}, issn = {1557-7740}, abstract = {Background/Objective: End-of-life health care utilization (EOLHCU) is largely uncharacterized among patients with recurrent/metastatic head and neck squamous cell carcinomas (RMHNSCC), particularly now that immune checkpoint inhibitors (ICI) have been introduced to the treatment landscape. We examined this in a single-institution, retrospective study. Design/Settings: We utilized a database of deceased, ICI-treated RMHNSCC patients to obtain demographic and EOLHCU data, the latter of which included advanced care plan documentation (ACPD) and systemic therapy or emergency room (ER)/hospital/intensive care unit (ICU) admission within 30 days of death (DOD). This was compared with a cohort of deceased thoracic malignancy (TM) patients in an exploratory analysis. Multivariate analysis was performed to examine for association between patient factors (such as age, Eastern Cooperative Oncology Group (ECOG) performance status, or smoking status) and overall survival (OS); associations between the said patient factors and EOLHCU were also evaluated. This study was conducted at an academic, tertiary center in the United States. Results: The RMHNSCC patients (n = 74) were more likely to have ACPD (p < 0.01), an emergency department visit (p < 0.01), and/or hospital admission (p < 0.01) within 30 DOD relative to the TM group. There was no difference in ICU admissions, ICU deaths, or systemic therapy at end of life (EOL). The OS declined in association with ECOG performance status (PS) and smoking. No association was observed between patient factors and any EOLHCU metric. Conclusions: At our center, patients with ICI-treated RMHNSCC have higher rates of both ACPD and EOLHCU, suggesting high symptom burden and representing opportunities for further study into supportive care augmentation.}, }
@article {pmid34781268, year = {2021}, author = {Go, RS and Jacobsen, E and Baiocchi, R and Buhtoiarov, I and Butler, EB and Campbell, PK and Coulter, DW and Diamond, E and Flagg, A and Goodman, AM and Goyal, G and Gratzinger, D and Hendrie, PC and Higman, M and Hogarty, MD and Janku, F and Karmali, R and Morgan, D and Raldow, AC and Stefanovic, A and Tantravahi, SK and Walkovich, K and Zhang, L and Bergman, MA and Darlow, SD}, title = {Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {11}, pages = {1277-1303}, doi = {10.6004/jnccn.2021.0053}, pmid = {34781268}, issn = {1540-1413}, abstract = {Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.}, }
@article {pmid34846918, year = {2021}, author = {Lo, A and Holmes, K and Kamlapurkar, S and Mundt, F and Moorthi, S and Fung, I and Fereshetian, S and Watson, J and Carr, SA and Mertins, P and Berger, AH}, title = {Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1.}, journal = {Science signaling}, volume = {14}, number = {711}, pages = {eabc4520}, doi = {10.1126/scisignal.abc4520}, pmid = {34846918}, issn = {1937-9145}, abstract = {[Figure: see text].}, }
@article {pmid34845983, year = {2021}, author = {Mayer-Blackwell, K and Schattgen, S and Cohen-Lavi, L and Crawford, JC and Souquette, A and Gaevert, JA and Hertz, T and Thomas, PG and Bradley, PG and Fiore-Gartland, A}, title = {TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.68605}, pmid = {34845983}, issn = {2050-084X}, support = {AI136514-03//National Institute of Allergy and Infectious Diseases/ ; ORIP S10OD028685/NH/NIH HHS/United States ; }, abstract = {T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.}, }
@article {pmid34845322, year = {2021}, author = {Traxinger, BR and Richert-Spuhler, LE and Lund, JM}, title = {Mucosal tissue regulatory T cells are integral in balancing immunity and tolerance at portals of antigen entry.}, journal = {Mucosal immunology}, volume = {}, number = {}, pages = {}, pmid = {34845322}, issn = {1935-3456}, abstract = {Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that exert suppressive control over other immune cells. Tregs are critical for preventing systemic autoimmunity and maintaining peripheral tolerance, and yet they also assist in orchestration of immunity to pathogenic insult, wherein they limit collateral immunopathology and assist in facilitating a fine balance between immune tolerance and effector activity. Tregs have been extensively studied in lymphoid tissues, and a growing body of work has characterized phenotypically distinct Tregs localized in various nonlymphoid tissue compartments. These tissue Tregs can perform location-specific, alternative functions, highlighting their dynamic, context-dependent roles. Tregs have also been identified in mucosal tissues where specialized physiological functions are paramount, including helping the host to respond appropriately to pathogenic versus innocuous antigens that are abundant at mucosal portals of antigen entry. As in other tissue Treg compartments, mucosal Tregs in the respiratory, gastrointestinal, and genitourinary tracts are distinct from circulating counterparts and can carry out mucosa-specific functions as well as classic suppressive functions that are the hallmark of Tregs. In this review, we summarize current knowledge regarding mucosal Tregs in both health and disease.}, }
@article {pmid34845211, year = {2021}, author = {Watt, GP and Knight, JA and Lin, C and Lynch, CF and Malone, KE and John, EM and Bernstein, L and Brooks, JD and Reiner, AS and Liang, X and Woods, M and Nguyen, TL and Hopper, JL and Pike, MC and Bernstein, JL}, title = {Mammographic texture features associated with contralateral breast cancer in the WECARE Study.}, journal = {NPJ breast cancer}, volume = {7}, number = {1}, pages = {146}, pmid = {34845211}, issn = {2374-4677}, support = {R01CA97397//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA008748//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01CA83178//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA129649//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA114236//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA97397//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA008748//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01CA83178//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA129649//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA114236//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R25CA214255//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA086862//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA008748//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1139144//Cancer Council Victoria/ ; TP900783//Cancer Council Victoria/ ; 1159399//Cure Cancer Australia Foundation (CCAF)/ ; }, abstract = {To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a "texture risk score" using pre-treatment mammograms in a case-control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01-1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.}, }
@article {pmid34845070, year = {2021}, author = {Evenson, KR and Bellettiere, J and Cuthbertson, CC and Di, C and Dushkes, R and Howard, AG and Parada, H and Schumacher, BT and Shiroma, EJ and Wang, G and Lee, IM and LaCroix, AZ}, title = {Cohort profile: the Women's Health Accelerometry Collaboration.}, journal = {BMJ open}, volume = {11}, number = {11}, pages = {e052038}, doi = {10.1136/bmjopen-2021-052038}, pmid = {34845070}, issn = {2044-6055}, abstract = {PURPOSE: This paper describes the Women's Health Accelerometry Collaboration, a consortium of two prospective cohort studies of women age 62 years or older, harmonised to explore the association of accelerometer-assessed physical activity and sedentary behaviour with cancer incidence and mortality.<br><br>PARTICIPANTS: A total of 23 443 women (age mean 73.4, SD 6.8) living in the USA and participating in an observational study were included; 17 061 from the Women's Health Study (WHS) and 6382 from the Women's Health Initiative Objective Physical Activity and Cardiovascular Health (WHI/OPACH) Study.<br><br>FINDINGS TO DATE: Accelerometry, cancer outcomes and covariate harmonisation was conducted to align the two cohort studies. Physical activity and sedentary behaviour were measured using similar procedures with an ActiGraph GT3X+ accelerometer, worn at the hip for 1 week, during 2011-2014 for WHS and 2012-2014 for WHI/OPACH. Cancer outcomes were ascertained via ongoing surveillance using physician adjudicated cancer diagnosis. Relevant covariates were measured using questionnaire or physical assessments. Among 23 443 women who wore the accelerometer for at least 10 hours on a single day, 22 868 women wore the accelerometer at least 10 hours/day on ≥4 of 7 days. The analytical sample (n=22 852) averaged 4976 (SD 2669) steps/day and engaged in an average of 80.8 (SD 46.5) min/day of moderate-to-vigorous, 105.5 (SD 33.3) min/day of light high and 182.1 (SD 46.1) min/day of light low physical activity. A mean of 8.7 (SD 1.7) hours/day were spent in sedentary behaviour. Overall, 11.8% of the cohort had a cancer diagnosis (other than non-melanoma skin cancer) at the time of accelerometry measurement. During an average of 5.9 (SD 1.6) years of follow-up, 1378 cancer events among which 414 were fatal have occurred.<br><br>FUTURE PLANS: Using the harmonised cohort, we will access ongoing cancer surveillance to quantify the associations of physical activity and sedentary behaviour with cancer incidence and mortality.}, }
@article {pmid34844835, year = {2021}, author = {Stephan, MT}, title = {Empowering patients from within: Emerging nanomedicines for in vivo immune cell reprogramming.}, journal = {Seminars in immunology}, volume = {}, number = {}, pages = {101537}, doi = {10.1016/j.smim.2021.101537}, pmid = {34844835}, issn = {1096-3618}, abstract = {Currently, medicine lacks the ability to reprogram selected immune cells so they possess all the functions which, from a clinical standpoint, physicians might wish them to have. To solve this problem, scientists have been marrying concepts from materials science, immunology, and genetic engineering to develop novel nanotherapeutics that directly genetically reprogram immune cells inside the body. These products could address key limitations of existing ex vivo-engineered cell immunotherapies and substantially enhance patient access and outcomes. This review highlights the latest advances in this rapidly emerging biotech field and discusses challenges in translating these preclinical studies into successful clinical nanomedicines.}, }
@article {pmid34843602, year = {2021}, author = {Fischinger, S and Cizmeci, D and Deng, D and Grant, SP and Frahm, N and McElrath, J and Fuchs, J and Bart, PA and Pantaleo, G and Keefer, M and O Hahn, W and Rouphael, N and Churchyard, G and Moodie, Z and Donastorg, Y and Streeck, H and Alter, G}, title = {Sequence and vector shapes vaccine induced antibody effector functions in HIV vaccine trials.}, journal = {PLoS pathogens}, volume = {17}, number = {11}, pages = {e1010016}, doi = {10.1371/journal.ppat.1010016}, pmid = {34843602}, issn = {1553-7374}, abstract = {Despite the advent of long-acting anti-retroviral therapy able to control and prevent infection, a preventative vaccine remains a global priority for the elimination of HIV. The moderately protective RV144 vaccine trial suggested functional IgG1 and IgG3 antibodies were a potential correlate of protection, but the RV144-inspired HVTN702 validation trial failed to demonstrate efficacy despite inducing targeted levels of IgG1/IgG3. Alterations in inserts, and antigens, adjuvant, and regimen also resulted in vaccine induced target quantitative levels of the immune correlates, but drove qualitative changes to the humoral immune response, pointing to the urgent need to define the influence of vaccine strategies on shaping antibody quality, not just quantity. Thus, defining how distinct prime/boost approaches tune long-lived functional antibodies represents an important goal in vaccine development. Here, we compared vaccine responses in Phase I and II studies in humans utilizing various combinations of DNA/vector, vector/vector and DNA/protein HIV vaccines. We found that adenoviral vector immunization, compared to pox-viral vectors, resulted in the most potent IgG1 and IgG3 responses, linked to highly functional antibody activity, including assisting NK cell related functions. Minimal differences were observed in the durability of the functional humoral immune response across vaccine regimens, except for antibody dependent phagocytic function, which persisted for longer periods in the DNA/rAd5 and rAd35/rAd5 regimen, likely driven by higher IgG1 levels. Collectively, these findings suggest adenoviral vectors drive superior antibody quality and durability that could inform future clinical vaccine studies. Trial registration: ClinicalTrials.gov NCT00801697, NCT00961883, NCT02207920, NCT00125970, NCT02852005).}, }
@article {pmid34841560, year = {2021}, author = {Rosen, EM and Martin, CL and Siega-Riz, AM and Dole, N and Basta, PV and Serrano, M and Fettweis, J and Wu, M and Sun, S and Thorp, JM and Buck, G and Fodor, AA and Engel, SM}, title = {Is prenatal diet associated with the composition of the vaginal microbiome?.}, journal = {Paediatric and perinatal epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ppe.12830}, pmid = {34841560}, issn = {1365-3016}, support = {P30ES010126/ES/NIEHS NIH HHS/United States ; T32ES007018/ES/NIEHS NIH HHS/United States ; DK61981/DK/NIDDK NIH HHS/United States ; HD37584//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; HD39373//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; RR00046//NIH Clinical Center/ ; R01MD011504/MD/NIMHD NIH HHS/United States ; }, abstract = {BACKGROUND: The vaginal microbiome has been associated with adverse pregnancy outcomes, but information on the impact of diet on microbiome composition is largely unexamined.<br><br>OBJECTIVE: To estimate the association between prenatal diet and vaginal microbiota composition overall and by race.<br><br>METHODS: We leveraged a racially diverse prenatal cohort of North Carolina women enrolled between 1995 and 2001 to conduct this analysis using cross-sectional data. Women completed food frequency questionnaires about diet in the previous 3 months and foods were categorised into subgroups: fruits, vegetables, nuts/seeds, whole grains, low-fat dairy, sweetened beverages and red meat. We additionally assessed dietary vitamin D, fibre and yogurt consumption. Stored vaginal swabs collected in mid-pregnancy were sequenced using 16S taxonomic profiling. Women were categorised into three groups based on predominance of species: Lactobacillus iners, Lactobacillus miscellaneous and Bacterial Vaginosis (BV)-associated bacteria. Adjusted Poisson models with robust variance estimators were run to assess the risk of being in a specific vagitype compared to the referent. Race-stratified models (Black/White) were also run.<br><br>RESULTS: In this study of 634 women, higher consumption of dairy was associated with increased likelihood of membership in the L. crispatus group compared to the L. iners group in a dose-dependent manner (RR quartile 4 vs. 1: 2.01 [95% CI: 1.36, 2.95]). Increased intake of fruit, vitamin D, fibre and yogurt was also associated with increased likelihood of membership in L. crispatus compared to L. iners, but only among black women. Statistical heterogeneity was only detected for fibre intake. There were no detected associations between any other food groups or risk of membership in the BV group.<br><br>CONCLUSIONS: Higher consumption of low-fat dairy was associated with increased likelihood of membership in a beneficial vagitype, potentially driven by probiotics.}, }
@article {pmid34841472, year = {2021}, author = {Huang, M and Ramsey, S and Xue, W and Xie, J and Pellissier, J and Briggs, A}, title = {Conceptual Framework and Methodological Challenges for Modeling Effectiveness in Oncology Treatment Sequence Models.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, pmid = {34841472}, issn = {1179-2027}, abstract = {In this review, we summarize the challenges faced by existing oncology treatment sequence decision models and introduce a general framework to conceptualize such models. In the proposed framework, patients with cancer receive at least two lines of therapy (LOTs) followed by palliative care throughout their lifetime. Patients cycle through progression-free and progressive disease health states in each LOT before death. Under this framework, four broad aspects of modeling effectiveness of treatment sequences need exploration. First, disease progression, treatment discontinuation, and the relationship between the two events should be considered. Second, the effectiveness of each LOT depends on its placement in a treatment sequence as the effectiveness of later LOTs may be influenced by the earlier LOTs. Third, the treatment-free interval (TFI; time between discontinuation of earlier LOT and initiation of later LOT) may impact a therapy's effectiveness. Fourth, in the absence of head-to-head trials directly comparing LOTs, indirect treatment comparison (ITC) of outcomes for a specific LOT or even for the entire treatment sequence is important to consider. A search of decision models that estimated effectiveness of at least two lines of oncology therapy was conducted in PubMed (N = 20) and technology appraisals by the National Institute for Health and Care Excellence (N = 26) to assess four methodological aspects related to the model framework: (1) selection of outcomes for effectiveness in a treatment sequence, (2) approaches to adjust the efficacy of a treatment in consideration of its place in the sequence, (3) approaches to address TFIs between LOTs, and (4) incorporation of ITCs to estimate comparators' effectiveness in the absence of direct head-to-head evidence. Most models defined health states based on disease progression on different LOTs while estimating treatment duration outside of the main model framework (30/46) and used data from multiple data sources in different LOTs to model efficacy of a treatment sequence (41/46). No models adjusted efficacy for the characteristics of patients who switched from an earlier LOT to a later LOT or adjusted for the impact of prior therapies, and just six models considered TFIs. While 11 models applied ITC results to estimate efficacy in comparator treatment sequences, the majority limited the ITC to one LOT in the sequence. Thus, there is substantial room to improve the estimation of effectiveness for treatment sequences using existing data when comparing effectiveness of alternative treatment sequences.}, }
@article {pmid34840720, year = {2021}, author = {Gopal, AK and Popat, R and Mattison, RJ and Menne, T and Bloor, A and Gaymes, T and Khwaja, A and Juckett, M and Chen, Y and Cotter, MJ and Mufti, GJ}, title = {A Phase I trial of talazoparib in patients with advanced hematologic malignancies.}, journal = {International journal of hematologic oncology}, volume = {10}, number = {3}, pages = {IJH35}, doi = {10.2217/ijh-2021-0004}, pmid = {34840720}, issn = {2045-1393}, abstract = {Aim: The objective of this study was to establish the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of talazoparib.<br><br>Patients &amp; methods: This Phase I, two-cohort, dose-escalation trial evaluated talazoparib monotherapy in advanced hematologic malignancies (cohort 1: acute myeloid leukemia/myelodysplastic syndrome; cohort 2: chronic lymphocytic leukemia/mantle cell lymphoma).<br><br>Results: Thirty-three (cohort 1: n = 25; cohort 2: n = 8) patients received talazoparib (0.1-2.0 mg once daily). The MTD was exceeded at 2.0 mg/day in cohort 1 and at 0.9 mg/day in cohort 2. Grade ≥3 adverse events were primarily hematologic. Eighteen (54.5%) patients reported stable disease.<br><br>Conclusion: Talazoparib is relatively well tolerated in hematologic malignancies, with a similar MTD as in solid tumors, and shows preliminary anti leukemic activity.Clinical trial registration: NCT01399840 (ClinicalTrials.gov).}, }
@article {pmid34839583, year = {2021}, author = {Rothschild, CW and Richardson, BA and Guthrie, BL and Kithao, P and Omurwa, T and Mukabi, J and Callegari, LS and Lokken, EL and John-Stewart, G and Unger, JA and Kinuthia, J and Drake, AL}, title = {Contributions of side effects to contraceptive discontinuation and method switch among Kenyan women: a prospective cohort study.}, journal = {BJOG : an international journal of obstetrics and gynaecology}, volume = {}, number = {}, pages = {}, doi = {10.1111/1471-0528.17032}, pmid = {34839583}, issn = {1471-0528}, abstract = {OBJECTIVE: To determine the contribution of specific contraceptive side effects to method switch and modern-method discontinuation among Kenyan women.<br><br>DESIGN: A prospective cohort study.<br><br>SETTING: Five counties in Western Kenya.<br><br>PARTICIPANTS: Women aged ≥18 years old and emancipated female minors ≥14 years old using modern, reversible contraception were recruited while attending 10 public health facilities.<br><br>METHODS: Patient-reported side effect symptoms, method switch, and discontinuation were reported through weekly text message-based surveys for 24 weeks.<br><br>MAIN OUTCOME MEASUREMENTS: Prevalence, hazards ratio (HR).<br><br>RESULTS: Among 825 women, 44% were using implants, 43% injectables, 7% intrauterine device, and 6% oral contraceptive pills at enrollment. Most (61%) women were continuing a method used in the previous month. During the 24-week follow-up, incidence of contraceptive switch was 61.3 per 100 person-years (95% confidence interval [CI] 52.4-71.8) and incidence of discontinuation was 38.5 per 100 person-years (95%CI 31.6-47.0). On average, one-quarter (prevalence [Pr] 0.24, 95%CI 0.22-0.26) of participants reported side effects or method problems weekly, with sexual side effects the most prevalent symptom (Pr 0.15, 95%CI 0.13-0.16). Lack of expected bleeding was associated with higher risk of method switch (adjusted hazard ratio [aHR] 2.36, 95%CI 1.22-4.57). Risk of all-modern method discontinuation was higher among women experiencing irregular bleeding (adjusted hazard ratio [aHR] 2.39, 95%CI 1.20-4.77), weight changes (aHR 2.72, 95%CI 1.47-4.68), and sexual side effects (aHR 2.42, 95%CI 1.40-4.20).<br><br>CONCLUSIONS: Addressing irregular bleeding, weight changes, and sexual side effects through development of new products that minimize these specific side effects and anticipatory counseling may reduce method-related discontinuation.}, }
@article {pmid34839469, year = {2021}, author = {Bauer, AE and Avery, CL and Shi, M and Weinberg, CR and Olshan, AF and Harmon, QE and Luo, J and Yang, J and Manuck, T and Wu, MC and Klungsøyr, K and Trogstad, L and Magnus, P and Engel, SM}, title = {Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?.}, journal = {American journal of perinatology}, volume = {}, number = {}, pages = {}, doi = {10.1055/s-0041-1740072}, pmid = {34839469}, issn = {1098-8785}, support = {Eunice Kennedy Shriver National Institute of Child Health and Human Development//R01HD058008/ ; National Institute of Environmental Health Sciences//U01NS047537-01/ ; Norges Forskningsråd//151918/S10/ ; Norwegian Ministry of Health//N01-ES-75558/ ; }, abstract = {OBJECTIVE: Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations.<br><br>STUDY DESIGN: We conducted a nested case-control study within the Norwegian Mother, Father and Child Birth Cohort (1999-2008) of 2,596 mother-child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy.<br><br>RESULTS: Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01).<br><br>CONCLUSION: Evidence for gene-smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene-environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures.<br><br>KEY POINTS: · Maternal and fetal genotype may differentially influence preeclampsia.. · Smoking-related genes did not strongly modify smoking-preeclampsia association.. · Smoking cessation reduced strength of gene by smoking interactions..}, }
@article {pmid34836718, year = {2021}, author = {Akaike, T and Nghiem, P}, title = {Scientific and clinical developments in Merkel cell carcinoma: A polyomavirus-driven, often-lethal skin cancer.}, journal = {Journal of dermatological science}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jdermsci.2021.10.004}, pmid = {34836718}, issn = {1873-569X}, abstract = {Merkel cell carcinoma (MCC) is a primary neuroendocrine skin cancer that recurs in ~40% of cases. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV)-induced mutations are two major causative factors of MCC. Virus-positive MCCs express polyomavirus oncoproteins that are highly immunogenic yet are required for ongoing tumor growth. Virus-negative MCCs have a high burden of UV-DNA mutations that encode tumor-specific UV-neoantigens. Thus, both UV- and virus-induced MCCs are highly immunogenic, enabling diverse T-cell targeted therapies. Optimal MCC management is challenging given its rarity, aggressive nature, rapidly evolving care guidelines, and fundamental differences in management compared to other skin cancers. MCC is often managed aggressively with extensive surgery, radiotherapy or systemic therapy, frequently leading to toxicities that might have been avoidable while still achieving optimal disease control. Thus, multi-disciplinary care is crucial for providing patients with the best possible outcomes. The outlook for many patients with advanced MCC has progressed remarkably over the past decade due to PD-1 pathway blocking agents that provide durable benefit for a substantial subset of MCC patients. The management of early-stage MCC has also improved due to better approaches to integrate surgery and radiotherapy. Prognostic accuracy and ongoing surveillance have advanced due to stage-specific recurrence data and sophisticated "liquid biopsies" that allow early detection of disease recurrence. Here we summarize both recent striking progress and pressing challenges such as PD-(L)1-refractory MCC, and management of MCC patients with immune dysfunction. We also highlight diverse resources to allow providers to take advantage of recent progress in this fast-moving field.}, }
@article {pmid34836419, year = {2021}, author = {Nounu, A and Richmond, RC and Stewart, ID and Surendran, P and Wareham, NJ and Butterworth, A and Weinstein, SJ and Albanes, D and Baron, JA and Hopper, JL and Figueiredo, JC and Newcomb, PA and Lindor, NM and Casey, G and Platz, EA and Marchand, LL and Ulrich, CM and Li, CI and van Dujinhoven, FJB and Gsur, A and Campbell, PT and Moreno, V and Vodicka, P and Vodickova, L and Amitay, E and Alwers, E and Chang-Claude, J and Sakoda, LC and Slattery, ML and Schoen, RE and Gunter, MJ and Castellví-Bel, S and Kim, HR and Kweon, SS and Chan, AT and Li, L and Zheng, W and Bishop, DT and Buchanan, DD and Giles, GG and Gruber, SB and Rennert, G and Stadler, ZK and Harrison, TA and Lin, Y and Keku, TO and Woods, MO and Schafmayer, C and Van Guelpen, B and Gallinger, S and Hampel, H and Berndt, SI and Pharoah, PDP and Lindblom, A and Wolk, A and Wu, AH and White, E and Peters, U and Drew, DA and Scherer, D and Bermejo, JL and Brenner, H and Hoffmeister, M and Williams, AC and Relton, CL}, title = {Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.}, journal = {Nutrients}, volume = {13}, number = {11}, pages = {}, doi = {10.3390/nu13114164}, pmid = {34836419}, issn = {2072-6643}, abstract = {Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.}, }
@article {pmid34835098, year = {2021}, author = {Duke, ER and Boshier, FAT and Boeckh, M and Schiffer, JT and Cardozo-Ojeda, EF}, title = {Mathematical Modeling of Within-Host, Untreated, Cytomegalovirus Infection Dynamics after Allogeneic Transplantation.}, journal = {Viruses}, volume = {13}, number = {11}, pages = {}, doi = {10.3390/v13112292}, pmid = {34835098}, issn = {1999-4915}, support = {contract number EP08050.002//Merck/ ; KL2 TR002317/NH/NIH HHS/United States ; K24 HL093294/NH/NIH HHS/United States ; P01 CA18029/NH/NIH HHS/United States ; }, abstract = {Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants' clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.}, }
@article {pmid34831841, year = {2021}, author = {Street, R and Mathee, A and Mangwana, N and Dias, S and Sharma, JR and Ramharack, P and Louw, J and Reddy, T and Brocker, L and Surujlal-Naicker, S and Berkowitz, N and Malema, MS and Nkambule, S and Webster, C and Mahlangeni, N and Gelderblom, H and Mdhluli, M and Gray, G and Muller, C and Johnson, R}, title = {Spatial and Temporal Trends of SARS-CoV-2 RNA from Wastewater Treatment Plants over 6 Weeks in Cape Town, South Africa.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {22}, pages = {}, doi = {10.3390/ijerph182212085}, pmid = {34831841}, issn = {1660-4601}, support = {96829//Michael and Susan Dell Foundation/ ; 40118//South African Medical Research Council/ ; }, abstract = {Recent scientific trends have revealed that the collection and analysis of data on the occurrence and fate of SARS-CoV-2 in wastewater may serve as an early warning system for COVID-19. In South Africa, the first COVID-19 epicenter emerged in the Western Cape Province. The City of Cape Town, located in the Western Cape Province, has approximately 4 million inhabitants. This study reports on the monitoring of SARS-CoV-2 RNA in the wastewater of the City of Cape Town's wastewater treatment plants (WWTPs) during the peak of the epidemic. During this period, the highest overall median viral RNA signal was observed in week 1 (9200 RNA copies/mL) and declined to 127 copies/mL in week 6. The overall decrease in the amount of detected viral SARS-CoV-2 RNA over the 6-week study period was associated with a declining number of newly identified COVID-19 cases in the city. The SARS-CoV-2 early warning system has now been established to detect future waves of COVID-19.}, }
@article {pmid34823030, year = {2021}, author = {Angeli, K and Gao, S and Danciu, I and Durbin, EB and Wu, XC and Stroup, A and Doherty, J and Schwartz, S and Wiggins, C and Damesyn, M and Coyle, L and Penberthy, L and Tourassi, GD and Yoon, HJ}, title = {Class Imbalance in Out-of-Distribution Datasets: Improving the Robustness of the TextCNN for the Classification of Rare Cancer Types.}, journal = {Journal of biomedical informatics}, volume = {}, number = {}, pages = {103957}, doi = {10.1016/j.jbi.2021.103957}, pmid = {34823030}, issn = {1532-0480}, abstract = {In the last decade, the widespread adoption of electronic health record documentation has created huge opportunities for information mining. Natural language processing (NLP) techniques using machine and deep learning are becoming increasingly widespread for information extraction tasks from unstructured clinical notes. Disparities in performance when deploying machine learning models in the real world have recently received considerable attention. In the clinical NLP domain, the robustness of convolutional neural networks (CNNs) for classifying cancer pathology reports under natural distribution shifts remains understudied. In this research, we aim to quantify and improve the performance of the CNN for text classification on out-of-distribution (OOD) datasets resulting from the natural evolution of clinical text in pathology reports. We identified class imbalance due to different prevalence of cancer types as one of the sources of performance drop and analyzed the impact of previous methods for addressing class imbalance when deploying models in real-world domains. Our results show that our novel class-specialized ensemble technique outperforms other methods for the classification of rare cancer types in terms of macro F1 scores. We also found that traditional ensemble methods perform better in top classes, leading to higher micro F1 scores. Based on our findings, we formulate a series of recommendations for other ML practitioners on how to build robust models with extremely imbalanced datasets in biomedical NLP applications.}, }
@article {pmid34819160, year = {2021}, author = {Alvarez, CS and Avilés-Santa, ML and Freedman, ND and Perreira, KM and Garcia-Bedoya, O and Kaplan, RC and Daviglus, ML and Graubard, BI and Talavera, GA and Thyagarajan, B and Camargo, MC}, title = {Associations of Helicobacter pylori and hepatitis A seropositivity with asthma in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL): addressing the hygiene hypothesis.}, journal = {Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology}, volume = {17}, number = {1}, pages = {120}, pmid = {34819160}, issn = {1710-1484}, support = {N01-HC65233/HL/NHLBI NIH HHS/United States ; N01-HC65234//university of miami/ ; N01-HC65235//albert einstein college of medicine/ ; N01-HC65236//northwestern university/ ; N01-HC65237//san diego university/ ; }, abstract = {BACKGROUND: The hygiene hypothesis posits that microbial exposure reduces risk of asthma and other respiratory-related diseases. Helicobacter pylori and hepatitis A virus (HAV) are common fecal-oral infections. Our study aimed to examine associations of seropositivity to these agents with asthma in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).<br><br>METHODS: A total of 12,471 HCHS/SOL participants with baseline data on self-reported physician-diagnosed asthma, and antibodies anti-H. pylori and anti-HAV were included in this cross-sectional analysis. Multivariable logistic regression models were used to estimate the odds ratios and 95% confidence intervals for the overall associations of seropositivity to each agent with asthma. Analyses were also stratified by Hispanic/Latino background. Effect modification by smoking status and nativity were tested. An analysis restricted to individuals with spirometry-defined chronic obstructive pulmonary disease (COPD) was also considered.<br><br>RESULTS: The weighted overall prevalence of asthma was 16.6%. The weighted seroprevalence of H. pylori was 56.6% and of HAV was 76.6%, and they significantly differed by Hispanic/Latino background. After accounting for age, sex, education and other key confounders, we found no associations between H. pylori or HAV seropositivity with asthma (with and without COPD), either for all individuals combined or for any of the six specific backgrounds. There were no significant interactions by smoking and nativity.<br><br>CONCLUSION: Our findings did not provide support for the role of H. pylori or HAV, as evidence of the hygiene hypothesis in asthma among the large and diverse Hispanic/Latino populations of the HCHS/SOL. Trial registration NCT02060344.}, }
@article {pmid34818981, year = {2021}, author = {Calis, P and Vojtech, L and Hladik, F and Gravett, MG}, title = {A review of ex vivo placental perfusion models: an underutilized but promising method to study maternal-fetal interactions.}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/14767058.2021.2005565}, pmid = {34818981}, issn = {1476-4954}, abstract = {Studying the placenta can provide information about the mechanistic pathways of pregnancy disease. However, analyzing placental tissues and manipulating placental function in real-time during pregnancy is not feasible. The ex vivo placental perfusion model allows observing important aspects of the physiology and pathology of the placenta, while maintaining its viability and functional integrity, and without causing harm to mother or fetus. In this review, we describe and compare setups for this technically complex model and summarize outcomes from various published studies. We hope that our review will encourage wider use of ex vivo placental perfusion, which in turn would generate more knowledge to improve pregnancy outcomes.}, }
@article {pmid34817305, year = {2021}, author = {Fuchs, HE and O'Connell, K and Du, M and Navarro, SL and Brasky, TM and Kantor, ED}, title = {Vitamin B12 Supplementation and Vitamin B12 Blood Serum Levels: Evaluation of Effect Modification by Gender and Smoking Status.}, journal = {Nutrition and cancer}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/01635581.2021.2007271}, pmid = {34817305}, issn = {1532-7914}, abstract = {Research suggests that high intake of supplemental vitamin B12 may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999-2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B12 supplement use and log-transformed serum B12 levels. Persons taking vitamin B12 through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B12 intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%-30%) higher than nonusers, whereas MVMM-exclusive users' geometric mean was 61% (95% CI: 53%-70%) higher than nonusers (p-trend < 0.001). Although a positive trend (p-trend < 0.001) was observed for both men and women, the association was stronger among women (p-interaction < 0.001). No interaction was observed for smoking status (p-interaction = 0.45). B12 supplementation is associated with higher levels of serum B12, with significant interaction by gender but not smoking. Further work is needed to better understand the interplay of B12 and gender.}, }
@article {pmid34815518, year = {2021}, author = {Meyers, G and Hamadani, M and Martens, M and Ali, H and Choe, H and Dawson, P and Harris, AC and van Hooren, E and Klaassen, W and Leifer, E and MacMillan, ML and van Oosterhout, Y and Perez, L and Pusic, I and Vo, P and Levine, JE}, title = {Lessons learned from early closure of a clinical trial for steroid-refractory acute GVHD.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34815518}, issn = {1476-5365}, support = {U10HL069294//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24HL138660//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, }
@article {pmid34815384, year = {2021}, author = {Xie, L and Shou, W}, title = {Steering ecological-evolutionary dynamics to improve artificial selection of microbial communities.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {6799}, pmid = {34815384}, issn = {2041-1723}, support = {R01GM124128//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM124128//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1917258//NSF | BIO | Division of Molecular and Cellular Biosciences (MCB)/ ; 1917258//NSF | BIO | Division of Molecular and Cellular Biosciences (MCB)/ ; }, abstract = {Microbial communities often perform important functions that depend on inter-species interactions. To improve community function via artificial selection, one can repeatedly grow many communities to allow mutations to arise, and "reproduce" the highest-functioning communities by partitioning each into multiple offspring communities for the next cycle. Since improvement is often unimpressive in experiments, we study how to design effective selection strategies in silico. Specifically, we simulate community selection to improve a function that requires two species. With a "community function landscape", we visualize how community function depends on species and genotype compositions. Due to ecological interactions that promote species coexistence, the evolutionary trajectory of communities is restricted to a path on the landscape. This restriction can generate counter-intuitive evolutionary dynamics, prevent the attainment of maximal function, and importantly, hinder selection by trapping communities in locations of low community function heritability. We devise experimentally-implementable manipulations to shift the path to higher heritability, which speeds up community function improvement even when landscapes are high dimensional or unknown. Video walkthroughs: https://go.nature.com/3GWwS6j ; https://online.kitp.ucsb.edu/online/ecoevo21/shou2/ .}, }
@article {pmid34815335, year = {2021}, author = {Q Bartlett, A and Vesco, KK and Purnell, JQ and Francisco, M and Goddard, E and Guan, X and DeBarber, A and Leo, MC and Baetscher, E and Rooney, W and Naugler, W and Guimaraes, AR and Catalano, P and Xia, Z and Schedin, P}, title = {Pregnancy and weaning regulate human maternal liver size and function.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {48}, pages = {}, doi = {10.1073/pnas.2107269118}, pmid = {34815335}, issn = {1091-6490}, abstract = {During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.}, }
@article {pmid34814844, year = {2021}, author = {Yang, Y and Du, Z and Liu, Y and Lao, J and Sun, X and Tang, F}, title = {Disability and the risk of subsequent mortality in elderly: a 12-year longitudinal population-based study.}, journal = {BMC geriatrics}, volume = {21}, number = {1}, pages = {662}, pmid = {34814844}, issn = {1471-2318}, abstract = {BACKGROUND: Assessment the impact of disability on mortality among the elderly is vital to healthy ageing. The present study aimed to assess the long-term influence of disability on death in the elderly based on a longitudinal study.<br><br>METHOD: This study used the Chinese Longitudinal Healthy Longevity Study (CLHLS) data from 2002 to 2014, including 13,666 participants aged 65 years and older in analyses. The Katz ADL index was used to assess disability status and levels. Cumulative mortality rates were estimated by the Kaplan-Meier method. Cox proportional hazards models were conducted to estimate associations between disability and all-cause mortality for overall participants, two age groups as well as specific chronic disease groups. All reported results were adjusted by survey weights to account for the complex survey design.<br><br>RESULTS: During the 12-year follow-up, the death density was 6.01 per 100 person-years. The 3-years' cumulative mortality rate of nondisabled elderly was 11.9% (95%CI: 10.9, 12.9%). As the level of disability increased, the cumulative mortality rate was from 28.1% (95%CI: 23.0, 33.1%) to 77.6% (95%CI: 63.8, 91.4%). Compared with non-disabled elderly, the multiple-adjusted hazard ratio of death due to disability was 1.68 (95% CI: 1.48, 1.90). The hazard ratios varied from 1.44 (95%CI: 1.23, 1.67) to 4.45 (95%CI: 2.69, 7.38) after classifying the disability levels. The hazard ratios of death in the young-old group (65-79 years) were higher than the old-old group (80 years and over) in both level B (HR = 1.58, 95%CI: 1.25, 2.00 vs. HR = 1.22, 95%CI: 1.06, 1.39, P = 0.029) and level G (HR = 24.09, 95%CI: 10.83, 53.60 vs. HR = 2.56, 95%CI: 1.75, 3.74, P < 0.001). For patients with hypertension, diabetes, heart disease, cerebrovascular disease as well as dementia, disability increases their relative risk of mortality by 1.64 (95%CI: 1.40, 1.93), 2.85 (95%CI: 1.46, 5.58), 1.45 (95%CI: 1.02, 2.05), 2.13 (95%CI: 1.54, 2.93) and 3.56 (95%CI: 1.22, 10.38) times, respectively.<br><br>CONCLUSIONS: Disability increases the risk of all-cause death in the elderly, especially those with chronic diseases and the young-old group. Further studies are needed to better understand how to effectively prevent disability in the older population.}, }
@article {pmid34814034, year = {2021}, author = {Kim, S and Ryu, H and Tai, S and Pedowitz, M and Rzasa, JR and Pennachio, DJ and Hajzus, JR and Milton, DK and Myers-Ward, R and Daniels, KM}, title = {Real-time ultra-sensitive detection of SARS-CoV-2 by quasi-freestanding epitaxial graphene-based biosensor.}, journal = {Biosensors &amp; bioelectronics}, volume = {197}, number = {}, pages = {113803}, doi = {10.1016/j.bios.2021.113803}, pmid = {34814034}, issn = {1873-4235}, abstract = {We report the rapid detection of SARS-CoV-2 in infected patients (mid-turbinate swabs and exhaled breath aerosol samples) in concentrations as low as 60 copies/mL of the virus in seconds by electrical transduction of the SARS-CoV-2 S1 spike protein antigen via SARS-CoV-2 S1 spike protein antibodies immobilized on bilayer quasi-freestanding epitaxial graphene without gate or signal amplification. The sensor demonstrates the spike protein antigen detection in a concentration as low as 1 ag/mL. The heterostructure of the SARS-CoV-2 antibody/graphene-based sensor is developed through a simple and low-cost fabrication technique. Furthermore, sensors integrated into a portable testing unit distinguished B.1.1.7 variant positive samples from infected patients (mid-turbinate swabs and saliva samples, 4000-8000 copies/mL) with a response time of as fast as 0.6 s. The sensor is reusable, allowing for reimmobilization of the crosslinker and antibodies on the biosensor after desorption of biomarkers by NaCl solution or heat treatment above 40 °C.}, }
@article {pmid34812653, year = {2021}, author = {Gilbert, PB and Montefiori, DC and McDermott, AB and Fong, Y and Benkeser, D and Deng, W and Zhou, H and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Flach, B and Lin, BC and O'Connell, S and McDanal, C and Eaton, A and Sarzotti-Kelsoe, M and Lu, Y and Yu, C and Borate, B and van der Laan, LWP and Hejazi, NS and Huynh, C and Miller, J and El Sahly, HM and Baden, LR and Baron, M and De La Cruz, L and Gay, C and Kalams, S and Kelley, CF and Andrasik, MP and Kublin, JG and Corey, L and Neuzil, KM and Carpp, LN and Pajon, R and Follmann, D and Donis, RO and Koup, RA and ,  and ,  and ,  and , }, title = {Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eab3435}, pmid = {34812653}, issn = {1095-9203}, abstract = {[Figure: see text].}, }
@article {pmid34811858, year = {2021}, author = {Klotz, AD and Caterino, JM and Durham, D and Rico, JF and Pallin, DJ and Grudzen, CR and McNaughton, C and Marcelin, I and Abar, B and Adler, D and Bastani, A and Bernstein, SL and Bischof, JJ and Coyne, CJ and Henning, DJ and Hudson, MF and Lyman, GH and Madsen, TE and Reyes-Gibby, CC and Ryan, RJ and Shapiro, NI and Swor, R and Thomas, CR and Venkat, A and Wilson, J and Jim Yeung, SC and Yilmaz, S and Stutman, R and Baugh, CW}, title = {Observation Unit Use Among Patients with Cancer Following Emergency Department Visits: Results of a Multicenter Prospective Cohort from CONCERN.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/acem.14392}, pmid = {34811858}, issn = {1553-2712}, abstract = {PURPOSE: Emergency department (ED) visits by patients with cancer frequently end in hospitalization. As concerns about ED and hospital crowding increase, observation unit care may be an important strategy to deliver safe and efficient treatment for eligible patients. In this investigation, we compared the prevalence and clinical characteristics of cancer patients who received observation unit care with those who were admitted to the hospital from the ED.<br><br>METHODS: We performed a multicenter prospective cohort study of patients with cancer presenting to an ED affiliated with one of 18 hospitals of the Comprehensive Oncologic Emergency Research Network (CONCERN) between March 1, 2016 and January 30, 2017. We compared patient characteristics with the prevalence of observation unit care usage, hospital admission, and length of stay.<br><br>RESULTS: Of 1,051 enrolled patients, 596 (56.7%) were admitted as inpatients, and 72 (6.9%) were placed in an observation unit. For patients admitted as inpatients, 23.7% had a length of stay ≤2 days. The conversion rate from observation to inpatient was 17.1% (95% CI 14.6-19.4) among those receiving care in an observation unit. The average observation unit length of stay was 14.7 hours. Patient factors associated ED disposition to observation unit care were female gender and low Charlson Comorbidity Index.<br><br>CONCLUSION: In this multicenter prospective cohort study, the discrepancy between observation unit care use and short inpatient hospitalization may represent underutilization of this resource and a target for process change.}, }
@article {pmid34810210, year = {2021}, author = {Lipshultz, ER and Chow, EJ and Doody, DR and Armenian, SH and Asselin, BL and Baker, KS and Bhatia, S and Constine, LS and Freyer, DR and Kopp, LM and Schwartz, CL and Lipshultz, SE and Vrooman, LM}, title = {Cardiometabolic risk in childhood cancer survivors: a report from the Children's Oncology Group.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0360}, pmid = {34810210}, issn = {1538-7755}, abstract = {BACKGROUND: Childhood cancer survivors are at risk for cardiovascular disease. We assessed the burden of potentially modifiable cardiometabolic risk factors (CRFs) among survivors compared with population-matched controls.<br><br>METHODS: Survivors previously enrolled on Pediatric Oncology Group protocols 9404, 9425, 9426, 9754, and DFCI 95-01 from 1996-2001 with acute lymphoblastic leukemia/lymphoma, Hodgkin lymphoma, or osteosarcoma were prospectively assessed for the prevalence of CRFs and compared with an age, sex, and race/ethnicity-matched 2013 NHANES population. We estimated future predicted cardiovascular risk based on general population (e.g. Framingham) and Childhood Cancer Survivor Study (CCSS) models.<br><br>RESULTS: Compared with NHANES (n=584), survivors (n=164; 44.5% female, median age 28 years [range: 16-38 years]; median 17.4 years [range: 13-22 years] since cancer diagnosis; median doxorubicin dose 300 mg/m2; 30.5% chest radiation) had similar rates of obesity, diabetes, and dyslipidemia, but more pre-hypertension/hypertension (38.4% vs. 30.1%, p=0.044). Survivors had fewer metabolic syndrome features compared with NHANES (2 or more features: 26.7% vs. 55.9%; p<0.001). Survivors were more physically active and smoked tobacco less (both p<0.0001). Therefore, general population cardiovascular risk scores were lower for survivors vs. NHANES. However, with CCSS models, 30.5% of survivors were at moderate risk of ischemic heart disease, and >95% at moderate/high risk for heart failure, with a 9-12% predicted incidence of these conditions by age 50 years.<br><br>CONCLUSIONS: Childhood cancer survivors exhibited similar or better cardiometabolic and lifestyle profiles compared with NHANES, but nonetheless are at risk for future clinically-significant cardiovascular disease.<br><br>IMPACT: Further strategies supporting optimal CRF control are warranted in survivors.}, }
@article {pmid34809631, year = {2021}, author = {Han, S and Williamson, BD and Fong, Y}, title = {Improving random forest predictions in small datasets from two-phase sampling designs.}, journal = {BMC medical informatics and decision making}, volume = {21}, number = {1}, pages = {322}, pmid = {34809631}, issn = {1472-6947}, support = {R01-AI122991//National Institute of Allergy and Infectious Diseases/ ; UM1-AI068635//National Institute of Allergy and Infectious Diseases/ ; S10OD028685/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: While random forests are one of the most successful machine learning methods, it is necessary to optimize their performance for use with datasets resulting from a two-phase sampling design with a small number of cases-a common situation in biomedical studies, which often have rare outcomes and covariates whose measurement is resource-intensive.<br><br>METHODS: Using an immunologic marker dataset from a phase III HIV vaccine efficacy trial, we seek to optimize random forest prediction performance using combinations of variable screening, class balancing, weighting, and hyperparameter tuning.<br><br>RESULTS: Our experiments show that while class balancing helps improve random forest prediction performance when variable screening is not applied, class balancing has a negative impact on performance in the presence of variable screening. The impact of the weighting similarly depends on whether variable screening is applied. Hyperparameter tuning is ineffective in situations with small sample sizes. We further show that random forests under-perform generalized linear models for some subsets of markers, and prediction performance on this dataset can be improved by stacking random forests and generalized linear models trained on different subsets of predictors, and that the extent of improvement depends critically on the dissimilarities between candidate learner predictions.<br><br>CONCLUSION: In small datasets from two-phase sampling design, variable screening and inverse sampling probability weighting are important for achieving good prediction performance of random forests. In addition, stacking random forests and simple linear models can offer improvements over random forests.}, }
@article {pmid34785769, year = {2021}, author = {Walter, RB and Gale, RP}, title = {Elihu H. Estey, MD: Leukaemia expert, statistician, and gentle soul (July 15, 1946-October 8, 2021).}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34785769}, issn = {1476-5365}, }
@article {pmid34807468, year = {2021}, author = {Ujjani, C and Greninger, AL and Shadman, M and Hill, JA and Lynch, RC and Warren, EH and Gopal, AK}, title = {Heterologous SARS-CoV-2 Vaccinations in Patients with B-cell Lymphoid Malignancies.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.26418}, pmid = {34807468}, issn = {1096-8652}, }
@article {pmid34806308, year = {2021}, author = {Miner, MD and Corey, L and Montefiori, D}, title = {Broadly neutralizing monoclonal antibodies for HIV prevention.}, journal = {Journal of the International AIDS Society}, volume = {24 Suppl 7}, number = {}, pages = {e25829}, doi = {10.1002/jia2.25829}, pmid = {34806308}, issn = {1758-2652}, abstract = {INTRODUCTION: The last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.<br><br>DISCUSSION: Recently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.<br><br>CONCLUSIONS: Iterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.}, }
@article {pmid34806048, year = {2021}, author = {Koester, ST and Li, N and Lachance, DM and Dey, N}, title = {Marker-based assays for studying gut transit in gnotobiotic and conventional mouse models.}, journal = {STAR protocols}, volume = {2}, number = {4}, pages = {100938}, doi = {10.1016/j.xpro.2021.100938}, pmid = {34806048}, issn = {2666-1667}, abstract = {Gastrointestinal motility is regulated by a variety of environmental factors including gut microbes and metabolites. The ability to interrogate mouse models of gut motility has enabled elucidation of these relationships. Here we describe integration of the red carmine dye and fluorescence isothiocyanate-dextran marker-based assays for characterizing gut transit with spatial resolution, along with an optional intracolonic infusion protocol for studying the effects of metabolites on colonic transit. These protocols can be adapted for use in gnotobiotic and conventional mouse models. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).}, }
@article {pmid34805425, year = {2021}, author = {Weil, AA and Sohlberg, SL and O'Hanlon, JA and Casto, AM and Emanuels, AW and Lo, NK and Greismer, EP and Magedson, AM and Wilcox, NC and Kim, AE and Back, L and Frazar, CD and Pelle, B and Sibley, TR and Ilcisin, M and Lee, J and Ryke, EL and Craft, JC and Schwabe-Fry, KM and Fay, KA and Cho, S and Han, PD and Heidl, SJ and Pfau, BA and Truong, M and Zhong, W and Srivatsan, SR and Harb, KF and Gottlieb, GS and Hughes, JP and Nickerson, DA and Lockwood, CM and Starita, LM and Bedford, T and Shendure, JA and Chu, HY}, title = {SARS-CoV-2 Epidemiology on a Public University Campus in Washington State.}, journal = {Open forum infectious diseases}, volume = {8}, number = {11}, pages = {ofab464}, doi = {10.1093/ofid/ofab464}, pmid = {34805425}, issn = {2328-8957}, abstract = {Background: We aimed to evaluate a testing program to facilitate control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission at a large university and measure spread in the university community using viral genome sequencing.<br><br>Methods: Our prospective longitudinal study used remote contactless enrollment, daily mobile symptom and exposure tracking, and self-swab sample collection. Individuals were tested if the participant was exposed to a known SARS-CoV-2-infected person, developed new symptoms, or reported high-risk behavior (such as attending an indoor gathering without masking or social distancing), if a member of a group experiencing an outbreak, or at enrollment. Study participants included students, staff, and faculty at an urban public university during the Autumn quarter of 2020.<br><br>Results: We enrolled 16 476 individuals, performed 29 783 SARS-CoV-2 tests, and detected 236 infections. Seventy-five percent of positive cases reported at least 1 of the following: symptoms (60.8%), exposure (34.7%), or high-risk behaviors (21.5%). Greek community affiliation was the strongest risk factor for testing positive, and molecular epidemiology results suggest that specific large gatherings were responsible for several outbreaks.<br><br>Conclusions: A testing program focused on individuals with symptoms and unvaccinated persons who participate in large campus gatherings may be effective as part of a comprehensive university-wide mitigation strategy to control the spread of SARS-CoV-2.}, }
@article {pmid34802773, year = {2021}, author = {Casto, AM and Fredricks, DN and Hill, JA}, title = {Diagnosis of infectious diseases in immunocompromised hosts using metagenomic next generation sequencing-based diagnostics.}, journal = {Blood reviews}, volume = {}, number = {}, pages = {100906}, doi = {10.1016/j.blre.2021.100906}, pmid = {34802773}, issn = {1532-1681}, abstract = {The diagnosis of infectious diseases in immunocompromised hosts presents unique challenges for the clinician. Metagenomic next generation sequencing (mNGS) based diagnostics that identify microbial nucleic acids in clinical samples (mNGS for pathogen identification or mNGSpi) may be a useful tool in addressing some of these challenges. Studies of mNGSpi in immunocompromised hosts have demonstrated that these diagnostics are capable of identifying causative organisms in a subset of patients for whom conventional testing has been negative. While these studies provide proof of concept for mNGSpi utility, they have a number of limitations, which make it difficult to confidently assess test performance and clinical impact based on current data. Future studies will likely feature larger cohort sizes and controlled interventional study designs that assess the impact of mNGSpi on clinical endpoints. They will also likely include assessments of the clinical value of data generated by mNGS beyond pathogen identification.}, }
@article {pmid34801976, year = {2021}, author = {Romine, PE and Voutsinas, J and Wu, V and Tratt, M and Liao, J and Parvathaneni, U and Barber, B and Dillon, J and Timoshchuk, MA and Futran, N and Houlton, J and Laramore, G and Martins, R and Eaton, KD and Rodriguez, C}, title = {Timing of postoperative radiation therapy and survival in resected salivary gland cancers: Long-term results from a single institution.}, journal = {Oral oncology}, volume = {123}, number = {}, pages = {105626}, doi = {10.1016/j.oraloncology.2021.105626}, pmid = {34801976}, issn = {1879-0593}, abstract = {OBJECTIVES: Timely administration of postoperative radiation therapy (PORT) impacts oncologic outcomes in resected squamous cell carcinomas of the head and neck. Salivary gland cancers (SGCs) are uncommon, and timing of PORT has not been extensively explored. We aimed to determine if the interval between surgery and PORT impacts outcomes in SGCs.<br><br>MATERIALS AND METHODS: This is a retrospective study of patients with SGCs who underwent curative intent surgical resection followed by adjuvant PORT. Locoregional recurrence free survival (LRFS), disease free survival (DFS), and overall survival (OS) were estimated using the Kaplan Meier method. A multivariate analysis explored the association between demographics, tumor characteristics, and PORT timing with oncologic outcomes using a stepwise Cox proportional hazards model.<br><br>RESULTS: 180 eligible patients were identified. The median time to PORT start was 61 (range 8-121) days. 169 (93.5%) of patients received neutron radiation. With a median follow up of 8.2 years in surviving patients, the 10-year OS and LRFS estimates were 61% and 53%. In a multivariate analysis, nodal involvement, histologic grade, and age at diagnosis were associated with OS, while nodal involvement, tumor size, and age at diagnosis were associated with LRFS and DFS. Time to PORT start or completion was not statistically associated with survival outcomes.<br><br>CONCLUSION: SGC patients who underwent surgery in our tertiary institution received PORT within a median of 61 days after surgery. With long term follow up, PORT timing in this retrospective series was not associated with worse oncologic outcomes, and support timely administration of PORT.}, }
@article {pmid34800530, year = {2021}, author = {VoPham, T and Bertrand, KA and Fisher, JA and Ward, MH and Laden, F and Jones, RR}, title = {Emissions of dioxins and dioxin-like compounds and incidence of hepatocellular carcinoma in the United States.}, journal = {Environmental research}, volume = {}, number = {}, pages = {112386}, doi = {10.1016/j.envres.2021.112386}, pmid = {34800530}, issn = {1096-0953}, abstract = {Ambient dioxin exposure from industrial sources, excluding exposures from occupations and accidental releases/contamination, may be associated with risk of developing hepatocellular carcinoma (HCC). The objective of this study was to examine the association between county-level ambient dioxin air emissions from industrial sources and HCC risk in the US. We obtained information on 90,359 incident HCC cases diagnosed between 2000 and 2016 from population-based cancer registries across the US in the Surveillance, Epidemiology, and End Results (SEER) database. Dioxin emissions from 1987 to 2007 from a nationwide spatial database of historical dioxin-emitting facilities were linked to the SEER county of residence at diagnosis using a geographic information system (GIS). Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between county-level dioxin emissions and HCC rates adjusting for individual-level age at diagnosis, sex, race/ethnicity, year of diagnosis, SEER registry, and county-level information on health conditions, lifestyle factors, and socioeconomic status. There was no association between dioxin emissions based on the number of dioxin-emitting facilities within a county or average annual emissions within a county and HCC risk. In analyses by facility type, there were positive associations between county-level dioxin emissions from coal-fired power plants (adjusted IRR 1.09, 95% CI 1.01-1.17), but not with the number of these facilities. Similarly, positive associations for industrial boilers and sewage sludge incinerators were evident, but not consistent across both exposure metrics. Future research should incorporate individual-level data to further explore the findings suggested by these ecologic analyses.}, }
@article {pmid34800474, year = {2021}, author = {Kariya, H and Buist, DSM and Anderson, ML and Lin, J and Gao, H and Ko, LK and Winer, RL}, title = {Does mailing unsolicited HPV self-sampling kits to women overdue for cervical cancer screening impact uptake of other preventive health services in a United States integrated delivery system?.}, journal = {Preventive medicine}, volume = {}, number = {}, pages = {106896}, doi = {10.1016/j.ypmed.2021.106896}, pmid = {34800474}, issn = {1096-0260}, abstract = {Women overdue for cervical cancer screening often have other preventive care gaps. We examined whether mailing unsolicited human papillomavirus (HPV) self-sampling kits to increase cervical cancer screening impacted receipt of other preventive services women were due for: mammography, colorectal cancer (CRC) screening, influenza vaccination, depression screening, and diabetic HbA1c monitoring. From 2014 to 2016, 16,590 underscreened women were randomized to receive a mailed kit or usual care Pap reminders within Kaiser Permanente Washington. We used logistic regression to estimate odds ratios (ORs) of preventive services receipt within 12-months between the intervention vs. control arms, and within the intervention arm (comparing those returning a kit vs. attending Pap vs. nothing), adjusting models for demographic variables. There were no significant between-arm differences in uptake of any of the preventive services: intervention vs. control: mammography OR = 1.01 (95% confidence interval:0.88-1.17), CRC screening OR = 0.98 (0.86-1.13), influenza vaccination OR = 0.99 (0.92-1.06), depression screening OR = 1.07 (0.99-1.16), HbA1c OR = 0.84 (0.62-1.13). Within the intervention arm, preventive services uptake was higher in women who completed cervical cancer screening vs. did not, with stronger effects for women who attended Pap: Pap vs. nothing: mammography OR = 11.81 (8.11-17.19), CRC screening OR = 7.31 (5.57-9.58), influenza vaccination OR = 2.06 (1.82-2.32), depression screening OR = 1.79 (1.57-2.05), HbA1c OR = 3.35 (1.49-7.52); kit vs. nothing: mammography OR = 2.26 (1.56-3.26), CRC screening OR = 5.05 (3.57-7.14), influenza vaccination OR = 1.67 (1.41-1.98), depression screening OR = 1.09 (0.89-1.33), HbA1c OR = 1.23 (0.57-2.65). Mailing HPV self-sampling kits to underscreened women did not negatively impact uptake of other preventive services. However, overall preventive service uptake was the highest among women who attended in-clinic cervical cancer screening.}, }
@article {pmid34799431, year = {2021}, author = {Malik, FS and Liese, AD and Reboussin, BA and Sauder, KA and Frongillo, EA and Lawrence, JM and Bellatorre, A and Pihoker, C and Loots, B and Dabelea, D and Mayer-Davis, E and Jensen, E and Turley, C and Mendoza, JA}, title = {Prevalence and Predictors of Household Food Insecurity and Supplemental Nutrition Assistance Program Use in Youth and Young Adults With Diabetes: The SEARCH for Diabetes in Youth Study.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc21-0790}, pmid = {34799431}, issn = {1935-5548}, abstract = {OBJECTIVE: To assess the prevalence of household food insecurity (HFI) and Supplemental Nutrition Assistance Program (SNAP) participation by youth and young adults (YYA) with diabetes overall and by type, and sociodemographic characteristics.<br><br>RESEARCH DESIGN AND METHODS: The study included participants with youth-onset type 1 diabetes and type 2 diabetes from the SEARCH for Diabetes in Youth study. HFI was assessed using the 18-item U.S. Household Food Security Survey Module (HFSSM) administered from 2016 to 2019; three or more affirmations on the HFSSM were considered indicative of HFI. Participants were asked about SNAP participation. We used χ2 tests to assess whether the prevalence of HFI and SNAP participation differed by diabetes type. Multivariable logistic regression models were used to examine differences in HFI by participant characteristics.<br><br>RESULTS: Of 2,561 respondents (age range, 10-35 years; 79.6% ≤25 years), 2,177 had type 1 diabetes (mean age, 21.0 years; 71.8% non-Hispanic White, 11.8% non-Hispanic Black, 13.3% Hispanic, and 3.1% other) and 384 had type 2 diabetes (mean age, 24.7 years; 18.8% non-Hispanic White, 45.8% non-Hispanic Black, 23.7% Hispanic, and 18.7% other). The overall prevalence of HFI was 19.7% (95% CI 18.1, 21.2). HFI was more prevalent in type 2 diabetes than type 1 diabetes (30.7% vs. 17.7%; P < 0.01). In multivariable regression models, YYA receiving Medicaid or Medicare or without insurance, whose parents had lower levels of education, and with lower household income had greater odds of experiencing HFI. SNAP participation was 14.1% (95% CI 12.7, 15.5), with greater participation among those with type 2 diabetes compared with those with type 1 diabetes (34.8% vs. 10.7%; P < 0.001).<br><br>CONCLUSIONS: Almost one in three YYA with type 2 diabetes and more than one in six with type 1 diabetes reported HFI in the past year-a significantly higher prevalence than in the general U.S.}, }
@article {pmid34798031, year = {2021}, author = {Irungu, EM and Mugwanya, KK and Mugo, NR and Bukusi, EA and Donnell, D and Odoyo, J and Wamoni, E and Peacock, S and Morton, JF and Ngure, K and Mugambi, M and Mukui, I and O'Malley, G and Baeten, JM and , }, title = {Integration of pre-exposure prophylaxis services into public HIV care clinics in Kenya: a pragmatic stepped-wedge randomised trial.}, journal = {The Lancet. Global health}, volume = {9}, number = {12}, pages = {e1730-e1739}, doi = {10.1016/S2214-109X(21)00391-0}, pmid = {34798031}, issn = {2214-109X}, abstract = {BACKGROUND: Successful and sustainable models for HIV pre-exposure prophylaxis (PrEP) delivery in public health systems in Africa are needed. We aimed to evaluate the implementation of PrEP delivery integrated in public HIV care clinics in Kenya.<br><br>METHODS: As part of Kenya's national PrEP roll-out, we conducted a stepped-wedge cluster-randomised pragmatic trial to catalyse scale-up of PrEP delivery integrated in 25 public HIV care clinics. We selected high-volume clinics in these regions (ie, those with a high number of people living with HIV enrolled in HIV care and treatment). Clinics (each representing a cluster) were stratified by region and randomly assigned to the order in which clinic staff would receive PrEP training and ongoing technical support using numbered opaque balls picked from a bag. There was no masking. PrEP provision was done by clinic staff without additional financial support. Data were abstracted from records of individuals initiating PrEP. The primary outcome was the number of people initiating PrEP per clinic per month comparing intervention to control periods. Other outcomes included PrEP continuation, adherence, and incident HIV infections. This trial is registered with ClinicalTrials.gov, NCT03052010.<br><br>FINDINGS: After the baseline period, which started in January, 2017, every month two to six HIV care clinics crossed over from control to intervention, until August, 2017, when all clinics were implementing the intervention. Of 4898 individuals initiating PrEP (27 during the control period and 4871 during the intervention period), 2640 (54%) were women, the median age was 31 years (IQR 25-39), and 4092 (84%) reported having a partner living with HIV. The mean monthly number of PrEP initiations per clinic was 0·1 (SD 0·5) before the intervention and 7·5 (2·7) after intervention introduction (rate ratio 23·7, 95% CI 14·2-39·5, p<0·0001). PrEP continuation was 57% at 1 month, 44% at 3 months, and 34% at 6 months, and 12% of those who missed a refill returned later for PrEP re-initiation. Tenofovir diphosphate was detected in 68 (96%) of 71 blood samples collected from a randomly selected subset of participants. Six HIV infections were observed over 2531 person-years of observation (incidence 0·24 cases per 100 person-years), three of which occurred at the first visit after PrEP initiation.<br><br>INTERPRETATION: We observed high uptake, reasonable continuation with high adherence, frequent PrEP restarts, and low HIV incidence. Integration of PrEP services within public HIV care clinics in Africa is feasible.<br><br>FUNDING: National Institute of Mental Health and Bill &amp; Melinda Gates Foundation.}, }
@article {pmid34797691, year = {2021}, author = {Haftmann, C and Zwicky, P and Ingelfinger, F and Mair, F and Floess, S and Riedel, R and Durek, P and Spalinger, MR and Friebel, E and Leung, BP and Lutz, M and Puertas, N and Amorim, A and Schärli, S and Becher, B and Kisielow, J and Waisman, A and Mashreghi, MF and Huehn, J and Becher, B}, title = {Protection against autoimmunity is driven by thymic epithelial cell-mediated regulation of Treg development.}, journal = {Science immunology}, volume = {6}, number = {65}, pages = {eabf3111}, doi = {10.1126/sciimmunol.abf3111}, pmid = {34797691}, issn = {2470-9468}, abstract = {[Figure: see text].}, }
@article {pmid34796077, year = {2021}, author = {Eaton, KD and Romine, PE and Martins, RG and Leblond, A and Carr, LL and Vesselle, HJ}, title = {Adaptive Fluorodeoxyglucose-Positron Emission Tomography Based Chemotherapy Selection for Metastatic Non-small Cell Lung Cancer.}, journal = {Cureus}, volume = {13}, number = {10}, pages = {e18804}, doi = {10.7759/cureus.18804}, pmid = {34796077}, issn = {2168-8184}, abstract = {Objectives The change in tumor fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) scan after one cycle of platinum-based chemotherapy has been shown to predict progression-free and overall survival (PFS and OS) among advanced non-small cell lung cancer (NSCLC) patients. Using early FDG-PET response to determine subsequent chemotherapy, we aim to evaluate the role that adaptive chemotherapy regimens have on later CT response, PFS, and OS in patients with advanced NSCLC. Materials and Methods Chemotherapy-naïve patients with metastatic NSCLC received carboplatin and paclitaxel (CP) on day one and repeated FDG-PET on day 18. PET-responding patients continued CP chemotherapy for a total of four cycles. PET non-responders were switched to alternate docetaxel and gemcitabine (DG) for three additional cycles. The primary outcome was the CT Response Evaluation Criteria in Solid Tumors (RECIST 1.0) response. Secondary endpoints included PFS and OS. Results Forty-six patients initiated treatment with chemotherapy on trial and were evaluable by PET/CT. Of these, 19 (41%) met the FDG-PET criteria for the response after a single cycle of CP. Only one non-responding patient had a CT response. Despite the lack of CT response in the DG arm, no trend for worse PFS or OS was seen between the two arms. Conclusions This work demonstrates that changing chemotherapy in the event of non-response by PET did not lead to improved CT RECIST response. However, non-responding patients who switched chemotherapy had similar PFS and OS to those who responded by PET and continued the same regimen.}, }
@article {pmid34795254, year = {2021}, author = {Phillips, D and Matusiak, M and Gutierrez, BR and Bhate, SS and Barlow, GL and Jiang, S and Demeter, J and Smythe, KS and Pierce, RH and Fling, SP and Ramchurren, N and Cheever, MA and Goltsev, Y and West, RB and Khodadoust, MS and Kim, YH and Schürch, CM and Nolan, GP}, title = {Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {6726}, pmid = {34795254}, issn = {2041-1723}, abstract = {Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.}, }
@article {pmid34795039, year = {2021}, author = {Cheng, GS and Evans, SE}, title = {The paradox of immunosuppressants and COVID-19.}, journal = {The European respiratory journal}, volume = {}, number = {}, pages = {}, doi = {10.1183/13993003.02828-2021}, pmid = {34795039}, issn = {1399-3003}, }
@article {pmid34794793, year = {2021}, author = {Clé, DV and Hirayama, AV and Alencar, AJ and Costa, LJ and Feliciano, JVP and Mattos, ER and Cordeiro, AC and Salvino, MA and Barros, GMN and de Lima, M and Scheinberg, P and Guerino-Cunha, RL}, title = {Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. I: Structuring centers for the multidisciplinary clinical administration and management of CAR-T cell therapy patients.}, journal = {Hematology, transfusion and cell therapy}, volume = {43 Suppl 2}, number = {}, pages = {S3-S12}, doi = {10.1016/j.htct.2021.09.001}, pmid = {34794793}, issn = {2531-1387}, abstract = {Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.}, }
@article {pmid34794792, year = {2021}, author = {Alencar, AJ and Hirayama, AV and Clé, DV and Salvino, MA and Perini, G and Arrais, C and Baiocchi, O and Palma, LC and Colturato, I and Vaz, J and Chiattone, R and de Lima, M and Filho, JS and Nabhan, S and Rocha, V and Guerino-Cunha, RL and Chiattone, CS}, title = {Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. III: anti-CD19 CAR-T cell therapy for patients with non-Hodgkin lymphoma.}, journal = {Hematology, transfusion and cell therapy}, volume = {43 Suppl 2}, number = {}, pages = {S22-S29}, doi = {10.1016/j.htct.2021.09.003}, pmid = {34794792}, issn = {2531-1387}, abstract = {The treatment and evolution of B-cell non-Hodgkin lymphoma (B-NHL) has undergone important changes in the last years with the emergence of targeted therapies, such as monoclonal antibodies, small molecules, antibody-drug conjugates, and bispecific antibodies. Nevertheless, a significant portion of patients remains refractory or relapsed (R/R) to the new therapeutic modalities, representing thus an unmet medical need. The use of CAR-T cells for the treatment of B-NHL patients has shown to be a promising therapy with impressive results in patients with R/R disease. The expectations are as high as the imminent approval of CAR-T cell therapy in Brazil, which it is expected to impact the prognosis of R/R B-NHL. The aim of this manuscript is to offer a consensus of specialists in the field of onco-hematology and cellular therapy, working in Brazil and United States, in order to discuss and offer recommendations in the present setting of the use of CAR-T cells for patients with B-NHL.}, }
@article {pmid34794791, year = {2021}, author = {Seber, A and de CastroJunior, CG and Kerbauy, LN and Hirayama, AV and Bonfim, C and Fernandes, JF and Souza, M and Schafell, R and Nabhan, S and Loggetto, SR and Simões, BP and Rocha, V and de Lima, M and Guerino-Cunha, RL and Bittencourt, H}, title = {Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. II: CAR-T cell therapy for patients with CD19+ acute lymphoblastic leukemia.}, journal = {Hematology, transfusion and cell therapy}, volume = {43 Suppl 2}, number = {}, pages = {S13-S21}, doi = {10.1016/j.htct.2021.09.002}, pmid = {34794791}, issn = {2531-1387}, abstract = {Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hematology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL.}, }
@article {pmid34794173, year = {2021}, author = {Wingood, M and Jones, SMW and Gell, NM and Brach, JS and Peters, DM}, title = {The Inventory of Physical Activity Barriers for Adults 50 Years and Older: Refinement and Validation.}, journal = {The Gerontologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/geront/gnab165}, pmid = {34794173}, issn = {1758-5341}, abstract = {BACKGROUND AND OBJECTIVES: Due to health consequences associated with insufficient physical activity (PA), particularly among aging adults, healthcare providers should assess and address lack of PA participation. Addressing lack of PA means developing individualized PA prescriptions that incorporate solutions to PA participation barriers. Assessing PA participation barriers can be done through the Social-Ecological Model-based Inventory of Physical Activity Barriers Scale (IPAB). This study aimed to refine the initial 40-item IPAB and determine its reliability and validity.<br><br>RESEARCH DESIGN AND METHODS: Five hundred and three community-dwelling adults 50 years and older completed a demographic and health questionnaire, the Physical Activity Vital Sign, the IPAB, and a feedback questionnaire. For scale refinement, half of the data was used for exploratory factor analysis and the other half for confirmatory factor analysis. The refined scale underwent reliability and validity assessment, including internal consistency, test-retest reliability, and construct validity.<br><br>RESULTS: The refined scale contains 27 items consisting of seven factors and one stand-alone item: 1) Environmental, 2) Physical Health, 3) PA-Related Motivation, 4) Emotional Health, 5) Time, 6) Skills, 7) Social, and 8) Energy (a stand-alone item). The 27-item IPAB has good internal consistency (alpha= 0.91) and high test-retest reliability (ICC= 0.99). The IPAB's mean scores were statistically different between those who met the recommended levels of PA and those who did not (p < 0.001).<br><br>DISCUSSION AND IMPLICATIONS: The information gathered through the IPAB can guide discussions related to PA participation barriers and develop individualized PA prescriptions that incorporate solutions to the identified barriers.}, }
@article {pmid34794066, year = {2021}, author = {Wills, C and He, Y and Summers, MG and Lin, Y and Phipps, AI and Watts, K and Law, PJ and Al-Tassan, NA and Maughan, TS and Kaplan, R and Houlston, RS and Peters, U and Newcomb, PA and Chan, AT and Buchanan, DD and Gallinger, S and Marchand, LL and Pai, RK and Shi, Q and Alberts, SR and Gray, V and West, HD and Escott-Price, V and Dunlop, MG and Cheadle, JP}, title = {A genome-wide search for determinants of survival in 1926 patients with advanced colorectal cancer with follow-up in over 22,000 patients.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {159}, number = {}, pages = {247-258}, doi = {10.1016/j.ejca.2021.09.047}, pmid = {34794066}, issn = {1879-0852}, abstract = {BACKGROUND: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome.<br><br>PATIENTS AND METHODS: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10-5), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas.<br><br>RESULTS: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10-7). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10-2) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10-8). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10-2).<br><br>CONCLUSIONS: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival.}, }
@article {pmid34793513, year = {2021}, author = {Bolouri, H and Ries, R and Pardo, L and Hylkema, T and Zhou, W and Smith, JL and Leonti, A and Loken, M and Farrar, JE and Triche, TJ and Meshinchi, S}, title = {A B-cell developmental gene regulatory network is activated in infant AML.}, journal = {PloS one}, volume = {16}, number = {11}, pages = {e0259197}, doi = {10.1371/journal.pone.0259197}, pmid = {34793513}, issn = {1932-6203}, abstract = {Infant Acute Myeloid Leukemia (AML) is a poorly-addressed, heterogeneous malignancy distinguished by surprisingly few mutations per patient but accompanied by myriad age-specific translocations. These characteristics make treatment of infant AML challenging. While infant AML is a relatively rare disease, it has enormous impact on families, and in terms of life-years-lost and life limiting morbidities. To better understand the mechanisms that drive infant AML, we performed integrative analyses of genome-wide mRNA, miRNA, and DNA-methylation data in diagnosis-stage patient samples. Here, we report the activation of an onco-fetal B-cell developmental gene regulatory network in infant AML. AML in infants is genomically distinct from AML in older children/adults in that it has more structural genomic aberrations and fewer mutations. Differential expression analysis of ~1500 pediatric AML samples revealed a large number of infant-specific genes, many of which are associated with B cell development and function. 18 of these genes form a well-studied B-cell gene regulatory network that includes the epigenetic regulators BRD4 and POU2AF1, and their onco-fetal targets LIN28B and IGF2BP3. All four genes are hypo-methylated in infant AML. Moreover, micro-RNA Let7a-2 is expressed in a mutually exclusive manner with its target and regulator LIN28B. These findings suggest infant AML may respond to bromodomain inhibitors and immune therapies targeting CD19, CD20, CD22, and CD79A.}, }
@article {pmid34792391, year = {2021}, author = {Kates, O and Starr, K and Bourassa, L}, title = {Erratum for Kates et al., "Closing the Brief Case: Nontoxigenic Corynebacterium diphtheriae in a Nonhealing Wound".}, journal = {Journal of clinical microbiology}, volume = {59}, number = {12}, pages = {e0192021}, doi = {10.1128/JCM.01920-21}, pmid = {34792391}, issn = {1098-660X}, }
@article {pmid34791836, year = {2021}, author = {Balasubramanian, S and Hodkinson, B and Schuster, SJ and Fowler, NH and Trotman, J and Hess, G and Cheson, BD and Schaffer, M and Sun, S and Deshpande, S and Vermeulen, J and Salles, G and Gopal, AK}, title = {Identification of a genetic signature enriching for response to ibrutinib in relapsed/refractory follicular lymphoma in the DAWN phase 2 trial.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.4422}, pmid = {34791836}, issn = {2045-7634}, support = {//Janssen Research &amp; Development, LLC/ ; }, abstract = {BACKGROUND: The single-arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment.<br><br>METHODS: Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer-related genes was examined. Responder- versus nonresponder-associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing "predicted nonresponders" set and were evaluated with 10-fold cross-validation.<br><br>RESULTS: Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to >500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in >10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder-associated genes FANCA, HISTH1B, ANXA6, BTG1, and PARP10, highlighting the importance of functions outside of B-cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle/proliferation, and cell motility/invasiveness. While nonresponder-associated genes included well-known TP53 and CARD11, genetic classifiers developed using nonresponder-associated genes included ATP6AP1, EP400, ARID1A, SOCS1, and TBL1XR1, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer-associated signaling pathways (mTOR, JAK/STAT, NF-κB).<br><br>CONCLUSION: The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder-associated genes, which warrants further investigation.<br><br>TRIAL REGISTRATION: NCT01779791.}, }
@article {pmid34791296, year = {2021}, author = {Brown, TT and Yuhas, K and Mayer, KH and Landovitz, RJ and Marzinke, MA and Hendrix, CW and Chen, YQ and Klingman, KL and Chege, W and Mccauley, MB and Gulick, RM and Wilkin, TJ}, title = {Bone changes with candidate PrEP regimens containing tenofovir disoproxil fumarate and/or maraviroc and/or emtricitabine in US men and women: HPTN 069/ACTG A5305.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {}, number = {}, pages = {}, doi = {10.1093/jac/dkab400}, pmid = {34791296}, issn = {1460-2091}, support = {//Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health/ ; UM1-AI068619//HIV Prevention Trials Network (HPTN)/ ; UM1-AI-068636//AIDS Clinical Trials Group (ACTG)/ ; }, abstract = {BACKGROUND: Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other non-tenofovir disoproxil fumarate candidate PrEP regimens are not well described.<br><br>METHODS: The HPTN 069/ACTG A5305 study randomized 406 US cisgender men and transgender women, and 188 cisgender women at risk for HIV infection to one of four double-blinded regimens: (i) maraviroc; (ii) maraviroc + emtricitabine; (iii) maraviroc + tenofovir disoproxil fumarate; or (iv) tenofovir disoproxil fumarate + emtricitabine. BMD was measured in a subset of participants at the lumbar spine (LS) and hip by dual-energy X-ray absorptiometry (DXA) at baseline and 48 weeks. Percentage change in LS and hip BMD was compared between the tenofovir disoproxil fumarate- and non-tenofovir disoproxil fumarate-containing arms by Wilcoxon rank-sum tests and multiple linear regression adjusting for sex, race and baseline BMI.<br><br>RESULTS: At baseline (n = 307), the median age was 33 years, 56% male and 43% black. At the hip, the median percentage change in BMD at 48 weeks was -1.05% in the tenofovir disoproxil fumarate arms and 0.0% in the non-tenofovir disoproxil fumarate arms (between group P = 0.001). No interaction by sex was observed. The median percentage change in LS BMD was not different between arms.<br><br>CONCLUSIONS: Tenofovir disoproxil fumarate-containing PrEP was associated with significantly greater bone loss compared with maraviroc ± emtricitabine PrEP at the hip, but not the LS. The BMD changes at the hip were similar in magnitude in men and women.}, }
@article {pmid34789871, year = {2021}, author = {Mirzayi, C and Renson, A and ,  and ,  and Zohra, F and Elsafoury, S and Geistlinger, L and Kasselman, LJ and Eckenrode, K and van de Wijgert, J and Loughman, A and Marques, FZ and MacIntyre, DA and Arumugam, M and Azhar, R and Beghini, F and Bergstrom, K and Bhatt, A and Bisanz, JE and Braun, J and Bravo, HC and Buck, GA and Bushman, F and Casero, D and Clarke, G and Collado, MC and Cotter, PD and Cryan, JF and Demmer, RT and Devkota, S and Elinav, E and Escobar, JS and Fettweis, J and Finn, RD and Fodor, AA and Forslund, S and Franke, A and Furlanello, C and Gilbert, J and Grice, E and Haibe-Kains, B and Handley, S and Herd, P and Holmes, S and Jacobs, JP and Karstens, L and Knight, R and Knights, D and Koren, O and Kwon, DS and Langille, M and Lindsay, B and McGovern, D and McHardy, AC and McWeeney, S and Mueller, NT and Nezi, L and Olm, M and Palm, N and Pasolli, E and Raes, J and Redinbo, MR and Rühlemann, M and Balfour Sartor, R and Schloss, PD and Schriml, L and Segal, E and Shardell, M and Sharpton, T and Smirnova, E and Sokol, H and Sonnenburg, JL and Srinivasan, S and Thingholm, LB and Turnbaugh, PJ and Upadhyay, V and Walls, RL and Wilmes, P and Yamada, T and Zeller, G and Zhang, M and Zhao, N and Zhao, L and Bao, W and Culhane, A and Devanarayan, V and Dopazo, J and Fan, X and Fischer, M and Jones, W and Kusko, R and Mason, CE and Mercer, TR and Sansone, SA and Scherer, A and Shi, L and Thakkar, S and Tong, W and Wolfinger, R and Hunter, C and Segata, N and Huttenhower, C and Dowd, JB and Jones, HE and Waldron, L}, title = {Reporting guidelines for human microbiome research: the STORMS checklist.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {34789871}, issn = {1546-170X}, support = {R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01CA230551//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; JPMJCR19U3//MEXT | JST | Accelerated Innovation Research Initiative Turning Top Science and Ideas into High-Impact Values (ACCEL)/ ; }, abstract = {The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.}, }
@article {pmid34789551, year = {2021}, author = {Zou, F and Faleck, D and Thomas, A and Harris, J and Satish, D and Wang, X and Charabaty, A and Ernstoff, MS and Glitza Oliva, IC and Hanauer, S and McQuade, J and Obeid, M and Shah, A and Richards, DM and Sharon, E and Wolchok, J and Thompson, J and Wang, Y}, title = {Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study.}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {11}, pages = {}, doi = {10.1136/jitc-2021-003277}, pmid = {34789551}, issn = {2051-1426}, abstract = {BACKGROUND: Current treatment guidelines for immune-mediated diarrhea and colitis (IMDC) recommend steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) for refractory cases. We aimed to compare the efficacy of these two SITs and their impact on cancer outcomes.<br><br>METHODS: We performed a two-center, retrospective observational cohort study of patients with IMDC who received SITs following steroids from 2016 to 2020. Patients' demographic, clinical, and overall survival data were collected and analyzed.<br><br>RESULTS: A total of 184 patients (62 vedolizumab, 94 infliximab, 28 combined sequentially) were included. The efficacy of achieving clinical remission of IMDC was similar (89% vs 88%, p=0.79) between the two groups. Compared with the infliximab group, the vedolizumab group had a shorter steroid exposure (35 vs 50 days, p<0.001), fewer hospitalizations (16% vs 28%, p=0.005), and a shorter hospital stay (median 10.5 vs 13.5 days, p=0.043), but a longer time to clinical response (17.5 vs 13 days, p=0.012). Longer durations of immune checkpoint inhibitors treatment (OR 1.01, p=0.004) and steroid use (OR 1.02, p=0.043), and infliximab use alone (OR 2.51, p=0.039) were associated with higher IMDC recurrence. Furthermore, ≥3 doses of SIT (p=0.011), and fewer steroid tapering attempts (p=0.012) were associated with favorable overall survival.<br><br>CONCLUSIONS: Treatment with vedolizumab as compared with infliximab for IMDC led to comparable IMDC response rates, shorter duration of steroid use, fewer hospitalizations, and lower IMDC recurrence, though with slightly longer time to IMDC response. Higher number of SIT doses was associated with better survival outcome, while more steroid exposure resulted in worse patient outcomes.}, }
@article {pmid34789512, year = {2022}, author = {Mammel, AE and Huang, HZ and Gunn, AL and Choo, E and Hatch, EM}, title = {Chromosome length and gene density contribute to micronuclear membrane stability.}, journal = {Life science alliance}, volume = {5}, number = {2}, pages = {}, doi = {10.26508/lsa.202101210}, pmid = {34789512}, issn = {2575-1077}, abstract = {Micronuclei are derived from missegregated chromosomes and frequently lose membrane integrity, leading to DNA damage, innate immune activation, and metastatic signaling. Here, we demonstrate that two characteristics of the trapped chromosome, length and gene density, are key contributors to micronuclei membrane stability and determine the timing of micronucleus rupture. We demonstrate that these results are not due to chromosome-specific differences in spindle position or initial protein recruitment during post-mitotic nuclear envelope assembly. Micronucleus size strongly correlates with lamin B1 levels and nuclear pore density in intact micronuclei, but, unexpectedly, lamin B1 levels do not completely predict nuclear lamina organization or membrane stability. Instead, small gene-dense micronuclei have decreased nuclear lamina gaps compared to large micronuclei, despite very low levels of lamin B1. Our data strongly suggest that nuclear envelope composition defects previously correlated with membrane rupture only partly explain membrane stability in micronuclei. We propose that an unknown factor linked to gene density has a separate function that inhibits the appearance of nuclear lamina gaps and delays membrane rupture until late in the cell cycle.}, }
@article {pmid34789503, year = {2021}, author = {Wu, P and Moon, JY and Daghlas, I and Franco, G and Porneala, BC and Ahmadizar, F and Richardson, TG and Isaksen, JL and Hindy, G and Yao, J and Sitlani, CM and Raffield, LM and Yanek, LR and Feitosa, MF and Cuadrat, RRC and Qi, Q and Arfan Ikram, M and Ellervik, C and Ericson, U and Goodarzi, MO and Brody, JA and Lange, L and Mercader, JM and Vaidya, D and An, P and Schulze, MB and Masana, L and Ghanbari, M and Olesen, MS and Cai, J and Guo, X and Floyd, JS and Jäger, S and Province, MA and Kalyani, RR and Psaty, BM and Orho-Melander, M and Ridker, PM and Kanters, JK and Uitterlinden, A and Davey Smith, G and Gill, D and Kaplan, RC and Kavousi, M and Raghavan, S and Chasman, DI and Rotter, JI and Meigs, JB and Florez, JC and Dupuis, J and Liu, CT and Merino, J}, title = {Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc21-1284}, pmid = {34789503}, issn = {1935-5548}, abstract = {OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown.<br><br>RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses.<br><br>RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04).<br><br>CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.}, }
@article {pmid34789482, year = {2021}, author = {Mato, AR and Davids, MS and Sharman, J and Roeker, LE and Kay, N and Kater, A and Rogers, K and Thompson, MC and Rhodes, J and Goy, A and Skarbnik, A and Schuster, SJ and Tam, CS and Eyre, TA and O'Brien, S and Nabhan, C and Lamanna, N and Sun, C and Shadman, M and Pagel, JM and Ujjani, C and Brander, D and Coombs, CC and Jain, N and Cheah, CY and Brown, JR and Seymour, JF and Woyach, JA}, title = {Recognizing Unmet Need in the Era of Targeted Therapy for CLL/SLL: "What's Past is Prologue" (Shakespeare).}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-21-1237}, pmid = {34789482}, issn = {1557-3265}, abstract = {The management of CLL has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor and venetoclax represent a new and rapidly growing unmet need in CLL. Here we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTK inhibitors and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.}, }
@article {pmid34789471, year = {2021}, author = {Brieger, KK and Phung, MT and Mukherjee, B and Bakulski, KM and Anton-Culver, H and Bandera, EV and Bowtell, DDL and Cramer, DW and DeFazio, A and Doherty, JA and Fereday, S and Fortner, RT and Gentry-Maharaj, A and Goode, EL and Goodman, MT and Harris, HR and Matsuo, K and Menon, U and Modugno, F and Moysich, KB and Qin, B and Ramus, SJ and Risch, HA and Rossing, MA and Schildkraut, JM and Trabert, B and Vierkant, RA and Winham, SJ and Wentzensen, N and Wu, AH and Ziogas, A and Khoja, L and Cho, KR and McLean, K and Richardson, J and Grout, B and Chase, A and McKinnon Deurloo, C and Odunsi, K and Nelson, BH and Brenton, JD and Terry, KL and Pharaoh, PD and Berchuck, A and Hanley, GE and Webb, PM and Pike, MC and Pearce, CL}, title = {High pre-diagnosis inflammation-related risk score associated with decreased ovarian cancer survival.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0977}, pmid = {34789471}, issn = {1538-7755}, abstract = {Background There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. Pre-diagnosis inflammatory-related exposures of interest included alcohol use, aspirin use, other nonsteroidal anti-inflammatory drug use, body mass index, environmental tobacco smoke exposure, history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis, menopausal hormone therapy use, physical inactivity, smoking status, and talc use. Using Cox proportional hazards (PH) models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed and its association with survival was assessed using Cox PH models in the remaining 50% of the data. Results There was a statistically significant trend of increasing risk of death per quartile of the IRRS (HR=1.09, 95% CI 1.03-1.14). Women in the upper quartile of the IRRS had 31% higher death rate compared to the lowest quartile (95% CI 1.11-1.54). Conclusions A higher pre-diagnosis IRRS was associated with increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether post-diagnosis exposures are also associated with survival. Impact Given that pre- and post-diagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among ovarian cancer patients.}, }
@article {pmid34788599, year = {2021}, author = {Kratochvil, S and Shen, CH and Lin, YC and Xu, K and Nair, U and Da Silva Pereira, L and Tripathi, P and Arnold, J and Chuang, GY and Melzi, E and Schön, A and Zhang, B and Dillon, M and Bonilla, B and Flynn, BJ and Kirsch, KH and Kisalu, NK and Kiyuka, PK and Liu, T and Ou, L and Pancera, M and Rawi, R and Reveiz, M and Seignon, K and Wang, LT and Waring, MT and Warner, J and Yang, Y and Francica, JR and Idris, AH and Seder, RA and Kwong, PD and Batista, FD}, title = {Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2021.10.017}, pmid = {34788599}, issn = {1097-4180}, abstract = {Repeat antigens, such as the Plasmodium falciparum circumsporozoite protein (PfCSP), use both sequence degeneracy and structural diversity to evade the immune response. A few PfCSP-directed antibodies have been identified that are effective at preventing malaria infection, including CIS43, but how these repeat-targeting antibodies might be improved has been unclear. Here, we engineered a humanized mouse model in which B cells expressed inferred human germline CIS43 (iGL-CIS43) B cell receptors and used both vaccination and bioinformatic analysis to obtain variant CIS43 antibodies with improved protective capacity. One such antibody, iGL-CIS43.D3, was significantly more potent than the current best-in-class PfCSP-directed antibody. We found that vaccination with a junctional epitope peptide was more effective than full-length PfCSP at recruiting iGL-CIS43 B cells to germinal centers. Structure-function analysis revealed multiple somatic hypermutations that combinatorically improved protection. This mouse model can thus be used to understand vaccine immunogens and to develop highly potent anti-malarial antibodies.}, }
@article {pmid34785790, year = {2021}, author = {Walter, RB and Hochhaus, A and Gale, RP}, title = {Elihu H. Estey, MD: leukemia expert, statistician, and gentle soul (July 15, 1946-October 8, 2021).}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {34785790}, issn = {1476-5551}, }
@article {pmid34784056, year = {2021}, author = {Emamekhoo, H and Olsen, MR and Carthon, BC and Drakaki, A and Percent, IJ and Molina, AM and Cho, DC and Bendell, JC and Gordan, LN and Rezazadeh Kalebasty, A and George, DJ and Hutson, TE and Arrowsmith, ER and Zhang, J and Zoco, J and Johansen, JL and Leung, DK and Tykodi, SS}, title = {Safety and efficacy of nivolumab plus ipilimumab in patients with advanced renal cell carcinoma with brain metastases: CheckMate 920.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.34016}, pmid = {34784056}, issn = {1097-0142}, support = {//Bristol Myers Squibb/ ; }, abstract = {BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here.<br><br>METHODS: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others.<br><br>RESULTS: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable).<br><br>CONCLUSIONS: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals.}, }
@article {pmid34783858, year = {2021}, author = {Bartlett, DA and Dileep, V and Handa, T and Ohkawa, Y and Kimura, H and Henikoff, S and Gilbert, DM}, title = {High-throughput single-cell epigenomic profiling by targeted insertion of promoters (TIP-seq).}, journal = {The Journal of cell biology}, volume = {220}, number = {12}, pages = {}, doi = {10.1083/jcb.202103078}, pmid = {34783858}, issn = {1540-8140}, support = {R21 HG010403/NH/NIH HHS/United States ; JPMJCR16G1//Japan Science and Technology Agency/ ; JP18H05527//Japan Society for the Promotion of Science/ ; }, abstract = {Chromatin profiling in single cells has been extremely challenging and almost exclusively limited to histone proteins. In cases where single-cell methods have shown promise, many require highly specialized equipment or cell type-specific protocols and are relatively low throughput. Here, we combine the advantages of tagmentation, linear amplification, and combinatorial indexing to produce a high-throughput single-cell DNA binding site mapping method that is simple, inexpensive, and capable of multiplexing several independent samples per experiment. Targeted insertion of promoters sequencing (TIP-seq) uses Tn5 fused to proteinA to insert a T7 RNA polymerase promoter adjacent to a chromatin protein of interest. Linear amplification of flanking DNA with T7 polymerase before sequencing library preparation provides ∼10-fold higher unique reads per single cell compared with other methods. We applied TIP-seq to map histone modifications, RNA polymerase II (RNAPII), and transcription factor CTCF binding sites in single human and mouse cells.}, }
@article {pmid34782395, year = {2021}, author = {Man, TK and Aubert, G and Richard, MA and LeJeune, W and Hariri, E and Goltsova, T and Gaikwad, A and Chen, Y and Whitton, J and Leisenring, WM and Arnold, MA and Neglia, JP and Yasui, Y and Robison, LL and Armstrong, GT and Bhatia, S and Gramatges, MM}, title = {Short NK and naïve T-cell telomere length is associated with thyroid cancer in childhood cancer survivors: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0791}, pmid = {34782395}, issn = {1538-7755}, abstract = {BACKGROUND: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear.<br><br>METHODS: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). 46 cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls.<br><br>RESULTS: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (p=0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI 1.07, 8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of 8 controls.<br><br>CONCLUSIONS: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN.<br><br>IMPACT: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.}, }
@article {pmid34782263, year = {2021}, author = {Lyou, Y and Rosenberg, JE and Hoffman-Censits, J and Quinn, DI and Petrylak, D and Galsky, M and Vaishampayan, U and De Giorgi, U and Gupta, S and Burris, H and Rearden, J and Li, A and Xu, C and Andresen, C and Moran, S and Daneshmand, S and Bajorin, D and Pal, SK and Grivas, P}, title = {Infigratinib in Early-Line and Salvage Therapy for FGFR3-Altered Metastatic Urothelial Carcinoma.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2021.10.004}, pmid = {34782263}, issn = {1938-0682}, abstract = {INTRODUCTION: To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1-3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC).<br><br>PATIENTS AND METHODS: Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed.<br><br>RESULTS: Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5-37.5) and DCR was 64.2% (95% CI 51.5-75.5). ORR was 30.8% (95% CI 9.1-61.4) with early-line infigratinib and 24.1% (95% CI 13.5-37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2-74.9) for early-line and 68.5% (95% CI 54.4-80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1-61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4-33.9); BOR was 38.5% (95% CI: 13.9-68.4%) and 42.6% (95% CI: 29.2-56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed.<br><br>CONCLUSION: Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.}, }
@article {pmid34780648, year = {2021}, author = {Zhao, H and Pomicter, AD and Eiring, AM and Franzini, A and Ahmann, J and Hwang, JY and Senina, AV and Helton, B and Iyer, SM and Yan, D and Khorashad, JS and Zabriskie, MS and Agarwal, A and Redwine, HM and Bowler, AD and Clair, PM and McWeeney, SK and Druker, BJ and Tyner, JW and Stirewalt, DL and Oehler, VG and Varambally, S and Berrett, KC and Vahrenkamp, JM and Gertz, J and Varley, KE and Radich, J and Deininger, MW}, title = {MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common β Chain Cytokine Receptor Endocytosis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021011802}, pmid = {34780648}, issn = {1528-0020}, abstract = {The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells, but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC differentiation may inform strategies to eliminate LSPCs. Upon performing a meta-analysis of published CML transcriptomes, we discovered that low expression of the MS4A3 transmembrane protein is a universal characteristic of LSPC quiescence, BCR-ABL1 independence, and transformation to blast phase. Several mechanisms are involved in suppressing MS4A3, including aberrant methylation and a MECOM-C/EBPε axis. Contrary to previous reports, we find that MS4A3 does not function as a G1/S phase inhibitor, but promotes endocytosis of common β chain (βc) cytokine receptors upon GM-CSF/IL-3 stimulation, enhancing downstream signaling and cellular differentiation. This suggests that LSPCs downregulate MS4A3 to evade βc cytokine-induced differentiation and maintain a more primitive, TKI-insensitive state. Accordingly, knockdown or deletion of MS4A3/Ms4a3 promotes TKI resistance and survival of CML cells ex vivo and enhance leukemogenesis in vivo, while targeted delivery of exogenous MS4A3 protein promotes differentiation. These data support a model in which MS4A3 governs response to differentiating myeloid cytokines, providing a unifying mechanism for the differentiation block characteristic of CML quiescence and blast phase CML. Promoting MS4A3 re-expression or delivery of ectopic MS4A3 may help eliminating LSPCs in vivo.}, }
@article {pmid34779012, year = {2021}, author = {Tapia, AL and Rowland, BT and Rosen, JD and Preuss, M and Young, K and Graff, M and Choquet, H and Couper, DJ and Buyske, S and Bien, SA and Jorgenson, E and Kooperberg, C and Loos, RJF and Morrison, AC and North, KE and Yu, B and Reiner, AP and Li, Y and Raffield, LM}, title = {Full title: A large-scale transcriptome-wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine-mapping.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22436}, pmid = {34779012}, issn = {1098-2272}, support = {R01 DK116738/DK/NIDDK NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; R01DK107786/DK/NIDDK NIH HHS/United States ; R01DK110113/NH/NIH HHS/United States ; R01HL129132/NH/NIH HHS/United States ; DGE-1650116//National Science Foundation/ ; EY027004/EY/NEI NIH HHS/United States ; R01 CA2416323/CA/NCI NIH HHS/United States ; KL2TR002490//North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill/ ; HL129982/HL/NHLBI NIH HHS/United States ; R01HL142302/HL/NHLBI NIH HHS/United States ; R01HG010297/HG/NHGRI NIH HHS/United States ; U01HG007376/HG/NHGRI NIH HHS/United States ; }, abstract = {Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.}, }
@article {pmid34778690, year = {2021}, author = {Taza, F and Holler, AE and Fu, W and Wang, H and Adra, N and Albany, C and Ashkar, R and Cheng, HH and Sokolova, AO and Agarwal, N and Kessel, A and Bryce, A and Nafissi, N and Barata, P and Sartor, AO and Bastos, D and Smaletz, O and Berchuck, JE and Taplin, ME and Aggarwal, R and Sternberg, CN and Vlachostergios, PJ and Alva, AS and Su, C and Marshall, CH and Antonarakis, ES}, title = {Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer.}, journal = {JCO precision oncology}, volume = {5}, number = {}, pages = {}, doi = {10.1200/PO.21.00070}, pmid = {34778690}, issn = {2473-4284}, abstract = {Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied.<br><br>METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC.<br><br>RESULTS: A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity.<br><br>CONCLUSION: PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.}, }
@article {pmid34778042, year = {2021}, author = {Yang, Y and Li, J and Till, BG and Wang, J and Zhang, B and Wang, H and Huang, H and Li, T and Gao, Q and Li, H and Wang, Z}, title = {Toxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma.}, journal = {Frontiers in oncology}, volume = {11}, number = {}, pages = {728253}, doi = {10.3389/fonc.2021.728253}, pmid = {34778042}, issn = {2234-943X}, abstract = {Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.}, }
@article {pmid34776242, year = {2021}, author = {Khoja, L and Weber, RP and ,  and Webb, PM and Jordan, SJ and Muthukumar, A and Chang-Claude, J and Fortner, RT and Jensen, A and Kjaer, SK and Risch, H and Doherty, JA and Harris, HR and Goodman, MT and Modugno, F and Moysich, K and Berchuck, A and Schildkraut, JM and Cramer, D and Terry, KL and Anton-Culver, H and Ziogas, A and Phung, MT and Hanley, GE and Wu, AH and Mukherjee, B and McLean, K and Cho, K and Pike, MC and Pearce, CL and Lee, AW}, title = {Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.}, journal = {Gynecologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ygyno.2021.10.088}, pmid = {34776242}, issn = {1095-6859}, abstract = {OBJECTIVE: To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association.<br><br>METHODS: We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs).<br><br>RESULTS: Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99).<br><br>CONCLUSIONS: The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.}, }
@article {pmid34776121, year = {2021}, author = {McClure, JB and Catz, SL and Chalal, C and Ciuffetelli, R and Coggeshall, S and DeFaccio, RJ and Fleehart, S and Heffner, JL and Thompson, E and Williams, EC and Crothers, K}, title = {Design and methods of a randomized trial testing the novel Wellness Intervention for Smokers Living with HIV (WISH).}, journal = {Contemporary clinical trials}, volume = {110}, number = {}, pages = {106486}, doi = {10.1016/j.cct.2021.106486}, pmid = {34776121}, issn = {1559-2030}, abstract = {Smoking rates are disproportionately high among people living with HIV. Smokers living with HIV (SLWH) are also largely unaware of the HIV-specific deleterious effects of smoking and often lack motivation and confidence in their ability to quit tobacco. To address these issues, we developed the Wellness Intervention for Smokers Living with HIV (WISH). WISH is grounded in the Information-Motivation-Behavioral Skills (IMB) Model and is designed for all SLWH, regardless of their initial motivation to quit. It follows evidence-based, best practice guidelines for nicotine dependence treatment, but is innovative in its use of a comprehensive wellness approach that addresses smoking within the context of HIV self-management including treatment adherence and engagement, stress management, substance use, and other personally relevant health behavior goals. The described randomized trial will enroll SLWH who are receiving care at Veterans Affairs (VA) medical centers and compare WISH's impact on smoking behavior to standard care services offered through the National VA Quitline and SmokefreeVET texting program. It will also assess intervention impact on markers of immune status and mortality risk. If effective, WISH could be disseminated to Veterans nationwide and could serve as a model for designing quitline interventions for other smokers who are ambivalent about quitting. The current paper outlines the rationale and methodology of the WISH trial, one of a series of studies recently funded by the National Cancer Institute to advance understanding of how to better promote smoking cessation among SLWH.}, }
@article {pmid34775986, year = {2021}, author = {Mahale, P and Nomburg, J and Song, JY and Steinberg, M and Starrett, G and Boland, J and Lynch, CF and Chadburn, A and Rubinstein, PG and Hernandez, BY and Weisenburger, DD and Bullman, S and Engels, EA}, title = {Metagenomic analysis to identify novel infectious agents in systemic anaplastic large cell lymphoma.}, journal = {Infectious agents and cancer}, volume = {16}, number = {1}, pages = {65}, pmid = {34775986}, issn = {1750-9378}, abstract = {Systemic anaplastic large cell lymphoma (ALCL) is a rare CD30-expressing T-cell non-Hodgkin lymphoma. Risk of systemic ALCL is highly increased among immunosuppressed individuals. Because risk of cancers associated with viruses is increased with immunosuppression, we conducted a metagenomic analysis of systemic ALCL to determine whether a known or novel pathogen is associated with this malignancy. Total RNA was extracted and sequenced from formalin-fixed paraffin-embedded tumor specimens from 19 systemic ALCL cases (including one case from an immunosuppressed individual with human immunodeficiency virus infection), 3 Epstein-Barr virus positive diffuse large B-cell lymphomas (DLBCLs) occurring in solid organ transplant recipients (positive controls), and 3 breast cancers (negative controls). We used a pipeline based on the Genome Analysis Toolkit (GATK)-PathSeq algorithm to subtract out human RNA reads and map the remaining RNA reads to microbes. No microbial association with ALCL was identified, but we found Epstein-Barr virus in the DLBCL positive controls and determined the breast cancers to be negative. In conclusion, we did not find a pathogen associated with systemic ALCL, but because we analyzed only one ALCL tumor from an immunosuppressed person, we cannot exclude the possibility that a pathogen is associated with some cases that arise in the setting of immunosuppression.}, }
@article {pmid34765082, year = {2019}, author = {Yan, D and Randolph, T and Zou, J and Gong, P}, title = {Incorporating Deep Features in the Analysis of Tissue Microarray Images.}, journal = {Statistics and its interface}, volume = {12}, number = {2}, pages = {283-293}, pmid = {34765082}, issn = {1938-7989}, support = {R01 GM114029/GM/NIGMS NIH HHS/United States ; }, abstract = {Tissue microarray (TMA) images have been used increasingly often in cancer studies and the validation of biomarkers. TACOMA-a cutting-edge automatic scoring algorithm for TMA images-is comparable to pathologists in terms of accuracy and repeatability. Here we consider how this algorithm may be further improved. Inspired by the recent success of deep learning, we propose to incorporate representations learnable through computation. We explore representations of a group nature through unsupervised learning, e.g., hierarchical clustering and recursive space partition. Information carried by clustering or spatial partitioning may be more concrete than the labels when the data are heterogeneous, or could help when the labels are noisy. The use of such information could be viewed as regularization in model fitting. It is motivated by major challenges in TMA image scoring-heterogeneity and label noise, and the cluster assumption in semi-supervised learning. Using this information on TMA images of breast cancer, we have reduced the error rate of TACOMA by about 6%. Further simulations on synthetic data provide insights on when such representations would likely help. Although we focus on TMAs, learnable representations of this type are expected to be applicable in other settings.}, }
@article {pmid34775478, year = {2021}, author = {Weise, N and Shaya, J and Javier-Desloges, J and Cheng, HH and Madlensky, L and McKay, RR}, title = {Disparities in germline testing among racial minorities with prostate cancer.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {34775478}, issn = {1476-5608}, abstract = {Germline testing is becoming increasingly relevant in prostate cancer (PCa) screening, prognosis, and management. A subset of patients with PCa harbor pathogenic/likely pathogenic variants (P/LPVs) in genes mediating DNA-repair processes, and these P/LPVs have implications for cancer screening, treatment, and cascade testing. As a result, it is recommended that all men with high-risk localized and metastatic PCa undergo routine germline testing. As more PCa patients undergo germline testing, it is important that clinicians and genetics experts recognize current disparities in germline testing rates among racial/ethnic minorities in the United States. The reasons for these disparities are multiple and require similarly manifold consideration to close the germline testing gap and reduce inequities in PCa screening, management, and treatment.}, }
@article {pmid34775146, year = {2021}, author = {O'Donnell, PV and Brunstein, CG and Fuchs, EJ and Zhang, MJ and Allbee-Johnson, M and Antin, JH and Leifer, ES and Elmariah, H and Grunwald, MR and Hashmi, H and Horowitz, MM and Magenau, JM and Majhail, N and Milano, F and Morris, LE and Rezvani, AR and McGuirk, JP and Jones, RJ and Eapen, M}, title = {Umbilical cord blood or HLA-haploidentical transplantation: Real world outcomes vs randomized trial outcomes.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.11.002}, pmid = {34775146}, issn = {2666-6367}, abstract = {BACKGROUND: Randomized clinical trials offer the highest quality data for modifying clinical practice. Results of a phase III randomized trial of non-myeloablative transplantation for adults with high- risk hematologic malignancies with two umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM) (n=154) revealed 2-year progression-free survival (PFS) of 41% and 35% after Haplo-BM and two-unit UCB transplantation, respectively (p=0.41); overall survival was 57% and 46%, respectively (p=0.04), BMT CTN 1101; NCT01597778.<br><br>OBJECTIVES: We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's pre-specified 2-year outcomes. All transplantation occurred between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial will be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM to those after haploidentical peripheral blood (Haplo-PB).<br><br>STUDY DESIGN: The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select non-trial subjects. Extended follow up of trial subjects was obtained from this data source. Three separate analyses were performed: 1) trial subjects beyond the trial's 2-year endpoint 2) comparison of trial subjects to a contemporaneous cohort of non-trial subjects (195 two-unit UCB, 358 Haplo-BM, 403 Haplo-PB) and 3) comparison of non-trial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups.<br><br>RESULTS: With longer follow up of the trial cohorts, 5-year PFS (37% versus 29%, p=0.08) and overall survival (42% versus 36%, p=0.06) were not significantly different between treatment groups. We then compared the trial results to comparable real-world transplantations. Five-year overall survival after trial and non-trial two-unit UCB (36% versus 41%, p=0.48) and trial and non-trial Haplo-BM (42% versus 47%, p=0.80) transplantation were not different confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in progression-free survival. With substantially larger numbers of non-trial Haplo-BM transplantations, 5-year survival was higher after non-trial Haplo-BM compared to trial two-unit UCB (47% versus 36%, p=0.012). Non-trial patients who received Haplo-PB transplantation had higher 5-year survival (54%) compared to trial (HR 0.76, p=0.044) and non-trial (HR 0.78, p=0.026) Haplo-BM. Similarly, survival was higher after Haplo-PB compared to trial (HR 0.57, p<0.0001) and non-trial UCB (HR 0.63, p=0.0002).<br><br>CONCLUSION: When considering alternative donor low intensity conditioning regimen transplantation, a haploidentical relative is preferred. Further, PB is the preferred graft.}, }
@article {pmid34775030, year = {2021}, author = {Wu, D and Kanaan, SB and Penewit, K and Waalkes, A and Urselli, F and Nelson, JL and Radich, J and Salipante, SJ}, title = {Ultrasensitive quantitation of genomic chimerism by single-molecule molecular inversion probe capture and high throughput sequencing of copy number deletion polymorphisms.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmoldx.2021.10.005}, pmid = {34775030}, issn = {1943-7811}, abstract = {Genomic chimerism represents co-existing cells with different genotypes and has diagnostic significance in transplant engraftment monitoring, residual cancer detection, and other contexts. We previously described an approach to chimerism detection by interrogating variably present or absent genomic loci using single-molecule molecular inversion probes (smMIP) and next-generation sequencing, which provided ultrasensitive limits of detection (at least <1 in 10,000 cells) but was not reliably quantitative. Here, we modified smMIP testing to accurately quantitate chimeric cells by incorporating copy number neutral control loci for data normalization and computationally modelling cell mixtures from individual-specific genotypes. We demonstrate precision and accuracy over three orders of magnitude (0.01% to 50% chimerism). We evaluated 70 hematopoietic stem cell transplant specimens from single (n=42) or double (n=28) donors, benchmarking smMIP against conventional variable number tandem repeat (VNTR) analysis and an unrelated, ultrasensitive polymorphism-specific quantitative PCR (PS-qPCR) assay. Quantitative concordance of all three assays was high (p<0.0005, Pearson Correlation coefficient), although smMIP correlated better with VNTR testing than PS-qPCR. smMIP and PS-qPCR collectively identified low-level chimerism in all specimens testing negative by VNTR (n=41 and n=45 of 48 specimens, respectively). This work demonstrates the feasibility of smMIP-based chimerism testing to achieve quantitative and ultrasensitive measurement of genomic chimerism at practical levels approaching one in one million chimeric cells, and provides cross-validation of the approach.}, }
@article {pmid34774819, year = {2021}, author = {Zou, J and Wang, T and He, M and Bolon, YT and Gadalla, SM and Marsh, SGE and Kuxhausen, M and Gale, RP and Sharma, A and Assal, A and Prestidge, T and Aljurf, M and Cerny, J and Paczesny, S and Spellman, SR and Lee, SJ and Ciurea, SO}, title = {Number of HLA mismatched eplets is not associated with major outcomes in haploidentical transplantation with post-transplantation cyclophosphamide: A Center for International Blood and Marrow Transplant Research Study.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.11.001}, pmid = {34774819}, issn = {2666-6367}, abstract = {The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) being performed has substantially increased in recent years. The immunogenicity derived from the mismatched HLA haplotype, assessed at an antigen level, has no reported significant impact on clinical outcomes. Single-center studies have previously used in silico algorithms to quantitively measure HLA disparity and shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD). However, the inconsistent results from the small studies make it difficult to convincingly demonstrate the full clinical impact of molecular mismatch in haplo-HSCT. In this study, we investigated whether the number of mismatched eplets (ME) score, generated by HLAMatchmaker, predicts outcomes in a registry-based cohort of patients with the first haplo-HST for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2013 to 2017. These results showed that neither ME derived from individual HLA locus nor ME derived from total class I or class II loci were significantly associated with any major transplantation outcome (P< .01). There were unexpected associations between HLA class II ME in the GVH direction with slower neutrophil (HR 0.82; 95% CI, 0.75 - 0.91; P < .0001) and platelet engraftment (HR 0.80; 95% CI, 0.72 - 0.88; P < .0001), likely attributable to the ME derived from HLA-DRB1 which was also correlated with slower neutrophil (HR 0.82; 95% CI, 0.73 - 0.92; P = .001) and platelet engraftment (HR 0.76; 95% CI, 0.70 - 0.84; P < .0001). The findings of this study do not support prior studies reporting that the number of ME, as classified by HLAMatchmaker, were associated with major haplo-HSCT outcomes.}, }
@article {pmid34774559, year = {2021}, author = {Lin, BM and Zhang, Y and Yu, B and Boerwinkle, E and Thygarajan, B and Yunes, M and Daviglus, ML and Qi, Q and Kaplan, R and Lash, J and Cai, J and Sofer, T and Franceschini, N}, title = {Metabolome-wide association study of estimated glomerular filtration rates in Hispanics.}, journal = {Kidney international}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.kint.2021.09.032}, pmid = {34774559}, issn = {1523-1755}, abstract = {Circulating metabolites are by-products of endogenous metabolism or exogenous sources and may inform disease states. Our study aimed to identify the source of variability in the association of metabolites with estimated glomerular filtration rate (eGFR) in Hispanics/Latinos with low chronic kidney disease prevalence and tested the association of 640 metabolites in 3,906 participants of the Hispanic Community Health Study/Study of Latinos. Metabolites were quantified in fasting serum through non-targeted mass spectrometry analysis. eGFR was regressed on inverse normally transformed metabolites in models accounting for study design and covariates. To identify the source of variation on eGFR associations, we tested the interaction of metabolites with lifestyle and clinical risk factors with results integrated with genotypes to identify metabolite genetic regulation. The mean age was 46 years, 43% were men, 22% were current smokers, 47% had a Caribbean Hispanic background,19% had diabetes and the mean cohort eGFR was 96.4 ml/min/1.73 m2. We identified 404 eGFR-metabolite associations (False Discovery Rate under 0.05). Of these, 69 were previously reported, and 79 were novel associations with eGFR replicated in one or more published studies. There were significant interactions with lifestyle and clinical risk factors, with larger differences in eGFR-metabolite associations within strata of age, urine albumin to creatinine ratio, diabetes and Hispanic/Latino background. Several newly identified metabolites were genetically regulated, and variants were located at genomic regions previously associated with eGFR. Thus, our results suggest complex mechanisms contribute to the association of eGFR with metabolites and provide new insights into these associations.}, }
@article {pmid34774151, year = {2021}, author = {David, YN and Issaka, RB}, title = {Advancing diversity: the role of international medical graduates.}, journal = {The lancet. Gastroenterology &amp; hepatology}, volume = {6}, number = {12}, pages = {980-981}, doi = {10.1016/S2468-1253(21)00376-9}, pmid = {34774151}, issn = {2468-1253}, }
@article {pmid34773794, year = {2021}, author = {Luger, SM and Wang, VX and Rowe, JM and Litzow, MR and Paietta, E and Ketterling, RP and Lazarus, H and Rybka, WB and Craig, MD and Karp, J and Cooper, BW and Makary, AZ and Kaminer, LS and Appelbaum, FR and Larson, RA and Tallman, MS}, title = {Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.}, journal = {Leukemia research}, volume = {111}, number = {}, pages = {106736}, doi = {10.1016/j.leukres.2021.106736}, pmid = {34773794}, issn = {1873-5835}, abstract = {PURPOSE: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse.<br><br>PATIENTS AND METHODS: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients.<br><br>RESULTS: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001).<br><br>CONCLUSION: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.}, }
@article {pmid34772791, year = {2021}, author = {Labadie, KP and Hamlin, DK and Kenoyer, A and Daniel, SK and Utria, AF and Ludwig, AD and Kenerson, HL and Li, L and Sham, JG and Chen, DL and Orozco, JJ and Yeung, RS and Orvig, C and Li, Y and Wilbur, DS and Park, JO}, title = {Glypican-3 targeted thorium-227 alpha therapy reduces tumor burden in an orthotopic xenograft murine model of hepatocellular carcinoma.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.121.262562}, pmid = {34772791}, issn = {1535-5667}, abstract = {Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227Th-labeled GPC3 targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. METHODS: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring percentage of protein-bound 227Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of 227Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. RESULTS: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, ≥97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in mice receiving 500 kBq/kg 227Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. CONCLUSION: 227Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.}, }
@article {pmid34767021, year = {2021}, author = {Schmidt, AL and Tucker, MD and Bakouny, Z and Labaki, C and Hsu, CY and Shyr, Y and Armstrong, AJ and Beer, TM and Bijjula, RR and Bilen, MA and Connell, CF and Dawsey, SJ and Faller, B and Gao, X and Gartrell, BA and Gill, D and Gulati, S and Halabi, S and Hwang, C and Joshi, M and Khaki, AR and Menon, H and Morris, MJ and Puc, M and Russell, KB and Shah, NJ and Sharifi, N and Shaya, J and Schweizer, MT and Steinharter, J and Wulff-Burchfield, EM and Xu, W and Zhu, J and Mishra, S and Grivas, P and Rini, BI and Warner, JL and Zhang, T and Choueiri, TK and Gupta, S and McKay, RR}, title = {Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19.}, journal = {JAMA network open}, volume = {4}, number = {11}, pages = {e2134330}, doi = {10.1001/jamanetworkopen.2021.34330}, pmid = {34767021}, issn = {2574-3805}, abstract = {Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2).<br><br>Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer.<br><br>This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease.<br><br>Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19.<br><br>Main Outcomes and Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching.<br><br>Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).<br><br>Conclusions and Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.}, }
@article {pmid34765442, year = {2021}, author = {Chang, EK and Gadzinski, AJ and Nyame, YA}, title = {Blood and urine biomarkers in prostate cancer: Are we ready for reflex testing in men with an elevated prostate-specific antigen?.}, journal = {Asian journal of urology}, volume = {8}, number = {4}, pages = {343-353}, pmid = {34765442}, issn = {2214-3882}, abstract = {Objective: There is no consensus on the role of biomarkers in determining the utility of prostate biopsy in men with elevated prostate-specific antigen (PSA). There are numerous biomarkers such as prostate health index, 4Kscore, prostate cancer antigen 3, ExoDX, SelectMDx, and Mi-Prostate Score that may be useful in this decision-making process. However, it is unclear whether any of these tests are accurate and cost-effective enough to warrant being a widespread reflex test following an elevated PSA. Our goal was to report on the clinical utility of these blood and urine biomarkers in prostate cancer screening.<br><br>Methods: We performed a systematic review of studies published between January 2000 and October 2020 to report the available parameters and cost-effectiveness of the aforementioned diagnostic tests. We focus on the negative predictive value, the area under the curve, and the decision curve analysis in comparing reflexive tests due to their relevance in evaluating diagnostic screening tests.<br><br>Results: Overall, the biomarkers are roughly equivalent in predictive accuracy. Each test has additional clinical utility to the current diagnostic standard of care, but the added benefit is not substantial to justify using the test reflexively after an elevated PSA.<br><br>Conclusions: Our findings suggest these biomarkers should not be used in binary fashion and should be understood in the context of pre-existing risk predictors, patient's ethnicity, cost of the test, patient life-expectancy, and patient goals. There are more recent diagnostic tools such as multi-parametric magnetic resonance imaging, polygenic single-nucleotide panels, IsoPSA, and miR Sentinel tests that are promising in the realm of prostate cancer screening and need to be investigated further to be considered a consensus reflexive test in the setting of prostate cancer screening.}, }
@article {pmid34764195, year = {2021}, author = {Grossmann, KF and Othus, M and Patel, SP and Tarhini, AA and Sondak, VK and Knopp, MV and Petrella, TM and Truong, TG and Khushalani, NI and Cohen, JV and Buchbinder, EI and Kendra, K and Funchain, P and Lewis, KD and Conry, RM and Chmielowski, B and Kudchadkar, RR and Johnson, DB and Li, H and Moon, J and Eroglu, Z and Gastman, B and Kovacsovics-Bankowski, M and Gunturu, KS and Ebbinghaus, SW and Ahsan, S and Ibrahim, N and Sharon, E and Korde, LA and Kirkwood, JM and Ribas, A}, title = {Adjuvant pembrolizumab versus interferon alfa-2b or ipilimumab in resected high-risk melanoma.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-21-1141}, pmid = {34764195}, issn = {2159-8290}, abstract = {We conducted a randomized phase 3 trial to evaluate whether adjuvant pembrolizumab for one year (648 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison to high-dose interferon alfa-2b for one year or ipilimumab for up to three years (655 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies (hazard ratio [HR] 0.77; 99.62% confidence interval [CI] 0.59-0.99; P=0.002). There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI 0.61-1.09; P=0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with interferon alfa-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared to the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.}, }
@article {pmid34763605, year = {2021}, author = {Carlson, JJ and Guzauskas, GF and Dann, RA and Ramsey, SD}, title = {Budget impact analysis of the DiviTum®TKa assay in postmenopausal women with hormone receptor positive metastatic breast cancer.}, journal = {Journal of medical economics}, volume = {}, number = {}, pages = {1-30}, doi = {10.1080/13696998.2021.2003674}, pmid = {34763605}, issn = {1941-837X}, abstract = {Background. DiviTum®TKa, a blood-based biomarker assay developed to monitor and predict treatment response in hormone receptor positive metastatic breast cancer (HR + mBC), may decrease traditional disease monitoring assessments and avoid prolongation of futile treatments.Objective. To estimate the diagnostic and treatment budget impact of the assay on a postmenopausal HR + HER2- mBC population in a one-million-member U.S. health plan.Methods. We developed a budget impact model comparing inclusion and exclusion of DiviTum®TKa to standard care under which DiviTum®TKa 1) reduces the frequency of traditional mBC monitoring tools, and 2) predicts treatment futility in advance of radiological disease progression. Traditional disease monitoring assessment schedules were based on guidelines and expert opinion. DiviTum®TKa's impact on therapy utilization was based on published literature and expert opinion. Modeled costs included DiviTum®TKa, NCCN-recommended treatments, imaging, biomarker testing, and adverse events. We calculated total and per-member per-month (PMPM) costs with a 3-year time horizon.Results. Inclusion of 416 DiviTum®TKa assays ($166,400) was largely offset by 193 fewer CT scans, 88 fewer bone scans, and 55 fewer biomarker tests over 3 years, a savings of -$128,400, resulting in a PMPM of $0.001. In scenario analyses, adding DiviTum®TKa resulted in additional treatment-related cost-savings (-$465,600), resulting in a PMPM cost-savings of -$0.013, or an average savings of -$7,400 per each patient initiating first-line cyclin-dependent kinase 4/6 inhibitor plus aromatase inhibitor therapy. Expected savings approached 3X the spend on the new test. Results were most sensitive to DiviTum®TKa cost, population parameters, and treatment costs.Conclusions. Clinical use of the DiviTum®TKa assay is expected to decrease traditional imaging and monitoring and may reduce the overall cost of managing mBC if it leads to clinical decisions to avoid futile therapy. Post-coverage, real world monitoring of palliative therapies among post-menopausal mBC populations is needed to better categorize cost savings over time.}, }
@article {pmid34763161, year = {2021}, author = {Dasgupta, S and Moore, MR and Dimitrov, DT and Hughes, JP}, title = {Bayesian validation framework for dynamic epidemic models.}, journal = {Epidemics}, volume = {37}, number = {}, pages = {100514}, doi = {10.1016/j.epidem.2021.100514}, pmid = {34763161}, issn = {1878-0067}, abstract = {Complex models of infectious diseases are used to understand the transmission dynamics of the disease, project the course of an epidemic, predict the effect of interventions and/or provide information for power calculations of community level intervention studies. However, there have been relatively few opportunities to rigorously evaluate the predictions of such models till now. Indeed, while there is a large literature on calibration (fitting model parameters) and validation (comparing model outputs to data) of complex models based on empirical data, the lack of uniformity in accepted criteria for such procedures for models of infectious diseases has led to simple procedures being prevalent for such steps. However, recently, several community level randomized trials of combination HIV intervention have been planned and/or initiated, and in each case, significant epidemic modeling efforts were conducted during trial planning which were integral to the design of these trials. The existence of these models and the (anticipated) availability of results from the related trials, provide a unique opportunity to evaluate the models and their usefulness in trial design. In this project, we outline a framework for evaluating the predictions of complex epidemiological models and describe experiments that can be used to test their predictions.}, }
@article {pmid34762770, year = {2021}, author = {Parikh, UM and Penrose, KJ and Heaps, AL and Halvas, EK and Goetz, BJ and Gordon, KC and Hardesty, R and Sethi, R and Schwarzmann, W and Szydlo, DW and Husnik, MJ and Chandran, U and Palanee-Phillips, T and Baeten, JM and Mellors, JW and , }, title = {HIV-1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial.}, journal = {Journal of the International AIDS Society}, volume = {24}, number = {11}, pages = {e25833}, doi = {10.1002/jia2.25833}, pmid = {34762770}, issn = {1758-2652}, support = {//National Institute of Allergy and Infectious Diseases (NIAID)/ ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; UM1AI068633/MH/NIMH NIH HHS/United States ; UM1AI068615/MH/NIMH NIH HHS/United States ; UM1AI106707/MH/NIMH NIH HHS/United States ; }, abstract = {INTRODUCTION: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV.<br><br>METHODS: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-bl cells. Statistical significance was calculated using the Fisher's exact test.<br><br>RESULTS: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others.<br><br>CONCLUSIONS: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.}, }
@article {pmid34762488, year = {2021}, author = {Humphreys, IR and Pei, J and Baek, M and Krishnakumar, A and Anishchenko, I and Ovchinnikov, S and Zhang, J and Ness, TJ and Banjade, S and Bagde, SR and Stancheva, VG and Li, XH and Liu, K and Zheng, Z and Barrero, DJ and Roy, U and Kuper, J and Fernández, IS and Szakal, B and Branzei, D and Rizo, J and Kisker, C and Greene, EC and Biggins, S and Keeney, S and Miller, EA and Fromme, JC and Hendrickson, TL and Cong, Q and Baker, D}, title = {Computed structures of core eukaryotic protein complexes.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eabm4805}, doi = {10.1126/science.abm4805}, pmid = {34762488}, issn = {1095-9203}, abstract = {[Figure: see text].}, }
@article {pmid34762093, year = {2021}, author = {Kutny, MA and Alonzo, TA and Abla, O and Rajpurkar, M and Gerbing, RB and Wang, YC and Hirsch, BA and Raimondi, S and Kahwash, S and Hardy, KK and Hardy, S and Meshinchi, S and Gamis, AS and Kolb, EA and Feusner, JH and Gregory, J}, title = {Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia: A Report From the Children's Oncology Group AAML1331 Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2021.5206}, pmid = {34762093}, issn = {2374-2445}, abstract = {Importance: All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL.<br><br>Objective: To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively.<br><br>The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/μL) and high-risk APL (white blood cell count ≥10 000/μL) cohorts.<br><br>Interventions: All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered.<br><br>Main Outcomes and Measures: Event-free survival (EFS) at 2 years after diagnosis.<br><br>Results: Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL).<br><br>Conclusions and Relevance: In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02339740.}, }
@article {pmid34761160, year = {2021}, author = {Tinker, LF and Huang, Y and Johnson, KC and Carbone, LD and Snetselaar, L and Van Horn, L and Manson, JE and Liu, S and Mossavar-Rahmani, Y and Prentice, RL and Lampe, JW and Neuhouser, ML}, title = {Estimating 24-Hour Urinary Excretion of Sodium and Potassium Is More Reliable from 24-Hour Urine Than Spot Urine Sample in a Feeding Study of US Older Postmenopausal Women.}, journal = {Current developments in nutrition}, volume = {5}, number = {11}, pages = {nzab125}, pmid = {34761160}, issn = {2475-2991}, abstract = {Background: Assessing estimated sodium (Na) and potassium (K) intakes derived from 24-h urinary excretions compared with a spot urine sample, if comparable, could reduce participant burden in epidemiologic and clinical studies.<br><br>Objectives: In a 2-week controlled-feeding study, Na and K excretions from a 24-h urine collection were compared with a first-void spot urine sample, applying established algorithms and enhanced models to estimate 24-h excretion. Actual and estimated 24-h excretions were evaluated relative to mean daily Na and K intakes in the feeding study.<br><br>Methods: A total of 153 older postmenopausal women ages 75.4 ± 3.5 y participated in a 2-wk controlled-feeding study with a 4-d repeating menu cycle based on their usual intake (ClinicalTrials.gov Identifier: NCT00000611). Of the 150 participants who provided both a first-void spot urine sample and a 24-h urine collection on the penultimate study day, statistical methods included Pearson correlations for Na and K between intake, 24-h collections, and the 24-h estimated excretions using 4 established algorithms: enhanced biomarker models by regressing ln-transformed intakes on ln-transformed 24-h excretions or ln-transformed 24-h estimated excretions plus participant characteristics and sensitivity analyses for factors potentially influencing Na or K excretion (e.g., possible kidney disease estimated glomerular filtration rate <60 mL/min/1.73 m2).<br><br>Results: Pearson correlation coefficients between Na and K intakes and actual 24-h excretions were 0.57 and 0.38-0.44 for estimated 24-h excretions, depending on electrolyte and algorithm used. Enhanced biomarker model cross-validated R 2 (CVR2) for 24-h excretions were 38.5% (Na), 40.2% (K), and 42.0% (Na/K). After excluding participants with possible kidney disease, the CVR2 values were 43.2% (Na), 40.2% (K), and 38.1% (Na/K).<br><br>Conclusions: Twenty-four-hour urine excretion measurement performs better than estimated 24-h excretion from a spot urine as a biomarker for Na and K intake among a sample of primarily White postmenopausal women.}, }
@article {pmid34760616, year = {2021}, author = {Nair, VS and Eaton, K and McGarry Houghton, A}, title = {A case series of morbid COPD exacerbations during immune checkpoint inhibitor therapy in cancer patients.}, journal = {Respiratory medicine case reports}, volume = {34}, number = {}, pages = {101541}, pmid = {34760616}, issn = {2213-0071}, abstract = {Background: Immune checkpoint inhibitor therapy is rapidly becoming front line adjuvant or primary therapy in a number of solid cancer types. Since many of these cancers are a result of tobacco smoking, a large number of these patients will have underlying comorbid conditions attributed to smoking such as Chronic Obstructive Pulmonary Disease (COPD). The effect of immune checkpoint inhibitor therapy on COPD is not well documented, and COPD exacerbations are not currently considered a pulmonary associated immune checkpoint inhibitor toxicity in current guidelines.<br><br>Case presentation: We describe and summarize here a series of patients with prolonged and severe COPD exacerbations upon the initiation of immune checkpoint inhibitor therapy for cancers of the skin and lung without radiographic evidence of pneumonitis.<br><br>Conclusions: COPD exacerbation from immune checkpoint inhibitor is not reported in the literature and is associated with prolonged and severe episodes without radiographic evidence of pneumonitis. Awareness of this potential morbid toxicity and research efforts to understand its etiology are required.}, }
@article {pmid34757794, year = {2021}, author = {Vick, SC and Frutoso, M and Mair, F and Konecny, AJ and Greene, E and Wolf, CR and Logue, JK and Franko, NM and Boonyaratanakornkit, J and Gottardo, R and Schiffer, JT and Chu, HY and Prlic, M and Lund, JM}, title = {A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections.}, journal = {Science advances}, volume = {7}, number = {46}, pages = {eabj0274}, doi = {10.1126/sciadv.abj0274}, pmid = {34757794}, issn = {2375-2548}, abstract = {[Figure: see text].}, }
@article {pmid34755860, year = {2021}, author = {Liese, AD and Wambogo, E and Lerman, JL and Boushey, CJ and Neuhouser, ML and Wang, S and Harmon, BE and Tinker, LF}, title = {Variations in Dietary Patterns Defined by the Healthy Eating Index 2015 and Associations with Mortality: Findings from the Dietary Patterns Methods Project.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxab383}, pmid = {34755860}, issn = {1541-6100}, abstract = {BACKGROUND: It is currently unknown if within high-quality dietary intake there exist distinct dietary patterns associated with health benefits that are identifiable with multidimensional dietary pattern analyses.<br><br>METHODS: We conducted sex-specific k-means cluster analyses within Healthy Eating Index 2015 (HEI-2015) quintile 5 in three US cohorts (NIH-AARP Diet and Health Study, the Multiethnic Cohort, Women's Health Initiative Observational Study), clusters ranging from n = 1,190 to 12,007. Characterizations incorporated HEI-2015 overall and component-specific % adherence goals, using untruncated and truncated radar graphs and shape analyses. Using cohort- and sex-specific Cox proportional hazards models, associations of quintile 5 clusters with all-cause, cardiovascular disease (CVD), and cancer mortality were evaluated relative to quintile 1.<br><br>RESULTS: In each cohort sex-specific sample, three identified clusters included 16%-62% of participants, providing evidence for variation within high-quality dietary intake. Clusters revealed commonalities in total fruits and whole fruits that exceeded goals and high sodium intake. Dairy and whole grain oftentimes fell below goal. Some clusters were additionally characterized by total vegetables, greens &amp; beans and seafood &amp; plant protein intakes exceeding goals. All high-quality dietary patterns were associated with a multivariable-adjusted significant 15-26% lower risk of all-cause death compared to diet intake in quintile 1 (except for cluster 2 in WHI OS), and with a 16-25% lower risk of CVD mortality in the AARP and MEC cohorts. Cancer mortality results were inconsistent.<br><br>CONCLUSIONS: Multiple ways to achieve a high-quality diet were identified and significant associations with lower all-cause and CVD mortality were seen in some cohorts.}, }
@article {pmid34755139, year = {2021}, author = {Yaffe, ZA and Overbaugh, J}, title = {HIV-1 protection: Antibodies move in for the kill.}, journal = {Cell reports. Medicine}, volume = {2}, number = {10}, pages = {100428}, doi = {10.1016/j.xcrm.2021.100428}, pmid = {34755139}, issn = {2666-3791}, abstract = {Identifying the immune responses needed for protection against HIV is critical to finding an effective vaccine. In this issue of Cell Reports Medicine, Thomas and colleagues1 show that antibodies that kill infected cells correlate with infant HIV infection outcomes more so than antibodies that block viral entry.}, }
@article {pmid34753703, year = {2021}, author = {Hirsch, FR and Redman, MW and Moon, J and Agustoni, F and Herbst, RS and Semrad, TJ and Varella-Garcia, M and Rivard, CJ and Kelly, K and Gandara, DR and Mack, PC}, title = {EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC.}, journal = {Clinical lung cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cllc.2021.10.002}, pmid = {34753703}, issn = {1938-0690}, abstract = {BACKGROUND: The phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC.<br><br>METHODS: FISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712.<br><br>RESULTS: Of 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen.<br><br>CONCLUSIONS: In NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.}, }
@article {pmid34751813, year = {2021}, author = {Maloney, E and Perez, FA and Iyer, RS and Otto, RK and Wright, JN and Menashe, SJ and Hippe, DS and Shaw, DWW and Stanescu, AL}, title = {Non-inferiority of a non-gadolinium-enhanced magnetic resonance imaging follow-up protocol for isolated optic pathway gliomas.}, journal = {Pediatric radiology}, volume = {}, number = {}, pages = {}, pmid = {34751813}, issn = {1432-1998}, abstract = {BACKGROUND: Pediatric patients with optic pathway gliomas (OPGs) typically undergo a large number of follow-up MRI brain exams with gadolinium-based contrast media (GBCM), which have been associated with gadolinium tissue retention. Therefore, careful consideration of GBCM use in these children is warranted.<br><br>OBJECTIVE: To investigate whether GBCM is necessary for OPG MR imaging response assessment using a blinded, non-inferiority, multi-reader study.<br><br>MATERIALS AND METHODS: We identified children with OPG and either stable disease or change in tumor size on MRI using a regional cancer registry serving the U.S. Pacific Northwest. For each child, the two relevant, consecutive MRI studies were anonymized and standardized into two imaging sets excluding or including GBCM-enhanced images. Exam pairs were compiled from 42 children with isolated OPG (19 with neurofibromatosis type 1), from a population of 106 children with OPG. We included 28 exam pairs in which there was a change in size between exams. Seven pediatric radiologists measured tumor sizes during three blinded sessions, spaced by at least 1 week. The first measuring session excluded GBCM-enhanced sequences; the others did not. The primary endpoint was intra-reader agreement for ≥ 25% change in axial cross-product measurement, using a 12% non-inferiority threshold.<br><br>RESULTS: Analysis demonstrated an overall 1.2% difference (95% confidence interval, -3.2% to 5.5%) for intra-reader agreement using a non-GBCM-enhanced protocol and background variability.<br><br>CONCLUSION: A non-GBCM-enhanced protocol was non-inferior to a GBCM-enhanced protocol for assessing change in size of isolated OPGs on follow-up MRI exams.}, }
@article {pmid34751662, year = {2021}, author = {Bricker, JB and Levin, M and Lappalainen, R and Mull, K and Sullivan, B and Santiago-Torres, M}, title = {Mechanisms of Smartphone Apps for Cigarette Smoking Cessation: Results of a Serial Mediation Model From the iCanQuit Randomized Trial.}, journal = {JMIR mHealth and uHealth}, volume = {9}, number = {11}, pages = {e32847}, doi = {10.2196/32847}, pmid = {34751662}, issn = {2291-5222}, abstract = {BACKGROUND: Engagement with digital interventions is a well-known predictor of treatment outcomes, but this knowledge has had limited actionable value. Instead, learning why engagement with digital interventions impact treatment outcomes can lead to targeted improvements in their efficacy.<br><br>OBJECTIVE: This study aimed to test a serial mediation model of an Acceptance and Commitment Therapy (ACT) smartphone intervention for smoking cessation.<br><br>METHODS: In this randomized controlled trial, participants (N=2415) from 50 US states were assigned to the ACT-based smartphone intervention (iCanQuit) or comparison smartphone intervention (QuitGuide). Their engagement with the apps (primary measure: number of logins) was measured during the first 3 months, ACT processes were measured at baseline and 3 months (acceptance of internal cues to smoke, valued living), and smoking cessation was measured at 12 months with 87% follow-up retention.<br><br>RESULTS: There was a significant serial mediation effect of iCanQuit on smoking cessation through multiple indicators of intervention engagement (ie, total number of logins, total number of minutes used, and total number of unique days of use) and in turn through increases in mean acceptance of internal cues to smoke from baseline to 3 months. Analyses of the acceptance subscales showed that the mediation was through acceptance of physical sensations and emotions, but not acceptance of thoughts. There was no evidence that the effect of the iCanQuit intervention was mediated through changes in valued living.<br><br>CONCLUSIONS: In this first study of serial mediators underlying the efficacy of smartphone apps for smoking cessation, our results suggest the effect of the iCanQuit ACT-based smartphone app on smoking cessation was mediated through multiple indicators of engagement and in turn through increases in the acceptance of physical sensations and emotions that cue smoking.<br><br>TRIAL REGISTRATION: Clinical Trials.gov NCT02724462; https://clinicaltrials.gov/ct2/show/NCT02724462.}, }
@article {pmid34751183, year = {2021}, author = {Lindsay, J and Othman, J and Heldman, MR and Slavin, MA}, title = {Epstein-Barr virus posttransplant lymphoproliferative disorder: update on management and outcomes.}, journal = {Current opinion in infectious diseases}, volume = {34}, number = {6}, pages = {635-645}, pmid = {34751183}, issn = {1473-6527}, abstract = {PURPOSE OF REVIEW: Management of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV PTLD) is complex, involving risk stratification, prevention and/or preemptive measures involving monitoring EBV DNAemia and balancing treatment options, using a combination of reduction of immune suppression, anti-B cell therapy, and cytotoxic T lymphocytes (CTLs).<br><br>RECENT FINDINGS: The highest risk factor for the development of EBV PTLD in hematopoietic cell transplant (HCT) remains T cell depletion, with increasing use of antithymocyte globulin (ATG) or alemtuzumab in conditioning. In solid organ transplantation (SOT), the incidence of PTLD is highest among EBV seronegative recipients who are at risk for primary EBV infection following transplant in the first 12 months. Prevention is a critical component of the management of EBV PTLD. Although preemptive therapy remains standard of care, there continues to be heterogenicity and debate over the optimal choice of EBV DNA quantification and the threshold to use. Novel therapies such as donor-derived multipathogen and EBV specific CTLs for the prevention and third party CTLs for the treatment of EBV PTLD are promising, with rapidly expanding evidence, including large scale Phase III trials currently underway.<br><br>SUMMARY: With an increasing number of risk groups for developing EBV PTLD in HCT and SOT, management strategies using prophylaxis or preemptive therapy remain standard of care, however the use of prophylactic or preemptive EBV specific or multipathogen CTLs show promising results and safety profiles.}, }
@article {pmid34750557, year = {2021}, author = {Forde, PM and Anagnostou, V and Sun, Z and Dahlberg, SE and Kindler, HL and Niknafs, N and Purcell, T and Santana-Davila, R and Dudek, AZ and Borghaei, H and Lanis, M and Belcaid, Z and Smith, KN and Balan, A and White, JR and Cherry, C and Ashok Sivakumar, IK and Shao, XM and Chan, HY and Singh, D and Thapa, S and Illei, PB and Pardoll, DM and Karchin, R and Velculescu, VE and Brahmer, JR and Ramalingam, SS}, title = {Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {34750557}, issn = {1546-170X}, support = {CA190755//U.S. Department of Defense (United States Department of Defense)/ ; CA121113//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R37CA251447//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; CA121113//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Mesothelioma is a rare and fatal cancer with limited therapeutic options until the recent approval of combination immune checkpoint blockade. Here we report the results of the phase 2 PrE0505 trial (NCT02899195) of the anti-PD-L1 antibody durvalumab plus platinum-pemetrexed chemotherapy for 55 patients with previously untreated, unresectable pleural mesothelioma. The primary endpoint was overall survival compared to historical control with cisplatin and pemetrexed chemotherapy; secondary and exploratory endpoints included safety, progression-free survival and biomarkers of response. The combination of durvalumab with chemotherapy met the pre-specified primary endpoint, reaching a median survival of 20.4 months versus 12.1 months with historical control. Treatment-emergent adverse events were consistent with known side effects of chemotherapy, and all adverse events due to immunotherapy were grade 2 or lower. Integrated genomic and immune cell repertoire analyses revealed that a higher immunogenic mutation burden coupled with a more diverse T cell repertoire was linked to favorable clinical outcome. Structural genome-wide analyses showed a higher degree of genomic instability in responding tumors of epithelioid histology. Patients with germline alterations in cancer predisposing genes, especially those involved in DNA repair, were more likely to achieve long-term survival. Our findings indicate that concurrent durvalumab with platinum-based chemotherapy has promising clinical activity and that responses are driven by the complex genomic background of malignant pleural mesothelioma.}, }
@article {pmid34749683, year = {2021}, author = {Domogalla, B and Ko, LK and Jones, R and Ali, WB and Rodriguez, E and Duggan, C and Perry, CK}, title = {Rural Latino parent and child physical activity patterns: family environment matters.}, journal = {BMC public health}, volume = {21}, number = {1}, pages = {2043}, pmid = {34749683}, issn = {1471-2458}, support = {R24MD008068-01//National Institute of Minority Health &amp; Health Disparities/ ; R24MD008068-01//National Institute of Minority Health &amp; Health Disparities/ ; }, abstract = {BACKGROUND: Rural Latino children and adults are less active than urban and non-Latino counterparts. We examined physical activity (PA) patterns of rural Latino children and their parents, and explored parental beliefs about and reported barriers of Latino family physical activity. Latino families in a rural area in eastern Washington state, with children in grades 3-5 were included.<br><br>METHODS: We used mixed methods. Children (n = 27) and parents (n = 25) wore an accelerometer for 5 days; parents (n = 31) participated in a semi-structured interview and completed a demographic survey. Parent and child activity levels were compared using paired t-tests; interviews were analyzed with qualitative content analysis.<br><br>RESULTS: Although 100% children and 46% parents met physical activity guidelines, parents and children spent most of the day in sedentary behaviors. Parent-reported PA barriers included their long work hours, lack of transportation, and their child's screen-time.<br><br>CONCLUSION: Addressing barriers and reducing sedentary time could increase PA of rural Latino families.}, }
@article {pmid34749576, year = {2021}, author = {Halpern, AB and Estey, EH}, title = {More general incorporation of hemoglobin level into response criteria for myelodysplastic syndrome and acute myeloid leukemia with increase in minimum red cell transfusion levels.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/10428194.2021.1999446}, pmid = {34749576}, issn = {1029-2403}, }
@article {pmid34748278, year = {2021}, author = {Glover, M and Hui, G and Chiang, R and Savage, P and Krell, J and Julve, M and Grivas, P and Lythgoe, M and Khaki, AR}, title = {Disparity of Race Reporting in FDA Drug Approvals for Urinary System Cancers from 2006 to 2021.}, journal = {BJU international}, volume = {}, number = {}, pages = {}, doi = {10.1111/bju.15629}, pmid = {34748278}, issn = {1464-410X}, abstract = {BACKGROUND: Significant racial disparity exists in urinary system cancers (urothelial carcinoma [UC] and renal cell carcinoma [RCC]), in terms of epidemiology, access to therapy and outcomes. We analyzed racial diversity and race reporting in FDA drug registration trials for UC and RCC.<br><br>METHOD: All FDA pivotal registration trials between 2006-2021 for both UC and RCC were identified. The trials were analyzed to check for compliance with current FDA recommendations for race reporting. Additional information on participant recruitment and race was obtained to assess representation based on cancer type.<br><br>RESULTS: From 2006-2021 there were 30 new drug registrations for the management of urinary systems cancers, of which 16 in RCC and 14 in UC. Overall, 70% of these trials reported data on racial representation, however, only 43% reported data stratified into five categories as recommended by the FDA.<br><br>CONCLUSION: We found a significant under-representation of non-white participants in FDA drug registration clinical trials in UC and RCC. Race reporting is inconsistent and FDA guidelines are not being universally followed. Considering the disproportionate disease burden in UC and RCC, clinical trials should prioritize recruiting a diverse population of participants.}, }
@article {pmid34747479, year = {2021}, author = {Wang, DD and Qi, Q and Wang, Z and Usyk, M and Sotres-Alvarez, D and Mattei, J and Tamez, M and Gellman, MD and Daviglus, M and Hu, FB and Stampfer, MJ and Huttenhower, C and Knight, R and Burk, RD and Kaplan, RC}, title = {The Gut Microbiome Modifies the Association between a Mediterranean Diet and Diabetes in US Hispanic / Latino Population.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgab815}, pmid = {34747479}, issn = {1945-7197}, abstract = {CONTEXT: The interrelationships among the gut microbiome, the MedDiet and a clinical endpoint of diabetes is unknown.<br><br>OBJECTIVES: To identify gut microbial features of a MedDiet and examine whether the association between MedDiet and diabetes varies across individuals with different gut microbial profiles.<br><br>METHODS: This study included 543 diabetes, 805 prediabetes and 394 normoglycemic participants from a cohort study of US Hispanic/Latino men and women. Fecal samples were profiled using 16S rRNA gene sequencing. Adherence to MedDiet was evaluated by an index based on two 24-hour dietary recalls.<br><br>RESULTS: A greater MedDiet adherence was associated with higher abundances of major dietary fiber metabolizers (e.g., Faecalibacterium Prausnitzii, FDR-adjusted p [q] =0.01), and lower abundances of biochemical specialists (e.g., Parabacteroides, q =0.04). The gut microbiomes of participants with greater MedDiet adherence were enriched for functions involved in dietary fiber degradation but depleted for those related to sulfur reduction and lactose and galactose degradation. The associations between MedDiet adherence and diabetes prevalence were significantly stronger among participants with depleted abundance of Prevotella (p interaction =0.03 for diabetes, 0.02 for prediabetes/diabetes, and 0.02 for prediabetes). A one-standard deviation increment in the MedDiet index was associated with 24% [odds ratio (OR) =0.76; 95% confidence interval (CI), 0.59-0.98] and 7% (OR =0.93; 95% CI, 0.72-1.20) lower odds of diabetes in Prevotella non-carriers and carriers, respectively.<br><br>CONCLUSIONS: Adherence to MedDiet is associated with diverse gut microorganisms and microbial functions. The inverse association between the MedDiet and diabetes prevalence varies significantly depending on gut microbial composition.}, }
@article {pmid34743536, year = {2021}, author = {Bhattacharya, R and Zekavat, SM and Haessler, J and Fornage, M and Raffield, L and Uddin, MM and Bick, AG and Niroula, A and Yu, B and Gibson, C and Griffin, G and Morrison, AC and Psaty, BM and Longstreth, WT and Bis, JC and Rich, SS and Rotter, JI and Tracy, RP and Correa, A and Seshadri, S and Johnson, A and Collins, JM and Hayden, KM and Madsen, TE and Ballantyne, CM and Jaiswal, S and Ebert, BL and Kooperberg, C and Manson, JE and Whitsel, EA and ,  and Natarajan, P and Reiner, AP}, title = {Clonal Hematopoiesis Is Associated With Higher Risk of Stroke.}, journal = {Stroke}, volume = {}, number = {}, pages = {STROKEAHA121037388}, doi = {10.1161/STROKEAHA.121.037388}, pmid = {34743536}, issn = {1524-4628}, abstract = {BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.<br><br>METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke.<br><br>RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke.<br><br>CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.}, }
@article {pmid34742340, year = {2021}, author = {Miner, MD and Bekker, LG and Kredo, T and Bhagwandin, N and Corey, L and Gray, GE}, title = {Meeting report: South African Medical Research Council Standard of Care in Clinical Research in Low- And Middle-Income Settings Summit, November 2017.}, journal = {Trials}, volume = {22}, number = {1}, pages = {778}, pmid = {34742340}, issn = {1745-6215}, support = {N/A//South African Medical Research Council/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {*Anti-HIV Agents/adverse effects ; *Biomedical Research ; *HIV Infections/diagnosis/drug therapy/prevention &amp; control ; Humans ; *Pre-Exposure Prophylaxis ; South Africa ; Standard of Care ; }, abstract = {A cornerstone of HIV prevention clinical trials is providing a combination prevention package to all trial participants. The elements included in that standard of care (SoC) package evolve as new prevention modalities are developed. Pre-exposure prophylaxis (PrEP) was recommended by the World Health Organization for persons at high risk of acquiring HIV, but not all countries immediately adopted those recommendations. The South African Medical Research Council (SAMRC) convened a summit to discuss issues relating to SoC and PrEP in HIV prevention clinical trials taking place in lower- to middle-income countries (LMIC). Policymakers, regulators, ethicists, experts in law, researchers, representatives of advocacy groups, and the HIV Vaccine Trials Network (HVTN) presented a framework within which SoC principles could be articulated. A group of subject matter experts presented on the regulatory, ethical, scientific, and historic framework of SoC in clinical trials, focusing on PrEP in South Africa. Summit participants discussed how and when to include new HIV treatment and prevention practices into existing clinical guidelines and trial protocols, as well as the opportunities for and challenges to scaling up interventions. The summit addressed challenges to PrEP provision, such as inconsistent efficacy amongst different populations and various biological, virological, and immunological explanations for this heterogeneity. Advocates and community members propagated the urgent need for accessible interventions that could avert HIV infection. The meeting recommended supporting access to PrEP in HIV prevention trials by (1) developing PrEP access plans for HIV vaccine trials, (2) creating a PrEP fund that would supply PrEP to sites conducting HIV prevention trials via a central procurement mechanism, and (3) supporting the safety monitoring of PrEP. This report summarizes the presentations and discussions from the summit in order to highlight the importance of SoC in HIV prevention clinical trials.}, }
@article {pmid34741817, year = {2021}, author = {Butler, CD and Jaakkola, JJK and Boylan, S and McFarlane, RA and Potter, JD}, title = {Restoring biodiversity and slowing climate change are crucial to protect health.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(21)02250-9}, pmid = {34741817}, issn = {1474-547X}, }
@article {pmid34741096, year = {2021}, author = {Yeh, AC and O'Donnell, PV and Schoch, G and Martin, PJ and McFarland, C and McCune, JS and Cooper, JP and Doney, K and Flowers, MED and Sorror, ML and Appelbaum, FR and Storer, BE and Gooley, T and Deeg, HJ}, title = {Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34741096}, issn = {1476-5365}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; Research Training Award for Fellows//American Society of Hematology (ASH)/ ; }, abstract = {We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m2) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.}, }
@article {pmid34724567, year = {2021}, author = {Fuchs, EJ and McCurdy, SR and Solomon, SR and Wang, T and Herr, MM and Modi, D and Grunwald, MR and Nishihori, T and Kuxhausen, M and Fingerson, S and McKallor, C and Bashey, A and Kasamon, YL and Bolon, YT and Saad, A and McGuirk, JP and Paczesny, S and Gadalla, SM and Marsh, SG and Shaw, BE and Spellman, SR and Lee, SJ and Petersdorf, EW}, title = {HLA Informs Risk Predictions after Haploidentical Stem Cell Transplantation with Post-transplantation Cyclophosphamide.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021013443}, pmid = {34724567}, issn = {1528-0020}, abstract = {Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence and survival after haploidentical donor transplantation with post-transplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.}, }
@article {pmid34739170, year = {2021}, author = {Cáceres-Gutiérrez, RE and Andonegui, MA and Oliva-Rico, DA and González-Barrios, R and Luna, F and Arriaga-Canon, C and López-Saavedra, A and Prada, D and Castro, C and Parmentier, L and Díaz-Chávez, J and Alfaro-Mora, Y and Navarro-Delgado, EI and Fabian-Morales, E and Tran, B and Shetty, J and Zhao, Y and Alcaraz, N and De la Rosa, C and Reyes, JL and Hédouin, S and Hubé, F and Francastel, C and Herrera, LA}, title = {Proteasome inhibition alters mitotic progression through the upregulation of centromeric α-satellite RNAs.}, journal = {The FEBS journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/febs.16261}, pmid = {34739170}, issn = {1742-4658}, abstract = {Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA-seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α-Satellite RNAs. We showed that α-Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α-Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α-Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor-binding motifs within α-Satellite centromeric arrays. Using high resolution three-dimensional immuno-FISH and ChIP-qPCR we showed an association between the α-Satellite upregulation and the recruitment of the transcription factor NFY-A to the centromere upon MG132-induced proteasome inhibition. Together, our results show that the proteasome controls α-Satellite RNAs associated to the regulation of mitosis.}, }
@article {pmid34738070, year = {2021}, author = {Alwers, E and Carr, PR and Banbury, B and Walter, V and Chang-Claude, J and Jansen, L and Drew, DA and Giovannucci, E and Nan, H and Berndt, SI and Huang, WY and Prizment, A and Hayes, RB and Sakoda, LC and White, E and Labadie, J and Slattery, M and Schoen, RE and Diergaarde, B and van Guelpen, B and Campbell, PT and Peters, U and Chan, AT and Newcomb, PA and Hoffmeister, M and Brenner, H}, title = {Smoking Behavior and Prognosis After Colorectal Cancer Diagnosis: A Pooled Analysis of 11 Studies.}, journal = {JNCI cancer spectrum}, volume = {5}, number = {5}, pages = {pkab077}, doi = {10.1093/jncics/pkab077}, pmid = {34738070}, issn = {2515-5091}, abstract = {Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies, but current evidence on smoking in association with survival after CRC diagnosis is limited.<br><br>Methods: We pooled data from 12 345 patients with stage I-IV CRC from 11 epidemiologic studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of prediagnostic smoking behavior with overall, CRC-specific, and non-CRC-specific survival.<br><br>Results: Among 12 345 patients with CRC, 4379 (35.5%) died (2515 from CRC) over a median follow-up time of 7.5 years. Smoking was strongly associated with worse survival in stage I-III patients, whereas no association was observed among stage IV patients. Among stage I-III patients, clear dose-response relationships with all survival outcomes were seen for current smokers. For example, current smokers with 40 or more pack-years had statistically significantly worse overall, CRC-specific, and non-CRC-specific survival compared with never smokers (hazard ratio [HR] =1.94, 95% confidence interval [CI] =1.68 to 2.25; HR = 1.41, 95% CI = 1.12 to 1.78; and HR = 2.67, 95% CI = 2.19 to 3.26, respectively). Similar associations with all survival outcomes were observed for former smokers who had quit for less than 10 years, but only a weak association with non-CRC-specific survival was seen among former smokers who had quit for more than 10 years.<br><br>Conclusions: This large consortium of CRC patient studies provides compelling evidence that smoking is strongly associated with worse survival of stage I-III CRC patients in a clear dose-response manner. The detrimental effect of smoking was primarily related to noncolorectal cancer events, but current heavy smoking also showed an association with CRC-specific survival.}, }
@article {pmid34737261, year = {2021}, author = {Che, M and Chaturvedi, A and Munro, SA and Pitzen, SP and Ling, A and Zhang, W and Mentzer, J and Ku, SY and Puca, L and Zhu, Y and Bergman, AM and Severson, TM and Forster, C and Liu, Y and Hildebrand, J and Daniel, M and Wang, TY and Selth, LA and Hickey, T and Zoubeidi, A and Gleave, M and Bareja, R and Sboner, A and Tilley, W and Carroll, JS and Tan, W and Kohli, M and Yang, R and Hsieh, AC and Murugan, P and Zwart, W and Beltran, H and Huang, RS and Dehm, SM}, title = {Opposing transcriptional programs of KLF5 and AR emerge during therapy for advanced prostate cancer.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {6377}, pmid = {34737261}, issn = {2041-1723}, support = {R01CA174777//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.}, }
@article {pmid34737208, year = {2021}, author = {Wolfson, JA and Bhatia, S and Ginsberg, JP and Becker, L and Bernstein, D and Henk, HJ and Lyman, GH and Nathan, PC and Puccetti, D and Wilkes, JJ and Winestone, LE and Kenzik, KM}, title = {Expenditures in Young Adults with Hodgkin Lymphoma: NCI-designated Comprehensive Cancer Centers vs. Other Sites.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0321}, pmid = {34737208}, issn = {1538-7755}, abstract = {BACKGROUND: Outcomes among Hodgkin Lymphoma (HL) patients diagnosed between 22 and 39 years are worse than among those diagnosed <21 years, and have not seen the same improvement over time. Treatment at an NCI-designated Comprehensive Cancer Center (CCC) mitigates outcome disparities, but may be associated with higher expenditures.<br><br>METHODS: We examined cancer-related expenditures among 22-39 year-old HL patients diagnosed between 2001-2016 using de-identified administrative claims data (OptumLabs® Data Warehouse) (CCC: n=1,154; non-CCC: n=643). Adjusting for sociodemographics, clinical characteristics and months enrolled, multivariable general linear models modeled average monthly health-plan paid (HPP) expenditures, and incidence rate ratios compared CCC/non-CCC monthly visit rates.<br><br>RESULTS: In the year following diagnosis, CCC patients had higher HPP-expenditures ($12,869 vs. $10,688, p=0.001), driven by higher monthly rates of CCC non-treatment outpatient hospital visits (p=0.001) and per-visit expenditures for outpatient hospital chemotherapy ($632 vs. $259); higher CCC inpatient expenditures ($1,813 vs. $1,091, p=0.001) were driven by 3.1-times higher rates of chemotherapy admissions (p=0.001). Out-of-pocket expenditures were comparable (p=0.3).<br><br>CONCLUSIONS: Young adults with Hodgkin lymphoma at CCCs saw higher health plan expenditures, but comparable out-of-pocket expenditures. Drivers of CCC expenditures included outpatient hospital utilization (monthly rates of non-therapy visits and per-visit expenditures for chemotherapy).<br><br>IMPACT: Higher HPP-expenditures at CCCs in the year following HL diagnosis likely reflect differences in facility structure and comprehensive care. For young adults, it is plausible to consider incentivizing CCC care to achieve superior outcomes while developing approaches to achieve long-term savings.}, }
@article {pmid34737207, year = {2021}, author = {Borozan, I and Zaidi, SH and Harrison, TA and Phipps, AI and Zheng, J and Lee, S and Trinh, QM and Steinfelder, RS and Adams, J and Banbury, BL and Berndt, SI and Brezina, S and Buchanan, DD and Bullman, S and Cao, Y and Farris, AB and Figueiredo, JC and Giannakis, M and Heisler, LE and Hopper, JL and Lin, Y and Luo, X and Nishihara, R and Mardis, ER and Papadopoulos, N and Qu, C and Reid, EEG and Thibodeau, SN and Harlid, S and Um, CY and Hsu, L and Gsur, A and Campbell, PT and Gallinger, S and Newcomb, PA and Ogino, S and Sun, W and Hudson, TJ and Ferretti, V and Peters, U}, title = {Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0463}, pmid = {34737207}, issn = {1538-7755}, abstract = {BACKGROUND: Fusobacterium nucleatum activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis.<br><br>METHODS: We characterized F nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer (CRC) specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 CRC patients and assessed associations between F nucleatum presence and clinical characteristics, CRC-specific mortality, and somatic mutations.<br><br>RESULTS: F nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors-particularly subspecies animalis. Presence of F nucleatum was associated with higher CRC-specific mortality (hazard ratio [HR], 1.97; P=0.0004). This association was restricted to non-hypermutated, microsatellite-stable tumors (HR, 2.13; P=0.0002) and those who received chemotherapy (HR = 1.92, CI: 1.07-3.45, p-value = 0.029). Only F nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with CRC-specific mortality (HR, 2.16; P=0.0016)-subspecies vincentii and nucleatum were not (HR, 1.07, P=0.86). Additional adjustment for tumor stage suggests that the effect of F nucleatum on mortality is partly driven by a stage shift. Presence of F nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, ERBB3 mutations, and suggestively associated with TP53 mutations.<br><br>CONCLUSIONS: F nucleatum, and particularly subspecies animalis, was associated with a higher CRC-specific mortality and specific somatic mutated genes.<br><br>IMPACT: Our findings identify the F nucleatum subspecies animalis as negatively impacting CRC mortality which may occur through a stage shift and its effect on chemoresistance.}, }
@article {pmid34737180, year = {2021}, author = {D'Agostino, EM and Haroz, EE and Linde, S and Layer, M and Green, M and Ko, LK}, title = {School-Academic Partnerships in Support of Safe Return to Schools During the COVID-19 Pandemic.}, journal = {Pediatrics}, volume = {}, number = {}, pages = {}, doi = {10.1542/peds.2021-054268C}, pmid = {34737180}, issn = {1098-4275}, }
@article {pmid34737178, year = {2021}, author = {Ko, LK and Tingey, L and Ramirez, M and Pablo, E and Grass, R and Larzelere, F and Cisneros, O and Chu, HY and D'Agostino, EM}, title = {Mobilizing Established School Partnerships to Reach Underserved Children During a Global Pandemic.}, journal = {Pediatrics}, volume = {}, number = {}, pages = {}, doi = {10.1542/peds.2021-054268F}, pmid = {34737178}, issn = {1098-4275}, }
@article {pmid34737173, year = {2021}, author = {Haroz, EE and Kalb, LG and Newland, JG and Goldman, JL and Mast, DK and Ko, LK and Grass, R and Shah, P and Walsh, T and Schuster, JE}, title = {Implementation of School-Based COVID-19 Testing Programs in Underserved Populations.}, journal = {Pediatrics}, volume = {}, number = {}, pages = {}, doi = {10.1542/peds.2021-054268G}, pmid = {34737173}, issn = {1098-4275}, }
@article {pmid34736425, year = {2021}, author = {Fredericksen, RJ and Whitney, BM and Trejo, E and Nance, RM and Fitzsimmons, E and Altice, FL and Carrico, AW and Cleland, CM and Del Rio, C and Duerr, A and El-Sadr, WM and Kahana, S and Kuo, I and Mayer, K and Mehta, S and Ouellet, LJ and Quan, VM and Rich, J and Seal, DW and Springer, S and Taxman, F and Wechsberg, W and Crane, HM and Delaney, JAC}, title = {Individual and poly-substance use and condomless sex among HIV-uninfected adults reporting heterosexual sex in a multi-site cohort.}, journal = {BMC public health}, volume = {21}, number = {1}, pages = {2002}, pmid = {34736425}, issn = {1471-2458}, support = {U01DA037702/DA/NIDA NIH HHS/United States ; BCAP1 R01DA032083/DA/NIDA NIH HHS/United States ; BRIGHT1 R01DA030771/DA/NIDA NIH HHS/United States ; STAR R01DA032100/DA/NIDA NIH HHS/United States ; STTS R01DA030796/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: We analyzed the association between substance use (SU) and condomless sex (CS) among HIV-negative adults reporting heterosexual sex in the Seek, Test, Treat, and Retain (STTR) consortium. We describe the impact of SU as well as person/partner and context-related factors on CS, identifying combinations of factors that indicate the highest likelihood of CS.<br><br>METHODS: We analyzed data from four US-based STTR studies to examine the effect of SU on CS using two SU exposures: 1) recent SU (within 3 months) and 2) SU before/during sex. Behavioral data were collected via 1:1 or self-administered computerized interviews. Adjusted individual-study, multivariable relative risk regression was used to examine the relationship between CS and SU. We also examined interactions with type of sex and partner HIV status. Pooled effect estimates were calculated using traditional fixed-effects meta-analysis. We analyzed data for recent SU (n = 6781; 82% men, median age = 33 years) and SU before/during sex (n = 2915; 69% men, median age = 40 years).<br><br>RESULTS: For both exposure classifications, any SU other than cannabis increased the likelihood of CS relative to non-SU (8-16%, p-values< 0.001). In the recent SU group, however, polysubstance use did not increase the likelihood of CS compared to single-substance use. Cannabis use did not increase the likelihood of CS, regardless of frequency of use. Type of sex was associated with CS; those reporting vaginal and anal sex had a higher likelihood of CS compared to vaginal sex only for both exposure classifications (18-21%, p < 0.001). Recent SU increased likelihood of CS among those reporting vaginal sex only (9-10%, p < 0.001); results were similar for those reporting vaginal and anal sex (5-8%, p < 0.01). SU before/during sex increased the likelihood of CS among those reporting vaginal sex only (20%; p < 0.001) and among those reporting vaginal and anal sex (7%; p = 0.002). Single- and poly-SU before/during sex increased the likelihood of CS for those with exclusively HIV-negative partners (7-8%, p ≤ 0.02), and for those reporting HIV-negative and HIV-status unknown partners (9-13%, p ≤ 0.03).<br><br>CONCLUSION: Except for cannabis, any SU increased the likelihood of CS. CS was associated with having perceived HIV-negative partners and with having had both anal/vaginal sex.}, }
@article {pmid34736042, year = {2021}, author = {Marthick, JR and Raspin, K and Foley, GR and Blackburn, NB and Banks, A and Donovan, S and Malley, RC and Field, MA and Stanford, JL and Ostrander, EA and FitzGerald, LM and Dickinson, JL}, title = {Massively parallel sequencing in hereditary prostate cancer families reveals a rare risk variant in the DNA repair gene, RAD51C.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {159}, number = {}, pages = {52-55}, doi = {10.1016/j.ejca.2021.09.038}, pmid = {34736042}, issn = {1879-0852}, }
@article {pmid34734806, year = {2021}, author = {Swygert, SG and Lin, D and Portillo-Ledesma, S and Lin, PY and Hunt, DR and Kao, CF and Schlick, T and Noble, WS and Tsukiyama, T}, title = {Local chromatin fiber folding represses transcription and loop extrusion in quiescent cells.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.72062}, pmid = {34734806}, issn = {2050-084X}, support = {T32CA009657/CA/NCI NIH HHS/United States ; R35GM139429/GM/NIGMS NIH HHS/United States ; F32GM120962/GM/NIGMS NIH HHS/United States ; K99GM134150/GM/NIGMS NIH HHS/United States ; AS-CFII-108-119//Academia Sinica/ ; R01GM055264/GM/NIGMS NIH HHS/United States ; R35GM122562/GM/NIGMS NIH HHS/United States ; 2030277//National Science Foundation/ ; U54DK107979/DK/NIDDK NIH HHS/United States ; R01GM111428/GM/NIGMS NIH HHS/United States ; }, abstract = {A longstanding hypothesis is that chromatin fiber folding mediated by interactions between nearby nucleosomes represses transcription. However, it has been difficult to determine the relationship between local chromatin fiber compaction and transcription in cells. Further, global changes in fiber diameters have not been observed, even between interphase and mitotic chromosomes. We show that an increase in the range of local inter-nucleosomal contacts in quiescent yeast drives the compaction of chromatin fibers genome-wide. Unlike actively dividing cells, inter-nucleosomal interactions in quiescent cells require a basic patch in the histone H4 tail. This quiescence-specific fiber folding globally represses transcription and inhibits chromatin loop extrusion by condensin. These results reveal that global changes in chromatin fiber compaction can occur during cell state transitions, and establish physiological roles for local chromatin fiber folding in regulating transcription and chromatin domain formation.}, }
@article {pmid34734193, year = {2021}, author = {Sun, D and Richard, M and Musani, SK and Sung, YJ and Winkler, TW and Schwander, K and Chai, JF and Guo, X and Kilpeläinen, TO and Vojinovic, D and Aschard, H and Bartz, TM and Bielak, LF and Brown, MR and Chitrala, K and Hartwig, FP and Horimoto, ARVR and Liu, Y and Manning, AK and Noordam, R and Smith, AV and Harris, SE and Kühnel, B and Lyytikäinen, LP and Nolte, IM and Rauramaa, R and van der Most, PJ and Wang, R and Ware, EB and Weiss, S and Wen, W and Yanek, LR and Arking, DE and Arnett, DK and Barac, A and Boerwinkle, E and Broeckel, U and Chakravarti, A and Chen, YI and Cupples, LA and Davigulus, ML and de Las Fuentes, L and de Mutsert, R and de Vries, PS and Delaney, JAC and Roux, AVD and Dörr, M and Faul, JD and Fretts, AM and Gallo, LC and Grabe, HJ and Gu, CC and Harris, TB and Hartman, CCA and Heikkinen, S and Ikram, MA and Isasi, C and Johnson, WC and Jonas, JB and Kaplan, RC and Komulainen, P and Krieger, JE and Levy, D and ,  and Liu, J and Lohman, K and Luik, AI and Martin, LW and Meitinger, T and Milaneschi, Y and O'Connell, JR and Palmas, WR and Peters, A and Peyser, PA and Pulkki-Råback, L and Raffel, LJ and Reiner, AP and Rice, K and Robinson, JG and Rosendaal, FR and Schmidt, CO and Schreiner, PJ and Schwettmann, L and Shikany, JM and Shu, XO and Sidney, S and Sims, M and Smith, JA and Sotoodehnia, N and Strauch, K and Tai, ES and Taylor, K and Uitterlinden, AG and van Duijn, CM and Waldenberger, M and Wee, HL and Wei, WB and Wilson, G and Xuan, D and Yao, J and Zeng, D and Zhao, W and Zhu, X and Zonderman, AB and Becker, DM and Deary, IJ and Gieger, C and Lakka, TA and Lehtimäki, T and North, KE and Oldehinkel, AJ and Penninx, BWJH and Snieder, H and Wang, YX and Weir, DR and Zheng, W and Evans, MK and Gauderman, WJ and Gudnason, V and Horta, BL and Liu, CT and Mook-Kanamori, DO and Morrison, AC and Pereira, AC and Psaty, BM and Amin, N and Fox, ER and Kooperberg, C and Sim, X and Bierut, L and Rotter, JI and Kardia, SLR and Franceschini, N and Rao, DC and Fornage, M}, title = {Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.}, journal = {HGG advances}, volume = {2}, number = {1}, pages = {}, doi = {10.1016/j.xhgg.2020.100013}, pmid = {34734193}, issn = {2666-2477}, abstract = {Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.}, }
@article {pmid34732684, year = {2021}, author = {Fong, Y and Markby, J and Andreotti, M and Beck, I and Bourlet, T and Brambilla, D and Frenkel, L and Lira, R and Nelson, JAE and Pollakis, G and Reigadas, S and Richman, D and Sawadogo, S and Waters, L and Yang, C and Zeh, C and Doherty, M and Vojnov, L}, title = {Diagnostic accuracy of dried plasma spot specimens for HIV-1 viral load testing: a systematic review and meta-analysis.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000002855}, pmid = {34732684}, issn = {1944-7884}, abstract = {BACKGROUND: Dried plasma spot specimens may be a viable alternative to traditional liquid plasma in field settings, but the diagnostic accuracy is not well understood.<br><br>METHODS: Standard databases (PubMed and Medline), conferences, and grey literature were searched until January 2019. The quality of evidence was evaluated using STARD and QUADAS-2 criteria. We used univariate and bivariate random effects models to determine misclassification, sensitivity, and specificity across multiple thresholds, overall and for each viral load technology and to account for between-study variation.<br><br>RESULTS: We identified 23 studies for inclusion in the systematic review that compared the diagnostic accuracy of dried plasma spots to plasma. Primary data from 16 of the 23 studies were shared and included in the meta-analysis, representing 18 countries, totaling 1,847 paired dried plasma spot:plasma data points. The mean bias of dried plasma spot specimens compared to plasma was 0.28 log10 copies/ml, while the difference in median viral load was 2.25 log10 copies/ml. More dried plasma spot values were undetectable compared to plasma values (43.6% vs. 29.8%). Analyzing all technologies together, the sensitivity and specificity of dried plasma spot specimens was >92% across all treatment failure thresholds compared and total misclassification <5.4% across all treatment failure thresholds compared. Some technologies had lower sensitivity or specificity; however, the results were typically consistent across treatment failure thresholds.<br><br>DISCUSSION: Overall, dried plasma spot specimens performed relatively well compared to plasma with sensitivity and specificity values greater than 90% and misclassification rates less than 10% across all treatment failure thresholds reviewed.}, }
@article {pmid34732526, year = {2021}, author = {Chen, GC and Arthur, R and Kamensky, V and Chai, JC and Yu, B and Shadyab, AH and Allison, M and Sun, Y and Saquib, N and Wild, RA and Bao, W and Dannenberg, AJ and Rohan, TE and Kaplan, RC and Wassertheil-Smoller, S and Qi, Q}, title = {Body Fat Distribution, Cardiometabolic Traits, and Risk of Major Lower-Extremity Arterial Disease in Postmenopausal Women.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc21-1565}, pmid = {34732526}, issn = {1935-5548}, abstract = {OBJECTIVE: To assess the relationship between body fat distribution and incident lower-extremity arterial disease (LEAD).<br><br>RESEARCH DESIGN AND METHODS: We included 155,925 postmenopausal women with anthropometric measures from the Women's Health Initiative who had no known LEAD at recruitment. A subset of 10,894 participants had body composition data quantified by DXA. Incident cases of symptomatic LEAD were ascertained and adjudicated through medical record review.<br><br>RESULTS: We identified 1,152 incident cases of LEAD during a median 18.8 years follow-up. After multivariable adjustment and mutual adjustment, waist and hip circumferences were positively and inversely associated with risk of LEAD, respectively (both P-trend < 0.0001). In a subset (n = 22,561) where various cardiometabolic biomarkers were quantified, a similar positive association of waist circumference with risk of LEAD was eliminated after adjustment for diabetes and HOMA of insulin resistance (P-trend = 0.89), whereas hip circumference remained inversely associated with the risk after adjustment for major cardiometabolic traits (P-trend = 0.0031). In the DXA subset, higher trunk fat (P-trend = 0.0081) and higher leg fat (P-trend < 0.0001) were associated with higher and lower risk of LEAD, respectively. Further adjustment for diabetes, dyslipidemia, and blood pressure diminished the association for trunk fat (P-trend = 0.49), yet the inverse association for leg fat persisted (P-trend = 0.0082).<br><br>CONCLUSIONS: Among U.S. postmenopausal women, a positive association of upper-body fat with risk of LEAD appeared to be attributable to traditional risk factors, especially insulin resistance. Lower-body fat was inversely associated with risk of LEAD beyond known risk factors.}, }
@article {pmid34730511, year = {2021}, author = {Shekhtman, L and Navasa, M and Sansone, N and Crespo, G and Subramanya, G and Chung, TL and Cardozo-Ojeda, EF and Pérez-Del-Pulgar, S and Perelson, AS and Cotler, SJ and Forns, X and Uprichard, SL and Dahari, H}, title = {Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.65297}, pmid = {34730511}, issn = {2050-084X}, support = {R01-AI078881//National Institute of Allergy and Infectious Diseases/ ; R01-AI116868//National Institute of Allergy and Infectious Diseases/ ; PI15/00151 and PI13/00155//Instituto de Salud Carlos III/ ; grant 2017_SGR_1753//Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement/ ; }, abstract = {While the liver, specifically hepatocytes, are widely accepted as the main source of hepatitis C virus (HCV) production, the role of the liver/hepatocytes in clearance of circulating HCV remains unknown. Frequent HCV kinetic data were recorded and mathematically modeled from 5 liver-transplant patients throughout the anhepatic (absence of liver) phase and for 4 hours post-reperfusion. During the anhepatic phase, HCV remained at pre-anhepatic levels (n=3) or declined (n=2) with t1/2~1h. Immediately post-reperfusion, virus declined in a biphasic manner in 4 patients consisting of a rapid decline (t1/2=5min) followed by a slower decline (t1/2=67min). Consistent with the majority of patients in the anhepatic phase, when we monitored HCV clearance at 37°C from culture medium in the absence/presence of chronically infected hepatoma cells that were inhibited from secreting HCV, the HCV t1/2 in cell culture was longer in the absence of chronically HCV-infected cells. The results suggest that the liver plays a major role in the clearance of circulating HCV and that hepatocytes may be involved.}, }
@article {pmid34730393, year = {2021}, author = {Mielke, D and Stanfield-Oakley, S and Borate, B and Fisher, LH and Faircloth, K and Tuyishime, M and Greene, K and Gao, H and Williamson, C and Morris, L and Ochsenbauer, C and Tomaras, G and Haynes, BF and Montefiori, D and Pollara, J and deCamp, AC and Ferrari, G}, title = {Selection of HIV Envelope strains for standardized assessments of vaccine-elicited antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {JVI0164321}, doi = {10.1128/JVI.01643-21}, pmid = {34730393}, issn = {1098-5514}, abstract = {Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with reduced risk of HIV-1 infection in several preclinical vaccine trials and the RV144 clinical trial, indicating this is a relevant antibody function to study. Given the diversity of HIV-1, the breadth of vaccine-induced antibody responses is a critical parameter to understand if a universal vaccine is to be realised. Moreover, breadth of ADCC responses can be influenced by different vaccine strategies and regimens, including adjuvants. Therefore, to accurately evaluate ADCC and to compare vaccine regimens, it is important to understand the range of HIV Envelope susceptibility to these responses. These evaluations have been limited because of the complexity of the assay and the lack of a comprehensive panel of viruses for the assessment of these humoral responses. Here, we used twenty-nine HIV-1 infectious molecular clones (IMCs) representing different Envelope subtypes and circulating recombinant forms to characterise susceptibility to ADCC from antibodies in plasma from infected individuals, including thirteen viraemic individuals, ten controllers and six with broadly neutralizing antibody responses. We found in our panel that ADCC susceptibility of the IMCs in our panel did not cluster by subtype, infectivity, level of CD4 downregulation, level of shedding, or neutralization sensitivity. Using partition-around-medoids (PAM) clustering to distinguish smaller groups of IMCs with similar ADCC susceptibility, we identified nested panels of four to eight IMCs that broadly represent the ADCC susceptibility of the entire 29 IMC panel. These panels, together with reagents developed to specifically accommodate circulating viruses at the geographical sites of vaccine trials, will provide a powerful tool to harmonise ADCC data generated across different studies, and detect common themes of ADCC responses elicited by various vaccines. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) responses were found to correlate with reduced risk of infection in the RV144 trial, the only human HIV-1 vaccine to show any efficacy to date. However, reagents to understand the breadth and magnitude of these responses across preclinical and clinical vaccine trials remain underdeveloped. In this study, we characterise HIV-1 infectious molecular clones encoding 29 distinct envelope strains (Env-IMCs) to understand factors which impact virus susceptibility to ADCC and use statistical methods to identify smaller nested panels of four to eight Env-IMCs which accurately represent the full set. These reagents can be used as standardized reagents across studies to fully understand how ADCC may affect efficacy of future vaccine studies, and how studies differed in the breadth of responses developed.}, }
@article {pmid34729250, year = {2021}, author = {Bouwman, LF and den Hamer, B and van den Heuvel, A and Franken, M and Jackson, M and Dwyer, CA and Tapscott, SJ and Rigo, F and van der Maarel, SM and de Greef, JC}, title = {Systemic delivery of a DUX4-targeting antisense oligonucleotide to treat facioscapulohumeral muscular dystrophy.}, journal = {Molecular therapy. Nucleic acids}, volume = {26}, number = {}, pages = {813-827}, doi = {10.1016/j.omtn.2021.09.010}, pmid = {34729250}, issn = {2162-2531}, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent skeletal muscle dystrophies. Skeletal muscle pathology in individuals with FSHD is caused by inappropriate expression of the transcription factor DUX4, which activates different myotoxic pathways. At the moment there is no molecular therapy that can delay or prevent skeletal muscle wasting in FSHD. In this study, a systemically delivered antisense oligonucleotide (ASO) targeting the DUX4 transcript was tested in vivo in ACTA1-MCM;FLExDUX4 mice that express DUX4 in skeletal muscles. We show that the DUX4 ASO was well tolerated and repressed the DUX4 transcript, DUX4 protein, and mouse DUX4 target gene expression in skeletal muscles. In addition, the DUX4 ASO alleviated the severity of skeletal muscle pathology and partially prevented the dysregulation of inflammatory and extracellular matrix genes. DUX4 ASO-treated ACTA1-MCM;FLExDUX4 mice performed better on a treadmill; however, the hanging grid and four-limb grip strength tests were not improved compared to control ASO-treated ACTA1-MCM;FLExDUX4 mice. This study shows that systemic delivery of ASOs targeting DUX4 is a promising therapeutic strategy for FSHD and strategies that further improve the ASO efficacy in skeletal muscle are warranted.}, }
@article {pmid34728467, year = {2021}, author = {Morais, S and Peleteiro, B and Araújo, N and Malekzadeh, R and Ye, W and Plymoth, A and Tsugane, S and Hidaka, A and Shigueaki Hamada, G and López-Carrillo, L and Zaridze, D and Maximovich, D and Aragonés, N and Castaño-Vinyals, G and Pakseresht, M and Hernández-Ramírez, RU and López-Cervantes, M and Leja, M and Gasenko, E and Pourfarzi, F and Zhang, ZF and Yu, GP and Derakhshan, MH and Pelucchi, C and Negri, E and La Vecchia, C and Lunet, N}, title = {Identifying the profile of Helicobacter pylori negative gastric cancers: a case only analysis within the Stomach cancer Pooling (StoP) Project.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0402}, pmid = {34728467}, issn = {1538-7755}, abstract = {BACKGROUND: The prevalence of Helicobacter pylori negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors.<br><br>METHODS: Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serological test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (ORs).<br><br>RESULTS: Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n=166/853) and decreased to 7.0% (n=55) when considering CagA status; estimates for all criteria were 21.8% (n=276/1325) and 6.6% (n=97), respectively. HpNGC had a family history of gastric cancer more often (OR=2.18, 95% confidence interval [CI]:1.03-4.61) and were current smokers (OR=2.16, 95%CI:0.52-9.02).<br><br>CONCLUSION: This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives.<br><br>IMPACT: Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.}, }
@article {pmid34727735, year = {2021}, author = {Hu, Y and Haessler, JW and Manansala, R and Wiggins, KL and Moscati, A and Beiser, A and Heard-Costa, NL and Sarnowski, C and Raffield, LM and Chung, J and Marini, S and Anderson, CD and Rosand, J and Xu, H and Sun, X and Kelly, TN and Wong, Q and Lange, LA and Rotter, JI and Correa, A and Vasan, RS and Seshadri, S and Rich, SS and Do, R and Loos, RJF and Longstreth, WT and Bis, JC and Psaty, BM and Tirschwell, DL and Assimes, TL and Silver, B and Liu, S and Jackson, R and Wassertheil-Smoller, S and Mitchell, BD and Fornage, M and Auer, PL and Reiner, AP and Kooperberg, C}, title = {Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project.}, journal = {Stroke}, volume = {}, number = {}, pages = {STROKEAHA120031792}, doi = {10.1161/STROKEAHA.120.031792}, pmid = {34727735}, issn = {1524-4628}, abstract = {BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).<br><br>METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.<br><br>RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1.<br><br>CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.}, }
@article {pmid34727513, year = {2021}, author = {Triplette, M and Wenger, DS and Shahrir, S and Kross, EK and Kava, C and Phipps, A and Hawes, SE and Cole, A and Snidarich, M and Crothers, K}, title = {Patient Identification of Lung Cancer Screening Follow-up Recommendations and the Association with Adherence.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1513/AnnalsATS.202107-887OC}, pmid = {34727513}, issn = {2325-6621}, abstract = {RATIONALE: Adherence to follow-up lung cancer screening (LCS) in real-world settings is suboptimal. Patient understanding of screening results and anticipated follow-up may be crucial to adherence.<br><br>OBJECTIVE: To determine patient-factors associated with identification of follow-up recommendations as a measure of patient understanding of screening results after LCS , and to determine whether misidentification of follow-up is associated with lower adherence to recommendations.<br><br>METHODS: We performed a prospective study of patients in the University of Washington/Seattle Cancer Care Alliance LCS registry who underwent an initial LCS exam between June 2017- September 2019. We mailed potential participants a survey following initial LCS exam, with additional data abstracted from the electronic health record and LCS registry. Participants were asked to identify the timing and next step for their follow-up, with answers corresponding to Lung-RADS recommendations. We examined associations between incorrect identification of recommended follow-up and patient-level characteristics, self-perceived benefit/harm of LCS, LCS knowledge, Lung-RADS score, and patient-reported method of LCS results communication (letter, telephone or in-person). We used multivariable logistic regression to evaluate associations with incorrect identification of recommendations and assessed incorrect identification of recommendations as a potential mechanism for poor adherence in a separate regression model.<br><br>RESULTS: One-hundred eighty-eight participants completed the survey (response rate 44%); 47% misidentified their follow-up recommendation. Those with lung-RADS scores ≥3 had higher odds of incorrectly identifying follow-up recommendations compared to those with scores <3, as did those with lower educational attainment. However, there was no significant association between incorrect identification of follow-up and ultimate adherence to follow-up.<br><br>CONCLUSION: Understanding of LCS follow-up appears to be poor, especially among those with lower education levels and positive findings. Among survey responders, incorrect identification of follow-up was not associated with poor adherence, suggesting other factors, such as provider interventions, may be driving adherence behavior. These results can inform efforts to target improved patient education regarding follow-up for LCS. Primary sources of funding. American Lung Association and American Thoracic Society.}, }
@article {pmid34725849, year = {2021}, author = {Naresh, KN and Lazzi, S and Santi, R and Granai, M and Onyango, N and Leoncini, L}, title = {A refined approach to the diagnosis of Burkitt lymphoma in a resource-poor setting.}, journal = {Histopathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/his.14594}, pmid = {34725849}, issn = {1365-2559}, abstract = {Burkitt lymphoma (BL) is among the most studied human malignancies. The distinction of BL from other aggressive B-cell lymphomas is important for providing optimal oncological care. In the revised 4th edition of the World Health Organization (WHO) classification, BL is defined as "a highly aggressive but curable lymphoma that often presents in extranodal sites or as an acute leukemia. It is composed of monomorphic medium-sized B-cells with basophilic cytoplasm and numerous mitotic figures, usually with a demonstrable MYC gene translocation to an IG locus. The frequency of EBV (Epstein Barr virus) infection varies according to the epidemiological subtype of BL. No single parameter, such as morphologic, genetic analysis or immunophenotyping can be used as the gold standard for diagnosis of BL; a combination of several diagnostic techniques is necessary."}, }
@article {pmid34725698, year = {2021}, author = {Arakaki, AKS and Szulzewsky, F and Gilbert, MR and Gujral, TS and Holland, EC}, title = {Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers.}, journal = {Neuro-oncology}, volume = {23}, number = {Supplement_5}, pages = {S4-S15}, doi = {10.1093/neuonc/noab183}, pmid = {34725698}, issn = {1523-5866}, support = {P30 CA008748/NH/NIH HHS/United States ; /CA/NCI NIH HHS/United States ; }, abstract = {Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.}, }
@article {pmid34720558, year = {2021}, author = {Gonzalez, S and Strizich, G and Isasi, CR and Hua, S and Comas, B and Sofer, T and Thyagarajan, B and Perreira, KM and Talavera, GA and Daviglus, ML and Nelson, SC and Giachello, AL and Schneiderman, N and Kaplan, RC}, title = {Consent for Use of Genetic Data among US Hispanics/Latinos: Results from the Hispanic Community Health Study/ Study of Latinos.}, journal = {Ethnicity &amp; disease}, volume = {31}, number = {4}, pages = {547-558}, doi = {10.18865/ed.31.4.547}, pmid = {34720558}, issn = {1945-0826}, abstract = {Inclusion of historically underrepresented populations in biomedical research is critical for large precision medicine research initiatives. Among 13,721 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) enrollees, we used multivariable-adjusted prevalence ratios to describe characteristics associated with participants' willingness to consent to different levels of biospecimen and genetic data analysis and sharing. At baseline (2008-2011), HCHS/SOL participants almost universally consented to the use of biospecimens and genetic data by study investigators and their collaborators (97.6%; 95%CI: 97.1, 98.0). Fewer consented to biospecimen and genetic data sharing with investigators not affiliated with the HCHS/SOL research team (81%, 95%CI: 80, 82) or any data sharing with commercial/for-profit entities (75%, 95%CI: 74, 76). Those refusing to share their data beyond the study investigators group were more often females, Spanish language-speakers and non-US born individuals. As expected, participants who were retained and reconsented at the six-year follow up visit tended to embrace broader data sharing, although this varied by group. Over time, Puerto Ricans and Dominicans were more likely to convert to broader data sharing than individuals of a Mexican background. Our analysis suggests that acculturation and immigration status of specific Hispanic/Latino communities may influence decisions about participation in genomic research projects and biobanks.}, }
@article {pmid34719869, year = {2021}, author = {van Dijk, AD and Hoff, FW and Qiu, Y and Gerbing, RB and Gamis, AS and Aplenc, R and Kolb, EA and Alonzo, TA and Meshinchi, S and Jenkins, G and de Bont, ESJM and Kornblau, SM and Horton, TM}, title = {Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA.}, journal = {Proteomics. Clinical applications}, volume = {}, number = {}, pages = {e2100072}, doi = {10.1002/prca.202100072}, pmid = {34719869}, issn = {1862-8354}, abstract = {The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin and etoposide,) did not improve overall outcome in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031). Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. RelA-total and phosphorylation at serine 536 (RelA-pSer536) levels were measured in 483 patient samples using reverse phase protein array technology. In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). RR in low-RelA-pSer536 patients significantly decreased in ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326 , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). Thus, bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326 . This article is protected by copyright. All rights reserved.}, }
@article {pmid34719389, year = {2021}, author = {Pronk, A and Nuckols, JR and De Roos, AJ and Airola, M and Colt, JS and Cerhan, JR and Morton, L and Cozen, W and Severson, R and Blair, A and Cleverly, D and Ward, MH}, title = {Correction to: Residential proximity to industrial combustion facilities and risk of non-Hodgkin lymphoma: a case-control study.}, journal = {Environmental health : a global access science source}, volume = {20}, number = {1}, pages = {113}, pmid = {34719389}, issn = {1476-069X}, }
@article {pmid34717591, year = {2021}, author = {Ko, LK and Jimenez, E and Cisneros, O and Brown, EVR and Ibarra, G and Bishop, S and Escareño, M and Serrano-Rubio, L and Rillamas-Sun, E and Mendoza, JA and Sutton, S}, title = {Participation and engagement of a rural community in Ciclovía: progressing from research intervention to community adoption.}, journal = {BMC public health}, volume = {21}, number = {1}, pages = {1964}, pmid = {34717591}, issn = {1471-2458}, support = {U01 MD010540/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Open streets events, where roads are temporarily closed to motorized vehicles, can provide safe spaces for physical activity (PA) and become sustainable community infrastructure. Since 2016, we have collaborated with a rural community to implement an open streets event, named ciclovía. In 2019, ciclovía was adopted as a community-wide program. This paper describes the process of building and progressing a ciclovía from a research intervention to a community-adopted program and participation of a rural community in ciclovía.<br><br>METHODS: We used community-based participatory research to foster bidirectional learning on how to optimize the content and implementation of ciclovía to be feasible and acceptable for rural communities. The community-academic partnership focused on: 1) understanding the science of ciclovía; 2) learning the implementation process; 3) creating tools to facilitate planning, implementation, and evaluation of ciclovía; and 4) developing transition steps from a research intervention to a community-adopted program.<br><br>RESULTS: The progression of the research intervention to community adoption spanned 2 years. First, the partnership met quarterly to discuss the science of ciclovía, its utility, and its adaptation for rural communities. Second, the partnership studied processes that facilitated ciclovía implementation. Third, the partnership created the ciclovía planning guide and tools for communities to establish their own ciclovía. The guide included forming a planning committee, setting meeting and communication plans, marketing and promotion, and selecting evaluation tools. Fourth, the transition steps from research intervention to community adoption included creating roles and responsibilities, implementing ciclovía using the planning guide, and convening listening sessions for improvement on implementation. Community attendance at ciclovía doubled from 189 individuals (126 children and 63 adults) when it was a research intervention to 394 individuals (277 children and 117 adults) when it was a community program.<br><br>CONCLUSIONS: The progression from a research intervention to a community-adopted program encompasses multiple steps that involve bidirectional learning and partnership with the community. Lessons learned from this study are integrated into a disseminatable ciclovía planning guide.}, }
@article {pmid34716407, year = {2021}, author = {Hallinan, JP and Doyle, LA and Shen, BW and Gewe, MM and Takushi, B and Kennedy, MA and Friend, D and Roberts, JM and Bradley, P and Stoddard, BL}, title = {Design of functionalised circular tandem repeat proteins with longer repeat topologies and enhanced subunit contact surfaces.}, journal = {Communications biology}, volume = {4}, number = {1}, pages = {1240}, pmid = {34716407}, issn = {2399-3642}, support = {R01 GM139752/GM/NIGMS NIH HHS/United States ; R01 GM123378/GM/NIGMS NIH HHS/United States ; }, abstract = {Circular tandem repeat proteins ('cTRPs') are de novo designed protein scaffolds (in this and prior studies, based on antiparallel two-helix bundles) that contain repeated protein sequences and structural motifs and form closed circular structures. They can display significant stability and solubility, a wide range of sizes, and are useful as protein display particles for biotechnology applications. However, cTRPs also demonstrate inefficient self-assembly from smaller subunits. In this study, we describe a new generation of cTRPs, with longer repeats and increased interaction surfaces, which enhanced the self-assembly of two significantly different sizes of homotrimeric constructs. Finally, we demonstrated functionalization of these constructs with (1) a hexameric array of peptide-binding SH2 domains, and (2) a trimeric array of anti-SARS CoV-2 VHH domains. The latter proved capable of sub-nanomolar binding affinities towards the viral receptor binding domain and potent viral neutralization function.}, }
@article {pmid34716198, year = {2021}, author = {Adams, S and Othus, M and Patel, SP and Miller, KD and Chugh, R and Schuetze, SM and Chamberlin, MD and Haley, BJ and Storniolo, AMV and Reddy, MP and Anderson, SA and Zimmerman, CT and O'Dea, AP and Mirshahidi, HR and Rodon Ahnert, J and Brescia, FJ and Hahn, O and Raymond, JM and Biggs, DD and Connolly, RM and Sharon, E and Korde, LA and Gray, RJ and Mayerson, E and Plets, M and Blanke, CD and Chae, YK and Kurzrock, R}, title = {A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609).}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-21-2182}, pmid = {34716198}, issn = {1557-3265}, abstract = {PURPOSE: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately eight months for metastatic disease. We report results for advanced MpBC treated with ipilimumab+nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013).<br><br>METHODS: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1mg/kg IV q6weeks) plus nivolumab (240mg IV q2weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity.<br><br>RESULTS: Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines, 2 (0-5). ORR was 18%; 3/17 patients achieved objective responses (1 complete, 2 partial responses) (2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+ and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AEs), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE); with adrenal insufficiency observed in all three responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1 and absent TILs.<br><br>CONCLUSION: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.}, }
@article {pmid34715067, year = {2021}, author = {Innis, EA and Levinger, C and Szaniawski, MA and Williams, ESCP and Alcamí, J and Bosque, A and Schiffer, JT and Coiras, M and Spivak, AM and Planelles, V}, title = {Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.}, journal = {Biochemical pharmacology}, volume = {}, number = {}, pages = {114816}, doi = {10.1016/j.bcp.2021.114816}, pmid = {34715067}, issn = {1873-2968}, abstract = {The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4+ T cells represents a major barrier to viral eradication. Proliferation of memory CD4+ T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4+ T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4+ T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby 65%, with a reduction in viability less than 45%, ex vivo. In memory CD4+ T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent, dasatinib, is an exciting candidate to be used as an anti-proliferative drug in a clinical trial since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).}, }
@article {pmid34714820, year = {2021}, author = {Barry, H and Mutua, G and Kibuuka, H and Anywaine, Z and Sirima, SB and Meda, N and Anzala, O and Eholie, S and Bétard, C and Richert, L and Lacabaratz, C and McElrath, MJ and De Rosa, S and Cohen, KW and Shukarev, G and Robinson, C and Gaddah, A and Heerwegh, D and Bockstal, V and Luhn, K and Leyssen, M and Douoguih, M and Thiébaut, R and , }, title = {Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa.}, journal = {PLoS medicine}, volume = {18}, number = {10}, pages = {e1003813}, doi = {10.1371/journal.pmed.1003813}, pmid = {34714820}, issn = {1549-1676}, abstract = {BACKGROUND: We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations.<br><br>METHODS AND FINDINGS: In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d'Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant's last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants.<br><br>CONCLUSIONS: Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT02564523.}, }
@article {pmid34714688, year = {2021}, author = {Price, RM and Self, CJ and Young, WC and Klein, ER and Al-Noori, S and Ma, EY and DeMarais, A}, title = {Brief Training and Intensive Mentoring Guide Postdoctoral Scholars to Student-Centered Instruction.}, journal = {CBE life sciences education}, volume = {20}, number = {4}, pages = {ar64}, doi = {10.1187/cbe.21-03-0083}, pmid = {34714688}, issn = {1931-7913}, abstract = {The Science Teaching Experience Program-Working in Science Education (STEP-WISE) provides teaching experience for postdoctoral scholars holding full-time research appointments. Through a combination of mentorship, deliberate practice, and feedback, the postdocs learn and apply inclusive, evidence-based pedagogies. STEP-WISE is integrated into postdocs' demanding schedules and is sustainable for institutions to run. Here, we assess the effectiveness of STEP-WISE. We used the Classroom Observation Protocol for Undergraduate STEM instruction to quantify instructor and student behaviors in 20 STEP-WISE class sessions from seven courses designed and taught by postdocs in the program. We found that all of the postdocs used student-centered teaching strategies. Also, using a design-based research framework, we studied the program to identify the salient components of its design. Four interconnected key elements contribute to the program's success: 1) two training sessions, 2) a precourse meeting with the mentor, 3) implementation of active-learning strategies with support, and 4) debriefing with the mentor after each class session. STEP-WISE is a replicable model to support postdocs seeking training and experience in evidence-based teaching practices geared to improving undergraduate education and transforming pedagogical practice. We conclude that high-impact teaching can be learned early in a career with streamlined training and intensive mentoring.}, }
@article {pmid34713080, year = {2021}, author = {Dietrich, JJ and Benadé, GL and Mulaudzi, M and Kagee, A and Hornschuh, S and Makhale, LM and Lemos, MP and Lazarus, E and Andrasik, MP and Horvath, KJ}, title = {"You Are on the Right Track With the App:" Qualitative Analysis of Mobile Phone Use and User Feedback Regarding Mobile Phone Sexual Risk Assessments for HIV Prevention Research.}, journal = {Frontiers in digital health}, volume = {3}, number = {}, pages = {576514}, doi = {10.3389/fdgth.2021.576514}, pmid = {34713080}, issn = {2673-253X}, abstract = {Background: Accurate self-report of sexual behavior assists in identifying potential HIV exposure in HIV prevention trials. Brief mobile phone assessments, completed daily or after sexual activity, can improve the validity and reliability of self-reported sexual behavior and allow for remote survey completion outside of the clinic setting. We conducted a qualitative study to better understand participants mobile phone use and to explore their perspectives on how to improve an existing mobile application-based sexual risk assessment. Methods: Sexually active, HIV seronegative men (n = 14) and women (n = 15) aged 18-39 years were recruited through an HIV counseling and testing clinic and community outreach in Soweto, South Africa. We conducted qualitative research through four age-stratified focus group discussions (FGDs) and analyzed a brief socio-demographics and mobile phone access questionnaire. All participants completed a sexual risk assessment before the FGD. Using a framework analytic approach, data were coded with Nvivo software. Results: All participants had access to mobile phones and internet, and 27 (93.1%) were able to download applications on their personal phones. Participants preferred mobile risk assessments to be offered in a choice of South African languages, using formal language (as opposed to emojis), with straight-forward wording and limited to five to 10 questions. Most participants found it acceptable to complete the assessment once a week, on a weekday, while a few were willing to complete it after each sexual encounter. It was suggested that a message reminder to complete the assessment should be sent at least daily until it is completed. The majority agreed that a password-protected application with a discreet logo was ideal for privacy, ease of use and flexibility for completion in any setting. A concern with this format, however, was the potential data use requirement. Participants expressed privacy concerns with using SMS, WhatsApp and other social media for risk assessments. Most agreed on an airtime incentive between ZAR5-10 (USD 0.29-0.58) per survey. Participants encouraged researchers to provide feedback to them about their sexual risk. Conclusions: Completion of mobile phone sexual risk assessments can be optimized with minimal incentives by ensuring that questionnaires are simple, brief, infrequent and have trusted privacy measures.}, }
@article {pmid34709943, year = {2021}, author = {Frederick, NN and Klosky, JL and Meacham, LR and Quinn, GP and Kelvin, JF and Cherven, B and Freyer, DR and Dvorak, CC and Brackett, J and Ahmed-Winston, S and Bryson, E and Chow, EJ and Levine, J}, title = {Infrastructure of Fertility Preservation Services for Pediatric Cancer Patients: A Report From the Children's Oncology Group.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2100275}, doi = {10.1200/OP.21.00275}, pmid = {34709943}, issn = {2688-1535}, abstract = {PURPOSE: Fertility preservation (FP) services are part of comprehensive care for those newly diagnosed with cancer. The capacity to offer these services to children and adolescents with cancer is unknown.<br><br>METHODS: A cross-sectional survey was sent to 220 Children's Oncology Group member institutions regarding institutional characteristics, structure and organization of FP services, and barriers to FP. Standard descriptive statistics were computed for all variables. The association between site-specific factors and selected outcomes was examined using multivariable logistic regression.<br><br>RESULTS: One hundred forty-four programs (65.5%) returned surveys. Fifty-three (36.8%) reported a designated FP individual or team. Sperm banking was offered at 135 (97.8%) institutions, and testicular tissue cryopreservation at 37 (27.0%). Oocyte and embryo cryopreservation were offered at 91 (67.9%) and 62 (46.6%) institutions, respectively; ovarian tissue cryopreservation was offered at 64 (47.8%) institutions. The presence of dedicated FP personnel was independently associated with the ability to offer oocyte or embryo cryopreservation (odds ratio [OR], 4.7; 95% CI, 1.7 to 13.5), ovarian tissue cryopreservation (OR, 2.7; 95% CI, 1.2 to 6.0), and testicular tissue cryopreservation (OR, 3.3; 95% CI, 1.4 to 97.8). Only 26 (18.1%) participating institutions offered all current nonexperimental FP interventions. Barriers included cost (70.9%), inadequate knowledge or training (60.7%), difficulty characterizing fertility risk (50.4%), inadequate staffing (45.5%), and logistics with reproductive specialties (38%-39%).<br><br>CONCLUSION: This study provides the most comprehensive view of the current landscape of FP infrastructure for children and adolescents with cancer and demonstrates that existing infrastructure is inadequate to offer comprehensive services to patients. We discuss modifiable factors to improve patient access to FP.}, }
@article {pmid34709529, year = {2021}, author = {Marín-Chollom, AM and Hale, C and Koch, P and Gaffney, AO and Contento, I and Shen, H and Hershman, DL and Brickman, AM and Greenlee, H}, title = {Cognitive Functioning and Health in Hispanic/Latina Breast Cancer Survivors.}, journal = {Journal of immigrant and minority health}, volume = {}, number = {}, pages = {}, pmid = {34709529}, issn = {1557-1920}, support = {R01 CA186080-01A1//foundation for the national institutes of health/ ; UL1TR00040/TR/NCATS NIH HHS/United States ; }, abstract = {We examined the effect of waist-to-hip ratio, body mass index (BMI), diet, and physical activity on cognitive functioning among Hispanic/Latina breast cancer survivors in a cross-sectional design study. Participants were 54 Hispanic/Latina breast cancer survivors and completed the NIH Toolbox Cognition Battery. Linear Regression Models tested if statistically significant correlations held with covariates. After controlling for covariates, moderate and hard physical activity were not associated with cognition. However, very hard physical activity was positively associated with faster processing speed (β = 0.56, p < 0.001) and composite cognition score (β = 0.36, p < 0.05). Total time (minutes) of moderate to very hard physical activity was positively associated with cognitive flexibility (β = 0.52, p < 0.001). Total caloric intake was positively associated with episodic memory (β = 0.35 p < 0.05). BMI and WHR were not associated with cognition. These findings showed positive association with engagement in more MVPA and harder intensity physical activity to better cognitive functioning among Hispanic/Latina breast cancer survivors.ClinicalTrials.gov NCT02780271.}, }
@article {pmid34709102, year = {2021}, author = {Nath, SS and Yadav, NU and Derkach, A and Perez-Johnston, R and Tachiki, L and Maguire, K and Babar, A and Maloy, MA and Klotz, A and Jee, J and Taur, Y and Chawla, S and Babady, E and Khaki, AR and Madeleine, MM and Grivas, P and Henning, DJ and Aaltonen, L and Lyman, GH and Groeger, J}, title = {Outcomes of Patients with COVID-19 from a Specialized Cancer Care Emergency Room.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07357907.2021.1985134}, pmid = {34709102}, issn = {1532-4192}, abstract = {PURPOSE: Our goal was to identify discrete clinical characteristics associated with safe discharge from an emergency department/urgent care for patients with a history of cancer and concurrent COVID-19 infection during the SARS-CoV-2 pandemic and prior to widespread vaccination.<br><br>PATIENTS AND METHODS: We retrospectively analyzed 255 adult patients with a history of cancer who presented to Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center (UCC) from March 1, 2020 to May 31, 2020 with concurrent COVID-19 infection. We evaluated associations between patient characteristics and 30-day mortality from initial emergency department (ED) or urgent care center (UCC) visit and the absence of a severe event within 30 days. External validation was performed on a retrospective data from 29 patients followed at Fred Hutchinson Cancer Research Center that presented to the local emergency department. A late cohort of 108 additional patients at MSKCC from June 1, 2020 to January 31, 2021 was utilized for further validation.<br><br>RESULTS: In the MSKCC cohort, 30-day mortality and severe event rate was 15% and 32% respectively. Using stepwise regression analysis, elevated BUN and glucose, anemia, and tachypnea were selected as the main predictors of 30-day mortality. Conversely, normal albumin, BUN, calcium, and glucose, neutrophil-lymphocyte ratio <3, lack of (severe) hypoxia, lack of bradycardia or tachypnea, and negative imaging were selected as the main predictors of an uneventful course as defined as a Lack Of a Severe Event within Thirty Days (LOSETD). Utilizing this information, we devised a tool to predict 30-day mortality and LOSETD which achieved an area under the operating curve (AUC) of 79% and 74% respectively. Similar estimates of AUC were obtained in an external validation cohort. A late cohort at MSKCC was consistent with the prior, albeit with a lower AUC.<br><br>CONCLUSION: We identified easily obtainable variables that predict 30-day mortality and the absence of a severe event for patients with a history of cancer and concurrent COVID-19. This has been translated into a bedside tool that the clinician may utilize to assist disposition of this group of patients from the emergency department or urgent care setting.}, }
@article {pmid34707608, year = {2021}, author = {Hou, J and Wang, S and Li, D and Carpp, LN and Zhang, T and Liu, Y and Jia, M and Peng, H and Liu, C and Wu, H and Huang, Y and Shao, Y}, title = {Early Pro-Inflammatory Signal and T-Cell Activation Associate With Vaccine-Induced Anti-Vaccinia Protective Neutralizing Antibodies.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {737487}, doi = {10.3389/fimmu.2021.737487}, pmid = {34707608}, issn = {1664-3224}, abstract = {Both vaccine "take" and neutralizing antibody (nAb) titer are historical correlates for vaccine-induced protection from smallpox. We analyzed a subset of samples from a phase 2a trial of three DNA/HIV-1 primes and a recombinant Tiantan vaccinia virus-vectored (rTV)/HIV-1 booster and found that a proportion of participants showed no anti-vaccinia nAb response to the rTV/HIV-1 booster, despite successful vaccine "take." Using a rich transcriptomic and vaccinia-specific immunological dataset with fine kinetic sampling, we investigated the molecular mechanisms underlying nAb response. Blood transcription module analysis revealed the downregulation of the activator protein 1 (AP-1) pathway in responders, but not in non-responders, and the upregulation of T-cell activation in responders. Furthermore, transcriptional factor network reconstruction revealed the upregulation of AP-1 core genes at hour 4 and day 1 post-rTV/HIV-1 vaccination, followed by a downregulation from day 3 until day 28 in responders. In contrast, AP-1 core and pro-inflammatory genes were upregulated on day 7 in non-responders. We speculate that persistent pro-inflammatory signaling early post-rTV/HIV-1 vaccination inhibits the nAb response.}, }
@article {pmid34706189, year = {2021}, author = {Gupta, A and Gonzalez-Rojas, Y and Juarez, E and Crespo Casal, M and Moya, J and Falci, DR and Sarkis, E and Solis, J and Zheng, H and Scott, N and Cathcart, AL and Hebner, CM and Sager, J and Mogalian, E and Tipple, C and Peppercorn, A and Alexander, E and Pang, PS and Free, A and Brinson, C and Aldinger, M and Shapiro, AE and , }, title = {Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2107934}, pmid = {34706189}, issn = {1533-4406}, abstract = {BACKGROUND: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease.<br><br>METHODS: In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization.<br><br>RESULTS: In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P = 0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively).<br><br>CONCLUSIONS: Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060.).}, }
@article {pmid34704738, year = {2021}, author = {Nagana Gowda, GA and Pascua, V and Raftery, D}, title = {Extending the Scope of 1H NMR-Based Blood Metabolomics for the Analysis of Labile Antioxidants: Reduced and Oxidized Glutathione.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.1c03763}, pmid = {34704738}, issn = {1520-6882}, abstract = {Glutathione is a ubiquitous cellular antioxidant, which is critically required to protect cells from oxidative damage and free radical injury. It is practically impossible to analyze glutathione in its native form after isolation from biological mixtures since the active form (reduced glutathione, GSH) spontaneously gets converted to the oxidized form (oxidized glutathione, GSSG). To address this challenge, numerous highly sensitive detection methods, including mass spectrometry, have been used in conjunction with derivatization to block the oxidation of GSH. Efforts so far to quantitate GSH and GSSG using the nuclear magnetic resonance (NMR) spectroscopy method have remained unsuccessful. With a focus on addressing this challenge, in this study, we describe an extension to our recent whole blood analysis method [ Anal. Chem. 2017, 89, 4620-4627] that includes the important antioxidants GSH and GSSG. Fresh and frozen human whole blood specimens as well as standard GSH and GSSG were comprehensively investigated using NMR without and with derivatization using N-ethylmaleimide (NEM). NMR experiments detect two diastereomers, distinctly, for the derivatized GSH and enable the analysis of both GSH and GSSG in human whole blood with an accuracy of >99%. Interestingly, the excess (unreacted) NEM used for blocking the GSH can be removed from the samples during a drying step after extraction, with no need for additional processing. This is an important characteristic that offers an added advantage for simultaneous analysis of the antioxidants (GSH and GSSG), redox coenzymes (oxidized nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide adenine dinucleotide (NADH), oxidized nicotinamide adenine dinucleotide phosphate (NADP+), reduced nicotinamide adenine dinucleotide phosphate (NADPH)), energy coenzymes (adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP)), and a large number of other blood metabolites using the same one-dimensional (1D) NMR spectrum. The presented method broadens the scope of global metabolite profiling and adds a new dimension to NMR-based blood metabolomics. Further, the method demonstrated here for human blood can be extended to virtually any biological specimen.}, }
@article {pmid34702753, year = {2021}, author = {Walti, CS and Loes, AN and Shuey, K and Krantz, EM and Boonyaratanakornkit, J and Keane-Candib, J and Loeffelholz, T and Wolf, CR and Taylor, JJ and Gardner, RA and Green, DJ and Cowan, AJ and Maloney, DG and Turtle, CJ and Pergam, SA and Chu, HY and Bloom, JD and Hill, JA}, title = {Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study.}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {10}, pages = {}, doi = {10.1136/jitc-2021-003428}, pmid = {34702753}, issn = {2051-1426}, abstract = {Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.}, }
@article {pmid34702087, year = {2021}, author = {Bachman, VF and Montaño, MA and Ulrich, A and Villaran, M and Cabello, R and Gonzalez, P and Sanchez, H and Lama, JR and Duerr, A}, title = {Correlates of condomless anal intercourse with different types of sexual partners among men who have sex with men and transgender women in Lima, Peru.}, journal = {AIDS care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/09540121.2021.1994517}, pmid = {34702087}, issn = {1360-0451}, abstract = {CLINICAL TRIAL REGISTRATION: The Sabes study was registered in March 2013 with the National Institutes of Health at ClinicalTrials.gov (identifier: NCT01815580).}, }
@article {pmid34701482, year = {2021}, author = {Horowitz, DP and Duong, M and Gholami, S and Guthrie, K and Ben-Josef, E and El-Khoueiry, A and Blanke, C and Philip, P and Rocha, F and Ahmad, S and Kachnic, LA}, title = {The Effect of Radiation Modality on Outcomes of Patients Receiving Adjuvant Chemoradiotherapy for Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma: A Secondary Analysis of SWOG S0809.}, journal = {International journal of radiation oncology, biology, physics}, volume = {111}, number = {3S}, pages = {e45}, doi = {10.1016/j.ijrobp.2021.07.373}, pmid = {34701482}, issn = {1879-355X}, abstract = {PURPOSE/OBJECTIVE(S): The phase II intergroup S0809 trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in patients with resected EHCC or GBCA demonstrated promising efficacy and tolerability, with a median overall survival of 35 months. Both 3-dimensional radiotherapy (3D) and intensity-modulated radiotherapy (IMRT) were permitted on the trial. Patients received 45 Gy to regional lymph nodes, with a tumor bed boost to a total of 52.5-59.4 Gy in 25-33 fractions, with radiation technique and dose given at the investigator's discretion. Given the range of permitted radiation modalities and doses administered, we performed a post hoc analysis of the effect of radiation modality on outcomes of patients treated on SWOG S0809.<br><br>MATERIALS/METHODS: Eligibility criteria included diagnosis of EHCC or GBCA after radical surgery, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine and capecitabine followed by concurrent capecitabine and radiotherapy, 45 Gy to regional nodes, with a tumor bed boost to 52.5-59.4 Gy [3D: 54 or 59.4 Gy (optional for R1) in 1.8 Gy fractions; IMRT 52.5 Gy or 55 Gy (optional for R1) in 2.1-2.2 Gy fractions]. Baseline characteristics were evaluated using the Mann-Whitney U-test for age and chi-squared test for categorical variables. Disease-free survival (DFS), local recurrence-free survival and distant metastasis-free survival were evaluated using the Kaplan-Meier method. Rates of adverse events were evaluated using Fisher's two-sided exact test.<br><br>RESULTS: Of the 79 patients enrolled on the trial from 2008 to 2012, 69 patients (87%) received radiotherapy. The minority (20.2%) of patients were treated with 3D, while 79.8% were treated with IMRT. There were no differences in utilization of 3D vs. IMRT based on site of disease, margin status or lymph node status. The 2-year DFS was 60% for 3D and 52% for IMRT (P = 0.73). Only 7.1% of patients treated with 3D experienced local recurrence, while 18.2% of patients treated with IMRT experienced local recurrence (P = 0.41). Distant metastases developed in 21.4% of patients treated with 3D and 47.3% of patients treated with IMRT (P = 0.15). While no patients treated with 3D experienced grade 3+ gastrointestinal (GI) toxicity, 18.2% of patients treated with IMRT experienced grade 3+ GI toxicity (P = 0.19). Grade 3+ hematologic toxicity was seen in 60% of patients treated with IMRT and 71.4% of patients treated with 3D (P = 0.54). One grade 5 GI toxicity was seen in the IMRT cohort.<br><br>CONCLUSION: Both 3D and IMRT are effective modalities for chemoradiotherapy in the adjuvant treatment of EHCC and GBCA, with similar rates of DFS, local control, and toxicity. Given potential for GI toxicity, future trials should include prospective contour and plan review.}, }
@article {pmid34701125, year = {2021}, author = {Eastman, B and Hippe, DS and Smith, SC and Till, BG and Lynch, R and Ujjani, C and Shadman, M and Warren, EH and Menon, M and Poh, C and Gopal, AK and Tseng, YD}, title = {Pilot Prognostic Model for Survival in r/r DLBCL Patients Receiving Palliative Radiation Therapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {111}, number = {3S}, pages = {e299-e300}, doi = {10.1016/j.ijrobp.2021.07.943}, pmid = {34701125}, issn = {1879-355X}, abstract = {PURPOSE/OBJECTIVE(S): Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) often require palliative radiotherapy (pRT) for symptomatic relief, bridging therapy, or salvage treatment (i.e., irradiation of only site of disease). Prognostication remains a challenge, especially with the advent of novel therapies such as chimeric antigen receptor (CAR)-T cells. We aimed to construct a predictive model for survival in r/r DLBCL treated with pRT.<br><br>MATERIALS/METHODS: Patients with r/r DLBCL who received their first course of pRT between 2009 and 2020 were included. OS was defined as time from pRT consult to death. A multivariable prognostic model was developed using Cox proportional hazard regression with LASSO (Least Absolute Shrinkage and Selection Operator)-regularization, which optimizes variable inclusion based on the model's overall prediction accuracy. Model discrimination performance was summarized using the concordance index after optimism-adjustment with the bootstrap (internal validation).<br><br>RESULTS: 82 patients met the inclusion criteria. Mean age at pRT was 62 years, with the majority of patients being male (59%) and Caucasian (80%). Most patients had an ECOG 0-1 (78%), despite being heavily pretreated (50% ≥3 systemic therapies, 22% transplant, 20% CAR-T cell therapy). pRT was most commonly delivered for symptoms (54%), followed by salvage (34%) and bridging (12%) to another systemic therapy. With a median follow-up of 6.3 months (range, 0.1- 91.2), 57 deaths (70%) were observed with median survival (MS) of 7.8 months. Treatment intent was associated with differences in MS: 4.1 mo (symptomatic), 10.4 mo (bridging), and 11.9 mo (salvage; P = 0.026). The LASSO method selected 5 co-variates for the multivariable OS model (Table 1), which was associated with an optimism-adjusted concordance index of 0.70 (95% CI, 0.61-0.80). Conversely, age, tachycardia, double/triple hit lymphoma, prior transplant or CAR-T cell therapy, and time from diagnosis were not selected by the LASSO for the model.<br><br>CONCLUSION: Our pilot prognostic model for survival of patients with r/r DLBCL treated with pRT has good predictive performance (concordance index 0.7), with performance status, treatment intent, and number of prior lines of therapy having the most impact on predictions. Interestingly, types of prior therapies (e.g., CAR-T cell) and pathologic features at diagnosis were not selected for the model. Future work will focus on validating these findings in other cohorts, where larger numbers may permit development and validation of a stronger prognostic model.}, }
@article {pmid34700645, year = {2021}, author = {Bates, JE and Shrestha, S and Liu, Q and Smith, S and Mulrooney, DA and Leisenring, WM and Gibson, T and Robison, LL and Chow, EJ and Oeffinger, KC and Armstromg, GT and Constine, LS and Hoppe, BS and Lee, C and Yasui, Y and Howell, RM}, title = {Impact of Cardiac Substructure Dosimetry on Late Cardiac Risk: A Report From the Childhood Cancer Survivor Study (CCSS).}, journal = {International journal of radiation oncology, biology, physics}, volume = {111}, number = {3S}, pages = {S83-S84}, doi = {10.1016/j.ijrobp.2021.07.200}, pmid = {34700645}, issn = {1879-355X}, abstract = {PURPOSE/OBJECTIVE(S): Prior estimates of radiation (RT)-associated cardiac disease risk in childhood cancer survivors are based on estimates of RT dose to the entire heart. We aimed to evaluate whether cardiac substructure RT dosimetry improves estimation of late cardiac disease risk.<br><br>MATERIALS/METHODS: We determined the cumulative incidence of CTCAE grade 3 - 5 cardiac disease (heart failure, coronary artery disease, valvular disease, arrhythmia, or pericardial disease) among 25,481 5-year survivors from CCSS diagnosed 1970 - 1999. Median age at diagnosis was 6.1 years (range 0 - 20) and at last follow-up was 29.8 years (5.6 - 65.9). We considered a single composite endpoint of any cardiac disease to best identify which substructures to prioritize for avoidance in RT planning to minimize the absolute risk of cardiac disease. We reconstructed RT fields for irradiated survivors (n = 12,228) on an age-scaled phantom and estimated mean RT dose to the heart, four chambers, four valves, and the left anterior descending (LAD), circumflex, main (LM), and right coronary arteries. Adjusted piecewise exponential models (including cumulative anthracycline dose) evaluated associations between mean RT dose to each structure and outcomes. Each substructure was individually added to a model with mean whole heart RT dose and the fit was assessed via the likelihood-ratio test to ascertain which substructures improved prediction of cardiac risk beyond whole heart dose.<br><br>RESULTS: At 35 years from diagnosis, the cumulative incidence of any cardiac disease was 7.0% (95% CI 6.5 - 7.6). When adding each substructure separately to a model with mean whole heart dose, the addition of mean LAD (χ2 = 29.1) or LM (χ2 = 34.6) RT dose significantly improved the risk estimation of any cardiac disease (P < 0.01). Among survivors with mean whole heart doses < 10 Gy, increasing mean LAD but not mean LM doses significantly increased risk of late cardiac disease. Even among those with a mean heart dose of < 5 Gy, mean LAD dose of ≥10 Gy was associated with a more than three-fold increased risk of cardiac disease (Table 1).<br><br>CONCLUSION: Even among survivors with low mean heart doses (< 5 Gy), mean LAD doses ≥10 Gy increased risk of cardiac disease. Thus, for pediatric RT planning we recommend limiting mean LAD dose to < 10 Gy, even when mean heart dose constraints can be achieved. Table 1. Relative rate of grade 3 - 5 cardiac disease in childhood cancer survivors by RT dose to the heart and LAD.}, }
@article {pmid34699779, year = {2021}, author = {Cannon, PM and Kiem, HP}, title = {The genome-editing decade.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2021.10.016}, pmid = {34699779}, issn = {1525-0024}, }
@article {pmid34699464, year = {2021}, author = {Roelofs, EJ and Dengel, DR and Wang, Q and Hodges, JS and Steinberger, J and Baker, KS}, title = {The Role of Follicle-Stimulating Hormone in Vascular Dysfunction Observed in Hematopoietic Cell Transplant Recipients.}, journal = {Journal of pediatric hematology/oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPH.0000000000002355}, pmid = {34699464}, issn = {1536-3678}, abstract = {Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all aged between 9 and 18 years. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P<0.01). Carotid compliance and distensibility were significantly lower in HCT and non-HCT recipients compared with healthy controls (P<0.05). Higher FSH was associated with decreased carotid compliance (P<0.05). This study's results suggest that higher levels of FSH in HCT recipients may result in significant reductions in vascular function compared with non-HCT recipients and healthy controls. Therefore, gonadotropin endocrine dysfunction, particularly abnormal FSH levels, may be an underlying mechanism of vascular dysfunction.}, }
@article {pmid34699294, year = {2021}, author = {Javadinia, SA and Ariamanesh, M and Nabavifard, M and Porouhan, P and PeyroShabany, B and Fazilat-Panah, D and Hatami, F and Ghasemi, A and Lyman, GH and Welsh, JS and Ashkar Tizabi, S and Dehghani, M}, title = {Multicenter Study of Antibody Seroprevalence against COVID-19 in Patients Presenting to Iranian Cancer Centers after one year of the COVID-19 Pandemic.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-25}, doi = {10.1080/07357907.2021.1995742}, pmid = {34699294}, issn = {1532-4192}, abstract = {Patients with cancer are at significantly greater risk of COVID-19 and its complications than the general population. Since IgG antibodies remain detectable well after infection with the SARS-CoV-2 virus, seroprevalence can be used to estimate the proportion of the cancer population previously infected and potentially immune to SARS-CoV-2. The current study is a multi-center, prospective observational study to assess seroprevalence of SARS-CoV-2 IgG antibody in a cancer population referred for vaccination between April and June 2021. Of a total of 270 adult patients with cancer accrued, 16% reported a history of COVID-19 more than four weeks previously confirmed by PCR. At the same time, serologic positivity for SARSCoV2 IgG was found in 29% of patients prior to vaccination including nearly 20% of patients without a history of confirmed COVID-19. Seropositivity was significantly greater in females consistent with higher rates in patients with breast cancer and gynecologic cancers. A seroconversion rate of 79.5% was observed in cancer patients with a history of PCR confirmed COVID-19, less than observed in the general population. In multivariable analysis, gender and prior history of COVID-19 were both independently associated with seropositivity prior to vaccination. Follow-up is continuing of this cohort of patients with cancer following vaccination to assess antibody and clinical outcomes.}, }
@article {pmid34697631, year = {2021}, author = {Lehrbach, NJ}, title = {NGLY1: Insights from C. elegans.}, journal = {Journal of biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1093/jb/mvab112}, pmid = {34697631}, issn = {1756-2651}, abstract = {Peptide:N-glycanase is an evolutionarily conserved deglycosylating enzyme that catalyzes the removal of N-linked glycans from cytosolic glycoproteins. Recessive mutations that inactivate this enzyme cause NGLY1 deficiency, a multisystemic disorder with symptoms including developmental delay and defects in cognition and motor control. Developing treatments for NGLY1 deficiency will require an understanding of how failure to deglycosylate NGLY1 substrates perturbs cellular and organismal function. In this review, I highlight insights into peptide:N-glycanase biology gained by studies in the highly tractable genetic model animal C. elegans. I focus on the recent discovery of SKN-1A/Nrf1, an N-glycosylated transcription factor, as a peptide:N-glycanase substrate critical for regulation of the proteasome. I describe the elaborate post-translational mechanism that culminates in activation of SKN-1A/Nrf1 via NGLY1-dependent 'sequence editing' and discuss the implications of these findings for our understanding of NGLY1 deficiency.}, }
@article {pmid34697055, year = {2021}, author = {Dixon, SB and Chen, Y and Yasui, Y and Pui, CH and Hunger, SP and Silverman, LB and Ness, KK and Green, DM and Howell, RM and Leisenring, WM and Kadan-Lottick, NS and Krull, KR and Oeffinger, KC and Neglia, JP and Hudson, MM and Robison, LL and Mertens, AC and Armstrong, GT and Nathan, PC}, title = {Impact of risk-stratified therapy on health status in survivors of childhood Acute Lymphoblastic Leukemia: a report from the Childhood Cancer Survivor Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0667}, pmid = {34697055}, issn = {1538-7755}, abstract = {BACKGROUND: Prior studies have identified that survivors of childhood acute lymphoblastic leukemia (ALL) report poor health status. It is unknown how risk-stratified therapy impacts the health status of ALL survivors.<br><br>METHODS: We estimated and compared the prevalence of self-reported poor health status among adult (≧18 years) survivors of childhood ALL diagnosed at age <21 years from 1970-1999 and sibling controls, excluding proxy reports. Therapy combinations defined treatment groups representative of 1970s therapy (70s), standard- and high-risk 1980s and 1990s therapy (80sSR, 80sHR, 90sSR, 90sHR), and relapse/bone marrow transplant (R/BMT). Log-binomial models, adjusted for clinical and demographic factors, compared outcomes between groups using prevalence ratios (PR) with 95% confidence intervals (CI).<br><br>RESULTS: Among 5 119 survivors and 4 693 siblings, survivors were more likely to report poor health status in each domain including poor general health (13.5% vs. 7.4%; PR 1.92, 95% CI 1.69-2.19). Compared to 70s, 90sSR and 90sHR were less likely to report poor general health (PR, 95% CI; 90sSR: 0.75, 0.57-0.98; 90sHR: 0.58, 0.39-0.87), functional impairment (90sSR: 0.56, 0.42-0.76; 90sHR: 0.63, 0.42-0.95), and activity limitations (90sSR: 0.61, 0.45-0.83; 90sHR: 0.59, 0.38-0.91). An added adjustment for chronic conditions in multivariable models partially attenuated 90sSR risk estimates.<br><br>CONCLUSIONS: Risk-stratified ALL therapy has succeeded in reducing risk for poor general health, functional impairment and activity limitations among more recent survivors of standard- and high-risk therapy.<br><br>IMPACT: Future research into the relationship between risk-stratified therapy, health status and late health outcomes may provide new opportunities to further improve late morbidity among survivors.}, }
@article {pmid34696386, year = {2021}, author = {Owuor, DC and de Laurent, ZR and Kikwai, GK and Mayieka, LM and Ochieng, M and Müller, NF and Otieno, NA and Emukule, GO and Hunsperger, EA and Garten, R and Barnes, JR and Chaves, SS and Nokes, DJ and Agoti, CN}, title = {Characterizing the Countrywide Epidemic Spread of Influenza A(H1N1)pdm09 Virus in Kenya between 2009 and 2018.}, journal = {Viruses}, volume = {13}, number = {10}, pages = {}, doi = {10.3390/v13101956}, pmid = {34696386}, issn = {1999-4915}, support = {107769/Z/10/Z//Wellcome Trust/United Kingdom ; GH002133//Centers for Disease Control and Prevention/ ; 1029745//Wellcome Trust/United Kingdom ; }, abstract = {The spatiotemporal patterns of spread of influenza A(H1N1)pdm09 viruses on a countrywide scale are unclear in many tropical/subtropical regions mainly because spatiotemporally representative sequence data are lacking. We isolated, sequenced, and analyzed 383 A(H1N1)pdm09 viral genomes from hospitalized patients between 2009 and 2018 from seven locations across Kenya. Using these genomes and contemporaneously sampled global sequences, we characterized the spread of the virus in Kenya over several seasons using phylodynamic methods. The transmission dynamics of A(H1N1)pdm09 virus in Kenya were characterized by (i) multiple virus introductions into Kenya over the study period, although only a few of those introductions instigated local seasonal epidemics that then established local transmission clusters, (ii) persistence of transmission clusters over several epidemic seasons across the country, (iii) seasonal fluctuations in effective reproduction number (Re) associated with lower number of infections and seasonal fluctuations in relative genetic diversity after an initial rapid increase during the early pandemic phase, which broadly corresponded to epidemic peaks in the northern and southern hemispheres, (iv) high virus genetic diversity with greater frequency of seasonal fluctuations in 2009-2011 and 2018 and low virus genetic diversity with relatively weaker seasonal fluctuations in 2012-2017, and (v) virus spread across Kenya. Considerable influenza virus diversity circulated within Kenya, including persistent viral lineages that were unique to the country, which may have been capable of dissemination to other continents through a globally migrating virus population. Further knowledge of the viral lineages that circulate within understudied low-to-middle-income tropical and subtropical regions is required to understand the full diversity and global ecology of influenza viruses in humans and to inform vaccination strategies within these regions.}, }
@article {pmid34696352, year = {2021}, author = {Swan, DA and Goyal, A and Bracis, C and Moore, M and Krantz, E and Brown, E and Cardozo-Ojeda, F and Reeves, DB and Gao, F and Gilbert, PB and Corey, L and Cohen, MS and Janes, H and Dimitrov, D and Schiffer, JT}, title = {Mathematical Modeling of Vaccines That Prevent SARS-CoV-2 Transmission.}, journal = {Viruses}, volume = {13}, number = {10}, pages = {}, doi = {10.3390/v13101921}, pmid = {34696352}, issn = {1999-4915}, support = {R01 AI121129-05S1//National Institute of Allergy and Infectious Diseases/ ; Inform Public Health Decision Making Funding Opportunity//Council of State and Territorial Epidemiologists/ ; }, abstract = {SARS-CoV-2 vaccine clinical trials assess efficacy against disease (VEDIS), the ability to block symptomatic COVID-19. They only partially discriminate whether VEDIS is mediated by preventing infection completely, which is defined as detection of virus in the airways (VESUSC), or by preventing symptoms despite infection (VESYMP). Vaccine efficacy against transmissibility given infection (VEINF), the decrease in secondary transmissions from infected vaccine recipients, is also not measured. Using mathematical modeling of data from King County Washington, we demonstrate that if the Moderna (mRNA-1273QS) and Pfizer-BioNTech (BNT162b2) vaccines, which demonstrated VEDIS > 90% in clinical trials, mediate VEDIS by VESUSC, then a limited fourth epidemic wave of infections with the highly infectious B.1.1.7 variant would have been predicted in spring 2021 assuming rapid vaccine roll out. If high VEDIS is explained by VESYMP, then high VEINF would have also been necessary to limit the extent of this fourth wave. Vaccines which completely protect against infection or secondary transmission also substantially lower the number of people who must be vaccinated before the herd immunity threshold is reached. The limited extent of the fourth wave suggests that the vaccines have either high VESUSC or both high VESYMP and high VEINF against B.1.1.7. Finally, using a separate intra-host mathematical model of viral kinetics, we demonstrate that a 0.6 log vaccine-mediated reduction in average peak viral load might be sufficient to achieve 50% VEINF, which suggests that human challenge studies with a relatively low number of infected participants could be employed to estimate all three vaccine efficacy metrics.}, }
@article {pmid34695837, year = {2021}, author = {Davis, JT and Chinazzi, M and Perra, N and Mu, K and Piontti, APY and Ajelli, M and Dean, NE and Gioannini, C and Litvinova, M and Merler, S and Rossi, L and Sun, K and Xiong, X and Longini, IM and Halloran, ME and Viboud, C and Vespignani, A}, title = {Cryptic transmission of SARS-CoV-2 and the first COVID-19 wave.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41586-021-04130-w}, pmid = {34695837}, issn = {1476-4687}, abstract = {Considerable uncertainty surrounds the timeline of introductions and onsets of local transmission of SARS-CoV-2 globally1-7. Although a limited number of SARS-CoV-2 introductions were reported in January and February 20208,9, the narrowness of the initial testing criteria, combined with a slow growth in testing capacity and porous travel screening10, left many countries vulnerable to unmitigated, cryptic transmission. Here we use a global metapopulation epidemic model to provide a mechanistic understanding of the early dispersal of infections, and the temporal windows of the introduction and onset of SARS-CoV-2 local transmission in Europe and the United States. We find that community transmission of SARS-CoV-2 was likely in several areas of Europe and the United States by January 2020, and estimate that by early March, only 1 to 3 in 100 SARS-CoV-2 infections were detected by surveillance systems. The modelling results highlight international travel as the key driver of the introduction of SARS-CoV-2 with possible introductions and transmission events as early as December 2019-January 2020. We find a heterogeneous, geographic distribution of cumulative infection attack rates by 4 July 2020, ranging from 0.78%-15.2% across US states and 0.19%-13.2% in European countries. Our approach complements phylogenetic analyses and other surveillance approaches and provides insights that can be used to design innovative, model-driven surveillance systems that guide enhanced testing and response strategies.}, }
@article {pmid34694632, year = {2021}, author = {Song, X and Chao, EC and Wang, CY}, title = {A smoothed corrected score approach for proportional hazards model with misclassified discretized covariates induced by error-contaminated continuous time-dependent exposure.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13595}, pmid = {34694632}, issn = {1541-0420}, abstract = {We consider the proportional hazards model in which the covariates include the discretized categories of a continuous time-dependent exposure variable measured with error. Naively ignoring the measurement error in the analysis may cause biased estimation and erroneous inference. Although various approaches have been proposed to deal with measurement error when the hazard depends linearly on the time-dependent variable, it has not yet been investigated how to correct when the hazard depends on the discretized categories of the time-dependent variable. To fill this gap in the literature, we propose a smoothed corrected score approach based on approximation of the discretized categories after smoothing the indicator function. The consistency and asymptotic normality of the proposed estimator are established. The observation times of the time-dependent variable are allowed to be informative. For comparison, we also extend to this setting two approximate approaches, the regression calibration and the risk-set regression calibration. The methods are assessed by simulation studies and by application to data from an HIV clinical trial. This article is protected by copyright. All rights reserved.}, }
@article {pmid34693991, year = {2021}, author = {Gao, F and Chan, KCG}, title = {Non-iterative adjustment to regression estimators with population-based auxiliary information for semiparametric models.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13585}, pmid = {34693991}, issn = {1541-0420}, abstract = {Disease registries, surveillance data, and other data sets with extremely large sample sizes become increasingly available in providing population-based information on disease incidence, survival probability or other important public health characteristics. Such information can be leveraged in studies that collect detailed measurements but with smaller sample sizes. In contrast to recent proposals that formulate additional information as constraints in optimization problems, we develop a general framework to construct simple estimators that update the usual regression estimators with some functionals of data that incorporate the additional information. We consider general settings which incorporate nuisance parameters in the auxiliary information, non-i.i.d. data such as those from case-control studies, and semiparametric models with infinite dimensional parameters common in survival analysis. Details of several important data and sampling settings are provided with numerical examples. This article is protected by copyright. All rights reserved.}, }
@article {pmid34693363, year = {2021}, author = {Levy, CN and Hughes, SM and Roychoudhury, P and Amstuz, C and Zhu, H and Huang, ML and Lehman, DA and Jerome, KR and Hladik, F}, title = {HIV reservoir quantification by five-target multiplex droplet digital PCR.}, journal = {STAR protocols}, volume = {2}, number = {4}, pages = {100885}, doi = {10.1016/j.xpro.2021.100885}, pmid = {34693363}, issn = {2666-1667}, abstract = {Most latent human immunodeficiency virus (HIV) proviruses are defective and cannot produce infectious virions. Thus, the number of HIV proviruses with intact genomes is a relevant clinical parameter to assess therapies for HIV cure. We describe high-molecular-weight DNA isolation, followed by restriction enzyme fragmentation that limits cutting within the HIV genome. Multiplexed droplet digital PCR quantifies five targets spanning the HIV genome to estimate potentially intact proviral copies. A reference assay counts the number of T lymphocytes and assesses the level of DNA shearing. For complete details on the use and execution of this protocol, please refer to Levy et al. (2021).}, }
@article {pmid34677081, year = {2021}, author = {Johnson, AM and Baker, KS and Haviland, MJ and Syrjala, KL and Abbey-Lambertz, M and Chow, EJ and Mendoza, JA}, title = {A Pilot Randomized Controlled Trial of a Fitbit- and Facebook-Based Physical Activity Intervention for Young Adult Cancer Survivors.}, journal = {Journal of adolescent and young adult oncology}, volume = {}, number = {}, pages = {}, doi = {10.1089/jayao.2021.0056}, pmid = {34677081}, issn = {2156-535X}, abstract = {Purpose: Most young adult cancer survivors (YACS) do not meet physical activity (PA) guidelines. Although PA can improve health and quality of life (QOL), few randomized controlled trials (RCTs) of PA interventions for YACS exist. We conducted a pilot RCT to test feasibility of a PA intervention among YACS. Methods: We recruited 18-39-year-olds (≥1 and <5 years postcancer therapy) from Seattle Cancer Care Alliance. The 12-week intervention involved a wrist-worn PA-tracking device (Fitbit), a peer-based Facebook support group, step count goal setting, and a self-selected support "buddy." Controls received Fitbit only. Baseline assessments occurred before randomization; follow-up assessments occurred during intervention weeks 10-12. Feasibility criteria are listed below. Exploratory outcomes included PA, sedentary time (ST), QOL measures (e.g., fatigue), and self-determination theory (SDT) construct measures. Results: All feasibility criteria were met: We recruited 50 YACS, intervention participants wore the Fitbit on the majority of intervention days (82.9%), ≥75% of participants completed questionnaires at baseline (100%) and follow-up (93.9%). Exploratory analyses, adjusted for wave, accelerometer wear time, race, and income, showed significant group differences for change in ST (-52.4 vs. 2.5 minutes/day; p = 0.002) but no change in moderate-to-vigorous intensity PA (0.0 vs. -0.2 minutes/day; p = 0.40), comparing intervention participants to controls. The intervention (vs. control) group had a greater increase in fatigue interference (p = 0.03). No other significant differences in SDT or QOL measures were found. Conclusion: This Fitbit and Facebook-based PA intervention was feasible to YACS, with promising effects on reducing ST, and warrants a fully powered RCT. Clinical Trial Registration no.: NCT03233581.}, }
@article {pmid34675432, year = {2021}, author = {Giannakis, M and Peters, U}, title = {Esophageal cancer mutational signatures around the world.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {34675432}, issn = {1546-1718}, }
@article {pmid34673903, year = {2021}, author = {Hamadani, M and Gopal, AK and Pasquini, MC and Kim, S and Qiu, X and Ahmed, S and Lazaryan, A and Bhatt, VR and Daly, A and Lulla, P and Ciurea, SO and Gauthier, J and Agrawal, V and Grover, NS and Lekakis, LJ and Modi, D and Dahi, PB and Herr, MM and Johnson, PC and Hashmi, H and Hematti, P and Locke, FL}, title = {Allogeneic Transplant and CAR-T Therapy After Autologous Transplant Failure in DLBCL: A Noncomparative Cohort Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005788}, pmid = {34673903}, issn = {2473-9537}, abstract = {Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR) T-cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto) HCT. While the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis we report outcomes of DLBCL patients (≥18 years), undergoing a reduced intensity alloHCT or CAR-T therapy during 2012-2019, after a prior auto-HCT failure, and apply CIBMTR prognostic model to CAR-T recipients. 584 patients were included. The 1-year relapse, non-relapse mortality, overall survival (OS) and progression-free survival (PFS) for CAR-T treatment after autoHCT failure were were 39.5%, 4.8%, 73.4% and 55.7%, respectively. The corresponding rates in alloHCT cohort were 26.2%, 20.0%, 65.6% and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3, respectively (p=0.002). The corresponding rates for low-, intermediate- and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (p<0.001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in subset of DLBCL patients relapsing after a prior autoHCT. The simple, CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high risk patients.}, }
@article {pmid34672684, year = {2021}, author = {Yadav, S and Hu, C and Nathanson, KL and Weitzel, JN and Goldgar, DE and Kraft, P and Gnanaolivu, RD and Na, J and Huang, H and Boddicker, NJ and Larson, N and Gao, C and Yao, S and Weinberg, C and Vachon, CM and Trentham-Dietz, A and Taylor, JA and Sandler, DR and Patel, A and Palmer, JR and Olson, JE and Neuhausen, S and Martinez, E and Lindstrom, S and Lacey, JV and Kurian, AW and John, EM and Haiman, C and Bernstein, L and Auer, PW and Anton-Culver, H and Ambrosone, CB and Karam, R and Chao, E and Yussuf, A and Pesaran, T and Dolinsky, JS and Hart, SN and LaDuca, H and Polley, EC and Domchek, SM and Couch, FJ}, title = {Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2100640}, doi = {10.1200/JCO.21.00640}, pmid = {34672684}, issn = {1527-7755}, abstract = {PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.<br><br>MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).<br><br>RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.<br><br>CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.}, }
@article {pmid34672050, year = {2021}, author = {Boehmer, U and Ozonoff, A and Winter, M and Berklein, F and Potter, J and Ceballos, RM and Clark, MA}, title = {Anxiety and Depression in Colorectal Cancer Survivors: Are there differences by sexual orientation?.}, journal = {Psycho-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/pon.5837}, pmid = {34672050}, issn = {1099-1611}, abstract = {OBJECTIVE: To examine sexual minority compared to heterosexual survivors' health-related anxiety, anxiety, and depression.<br><br>METHODS: Four-hundred-eighty eligible survivors participated in a telephone survey, which measured their anxiety and depression. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of three years prior to the survey and were recruited from four cancer registries. As explanatory factors, we considered individual, social and contextual characteristics, prior psychological factors, psychological responses to cancer, and characteristics of cancer and its treatments. Using forward selection with generalized linear models or logistic regression models, we identified significant correlates for each outcome.<br><br>RESULTS: Prior to adjusting for covariates, depression was similar for all survivors, while sexual minority survivors had worse health-related anxiety and anxiety compared to heterosexual survivors. After adjustment, these differences were no longer statistically significant. Individual, social and contextual characteristics, characteristics of cancer, and psychological responses to cancer explained 44% of the variance in anxiety and 60% of the variance in depression.<br><br>CONCLUSION: There are modifiable factors associated with health-related and generalized anxiety as well as depression that can be changed to improve cancer survivorship among diverse survivors. This article is protected by copyright. All rights reserved.}, }
@article {pmid34666313, year = {2021}, author = {Streiff, MB and Holmstrom, B and Angelini, D and Ashrani, A and Elshoury, A and Fanikos, J and Fertrin, KY and Fogerty, AE and Gao, S and Goldhaber, SZ and Gundabolu, K and Ibrahim, I and Kraut, E and Leavitt, AD and Lee, A and Lee, JT and Lim, M and Mann, J and Martin, K and McMahon, B and Moriarty, J and Morton, C and Ortel, TL and Paschal, R and Schaefer, J and Shattil, S and Siddiqi, T and Sudheendra, D and Williams, E and Hollinger, L and Nguyen, MQ}, title = {Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {10}, pages = {1181-1201}, doi = {10.6004/jnccn.2021.0047}, pmid = {34666313}, issn = {1540-1413}, abstract = {NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.}, }
@article {pmid34666312, year = {2021}, author = {Weiss, JM and Gupta, S and Burke, CA and Axell, L and Chen, LM and Chung, DC and Clayback, KM and Dallas, S and Felder, S and Gbolahan, O and Giardiello, FM and Grady, W and Hall, MJ and Hampel, H and Hodan, R and Idos, G and Kanth, P and Katona, B and Lamps, L and Llor, X and Lynch, PM and Markowitz, AJ and Pirzadeh-Miller, S and Samadder, NJ and Shibata, D and Swanson, BJ and Szymaniak, BM and Wiesner, GL and Wolf, A and Yurgelun, MB and Zakhour, M and Darlow, SD and Dwyer, MA and Campbell, M}, title = {NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {10}, pages = {1122-1132}, doi = {10.1164/jnccn.2021.0048}, pmid = {34666312}, issn = {1540-1413}, abstract = {Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.}, }
@article {pmid34593322, year = {2021}, author = {Nutt, WS and Srivastava, S}, title = {Special delivery! CAR-T cells transport RN7SL1 to the tumor microenvironment.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2021.09.002}, pmid = {34593322}, issn = {1471-499X}, abstract = {In a recent Cell publication, Johnson et al. demonstrate that engineering chimeric antigen receptor (CAR)-T cells to produce RN7SL1, a novel RNA adjuvant that activates the viral sensors RIG-I and MDA5, improves intrinsic CAR-T cell function, activates tumor-infiltrating myeloid cells, and enhances endogenous tumor-specific T cell responses, resulting in improved tumor control despite CAR antigen loss in multiple mouse models.}, }
@article {pmid34686472, year = {2021}, author = {Brem, EA and Li, H and Beaven, AW and Caimi, PF and Cerchietti, L and Alizadeh, AA and Olin, R and Henry, NL and Dillon, H and Little, RF and Laubach, C and LeBlanc, M and Friedberg, JW and Smith, SM}, title = {SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - Aiming to improve therapy, outcomes, and validate a prospective frailty tool.}, journal = {Journal of geriatric oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jgo.2021.10.003}, pmid = {34686472}, issn = {1879-4076}, abstract = {Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.}, }
@article {pmid34686314, year = {2021}, author = {Jobava, R and Mao, Y and Guan, BJ and Hu, D and Krokowski, D and Chen, CW and Shu, XE and Chukwurah, E and Wu, J and Gao, Z and Zagore, LL and Merrick, WC and Trifunovic, A and Hsieh, AC and Valadkhan, S and Zhang, Y and Qi, X and Jankowsky, E and Topisirovic, I and Licatalosi, DD and Qian, SB and Hatzoglou, M}, title = {Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.}, journal = {Molecular cell}, volume = {81}, number = {20}, pages = {4191-4208.e8}, doi = {10.1016/j.molcel.2021.09.029}, pmid = {34686314}, issn = {1097-4164}, abstract = {To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.}, }
@article {pmid34683974, year = {2021}, author = {Connerty, P and Moles, E and de Bock, CE and Jayatilleke, N and Smith, JL and Meshinchi, S and Mayoh, C and Kavallaris, M and Lock, RB}, title = {Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia.}, journal = {Pharmaceutics}, volume = {13}, number = {10}, pages = {}, doi = {10.3390/pharmaceutics13101681}, pmid = {34683974}, issn = {1999-4923}, support = {Grant #: RSP-00122-19/20//Tour De Cure, Australia/ ; APP1059804//National Health and Medical Research Council/ ; APP1157871//National Health and Medical Research Council/ ; APP1119152//National Health and Medical Research Council/ ; APP1091261//National Health and Medical Research Council/ ; PG16-01//Cancer Council Australia/ ; FR 854/8-1//German Research Foundation/ ; CE140100036//Australian Research Council/ ; }, abstract = {Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered 'undruggable' targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8;21) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤ 0.22 along with a >85% siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells (>95% of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML.}, }
@article {pmid34683845, year = {2021}, author = {Esfandiari Nazzaro, E and Sabei, FY and Vogel, WK and Nazari, M and Nicholson, KS and Gafken, PR and Taratula, O and Taratula, O and Davare, MA and Leid, M}, title = {Discovery and Validation of a Compound to Target Ewing's Sarcoma.}, journal = {Pharmaceutics}, volume = {13}, number = {10}, pages = {}, doi = {10.3390/pharmaceutics13101553}, pmid = {34683845}, issn = {1999-4923}, support = {N/A//Oregon Health and Science University/ ; N/A//Sam Day Foundation/ ; R01CA237569//National Institutes of Health/ ; R37CA234006//National Institutes of Health/ ; P30CA015704//National Institutes of Health/ ; }, abstract = {Ewing's sarcoma, characterized by pathognomonic t (11; 22) (q24; q12) and related chromosomal ETS family translocations, is a rare aggressive cancer of bone and soft tissue. Current protocols that include cytotoxic chemotherapeutic agents effectively treat localized disease; however, these aggressive therapies may result in treatment-related morbidities including second-site cancers in survivors. Moreover, the five-year survival rate in patients with relapsed, recurrent, or metastatic disease is less than 30%, despite intensive therapy with these cytotoxic agents. By using high-throughput phenotypic screening of small molecule libraries, we identified a previously uncharacterized compound (ML111) that inhibited in vitro proliferation of six established Ewing's sarcoma cell lines with nanomolar potency. Proteomic studies show that ML111 treatment induced prometaphase arrest followed by rapid caspase-dependent apoptotic cell death in Ewing's sarcoma cell lines. ML111, delivered via methoxypoly(ethylene glycol)-polycaprolactone copolymer nanoparticles, induced dose-dependent inhibition of Ewing's sarcoma tumor growth in a murine xenograft model and invoked prometaphase arrest in vivo, consistent with in vitro data. These results suggest that ML111 represents a promising new drug lead for further preclinical studies and is a potential clinical development for the treatment of Ewing's sarcoma.}, }
@article {pmid34682466, year = {2021}, author = {Hanna, DB and Hua, S and Gonzalez, F and Kershaw, KN and Rundle, AG and Van Horn, LV and Wylie-Rosett, J and Gellman, MD and Lovasi, GS and Kaplan, RC and Mossavar-Rahmani, Y and Shaw, PA}, title = {Higher Neighborhood Population Density Is Associated with Lower Potassium Intake in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {International journal of environmental research and public health}, volume = {18}, number = {20}, pages = {}, doi = {10.3390/ijerph182010716}, pmid = {34682466}, issn = {1660-4601}, support = {K01-HL-137557//National Heart, Lung, and Blood Institute/ ; R01-HL-095856//National Heart, Lung, and Blood Institute/ ; N01-HC65233//National Heart, Lung, and Blood Institute/ ; N01-HC65234//National Heart, Lung, and Blood Institute/ ; N01-HC65235//National Heart, Lung, and Blood Institute/ ; N01-HC65236//National Heart, Lung, and Blood Institute/ ; N01-HC65237//National Heart, Lung, and Blood Institute/ ; }, abstract = {Current U.S. dietary guidelines recommend a daily potassium intake of 3400 mg/day for men and 2600 mg/day for women. Sub-optimal access to nutrient-rich foods may limit potassium intake and increase cardiometabolic risk. We examined the association of neighborhood characteristics related to food availability with potassium intake in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). 13,835 participants completed a 24-h dietary recall assessment and had complete covariates. Self-reported potassium intake was calibrated with an objective 24-h urinary potassium biomarker, using equations developed in the SOL Nutrition &amp; Physical Activity Assessment Study (SOLNAS, N = 440). Neighborhood population density, median household income, Hispanic/Latino diversity, and a retail food environment index by census tract were obtained. Linear regression assessed associations with 24-h potassium intake, adjusting for individual-level and neighborhood confounders. Mean 24-h potassium was 2629 mg/day based on the SOLNAS biomarker and 2702 mg/day using multiple imputation and HCHS/SOL biomarker calibration. Compared with the lowest quartile of neighborhood population density, living in the highest quartile was associated with a 26% lower potassium intake in SOLNAS (adjusted fold-change 0.74, 95% CI 0.59-0.94) and a 39% lower intake in HCHS/SOL (adjusted fold-change 0.61 95% CI 0.45-0.84). Results were only partially explained by the retail food environment. The mechanisms by which population density affects potassium intake should be further studied.}, }
@article {pmid34680866, year = {2021}, author = {Cargill, M and Venkataraman, R and Lee, S}, title = {DEAD-Box RNA Helicases and Genome Stability.}, journal = {Genes}, volume = {12}, number = {10}, pages = {}, doi = {10.3390/genes12101471}, pmid = {34680866}, issn = {2073-4425}, abstract = {DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between genomic stability and several DEAD-box RNA helicase family proteins including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, and DDX41. For each helicase, we have reviewed evidence supporting their role in protecting the genome and their suggested mechanisms. Such helicases regulate the expression of factors promoting genomic stability, prevent DNA damage, and can participate directly in the response and repair of DNA damage. Finally, we summarized the pathological and therapeutic relationship between DEAD-box RNA helicases and cancer with respect to their novel role in genome stability.}, }
@article {pmid34671754, year = {2021}, author = {Whiteaker, JR and Sharma, K and Hoffman, MA and Kuhn, E and Zhao, L and Cocco, AR and Schoenherr, RM and Kennedy, JJ and Voytovich, U and Lin, C and Fang, B and Bowers, K and Whiteley, G and Colantonio, S and Bocik, W and Roberts, R and Hiltke, T and Boja, E and Rodriguez, H and McCormick, F and Holderfield, M and Carr, SA and Koomen, JM and Paulovich, AG}, title = {Targeted mass spectrometry-based assays enable multiplex quantification of receptor tyrosine kinase, MAP Kinase, and AKT signaling.}, journal = {Cell reports methods}, volume = {1}, number = {3}, pages = {}, pmid = {34671754}, issn = {2667-2375}, support = {U24 CA160034/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; U01 CA214114/CA/NCI NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, abstract = {Summary: A primary goal of the US National Cancer Institute's Ras initiative at the Frederick National Laboratory for Cancer Research is to develop methods to quantify RAS signaling to facilitate development of novel cancer therapeutics. We use targeted proteomics technologies to develop a community resource consisting of 256 validated multiple reaction monitoring (MRM)-based, multiplexed assays for quantifying protein expression and phosphorylation through the receptor tyrosine kinase, MAPK, and AKT signaling networks. As proof of concept, we quantify the response of melanoma (A375 and SK-MEL-2) and colorectal cancer (HCT-116 and HT-29) cell lines to BRAF inhibition by PLX-4720. These assays replace over 60 Western blots with quantitative mass spectrometry-based assays of high molecular specificity and quantitative precision, showing the value of these methods for pharmacodynamic measurements and mechanism of action studies. Methods, fit-for-purpose validation, and results are publicly available as a resource for the community at assays.cancer.gov.<br><br>Motivation: A lack of quantitative, multiplexable assays for phosphosignaling limits comprehensive investigation of aberrant signaling in cancer and evaluation of novel treatments. To alleviate this limitation, we sought to develop assays using targeted mass spectrometry for quantifying protein expression and phosphorylation through the receptor tyrosine kinase, MAPK, and AKT signaling networks. The resulting assays provide a resource for replacing over 60 Western blots in examining cancer signaling and tumor biology with high molecular specificity and quantitative rigor.}, }
@article {pmid34606137, year = {2021}, author = {Hudson, MF and Strassels, SA and Durham, DD and Siddique, S and Adler, D and Yeung, SJ and Bernstein, SL and Baugh, CW and Coyne, CJ and Grudzen, CR and Henning, DJ and Klotz, A and Madsen, TE and Pallin, DJ and Rico, JF and Ryan, RJ and Shapiro, NI and Swor, R and Venkat, A and Wilson, J and Thomas, CR and Bischof, JJ and Lyman, GH and Caterino, JM}, title = {Examining pain among non-Hispanic Black and non-Hispanic White patients with cancer visiting emergency departments: CONCERN (Comprehensive Oncologic Emergencies Research Network).}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/acem.14395}, pmid = {34606137}, issn = {1553-2712}, }
@article {pmid34670275, year = {2021}, author = {Dávila Saldaña, BJ and John, TD and Bonifant, CL and Buchbinder, D and Chandra, S and Chandrakasan, S and Chang, W and Chen, L and Elfassy, HL and Geerlinks, AV and Giller, RH and Goyal, RK and Hagin, D and Islam, S and Mallhi, KK and Miller, HK and Owen, WC and Pacheco, M and Patel, N and Querfeld, C and Quigg, T and Richard, N and Schiff, DE and Shereck, E and Stenger, EO and Jordan, MB and Heslop, HE and Bollard, CM and Cohen, JI}, title = {High risk of relapsed disease in patients with NK/T cell chronic active Epstein-Barr virus disease outside of Asia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005291}, pmid = {34670275}, issn = {2473-9537}, abstract = {Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or NK cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis (HLH) and/or lymphoma. The disease is more common in Asia than in the United States and Europe. While allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment for the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% v 25%, p<0.01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% v 35%, p=0.1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.}, }
@article {pmid34669700, year = {2021}, author = {Carroll, PA and Freie, BW and Cheng, PF and Kasinathan, S and Gu, H and Hedrich, T and Dowdle, JA and Venkataramani, V and Ramani, V and Wu, X and Raftery, D and Shendure, J and Ayer, DE and Muller, CH and Eisenman, RN}, title = {The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis.}, journal = {PLoS biology}, volume = {19}, number = {10}, pages = {e3001085}, doi = {10.1371/journal.pbio.3001085}, pmid = {34669700}, issn = {1545-7885}, abstract = {Male germ cell (GC) production is a metabolically driven and apoptosis-prone process. Here, we show that the glucose-sensing transcription factor (TF) MAX-Like protein X (MLX) and its binding partner MondoA are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and GC apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific GC transcripts and proteins. Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, obligate components of male-specific GC development, and apoptotic effectors. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors (MGCTs).}, }
@article {pmid34669358, year = {2021}, author = {Sokolova, A and Cheng, H}, title = {Germline Testing in Prostate Cancer: When and Who to Test.}, journal = {Oncology (Williston Park, N.Y.)}, volume = {35}, number = {10}, pages = {645-653}, doi = {10.46883/ONC.2021.3510.0645}, pmid = {34669358}, issn = {0890-9091}, abstract = {The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.}, }
@article {pmid34668728, year = {2021}, author = {Itell, HL and Weight, H and Fish, CS and Logue, JK and Franko, N and Wolf, CR and McCulloch, DJ and Galloway, J and Matsen, FA and Chu, HY and Overbaugh, J}, title = {SARS-CoV-2 Antibody Binding and Neutralization in Dried Blood Spot Eluates and Paired Plasma.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0129821}, doi = {10.1128/Spectrum.01298-21}, pmid = {34668728}, issn = {2165-0497}, abstract = {Wide-scale assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies is critical to understanding population seroprevalence, correlates of protection, and the longevity of vaccine-elicited responses. Most SARS-CoV-2 studies characterize antibody responses in plasma/sera. While reliable and broadly used, these samples pose several logistical restrictions, such as requiring venipuncture for collection and a cold chain for transportation and storage. Dried blood spots (DBS) overcome these barriers as they can be self-collected by fingerstick and mailed and stored at ambient temperature. Here, we evaluate the suitability of DBS for SARS-CoV-2 antibody assays by comparing several antibody responses between paired plasma and DBS from SARS-CoV-2 convalescent and vaccinated individuals. We found that DBS not only reflected plasma antibody binding by enzyme-linked immunosorbent assay (ELISA) and epitope profiles using phage display, but also yielded SARS-CoV-2 neutralization titers that highly correlated with paired plasma. Neutralization measurement was further streamlined by adapting assays to a high-throughput 384-well format. This study supports the adoption of DBS for numerous SARS-CoV-2 binding and neutralization assays. IMPORTANCE Plasma and sera isolated from venous blood represent conventional sample types used for the evaluation of SARS-CoV-2 antibody responses after infection or vaccination. However, collection of these samples is invasive and requires trained personnel and equipment for immediate processing. Once collected, plasma and sera must be stored and shipped at cold temperatures. To define the risk of emerging SARS-CoV-2 variants and the longevity of immune responses to natural infection and vaccination, it will be necessary to measure various antibody features in populations around the world, including in resource-limited areas. A sampling method that is compatible with these settings and is suitable for a variety of SARS-CoV-2 antibody assays is therefore needed to continue to understand and curb the COVID-19 pandemic.}, }
@article {pmid34668387, year = {2021}, author = {Cai, LM and Hippe, DS and Zamora, DA and Cao, J and Parakh, A and Kambadakone, AR and Xiao, JM and Wang, SS and Toia, GV and Gunn, ML and Wang, CL and Mileto, A}, title = {A Method for Reducing Variability Across Dual-Energy CT Manufacturers in Quantification of Low Iodine Content Levels.}, journal = {AJR. American journal of roentgenology}, volume = {}, number = {}, pages = {}, doi = {10.2214/AJR.21.26714}, pmid = {34668387}, issn = {1546-3141}, abstract = {Background: Clinical use of the dual-energy CT (DECT) iodine quantification technique is hindered by between-platform (i.e., across different manufacturers) variability in iodine concentration (IC), particularly at low iodine levels. Objective: To develop in an anthropomorphic phantom a method for reducing between-platform variability in quantification of low iodine content levels using DECT and to evaluate the method's performance in patients undergoing serial clinical DECT examinations on different platforms. Methods: An anthropomorphic phantom in three body sizes, incorporating varied lesion types and scanning conditions, was imaged with three distinct DECT implementations from different manufacturers at varying radiation exposures. A cross-platform iodine quantification model for correcting between-platform variability at low iodine content was developed using the phantom data. The model was tested in a retrospective series of 30 patients (20 men, 10 women; median age, 62 years) who each underwent three serial contrast-enhanced DECT examinations of the abdomen and pelvis (90 scans total) for routine oncology surveillance, using the same three DECT platforms as in the phantom. Estimated accuracy of phantom IC values was summarized using rootmean-squared error (RMSE) relative to known IC. Between-platform variability in patients was summarized using root-mean-square-deviation (RMSD). RMSE and RMSD were compared between platform-based IC (ICPB) and cross-platform IC (ICCP). ICPB was normalized to aorta and portal vein. Results: In the phantom study, mean RMSE of ICPB across platforms and other experimental conditions was 0.65 ± 0.18 mgI/mL compared with 0.40 ± 0.075 mgI/mL for ICCP (38% decrease in mean RMSE; P<.05). Intra-patient between-platform variability across serial DECT examinations was lower for ICPB than ICCP (RMSD: 97% vs 88%; P<.001). Between-platform variability was not reduced by normalization of ICPB to aorta (RMSD: 97% vs 101%; P=.12) or portal vein (RMSD: 97% vs 97%; P=.81). Conclusion: The developed cross-platform method significantly decreased between-platform variability occurring at low iodine content with platform-based DECT iodine quantification. Clinical Impact: With further validation, the cross-platform method, which has been implemented as a webbased app, may expand clinical use of DECT iodine quantification, yielding meaningful IC values that reflect tissue biologic viability or treatment response in patients who undergo serial examinations on different platforms.}, }
@article {pmid34661143, year = {2020}, author = {Simon, S and Riddell, SR}, title = {Dual Targeting with CAR T Cells to Limit Antigen Escape in Multiple Myeloma.}, journal = {Blood cancer discovery}, volume = {1}, number = {2}, pages = {130-133}, doi = {10.1158/2643-3230.BCD-20-0122}, pmid = {34661143}, issn = {2643-3249}, abstract = {Adoptive T-cell therapy targeting a single tumor antigen can induce remissions of hematologic cancers but relapses often occur due to the outgrowth of tumor cells with absent or low expression of the antigen. Strategies to simultaneousy target multiple antigens are needed to fully capitalize on the promise of this therapeutic strategy. In this issue of Blood Cancer Discovery, Fernández de Larrea and colleagues demonstrate in preclinical models of multiple myeloma that targeting BCMA and GPRC5D simultaneously with T cells engineered to express chimeric antigen receptors specific for these antigens may prevent tumor cell escape. See related article by Fernández de Larrea et al., p. 146.}, }
@article {pmid34666344, year = {2021}, author = {Juluri, KR and Wu, V and Voutsinas, JM and Hou, J and Hirayama, AV and Mullane, E and Miles, N and Maloney, DG and Turtle, CJ and Bar, M and Gauthier, J}, title = {Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2020004142}, pmid = {34666344}, issn = {2473-9537}, abstract = {CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies, however, is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy on a phase I/II clinical trial (NCT01865617), with primary endpoints of absolute neutrophil count (ANC) and platelet count at day-28 following CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75% respectively, at 28 days post-CAR T-cell infusion. Hematologic toxicity was noted in a significant subset of patients with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Utilizing debiased LASSO regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower pre-lymphodepletion platelet count as independent predictors for both decreased neutrophil and platelet counts following CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of IL-6 and lower day-28 counts; in contrast, higher serum concentrations of TGF-β were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy.}, }
@article {pmid34666043, year = {2021}, author = {Gaba, A and Hix, MA and Suhail, S and Flath, B and Boysan, B and Williams, DR and Pelletier, T and Emerman, M and Morcos, F and Andrés Cisneros, G and Chelico, L}, title = {Divergence in dimerization and activity of primate APOBEC3C.}, journal = {Journal of molecular biology}, volume = {}, number = {}, pages = {167306}, doi = {10.1016/j.jmb.2021.167306}, pmid = {34666043}, issn = {1089-8638}, abstract = {The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and we determined that Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity, 44, 45, and 144, also promoted dimerization and changes to the dynamics of loop 1, near the enzyme active site. Although forced evolution of rhA3C resulted in a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C and establish the amino acid network for dimerization and increased activity. Based on identification of the key amino acids determining Old World Monkey antiviral activity we predict that other Old World Monkey A3Cs did not impart anti-lentiviral activity, despite fixation of a key residue needed for hominid A3C activity. Overall, the coevolutionary analysis of the A3C dimerization interface presented also provides a basis from which to analyze dimerization interfaces of other A3 family members.}, }
@article {pmid34666003, year = {2021}, author = {Lynch, KL and Dillon, MR and Bat-Erdene, M and Lewis, HC and Kaai, RJ and Arnold, EA and Avgousti, DC}, title = {A viral histone-like protein exploits antagonism between linker histones and HMGB proteins to obstruct the cell cycle.}, journal = {Current biology : CB}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cub.2021.09.050}, pmid = {34666003}, issn = {1879-0445}, abstract = {Virus infection necessarily requires redirecting cellular resources toward viral progeny production. Adenovirus encodes the histone-like protein VII, which causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher-order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle, even in the presence of E1A and E1B. We further show that, in a protein-VII-deleted infection, several cell cycle markers are regulated differently compared to wild-type infection, supporting our model that protein VII plays an integral role in hijacking cell cycle regulation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit.}, }
@article {pmid34665829, year = {2021}, author = {Andrasik, MP and Broder, GB and Wallace, SE and Chaturvedi, R and Michael, NL and Bock, S and Beyrer, C and Oseso, L and Aina, J and Lucas, J and Wilson, DR and Kublin, JG and Mensah, GA}, title = {Increasing Black, Indigenous and People of Color participation in clinical trials through community engagement and recruitment goal establishment.}, journal = {PloS one}, volume = {16}, number = {10}, pages = {e0258858}, doi = {10.1371/journal.pone.0258858}, pmid = {34665829}, issn = {1932-6203}, abstract = {Longstanding social and economic inequities elevate health risks and vulnerabilities for Black, Indigenous and People of Color (BIPOC) communities. Engagement of BIPOC communities in infectious disease research is a critical component in efforts to increase vaccine confidence, acceptability, and uptake of future approved products. Recent data highlight the relative absence of BIPOC communities in vaccine clinical trials. Intentional and effective community engagement methods are needed to improve BIPOC inclusion. We describe the methods utilized for the successful enrollment of BIPOC participants in the U.S. Government (USG)-funded COVID-19 Prevention Network (CoVPN)-sponsored vaccine efficacy trials and analyze the demographic and enrollment data across the efficacy trials to inform future efforts to ensure inclusive participation. Across the four USG-funded COVID-19 vaccine clinical trials for which data are available, 47% of participants enrolled at CoVPN sites in the US were BIPOC. White enrollment outpaced enrollment of BIPOC participants throughout the accrual period, requiring the implementation of strategies to increase diverse and inclusive enrollment. Trials opening later benefitted considerably from strengthened community engagement efforts, and greater and more diverse volunteer registry records. Despite robust fiscal resources and a longstanding collaborative and collective effort, enrollment of White persons outpaced that of BIPOC communities. With appropriate resources, commitment and community engagement expertise, the equitable enrollment of BIPOC individuals can be achieved. To ensure this goal, intentional efforts are needed, including an emphasis on diversity of enrollment in clinical trials, establishment of enrollment goals, ongoing robust community engagement, conducting population-specific trials, and research to inform best practices.}, }
@article {pmid34665672, year = {2021}, author = {Roberts, ST and Hawley, I and Luecke, E and Mensch, B and Wagner, T and Hoesley, C and McClure, T and Dominguez Islas, CP and Piper, JM and Liu, AY and van der Straten, A}, title = {Acceptability and Preference for 3-Month Versus 1-Month Vaginal Rings for HIV-1 Risk Reduction Among Participants in a Phase 1 Trial.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1089/jwh.2021.0121}, pmid = {34665672}, issn = {1931-843X}, abstract = {Background: The monthly dapivirine vaginal ring provides partial protection against HIV, and a longer duration ring may reduce user burden and improve adherence. We examined acceptability and preference for 3-month versus 1-month rings for HIV-1 risk reduction in a phase 1 clinical trial. Materials and Methods: In Microbicide Trials Network-036/International Partnership for Microbicides 047, 49 HIV-negative participants aged 18-45 were randomized to one of two 3-month rings or the 1-month ring. Acceptability ratings were collected at enrollment, week 4, and study exit (week 13). At exit, ring preference was assessed quantitatively among all participants and a randomly selected subset of 24 participants completed in-depth interviews. Quantitative and qualitative findings were integrated to explore factors influencing acceptability and preference. Results: Acceptability of each ring was initially moderate and increased during the trial. Ratings were lower in the 3-month ring arms than the 1-month arm at each time point, including baseline. Most participants (34/47; 72%) preferred a 3-month ring at exit; however, this proportion was significantly lower within some subgroups characterized by site, education, race/ethnicity, and experiences with ring use. Qualitative interviews revealed reservations about hygiene and safety of the 3-month ring, including discomfort with use during menses, but these were usually outweighed by its increased convenience. Conclusions: Both ring durations were highly acceptable at study exit. Although most participants preferred a 3-month ring, preference was more divided in certain subgroups, highlighting the benefit of offering different duration options. Providing additional support to address concerns about hygiene and safety may improve acceptability of a 3-month vaginal ring.}, }
@article {pmid34665364, year = {2021}, author = {Newcomb, PA and Ton, M and Malen, RC and Heffner, JL and Labadie, J and Phipps, AI and Burnett-Hartman, AN}, title = {Correction to: Cannabis use is associated with patient and clinical factors in a population-based sample of colorectal cancer survivors.}, journal = {Cancer causes &amp; control : CCC}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10552-021-01499-x}, pmid = {34665364}, issn = {1573-7225}, }
@article {pmid34664836, year = {2021}, author = {Zifodya, JS and Triplette, M and Shahrir, S and Attia, EF and Akgun, KM and Soo Hoo, GW and Rodriguez-Barradas, MC and Wongtrakool, C and Huang, L and Crothers, K}, title = {A cross-sectional analysis of diagnosis and management of chronic obstructive pulmonary disease in people living with HIV: Opportunities for improvement.}, journal = {Medicine}, volume = {100}, number = {37}, pages = {e27124}, doi = {10.1097/MD.0000000000027124}, pmid = {34664836}, issn = {1536-5964}, support = {T32 HL007287/NH/NIH HHS/United States ; K24 HL087713/NH/NIH HHS/United States ; R01 HL128156/NH/NIH HHS/United States ; U01HL142103/NH/NIH HHS/United States ; R01HL090342/NH/NIH HHS/United States ; Kl2 HD043451//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {ABSTRACT: Chronic obstructive pulmonary disease (COPD) is common in people living with HIV (PLWH). We sought to evaluate the appropriateness of COPD diagnosis and management in PLWH, comparing results to HIV-uninfected persons.We conducted a cross-sectional analysis of Veterans enrolled in the Examinations of HIV-Associated Lung Emphysema study, in which all participants underwent spirometry at enrollment and reported respiratory symptoms on self-completed surveys. Primary outcomes were misdiagnosis and under-diagnosis of COPD, and the frequency and appropriateness of inhaler prescriptions. Misdiagnosis was defined as having an International Classification of Diseases (ICD)-9 diagnosis of COPD without spirometric airflow limitation (post-bronchodilator forced expiratory volume in 1-second [FEV1]/Forced vital capacity [FVC] < 0.7). Under-diagnosis was defined as having spirometry-defined COPD without a prior ICD-9 diagnosis.The analytic cohort included 183 PLWH and 152 HIV-uninfected participants. Of 25 PLWH with an ICD-9 diagnosis of COPD, 56% were misdiagnosed. Of 38 PLWH with spirometry-defined COPD, 71% were under-diagnosed. In PLWH under-diagnosed with COPD, 85% reported respiratory symptoms. Among PLWH with an ICD-9 COPD diagnosis as well as in those with spirometry-defined COPD, long-acting inhalers, particularly long-acting bronchodilators (both beta-agonists and muscarinic antagonists) were prescribed infrequently even in symptomatic individuals. Inhaled corticosteroids were the most frequently prescribed long-acting inhaler in PLWH (28%). Results were overall similar amongst the HIV-uninfected.COPD was frequently misdiagnosed and under-diagnosed in PLWH, similar to uninfected-veterans. Among PLWH with COPD and a likely indication for therapy, long-acting inhalers were prescribed infrequently, particularly guideline-concordant, first-line long-acting bronchodilators. Although not a first-line controller therapy for COPD, inhaled corticosteroids were prescribed more often.}, }
@article {pmid34663924, year = {2021}, author = {Janssens, DH and Meers, MP and Wu, SJ and Babaeva, E and Meshinchi, S and Sarthy, JF and Ahmad, K and Henikoff, S}, title = {Automated CUT&amp;Tag profiling of chromatin heterogeneity in mixed-lineage leukemia.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {34663924}, issn = {1546-1718}, support = {R01 HG010492/HG/NHGRI NIH HHS/United States ; 4DN TCPA A093//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; F32 GM129954/GM/NIGMS NIH HHS/United States ; Henikoff//Howard Hughes Medical Institute (HHMI)/ ; Sarthy//Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)/ ; Sarthy//Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation)/ ; }, abstract = {Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&amp;Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&amp;Tag profiling reveals that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&amp;Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.}, }
@article {pmid34663616, year = {2021}, author = {Oh, H and Saquib, N and Ochs-Balcom, HM and Pfeiffer, RM and Richey, PA and Shadyab, AH and Wild, RA and Underland, L and Anderson, GL and Xu, X and Trabert, B}, title = {Recreational physical activity, sitting, and androgen metabolism among postmenopausal women in the Women's Health Initiative Observational Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0809}, pmid = {34663616}, issn = {1538-7755}, abstract = {BACKGROUND: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women.<br><br>METHODS: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means(GMs) of androgen/androgen metabolite concentrations(pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy(MHT) use.<br><br>RESULTS: Physical activity (>15 vs. 0 MET-hour/week) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM=37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all p-trend<0.03) but was not associated among current MHT users. Prolonged sitting(>10 vs. <5 hours/day) was positively associated with these ratios among both never/former (adj-GM=44.2 vs. 38.3, p-trend=0.10; adj-GM=23.4 vs. 20.2, p-trend=0.17; respectively) and current MHT users (adj-GM=197 vs. 147; 105 vs. 75.5; respectively; all p-trend<0.02) but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites.<br><br>CONCLUSIONS: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites.<br><br>IMPACT: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women.}, }
@article {pmid34663435, year = {2021}, author = {Makarov, DV and Ciprut, S and Kelly, M and Walter, D and Shedlin, MG and Braithwaite, RS and Tenner, CT and Gold, HT and Zeliadt, S and Sherman, SE}, title = {Protocol: A multi-modal, physician-centered intervention to improve guideline-concordant prostate cancer imaging.}, journal = {Trials}, volume = {22}, number = {1}, pages = {711}, pmid = {34663435}, issn = {1745-6215}, support = {15-356//Health Services Research and Development/ ; }, mesh = {Diagnostic Imaging ; Feedback ; Humans ; Male ; *Physicians ; *Prostatic Neoplasms/diagnostic imaging/therapy ; Trust ; }, abstract = {BACKGROUND: Almost half of Veterans with localized prostate cancer receive inappropriate, wasteful staging imaging. Our team has explored the barriers and facilitators of guideline-concordant prostate cancer imaging and found that (1) patients with newly diagnosed prostate cancer have little concern for radiographic staging but rather focus on treatment and (2) physicians trust imaging guidelines but are apt to follow their own intuition, fear medico-legal consequences, and succumb to influence from imaging-avid colleagues. We used a theory-based approach to design a multi-level intervention strategy to promote guideline-concordant imaging to stage incident prostate cancer.<br><br>METHODS: We designed the Prostate Cancer Imaging Stewardship (PCIS) intervention: a multi-site, stepped wedge, cluster-randomized trial to determine the effect of a physician-focused behavioral intervention on Veterans Health Administration (VHA) prostate cancer imaging use. The multi-level intervention, developed according to the Theoretical Domains Framework (TDF) and Behavior Change Wheel, combines traditional physician behavior change methods with novel methods of communication and data collection. The intervention consists of three components: (1) a system of audit and feedback to clinicians informing individual clinicians and their sites about how their behavior compares to their peers' and to published guidelines, (2) a program of academic detailing with the goal to educate providers about prostate cancer imaging, and (3) a CPRS Clinical Order Check for potentially guideline-discordant imaging orders. The intervention will be introduced to 10 participating geographically distributed study sites.<br><br>DISCUSSION: This study is a significant contribution to implementation science, providing VHA an opportunity to ensure delivery of high-quality care at the lowest cost using a theory-based approach. The study is ongoing. Preliminary data collection and recruitment have started; analysis has yet to be performed.<br><br>TRIAL REGISTRATION: CliniclTrials.gov NCT03445559. Prospectively registered on February 26, 2018.}, }
@article {pmid34661153, year = {2021}, author = {Wu, X and Eisenman, RN}, title = {MYC and TFEB Control DNA Methylation and Differentiation in AML.}, journal = {Blood cancer discovery}, volume = {2}, number = {2}, pages = {116-118}, doi = {10.1158/2643-3230.BCD-20-0230}, pmid = {34661153}, issn = {2643-3249}, abstract = {Although the MYC transcription factor has been consistently implicated in acute myeloid leukemia (AML), its gene targets and precise role in leukemogenesis remain unknown. In this issue of Blood Cancer Discovery, Yun and colleagues provide evidence that MYC directly suppresses the expression of TFEB, an mTORC1-regulated transcription factor. They show that, in the context of the myelocytic/granulocytic lineage, TFEB acts as a tumor suppressor by inducing the IDH1/2-TET pathway, which in turn, leads to altered DNA methylation and increased expression of genes involved in myeloid differentiation and apoptosis. Therefore, high levels of MYC suppress an epigenetic pathway that should normally act to attenuate leukemic progression. Identification of the components of this pathway is likely to inform new therapeutic tactics for AML and possibly other cancers. See related article by Yun et al., p. 162.}, }
@article {pmid34658056, year = {2021}, author = {Yue, K and Ma, J and Thornton, T and Shojaie, A}, title = {REHE: Fast variance components estimation for linear mixed models.}, journal = {Genetic epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1002/gepi.22432}, pmid = {34658056}, issn = {1098-2272}, support = {R01-GM114029/NH/NIH HHS/United States ; R01-GM133848/NH/NIH HHS/United States ; R01-HL141989/NH/NIH HHS/United States ; }, abstract = {Linear mixed models are widely used in ecological and biological applications, especially in genetic studies. Reliable estimation of variance components is crucial for using linear mixed models. However, standard methods, such as the restricted maximum likelihood (REML), are computationally inefficient in large samples and may be unstable with small samples. Other commonly used methods, such as the Haseman-Elston (HE) regression, may yield negative estimates of variances. Utilizing regularized estimation strategies, we propose the restricted Haseman-Elston (REHE) regression and REHE with resampling (reREHE) estimators, along with an inference framework for REHE, as fast and robust alternatives that provide nonnegative estimates with comparable accuracy to REML. The merits of REHE are illustrated using real data and benchmark simulation studies.}, }
@article {pmid34657218, year = {2021}, author = {Bauermeister, JA and Tingler, RC and Dominguez, C and Dunne, EF and Hoesley, C and Ho, K and Johnson, S and Lucas, J and Macagna, N and Brown, E and Gundacker, H and Peda, M and Jacobson, CE and Kramzer, L and Singh, D and Dezzutti, CS and Ayudhya, RPKN and Marzinke, MA and Piper, J and Devlin, B and Nuttall, J and McGowan, I and Hendrix, CW and Cranston, RD and , }, title = {Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026).}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {34657218}, issn = {1573-3254}, support = {UM1AI068633/NH/NIH HHS/United States ; UM1AI068615/NH/NIH HHS/United States ; UM1AI106707/NH/NIH HHS/United States ; }, abstract = {This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants' acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.Trial Registration: NCT03239483.}, }
@article {pmid34657145, year = {2021}, author = {Vo, P and Onstad, L and Flowers, ME and Storb, R}, title = {Cancers after HLA-matched related bone marrow transplantation for aplastic anemia.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34657145}, issn = {1476-5365}, support = {P01 HL122173/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {We analyzed subsequent cancers in 329 patients with aplastic anemia given HLA-matched related marrow grafts. Median follow-up: 26 (range 1-47) years. Conditioning: cyclophosphamide ± antithymocyte globulin; graft-vs.-host disease (GVHD) prevention: methotrexate ± cyclosporine. The long follow-up and homogeneous treatment allowed definitive analyses of incidence, nature, time of onset, and potential causes of cancers. Fifty-three cancers occurred in 46 patients, 42 had solid tumors and 4 blood cancers. Of the 42, 22 had non-melanoma skin and 7 oropharyngeal cancers. The remainder had a spectrum of other cancers including two liver cancers from pre-transplant hepatitis C. The 26-year cumulative incidence (CI) of cancer was 11% and mortality 5%. Excluding non-melanoma skin cancers, the 26-year CI of cancer was 7%. Cancers were 2.03-fold more than expected from SEER data; that number was 1.89-fold after excluding liver cancers. Nearly all cancers developed between 14 and 34 years. Skin and oropharyngeal cancers showed significant association with chronic GVHD, whereby GVHD had resolved in most patients within 7 years of transplantation. Thus, tumors evolved after a lag time of 7-27 years. Other cancers showed no clear associations with chronic GVHD or drugs used for transplantation. Results reemphasize the importance of preventing chronic GVHD.}, }
@article {pmid34657125, year = {2021}, author = {Cicconi, L and Testi, AM and Montesinos, P and Rego, E and Zhu, HH and Takahashi, H and Dworzak, M and Estey, E and Schwarer, A and Esteve, J and Annibali, O and Castelli, R and Mirabile, M and Angelini, M and Lazarevic, V and Kumar, J and Avvisati, G and Gurnari, C and Locatelli, F and Voso, MT and Sanz, MA and Lo-Coco, F and Abla, O}, title = {Characteristics and outcome of acute myeloid leukemia with uncommon retinoic acid receptor-alpha (RARA) fusion variants.}, journal = {Blood cancer journal}, volume = {11}, number = {10}, pages = {167}, pmid = {34657125}, issn = {2044-5385}, }
@article {pmid34655611, year = {2021}, author = {Snow, SM and Matkowskyj, KA and Maresh, M and Clipson, L and Vo, TN and Johnson, KA and Deming, DA and Newton, MA and Grady, WM and Pickhardt, PJ and Halberg, RB}, title = {Validation of genetic classifiers derived from mouse and human tumors to identify molecular subtypes of colorectal cancer.}, journal = {Human pathology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.humpath.2021.10.002}, pmid = {34655611}, issn = {1532-8392}, abstract = {Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Standard treatment for advanced stage CRC for decades has included 5-fluorouracil based chemotherapy. More recently, targeted therapies for metastatic CRC are being used based on the individual cancer's molecular profile. In the past few years, several different molecular subtype schemes for human CRC have been developed. The molecular subtypes can be distinguished by gene expression signatures and have the potential to be used to guide treatment decisions. However, many subtyping classification methods were developed using mRNA expression levels of hundreds to thousands of genes, making them impractical for clinical use. In this study, we assessed whether an immunohistochemical approach could be used for molecular subtyping of colorectal cancers. We validated two previously published, independent sets of immunohistochemistry classifiers and modified the published methods to improve the accuracy of the scoring methods. In addition, we evaluated whether protein and genetic signatures identified originally in the mouse were linked to clinical outcomes of patients with CRC. We found that low DDAH1 or low GAL3ST2 protein levels in human CRCs correlate with poor patient outcome. The results of this study have the potential to impact methods for determining the prognosis and therapy selection for CRC patients.}, }
@article {pmid34655327, year = {2021}, author = {Petermann, V and Zahnd, WE and Vanderpool, RC and Eberth, JM and Rohweder, C and Teal, R and Vu, M and Stradtman, L and Frost, E and Trapl, E and Koopman Gonzalez, S and Vu, T and Ko, LK and Cole, A and Farris, PE and Shannon, J and Lee, J and Askelson, N and Seegmiller, L and White, A and Edward, J and Davis, M and Wheeler, SB}, title = {How cancer programs identify and address the financial burdens of rural cancer patients.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {}, number = {}, pages = {}, pmid = {34655327}, issn = {1433-7339}, support = {U48-DP005017/DP/NCCDPHP CDC HHS/United States ; U48-DP005053/DP/NCCDPHP CDC HHS/United States ; U48-DP005014/DP/NCCDPHP CDC HHS/United States ; U48-DP005030/DP/NCCDPHP CDC HHS/United States ; U48-DP005013/DP/NCCDPHP CDC HHS/United States ; U48-DP005006/DP/NCCDPHP CDC HHS/United States ; U48-DP005021/DP/NCCDPHP CDC HHS/United States ; U48-DP005017/DP/NCCDPHP CDC HHS/United States ; U48-DP005053/DP/NCCDPHP CDC HHS/United States ; U48-DP005014/DP/NCCDPHP CDC HHS/United States ; U48-DP005030/DP/NCCDPHP CDC HHS/United States ; U48-DP005013/DP/NCCDPHP CDC HHS/United States ; U48-DP005006/DP/NCCDPHP CDC HHS/United States ; U48-DP005021/DP/NCCDPHP CDC HHS/United States ; }, abstract = {PURPOSE: Financial toxicity is associated with negative patient outcomes, and rural populations are disproportionately affected by the high costs of cancer care compared to urban populations. Our objective was to (1) understand cancer programs' perceptions of rural-urban differences in cancer patients' experiences of financial hardship, (2) evaluate the resources available to cancer patients across the rural-urban continuum, and (3) determine how rural and urban health care teams assess and address financial distress in cancer patients.<br><br>METHODS: Seven research teams within the Cancer Prevention and Research Control Network conducted semi-structured interviews with cancer program staff who have a role in connecting cancer patients with financial assistance services in both rural and urban counties. Interviews were audio-recorded and transcribed. We identified themes using descriptive content and thematic analysis.<br><br>RESULTS: We interviewed 35 staffs across 29 cancer care programs in seven states, with roughly half of respondents from programs in rural counties. Participants identified differences in rural and urban patients' experiences of financial hardship related to distance required to travel for treatment, underinsurance, and low socioeconomic status. Insufficient staffing was an identified barrier to addressing rural and urban patients' financial concerns.<br><br>CONCLUSIONS: Improved financial navigation services could mitigate the effects of financial toxicity experienced by cancer patients, particularly rural patients, throughout treatment and survivorship. Future research is needed to improve how cancer programs assess financial hardship in patients and to expand financial navigation services to better serve rural cancer patients.}, }
@article {pmid34643090, year = {2021}, author = {Lotan, Y and de Jong, J and Liu, VYT and Bismar, TA and Boorjian, SA and Huang, HC and Davicioni, E and Mian, OY and Wright, JL and Necchi, A and Dall'Era, MA and Kaimakliotis, HZ and Black, PC and Gibb, EA and Boormans, J}, title = {Patients With Muscle Invasive Bladder Cancer with Non-luminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000002261}, doi = {10.1097/JU.0000000000002261}, pmid = {34643090}, issn = {1527-3792}, abstract = {PURPOSE: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with non-metastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC.<br><br>MATERIALS AND METHODS: Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex, and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan Meier (KM) curves. Cox proportional hazards (PH) models were used to evaluate the primary and secondary study endpoints of overall survival (OS) and cancer-specific survival (CSS), respectively.<br><br>RESULTS: A total of 601 patients with MIBC were included, where 247 had been treated with NAC and RC and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and CSS at three years was 7% and 5%, respectively. After controlling for clinicopathologic variables, non-luminal tumors had greatest benefit from NAC with 10% greater OS at 3 years (71% vs 61%) while luminal tumors had minimal benefit (63% vs 65%) for NAC vs. non-NAC, respectively.<br><br>CONCLUSIONS: In patients with MIBC, a commercially available molecular subtyping assay revealed non-luminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.}, }
@article {pmid34607839, year = {2021}, author = {Sato, S and Li, N and Dixon, SB and Kato, M and Zhang, H and Li, CK and Howell, RM and Leisenring, WM and Bhatia, S and Oeffinger, KC and Armstrong, GT and Yasui, Y and Krull, KR and Cheung, YT}, title = {Functional Outcomes and Social Attainment in Asian/Pacific Islander Childhood Cancer Survivors in the United States: A Report from the Childhood Cancer Survivor Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0628}, pmid = {34607839}, issn = {1538-7755}, abstract = {BACKGROUND: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors.<br><br>METHODS: This study included 203 API five-year survivors (age at follow-up: 29.2 [SD=6.3] years) and 12,186 NHW survivors (age at follow-up 31.5[SD=7.3] years) from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment.<br><br>RESULTS: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors (mean 54.11 [SD=8.98] vs. 51.32 [SD=10.12]; P<.001). NHW survivors were less likely to have attained at least a college degree than API survivors (odds ratio[OR]=0.50; 95% confidence interval[CI]=0.34, 0.73). API survivors were more likely than NHW survivors to be never-married (OR=2.83, 95% CI=1.93, 4.13) and to live dependently (OR=3.10; 95% CI=2.02, 4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P's<0.05).<br><br>CONCLUSION: We observed differences in social attainment between API and NHW survivors, though statistically significant differences in neurocognitive and emotional outcomes were not identified.<br><br>IMPACT: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.}, }
@article {pmid34653370, year = {2021}, author = {Duggan, C and Trapani, D and Ilbawi, AM and Fidarova, E and Laversanne, M and Curigliano, G and Bray, F and Anderson, BO}, title = {National health system characteristics, breast cancer stage at diagnosis, and breast cancer mortality: a population-based analysis.}, journal = {The Lancet. Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1470-2045(21)00462-9}, pmid = {34653370}, issn = {1474-5488}, abstract = {BACKGROUND: In some countries, breast cancer age-standardised mortality rates have decreased by 2-4% per year since the 1990s, but others have yet to achieve this outcome. In this study, we aimed to characterise the associations between national health system characteristics and breast cancer age-standardised mortality rate, and the degree of breast cancer downstaging correlating with national age-standardised mortality rate reductions.<br><br>METHODS: In this population-based study, national age-standardised mortality rate estimates for women aged 69 years or younger obtained from GLOBOCAN 2020 were correlated with a broad panel of standardised national health system data as reported in the WHO Cancer Country Profiles 2020. These health system characteristics include health expenditure, the Universal Health Coverage Service Coverage Index (UHC Index), dedicated funding for early detection programmes, breast cancer early detection guidelines, referral systems, cancer plans, number of dedicated public and private cancer centres per 10 000 patients with cancer, and pathology services. We tested for differences between continuous variables using the non-parametric Kruskal-Wallis test, and for categorical variables using the Pearson χ2 test. Simple and multiple linear regression analyses were fitted to identify associations between health system characteristics and age-standardised breast cancer mortality rates. Data on TNM stage at diagnosis were obtained from national or subnational cancer registries, supplemented by a literature review of PubMed from 2010 to 2020. Mortality trends from 1950 to 2016 were assessed using the WHO Cancer Mortality Database. The threshold for significance was set at a p value of 0·05 or less.<br><br>FINDINGS: 148 countries had complete health system data. The following variables were significantly higher in high-income countries than in low-income countries in unadjusted analyses: health expenditure (p=0·0002), UHC Index (p<0·0001), dedicated funding for early detection programmes (p=0·0020), breast cancer early detection guidelines (p<0·0001), breast cancer referral systems (p=0·0030), national cancer plans (p=0·014), cervical cancer early detection programmes (p=0·0010), number of dedicated public (p<0·0001) and private (p=0·027) cancer centres per 10 000 patients with cancer, and pathology services (p<0·0001). In adjusted multivariable regression analyses in 141 countries, two health system characteristics were significantly associated with lower age-standardised mortality rates: higher UHC Index levels (β=-0·12, 95% CI -0·16 to -0·08) and increasing numbers of public cancer centres (β=-0·23, -0·36 to -0·10). These findings indicate that each unit increase in the UHC Index was associated with a 0·12-unit decline in age-standardised mortality rates, and each additional public cancer centre per 10 000 patients with cancer was associated with a 0·23-unit decline in age-standardised mortality rate. Among 35 countries with available breast cancer TNM staging data, all 20 that achieved sustained mean reductions in age-standardised mortality rate of 2% or more per year for at least 3 consecutive years since 1990 had at least 60% of patients with invasive breast cancer presenting as stage I or II disease. Some countries achieved this reduction without most women having access to population-based mammographic screening.<br><br>INTERPRETATION: Countries with low breast cancer mortality rates are characterised by increased levels of coverage of essential health services and higher numbers of public cancer centres. Among countries achieving sustained mortality reductions, the majority of breast cancers are diagnosed at an early stage, reinforcing the value of clinical early diagnosis programmes for improving breast cancer outcomes.<br><br>FUNDING: None.}, }
@article {pmid34653248, year = {2021}, author = {Docampo, MD and Burgos da Silva, M and Lazrak, A and Nichols, KB and Lieberman, SR and Slingerland, AE and Armijo, GK and Shono, Y and Nguyen, CL and Monette, S and Dwomoh, E and Lee, N and Geary, CD and Perobelli, SM and Smith, M and Markey, KA and Vardhana, SA and Kousa, AI and Zamir, E and Greenfield, I and Sun, JC and Cross, JR and Peled, JU and Jenq, RR and Stein-Thoeringer, C and van den Brink, MRMR}, title = {Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021010719}, pmid = {34653248}, issn = {1528-0020}, abstract = {The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared to recipients of wild type T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at steady state, following allo-activation Gpr109a-/- T cells underwent increased apoptosis and had impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetyl cysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.}, }
@article {pmid34652432, year = {2021}, author = {Townsend, MK and Trabert, B and Fortner, RT and Arslan, AA and Buring, JE and Carter, BD and Giles, GG and Irvin, SR and Jones, ME and Kaaks, R and Kirsh, VA and Knutsen, SF and Koh, WP and Lacey, JV and Langseth, H and Larsson, SC and Lee, IM and Martínez, ME and Merritt, MA and Milne, RL and O'Brien, KM and Orlich, MJ and Palmer, JR and Patel, AV and Peters, U and Poynter, JN and Robien, K and Rohan, TE and Rosenberg, L and Sandin, S and Sandler, DP and Schouten, LJ and Setiawan, VW and Swerdlow, AJ and Ursin, G and van den Brandt, PA and Visvanathan, K and Weiderpass, E and Wolk, A and Yuan, JM and Zeleniuch-Jacquotte, A and Tworoger, SS and Wentzensen, N}, title = {Cohort Profile: The Ovarian Cancer Cohort Consortium (OC3).}, journal = {International journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ije/dyab211}, pmid = {34652432}, issn = {1464-3685}, support = {W81XWH-12-1-0561//U.S. Department of Defense Ovarian Cancer Research Program/ ; R01 CA258679/CA/NCI NIH HHS/United States ; //Intramural Research Program of the National Cancer Institute at the National Institutes of Health/ ; 1U01CA152939//National Cancer Institute at the National Institutes of Health/ ; 2009/93//World Cancer Research Fund/ ; //Ardmore Institute of Health (Adventist Health Study II)/ ; //American Cancer Society and National Cancer Institute at the National Institutes of Health (Breast Cancer Detection Demonstration Project)/ ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA39742//National Cancer Institute at the National Institutes of Health/ ; CA164973//National Cancer Institute at the National Institutes of Health/ ; //Intramural Research Program of the National Cancer Institute at the National Institutes of Health/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA182934/CA/NCI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; Z01ES044005//Intramural Research Program of the National Institute of Environmental Health Sciences at the National Institutes of Health/ ; //Swedish Research Council (Swedish Mammography Cohort)/ ; K05 CA154337/CA/NCI NIH HHS/United States ; CA047988/CA/NCI NIH HHS/United States ; HL043851//National Heart, Lung, and Blood Institute at the National Institutes of Health/ ; U01 CA199277/CA/NCI NIH HHS/United States ; //California Department of Public Health pursuant to California Health and Safety Code Section 103885/ ; 5NU58DP006344//Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; HHSN261201800032I/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; //Intramural Research Program of the American Cancer Society/ ; //National Cancer Institute at the National Institutes of Health Intramural Research Program/ ; //European Commission (DG-SANCO) and the International Agency for Research on Cancer/ ; //Danish Cancer Society (Denmark)/ ; //Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France)/ ; //German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany)/ ; //Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy)/ ; //Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands)/ ; PI13/00061//Health Research Fund (FIS)/ ; RD06/0020//EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC/ ; //Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden)/ ; 14136 to EPIC-Norfolk/CRUK_/Cancer Research UK/United Kingdom ; 1000143/MRC_/Medical Research Council/United Kingdom ; //Breakthrough Breast Cancer and the Institute of Cancer Research/ ; //VicHealth and Cancer Council Victoria/ ; 209057/WT_/Wellcome Trust/United Kingdom ; //Cancer Council Victoria/ ; //Swedish Cancer Society and Swedish Research Council/ ; }, }
@article {pmid34651254, year = {2021}, author = {Lorona, NC and Malone, KE and Li, CI}, title = {Racial/ethnic disparities in risk of breast cancer mortality by molecular subtype and stage at diagnosis.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {34651254}, issn = {1573-7217}, support = {3R01CA189184-04S1/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Previous research has found significant survival disparities between Black and White women among select stages and subtypes of breast cancer, however other racial/ethnic groups have been less well-studied. This study expands on previous research, examining differences in breast cancer-specific mortality across multiple racial and ethnic groups.<br><br>METHODS: Women diagnosed with a first primary invasive breast cancer between 2010 and 2016 who were 20-85 years of age at diagnosis were identified from 18 Surveillance, Epidemiology, and End Results (SEER) registries. Subtypes were defined by joint hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Cox proportional hazards models for each stage and subtype were fit, with non-Hispanic white women as the reference group. Effect modification by age at diagnosis (< 50, ≥ 50) was found and thus analyses were age-stratified.<br><br>RESULTS: After multivariable adjustment, younger Black women had greater risks of breast cancer-specific death for all stages of HR+/HER2-, and certain stages of HR+/HER2+ , TN, and HR-/HER2 + breast cancer. Asian/Pacific Islander women generally had a lower hazard of breast cancer-specific death. Older Hispanic White women had a lower hazard of breast cancer-specific death for stages I-III HR + /HER2- and stage II TN breast cancer.<br><br>CONCLUSIONS: These findings demonstrate that different racial/ethnic groups experience different risks of breast cancer-specific mortality by stage and subtype. Efforts to address survival disparities should place additional focus on young Black women, as they experience meaningful disparities in breast cancer-specific mortality.}, }
@article {pmid34651094, year = {2021}, author = {Martin, NA and Tepper, JE and Giri, VN and Stinchcombe, TE and Cheng, HH and Javle, MM and Konnick, EQ}, title = {Adopting Consensus Terms for Testing in Precision Medicine.}, journal = {JCO precision oncology}, volume = {5}, number = {}, pages = {}, pmid = {34651094}, issn = {2473-4284}, abstract = {Despite the well-understood benefits of biomarker and genetic testing in precision medicine, uptake remains low, particularly for patients with low socioeconomic status and minority ethnic backgrounds. Patients report having limited familiarity with testing terminology and may not be able to accurately explain testing's role in treatment decisions. Patient confusion and lack of understanding is exacerbated by a multiplicity of overlapping terms used in communicating about testing. A LUNGevity Foundation-led working group composed of five professional societies, 23 patient advocacy groups, and 19 industry members assessed and recommended specific terms for communicating with patients on testing for tumor characteristics and germline mutations.<br><br>METHODS: Members completed a precision oncology testing framework analysis (biomarkers, germline variants, testing modalities, biospecimen, and commonly used testing terms) for nine solid tumors and blood cancers. The evaluation was segmented into terms that distinguish between somatic and germline testing. Additional data were captured in a comprehensive survey (1,650 respondents) led by FORCE (Facing Our Risk of Cancer Empowered) on patient preferences on germline testing terms.<br><br>RESULTS: Thirty-three terms were noted in patient education related to biomarker, genetic, and genomic testing. Biomarker testing was selected as the preferred term for testing for somatic (acquired) alterations and other biomarkers. Genetic testing for an inherited mutation and genetic testing for inherited cancer risk were selected as the preferred terms for testing for germline variants.<br><br>CONCLUSION: Democratizing comprehension about precision oncology testing through intentional use of plain language and common umbrella terminology by oncology health care providers and others in the oncology ecosystem may help improve understanding and communication, and facilitate shared decision making about the role of appropriate testing in treatment decisions and other aspects of oncology care.}, }
@article {pmid34650833, year = {2021}, author = {Hasanov, M and Milton, DR and Sharfman, WH and Taback, B and Cranmer, LD and Daniels, GA and Flaherty, L and Hallmeyer, S and Milhem, M and Feun, L and Hauke, R and Doolittle, G and Gregory, N and Patel, S}, title = {An Open-Label, Randomized, Multi-Center Study Comparing the Sequence of High Dose Aldesleukin (Interleukin-2) and Ipilimumab (Yervoy) in Patients with Metastatic Melanoma.}, journal = {Oncoimmunology}, volume = {10}, number = {1}, pages = {1984059}, pmid = {34650833}, issn = {2162-402X}, abstract = {Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.}, }
@article {pmid34649960, year = {2021}, author = {Bastani, R and Glenn, BA and Singhal, R and Crespi, CM and Nonzee, NJ and Tsui, J and Chang, LC and Herrmann, AK and Taylor, VM}, title = {Increasing HPV Vaccination among Low-income, Ethnic Minority Adolescents: Effects of a Multicomponent System Intervention through a County Health Department Hotline.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-1578}, pmid = {34649960}, issn = {1538-7755}, abstract = {BACKGROUND: Introduction of the human papillomavirus (HPV) vaccine in 2006 was a game-changing advance in cancer control. Despite the vaccine's potential cancer prevention benefits, uptake remains low. We utilized a randomized design to evaluate a multicomponent intervention to improve HPV vaccine uptake among low-income, ethnic minority adolescents seeking services through a county health department telephone hotline.<br><br>METHODS: Hotline callers who were caregivers of never-vaccinated adolescents (11-17 years) were randomized by call-week to intervention or control conditions. The intervention included brief telephone and print education, delivered in multiple languages, and personalized referral to a low-cost/free vaccine provider. Participants completed baseline (n=238), 3-month (n=215), and 9-month (n=204) telephone follow-up surveys.<br><br>RESULTS: HPV vaccine initiation rates increased substantially by 9-month follow-up overall, though no differences were observed between intervention and control groups (45% vs. 42%, respectively, p>0.05). We also observed significant improvements in perceived HPV risk, barriers to vaccination, and perceived knowledge in both study conditions (p<0.05).<br><br>CONCLUSIONS: A low-intensity county hotline intervention did not produce a greater increase in HPV vaccination rates than routine practice. However, 44% of unvaccinated adolescents in both conditions received at least one dose of the vaccine, which can be viewed as a successful public health outcome. Future studies should evaluate more intensive interventions that address accessing and utilizing services in complex safety net settings.<br><br>IMPACT: Study results suggest the need for investigators to be aware of the potential priming effects of study participation, which may obscure the effect of low-intensity interventions.}, }
@article {pmid34649279, year = {2021}, author = {Lazaryan, A and Lee, SJ and Arora, M and Kim, J and Betts, BC and Khimani, F and Nishihori, T and Bejanyan, N and Liu, H and Kharfan-Dabaja, MA and Locke, FL and Gonzalez, R and Jain, MD and Davila, ML and Perez, LE and Mishra, A and Perez Perez, A and Balke, K and Ayala, E and Ochoa, L and Castaneda Puglianini, O and Faramand, RG and Alsina, M and Elmariah, H and Nieder, M and Fernandez, H and Anasetti, C and Pidala, J}, title = {Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005552}, pmid = {34649279}, issn = {2473-9537}, abstract = {Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.}, }
@article {pmid34649272, year = {2021}, author = {Chow, VA and Cassaday, RD and Gooley, TA and Smith, SD and Sandmaier, BM and Green, DJ and Orozco, JJ and Tuazon, SA and Matesan, M and Fisher, DR and Maloney, DG and Press, OW and Gopal, AK}, title = {Mega-dose 90Y-Ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005056}, pmid = {34649272}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCL), though outcomes are worse in aggressive disease and most patients will still experience relapse. Radioimmunotherapy (RIT) using 90Y-Ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that mega-doses of 90Y-Ibritumomab tiuxetan with reduced-intensity conditioning (RIC) could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-Ibritumomab tiuxetan (1.5mCi/kg, maximum 120mCi), fludarabine, then 2Gy total body irradiation (TBI) prior to HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y activity of 113.6 mCi (range 71.2-129.2) was administered delivering a median of 552cGy to liver (range 499-2411cGy). The estimated 1 and 5-year PFS was 55% (95% CI, 31-73%) and 50% (95% CI, 27-69%) with a median PFS of 1.57 years. The estimated 1- and 5-year overall survival (OS) was 80% (95% CI, 54-92%) and 63% (95% CI, 38-81%) with a median OS of 6.45 years. Sixteen patients (80%) experienced grade ≥3 toxicities, although nonrelapse mortality was 10% at 1-year. No patients developed secondary AML/MDS. Mega-dose 90Y-Ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified endpoint while producing nonhematologic toxicities comparable to standard RIC regimens. (Registered at ClinicalTrials.gov as NCT01434472).}, }
@article {pmid34648489, year = {2021}, author = {Zarnitsyna, VI and Akondy, RS and Ahmed, H and McGuire, DJ and Zarnitsyn, VG and Moore, M and Johnson, PLF and Ahmed, R and Li, KW and Hellerstein, MK and Antia, R}, title = {Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination.}, journal = {PLoS computational biology}, volume = {17}, number = {10}, pages = {e1009468}, doi = {10.1371/journal.pcbi.1009468}, pmid = {34648489}, issn = {1553-7358}, abstract = {Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency of YFV-specific memory CD8 T cells and deuterium enrichment in those cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.1% per day, ∼ double the estimated values for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically.}, }
@article {pmid34648466, year = {2021}, author = {Cranmer, LD and Chau, B and Mantilla, JG and Loggers, ET and Pollack, SM and Kim, TS and Kim, EY and Kane, GM and Thompson, MJ and Harwood, JL and Wagner, MJ}, title = {Is Chemotherapy Associated with Improved Overall Survival in Patients with Dedifferentiated Chondrosarcoma? A SEER Database Analysis.}, journal = {Clinical orthopaedics and related research}, volume = {}, number = {}, pages = {}, doi = {10.1097/CORR.0000000000002011}, pmid = {34648466}, issn = {1528-1132}, abstract = {BACKGROUND: Dedifferentiated chondrosarcoma is a chondrosarcoma subtype associated with high rates of recurrence and a poor prognosis. Others have proposed treatment of dedifferentiated chondrosarcoma using osteosarcoma protocols, including perioperative chemotherapy. However, the rarity of this condition poses difficulties in undertaking single- institution studies of sufficient sample size.<br><br>QUESTION/PURPOSE: Is perioperative chemotherapy associated with improved overall survival in patients with dedifferentiated chondrosarcoma?<br><br>METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) 1973 to 2016 database for patients with a diagnosis of dedifferentiated chondrosarcoma (n = 308). As dedifferentiated chondrosarcoma was only classified as a distinct entity in SEER starting in 2000, only patients treated in 2000 and later were included. We excluded from our analyses those patients with distant disease at diagnosis, a primary site of disease other than bone or joints, and those who did not receive cancer-directed surgery. These criteria yielded 185 dedifferentiated chondrosarcoma patients for inclusion. We used Kaplan-Meier analyses and Cox proportional hazards models to assess the association of clinical, demographic, and treatment characteristics on overall survival (OS).<br><br>RESULTS: After controlling for confounding variables, including age, sex, tumor size, stage, grade, location, and radiation treatment status, and after adjusting for missing data, no overall survival benefit was associated with receipt of chemotherapy in patients with dedifferentiated chondrosarcoma (hazard ratio 0.75 [95% confidence interval 0.49 to 1.12]; p = 0.16).<br><br>CONCLUSION: Chemotherapy treatment of dedifferentiated chondrosarcoma was not associated with improved OS. These results must be viewed cautiously, given the limited granularity of information on chemotherapy treatment, the concerns regarding chemotherapy misclassification in SEER data, and the small sample of patients with dedifferentiated chondrosarcoma, all of which limit the power to detect a difference. Our findings are nevertheless consistent with those of prior reports in which no benefit of chemotherapy could be detected. Lack of clear benefit from perioperative chemotherapy in dedifferentiated chondrosarcoma argues that it should be used only after careful consideration, and ideally in the context of a clinical trial.<br><br>LEVEL OF EVIDENCE: Level III, therapeutic study.}, }
@article {pmid34648061, year = {2021}, author = {Knoerl, R and Giobbie-Hurder, A and Sannes, TS and Chagpar, AB and Dillon, D and Dominici, LS and Frank, ES and Golshan, M and McTiernan, A and Rhei, E and Tolaney, SM and Winer, EP and Yung, RL and Irwin, ML and Ligibel, JA}, title = {Exploring the impact of exercise and mind-body prehabilitation interventions on physical and psychological outcomes in women undergoing breast cancer surgery.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {}, number = {}, pages = {}, pmid = {34648061}, issn = {1433-7339}, support = {SPSWHR1001//susan g. komen (society for women's health)/ ; no grant number//american institute for cancer research/ ; }, abstract = {PURPOSE: To compare the impact of exercise and mind-body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer.<br><br>METHODS: The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind-body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models.<br><br>RESULTS: Mind-body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind-body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind-body: average change = -2.59, p = 0.05, d = 0.29), while mind-body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67).<br><br>CONCLUSIONS: Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind-body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012.}, }
@article {pmid34647959, year = {2021}, author = {Sarangapani, KK and Koch, LB and Nelson, CR and Asbury, CL and Biggins, S}, title = {Kinetochore-bound Mps1 regulates kinetochore-microtubule attachments via Ndc80 phosphorylation.}, journal = {The Journal of cell biology}, volume = {220}, number = {12}, pages = {}, doi = {10.1083/jcb.202106130}, pmid = {34647959}, issn = {1540-8140}, support = {DGE-1256082//National Science Foundation/ ; 2006-30521//Packard/ ; R01GM079373/NH/NIH HHS/United States ; //Fred Hutchinson/ ; P30 CA015704/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, abstract = {Dividing cells detect and correct erroneous kinetochore-microtubule attachments during mitosis, thereby avoiding chromosome missegregation. The Aurora B kinase phosphorylates microtubule-binding elements specifically at incorrectly attached kinetochores, promoting their release and providing another chance for proper attachments to form. However, growing evidence suggests that the Mps1 kinase is also required for error correction. Here we directly examine how Mps1 activity affects kinetochore-microtubule attachments using a reconstitution-based approach that allows us to separate its effects from Aurora B activity. When endogenous Mps1 that copurifies with kinetochores is activated in vitro, it weakens their attachments to microtubules via phosphorylation of Ndc80, a major microtubule-binding protein. This phosphorylation contributes to error correction because phospho-deficient Ndc80 mutants exhibit genetic interactions and segregation defects when combined with mutants in other error correction pathways. In addition, Mps1 phosphorylation of Ndc80 is stimulated on kinetochores lacking tension. These data suggest that Mps1 provides an additional mechanism for correcting erroneous kinetochore-microtubule attachments, complementing the well-known activity of Aurora B.}, }
@article {pmid34645978, year = {2021}, author = {Huang, D and Savage, SR and Calinawan, AP and Lin, C and Zhang, B and Wang, P and Starr, TK and Birrer, MJ and Paulovich, AG}, title = {A highly annotated database of genes associated with platinum resistance in cancer.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, pmid = {34645978}, issn = {1476-5594}, support = {U01CA214114//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R21CA216652//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U01CA214114//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; W81XWH-16-2-0038//United States Department of Defense | United States Army | Army Medical Command | Medical Research and Materiel Command (U.S. Army Medical Research and Materiel Command)/ ; U24CA210993//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .}, }
@article {pmid34645621, year = {2021}, author = {Finn, OJ and Bhardwaj, N and Fling, SP and Kaiser, JC}, title = {Martin A. "Mac" Cheever, MD: In Memoriam (1944-2021).}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-21-0823}, pmid = {34645621}, issn = {2326-6074}, }
@article {pmid34644605, year = {2021}, author = {Summers, C and Wu, QV and Annesley, C and Bleakley, M and Dahlberg, A and Narayanaswamy, P and Huang, W and Voutsinas, J and Brand, A and Leisenring, W and Jensen, MC and Park, JR and Gardner, RA}, title = {Hematopoietic cell transplantation after CD19 CAR T cell-induced ALL remission confers leukemia-free survival advantage.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.10.003}, pmid = {34644605}, issn = {2666-6367}, abstract = {BACKGROUND: Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment.<br><br>OBJECTIVES: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission.<br><br>STUDY DESIGN: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a Phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled onto PLAT-02 Phase 1 and early Phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed or died prior to day 63 post-CAR T cell therapy.<br><br>RESULTS: An improved LFS (P=0.01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend towards significance (P=0.09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of a prior HCT (P=0.45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P=0.01).<br><br>CONCLUSIONS: These data support consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT or for those with short functional CAR T cell persistence.}, }
@article {pmid34644414, year = {2021}, author = {Chow, EJ and Aplenc, R and Vrooman, LM and Doody, DR and Huang, YV and Aggarwal, S and Armenian, SH and Baker, KS and Bhatia, S and Constine, LS and Freyer, DR and Kopp, LM and Leisenring, WM and Asselin, BL and Schwartz, CL and Lipshultz, SE}, title = {Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33974}, pmid = {34644414}, issn = {1097-0142}, support = {P30 CA21765/CA/NCI NIH HHS/United States ; R01 CA211996/CA/NCI NIH HHS/United States ; U10 CA095861/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U24 CA55727/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; //St. Baldrick's Foundation/ ; //American Lebanese Syrian Associated Charities/ ; 6243-13//Leukemia and Lymphoma Society/ ; }, abstract = {BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.<br><br>METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.<br><br>RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).<br><br>CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.}, }
@article {pmid34644389, year = {2021}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Kwon, DM and Nez Henderson, P and Nelson, LA and Patten, CA and Bricker, JB}, title = {Efficacy and Utilization of Smartphone Applications for Smoking Cessation among American Indians and Alaska Natives: Results from the iCanQuit Trial.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntab213}, pmid = {34644389}, issn = {1469-994X}, abstract = {INTRODUCTION: There is tremendous need for efficacious and accessible interventions for smoking cessation among American Indians and Alaska Natives. We tested the efficacy of an Acceptance and Commitment Therapy (ACT)-based smartphone application (iCanQuit) vs. US Clinical Practice Guidelines based smartphone application (QuitGuide) for smoking cessation among American Indians and Alaska Natives.<br><br>METHODS: We compared cessation, changes in ACT-based processes, engagement and satisfaction between American Indians and Alaska Natives iCanQuit (n=89) and QuitGuide (n=80) trial participants enrolled in the iCanQuit trial. The primary outcome was self-reported, complete-case, 30-day point-prevalence abstinence (PPA). Follow-up timepoints were 12, 6, and 3-months.<br><br>RESULTS: Randomized American Indians and Alaska Natives from 31 US states (70% urban, 30% rural, with 25% of participants residing on tribal land). The outcome data retention rates were 93%, 92%, and 90% at the 12, 6, and 3-month follow-ups, respectively, with no differential retention between arms. The 30-day PPA for iCanQuit vs. QuitGuide was 30% vs. 18% at 12-months (OR=1.96; 95% CI: 0.90, 4.26) 25% vs. 11% at 6-months (OR=2.62; 95% CI: 1.06, 6.45), and 15% vs. 6% at 3-months (OR=2.93; 95% CI: 0.90, 9.59). Increases in acceptance of internal cues to smoke mediated the effect of treatment on smoking cessation at 12-months. iCanQuit arm participants were also significantly more engaged and satisfied with their assigned application.<br><br>CONCLUSIONS: In a nationwide sample with high data retention and participant engagement, this is the first study to show that a digital intervention may be efficacious for helping American Indians and Alaska Natives quit smoking.<br><br>IMPLICATONS: This is the first study to provide evidence of an efficacious, accessible, and engaging treatment for helping American Indians and Alaska Natives quit smoking. Compared to a USCPG-based smartphone application (QuitGuide), an ACT-based smartphone application (iCanQuit) was more efficacious, engaging, and satisfactory among American Indians and Alaska Natives nationwide. Our results will inform the tailoring of the iCanQuit smartphone application for American Indian and Alaska Native tribal communities and organizations with potential for broad dissemination and high impact.}, }
@article {pmid34644300, year = {2021}, author = {Forsberg, KJ and Schmidtke, DT and Werther, R and Uribe, RV and Hausman, D and Sommer, MOA and Stoddard, BL and Kaiser, BK and Malik, HS}, title = {The novel anti-CRISPR AcrIIA22 relieves DNA torsion in target plasmids and impairs SpyCas9 activity.}, journal = {PLoS biology}, volume = {19}, number = {10}, pages = {e3001428}, doi = {10.1371/journal.pbio.3001428}, pmid = {34644300}, issn = {1545-7885}, abstract = {To overcome CRISPR-Cas defense systems, many phages and mobile genetic elements (MGEs) encode CRISPR-Cas inhibitors called anti-CRISPRs (Acrs). Nearly all characterized Acrs directly bind Cas proteins to inactivate CRISPR immunity. Here, using functional metagenomic selection, we describe AcrIIA22, an unconventional Acr found in hypervariable genomic regions of clostridial bacteria and their prophages from human gut microbiomes. AcrIIA22 does not bind strongly to SpyCas9 but nonetheless potently inhibits its activity against plasmids. To gain insight into its mechanism, we obtained an X-ray crystal structure of AcrIIA22, which revealed homology to PC4-like nucleic acid-binding proteins. Based on mutational analyses and functional assays, we deduced that acrIIA22 encodes a DNA nickase that relieves torsional stress in supercoiled plasmids. This may render them less susceptible to SpyCas9, which uses free energy from negative supercoils to form stable R-loops. Modifying DNA topology may provide an additional route to CRISPR-Cas resistance in phages and MGEs.}, }
@article {pmid34644150, year = {2021}, author = {Kalia, V and Yuzefpolskiy, Y and Vegaraju, A and Xiao, H and Baumann, F and Jatav, S and Church, C and Prlic, M and Jha, A and Nghiem, P and Riddell, S and Sarkar, S}, title = {Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.}, journal = {Science translational medicine}, volume = {13}, number = {615}, pages = {eaba6006}, doi = {10.1126/scitranslmed.aba6006}, pmid = {34644150}, issn = {1946-6242}, abstract = {[Figure: see text].}, }
@article {pmid34637965, year = {2021}, author = {Bhatt, VR and Wang, T and Chen, K and Kitko, CL and MacMillan, ML and Pidala, JA and Malki, MMA and Badawy, SM and Beitinjaneh, A and Ganguly, S and Hamilton, B and Hildebrandt, GC and Lekakis, LJ and Liu, H and Maziarz, RT and Modi, D and Murthy, HS and Preussler, JM and Sharma, A and Spellman, SR and Arora, M and Lee, SJ}, title = {Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.10.002}, pmid = {34637965}, issn = {2666-6367}, abstract = {BACKGROUND: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).<br><br>METHODS: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.<br><br>RESULTS: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.<br><br>CONCLUSIONS: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.}, }
@article {pmid34637399, year = {2021}, author = {Inoue, T and Koyama, M and Kaida, K and Ikegame, K and Ensbey, KS and Samson, L and Takahashi, S and Zhang, P and Minnie, SA and Maruyama, S and Ishii, S and Daimon, T and Fukuda, T and Nakamae, H and Ara, T and Maruyama, Y and Ishiyama, K and Ichinohe, T and Atsuta, Y and Blazar, BR and Furlan, SN and Ogawa, H and Hill, GR}, title = {Peri-transplant glucocorticoids redistribute donor T-cells to the bone marrow and prevent relapse after haploidentical SCT.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.153551}, pmid = {34637399}, issn = {2379-3708}, abstract = {Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency. This results in significant reductions in GVHD whilst promoting potent GVL effects (relapse in recipients receiving glucocorticoids, vehicle or PT-Cy was 12%, 56% and 100% respectively). Intriguingly, patients with acute myeloid leukemia not in remission that received unmanipulated haplo-SCT and peri-transplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%: 95% CI, 18%-47%) with high overall survival at 3 years (58%: 95% CI, 38-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.}, }
@article {pmid34637337, year = {2021}, author = {Wagner, AJ and Ravi, V and Riedel, RF and Ganjoo, K and Van Tine, BA and Chugh, R and Cranmer, L and Gordon, EM and Hornick, JL and Du, H and Grigorian, B and Schmid, AN and Hou, S and Harris, K and Kwiatkowski, DJ and Desai, NP and Dickson, MA}, title = {nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2101728}, doi = {10.1200/JCO.21.01728}, pmid = {34637337}, issn = {1527-7755}, abstract = {PURPOSE: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570).<br><br>PATIENTS AND METHODS: Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.<br><br>RESULTS: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred.<br><br>CONCLUSION: nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.}, }
@article {pmid34636876, year = {2021}, author = {Huang, AS and Ramos, V and Oliveira, TY and Gaebler, C and Jankovic, M and Nussenzweig, MC and Cohn, LB}, title = {Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.}, journal = {The Journal of experimental medicine}, volume = {218}, number = {12}, pages = {}, doi = {10.1084/jem.20211427}, pmid = {34636876}, issn = {1540-9538}, support = {//National Institute of Allergy and Infectious Diseases/ ; UM1AI126611/NH/NIH HHS/United States ; OPP1092074//Bill and Melinda Gates Foundation/ ; 1P30AI124414-01A1//Einstein-Rockefeller-City University of New York Center for AIDS Research/ ; UM1 AI126620/AI/NIAID NIH HHS/United States ; //Robertson Foundation/ ; //Robert S. Wennett Post-Doctoral Fellowship/ ; /TR/NCATS NIH HHS/United States ; UL1 TR001866/NH/NIH HHS/United States ; //Shapiro-Silverberg Fund for the Advancement of Translational Research/ ; UM1AI164565/NH/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, abstract = {Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain-containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.}, }
@article {pmid34636627, year = {2021}, author = {Sartor, O and George, D and Tombal, B and Agarwal, N and Higano, CS and Sternberg, CN and Miller, K and Jiao, X and Guo, H and Sandström, P and Bruno, A and Verholen, F and Saad, F and Shore, N}, title = {Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.2217/fon-2021-0886}, pmid = {34636627}, issn = {1744-8301}, support = {//Bayer HealthCare/ ; }, abstract = {Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients &amp; methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.}, }
@article {pmid34635391, year = {2021}, author = {Thomas, R and Chansinghakul, D and Limkittikul, K and Gilbert, PB and Hattasingh, W and Moodie, Z and Shangguan, S and Frago, C and Dulyachai, W and Li, SS and Jarman, RG and Geretz, A and Bouckenooghe, A and Sabchareon, A and Juraska, M and Ehrenberg, P and Michael, NL and Bailleux, F and Bryant, C and Gurunathan, S}, title = {Associations of human leukocyte antigen with neutralizing antibody titers in a tetravalent dengue vaccine phase 2 efficacy trial in Thailand.}, journal = {Human immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.humimm.2021.09.006}, pmid = {34635391}, issn = {1879-1166}, abstract = {The recombinant, live, attenuated, tetravalent dengue vaccine CYD-TDV has shown efficacy against all four dengue serotypes. In this exploratory study (CYD59, NCT02827162), we evaluated potential associations of host human leukocyte antigen (HLA) alleles with dengue antibody responses, CYD-TDV vaccine efficacy, and virologically-confirmed dengue (VCD) cases. Children 4-11 years old, who previously completed a phase 2b efficacy study of CYD-TDV in a single center in Thailand, were included in the study. Genotyping of HLA class I and II loci was performed by next-generation sequencing from DNA obtained from 335 saliva samples. Dengue neutralizing antibody titers (NAb) were assessed as a correlate of risk and protection. Regression analyses were used to assess associations between HLA alleles and NAb responses, vaccine efficacy, and dengue outcomes. Month 13 NAb log geometric mean titers (GMTs) were associated with decreased risk of VCD. In the vaccine group, HLA-DRB1*11 was significantly associated with higher NAb log GMT levels (beta: 0.76; p = 0.002, q = 0.13). Additionally, in the absence of vaccination, HLA associations were observed between the presence of DPB1*03:01 and increased NAb log GMT levels (beta: 1.24; p = 0.005, q = 0.17), and between DPB1*05:01 and reduced NAb log GMT levels (beta: -1.1; p = 0.001, q = 0.07). This study suggests associations of HLA alleles with NAb titers in the context of dengue outcomes. This study was registered with clinicaltrials.gov: NCT02827162.}, }
@article {pmid34634254, year = {2021}, author = {Basu, P and Malvi, SG and Joshi, S and Bhatla, N and Muwonge, R and Lucas, E and Verma, Y and Esmy, PO and Poli, URR and Shah, A and Zomawia, E and Pimple, S and Jayant, K and Hingmire, S and Chiwate, A and Divate, U and Vashist, S and Mishra, G and Jadhav, R and Siddiqi, M and Sankaran, S and Prabhu, PR and Kannan, TPRA and Varghese, R and Shastri, SS and Anantharaman, D and Gheit, T and Tommasino, M and Sauvaget, C and Pillai, MR and Sankaranarayanan, R}, title = {Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.}, journal = {The Lancet. Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1470-2045(21)00453-8}, pmid = {34634254}, issn = {1474-5488}, abstract = {BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination.<br><br>METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp &amp; Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702.<br><br>FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed).<br><br>INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses.<br><br>FUNDING: Bill &amp; Melinda Gates Foundation.}, }
@article {pmid34633422, year = {2021}, author = {Nicholl, A and Deering, KE and Evelegh, K and Lyons-Wall, P and Lawrence, D and Mori, TA and Kratz, M and O'Sullivan, TA}, title = {Whole-fat dairy products do not adversely affect adiposity or cardiometabolic risk factors in children in the Milky Way Study: a double-blind randomized controlled pilot study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqab288}, pmid = {34633422}, issn = {1938-3207}, support = {12012//Telethon Kids Institute/ ; //Telethon Perth Children's Hospital Research Fund/ ; /DH_/Department of Health/United Kingdom ; TPCHRF R4 2015//Channel 7 Telethon Trust/ ; //Children's Diabetes Center/ ; //University of Western Australia/ ; //National Health and Medical Research Council of Australia/ ; }, abstract = {BACKGROUND: Limited evidence supports the common public health guideline that children >2 y of age should consume dairy with reduced fat content.<br><br>OBJECTIVES: We aimed to investigate the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity and biomarkers of cardiometabolic risk in healthy 4- to 6-y-old children.<br><br>METHODS: The Milky Way Study enrolled 49 children (mean ± SD age: 5.2 ± 0.9 y; 47% girls) who were habitual consumers of whole-fat dairy, then randomly assigned them in a double-blind fashion to remain on whole-fat dairy or switch their dairy consumption to reduced-fat products for 3 mo. Primary endpoints included measures of adiposity, body composition, blood pressure, fasting serum lipids, blood glucose, glycated hemoglobin (HbA1c), and C-reactive protein (CRP) and were assessed at baseline and study end. Pre- and postintervention results were compared using linear mixed models, adjusted for growth, age, and sex.<br><br>RESULTS: Dairy fat intake was reduced by an adjusted (mean ± SEM) 12.9 ± 4.1 g/d in the reduced-fat compared with the whole-fat dairy group (95% CI: -21.2, -4.6 g/d; P = 0.003), whereas dietary energy intakes remained similar (P = 0.936). We found no significant differential changes between dairy groups in any measure of adiposity, body composition, blood pressure, or fasting serum lipids, glucose, HbA1c, and CRP.<br><br>CONCLUSIONS: Our results suggest that although changing from whole-fat to reduced-fat dairy products does reduce dairy fat intake, it does not result in changes to markers of adiposity or cardiometabolic disease risk in healthy children.This trial was registered at www.anzctr.org.au as ACTRN12616001642471.}, }
@article {pmid34632583, year = {2021}, author = {Duetz, C and Cucchi, DGJ and Polak, TB and Janssen, JJWM and Ossenkoppele, GJ and Estey, EH and van de Loosdrecht, AA}, title = {The wider perspective: twenty years of clinical trials in myelodysplastic syndromes.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.17892}, pmid = {34632583}, issn = {1365-2141}, abstract = {Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS-specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.}, }
@article {pmid34632478, year = {2021}, author = {Hess, JM and Stephensen, CB and Kratz, M and Bolling, BW}, title = {Exploring the Links between Diet and Inflammation: Dairy Foods as Case Studies.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {12}, number = {Supplement_1}, pages = {1S-13S}, doi = {10.1093/advances/nmab108}, pmid = {34632478}, issn = {2156-5376}, support = {//National Dairy Council/ ; }, abstract = {Systemic chronic inflammation may be a contributing factor to many noncommunicable diseases, including diabetes, cardiovascular disease, and obesity. With the rapid rise of these conditions, identifying the causes of and treatment for chronic inflammation is an important research priority, especially with regard to modifiable lifestyle factors such as diet. An emerging body of evidence indicates that consuming certain foods, including dairy foods like milk, cheese, and yogurt, may be linked to a decreased risk for inflammation. To discuss both broader research on diet and inflammation as well as research on links between individual foods and inflammation, the National Dairy Council sponsored a satellite session entitled "Exploring the Links between Diet and Inflammation: Dairy Foods as Case Studies" at the American Society for Nutrition's 2020 LIVE ONLINE Conference. This article, a review based on the topics discussed during that session, explores the links between diet and inflammation, focusing most closely on the relations between intake of dairy fat and dairy foods like milk, cheese, and yogurt, and biomarkers of inflammation from clinical trials. While there is currently insufficient evidence to prove an "anti-inflammatory" effect of dairy foods, the substantial body of clinical research discussed in this review indicates that dairy foods do not increase concentrations of biomarkers of chronic systemic inflammation.}, }
@article {pmid34632388, year = {2021}, author = {Little, P and Jo, H and Hoyle, A and Mazul, A and Zhao, X and Salazar, AH and Farquhar, D and Sheth, S and Masood, M and Hayward, MC and Parker, JS and Hoadley, KA and Zevallos, J and Hayes, DN}, title = {UNMASC: tumor-only variant calling with unmatched normal controls.}, journal = {NAR cancer}, volume = {3}, number = {4}, pages = {zcab040}, doi = {10.1093/narcan/zcab040}, pmid = {34632388}, issn = {2632-8674}, abstract = {Despite years of progress, mutation detection in cancer samples continues to require significant manual review as a final step. Expert review is particularly challenging in cases where tumors are sequenced without matched normal control DNA. Attempts have been made to call somatic point mutations without a matched normal sample by removing well-known germline variants, utilizing unmatched normal controls, and constructing decision rules to classify sequencing errors and private germline variants. With budgetary constraints related to computational and sequencing costs, finding the appropriate number of controls is a crucial step to identifying somatic variants. Our approach utilizes public databases for canonical somatic variants as well as germline variants and leverages information gathered about nearby positions in the normal controls. Drawing from our cohort of targeted capture panel sequencing of tumor and normal samples with varying tumortypes and demographics, these served as a benchmark for our tumor-only variant calling pipeline to observe the relationship between our ability to correctly classify variants against a number of unmatched normals. With our benchmarked samples, approximately ten normal controls were needed to maintain 94% sensitivity, 99% specificity and 76% positive predictive value, far outperforming comparable methods. Our approach, called UNMASC, also serves as a supplement to traditional tumor with matched normal variant calling workflows and can potentially extend to other concerns arising from analyzing next generation sequencing data.}, }
@article {pmid34630506, year = {2021}, author = {Guimarães Alves, AC and Sukow, NM and Adelman Cipolla, G and Mendes, M and Leal, TP and Petzl-Erler, ML and Lehtonen Rodrigues Souza, R and Rainha de Souza, I and Sanchez, C and Santolalla, M and Loesch, D and Dean, M and Machado, M and Moon, JY and Kaplan, R and North, KE and Weiss, S and Barreto, ML and Lima-Costa, MF and Guio, H and Cáceres, O and Padilla, C and Tarazona-Santos, E and Mata, IF and Dieguez, E and Raggio, V and Lescano, A and Tumas, V and Borges, V and Ferraz, HB and Rieder, CR and Schumacher-Schuh, A and Santos-Lobato, BL and Chana-Cuevas, P and Fernandez, W and Arboleda, G and Arboleda, H and Arboleda-Bustos, CE and O'Connor, TD and Beltrame, MH and Borda, V}, title = {Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {671079}, doi = {10.3389/fgene.2021.671079}, pmid = {34630506}, issn = {1664-8021}, abstract = {In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.}, }
@article {pmid34629570, year = {2021}, author = {Prentice, RL and Zhao, S}, title = {Regression Models and Multivariate Life Tables.}, journal = {Journal of the American Statistical Association}, volume = {116}, number = {535}, pages = {1330-1345}, doi = {10.1080/01621459.2020.1713792}, pmid = {34629570}, issn = {0162-1459}, abstract = {Semiparametric, multiplicative-form regression models are specified for marginal single and double failure hazard rates for the regression analysis of multivariate failure time data. Cox-type estimating functions are specified for single and double failure hazard ratio parameter estimation, and corresponding Aalen-Breslow estimators are specified for baseline hazard rates. Generalization to allow classification of failure times into a smaller set of failure types, with failures of the same type having common baseline hazard functions, is also included. Asymptotic distribution theory arises by generalization of the marginal single failure hazard rate estimation results of Danyu Lin, L.J. Wei and colleagues. The Péano series representation for the bivariate survival function in terms of corresponding marginal single and double failure hazard rates leads to novel estimators for pairwise bivariate survival functions and pairwise dependency functions, at specified covariate history. Related asymptotic distribution theory follows from that for the marginal single and double failure hazard rates and the continuity, compact differentiability of the Péano series transformation and bootstrap applicability. Simulation evaluation of the proposed estimation procedures are presented, and an application to multiple clinical outcomes in the Women's Health Initiative Dietary Modification Trial is provided. Higher dimensional marginal hazard rate regression modeling is briefly mentioned.}, }
@article {pmid34629415, year = {2021}, author = {Longino, AA and Paul, R and Wang, Y and Lama, JR and Brandes, P and Ruiz, E and Correa, C and Keating, S and Spudich, SS and Pilcher, C and Vecchio, A and Pasalar, S and Bender Ignacio, RA and Valdez, R and Dasgupta, S and Robertson, K and Duerr, A}, title = {HIV disease dynamics, markers of inflammation and CNS injury during primary HIV infection and their relationship to cognitive performance.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAI.0000000000002832}, pmid = {34629415}, issn = {1944-7884}, abstract = {INTRODUCTION: Early systemic and central nervous system viral replication and inflammation may impact brain integrity in people with HIV (PWH), leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART.<br><br>METHODS: HIV-infected MSM and transgender women (average age: 27 and education: 13 years) enrolled within 100 days from estimated date of detectable infection [EDDI]. A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n=87) and cerebrospinal fluid (CSF; n=29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ.<br><br>RESULTS: Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ=.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART.<br><br>CONCLUSIONS: Biomarkers of CNS inflammation, immune activation and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.}, }
@article {pmid34628439, year = {2021}, author = {Eastment, MC and Wanje, G and Richardson, BA and Mwaringa, E and Sherr, K and Barnabas, RV and Perla, M and Mandaliya, K and Jaoko, W and Mcclelland, RS}, title = {Results of a cluster randomized trial testing the systems analysis and improvement approach to increase HIV testing in family planning clinics in Mombasa, Kenya.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000003099}, pmid = {34628439}, issn = {1473-5571}, abstract = {OBJECTIVE: To test an implementation strategy, the Systems Analysis and Improvement Approach (SAIA), to increase rates of HIV testing and counseling (HTC) in family planning (FP) clinics in Mombasa, Kenya.<br><br>DESIGN: Cluster randomized trial.<br><br>METHODS: Twenty-four FP clinics were randomized 1:1 to implementing SAIA versus usual procedures. Study staff implemented monthly SAIA cycles with FP clinic staff for 12 months. SAIA has five steps. Step 1 uses a "cascade analysis" tool to quantify the number of individuals who complete each step of a process. Step 2 involves sequential process flow mapping to identify modifiable bottlenecks in the system. Step 3 develops and implements workflow modifications to address bottlenecks. Step 4 assesses impact of the modification by recalculating the cascade analysis. Step 5 repeats the cycle. The primary outcome was the proportion of new FP clients tested for HIV during the last quarter of the trial.<br><br>RESULTS: During the last three months of the trial, 85% (740/868) of new FP clients were counseled for HIV in intervention clinics compared to 67% (1036/1542) in control clinics (prevalence rate ratio [PRR] 1.27, 95% confidence interval [CI] 1.15-1.30). Forty-two percent (364/859) of FP clients were tested for HIV at intervention clinics compared to 32% (485/1521) at control clinics (PRR 1.33, 95%CI 1.16-1.52).<br><br>CONCLUSION: SAIA led to a significant increase in HIV testing in FP clinics in Mombasa. Integrating routine HTC into FP clinics is a promising strategy to achieve the UNAIDS goal of 95% of people living with HIV being aware of their status.}, }
@article {pmid34628209, year = {2021}, author = {Poudel, B and Desman, J and Aihara, G and Weidman, DI and Tsang, A and Kovrizhkin, K and Pereira, T and Arun, S and Pradeep, T and Matin, S and Liddell, RP}, title = {Adequacy of samples obtained via percutaneous core-needle rebiopsy for EGFR T790M molecular analysis in patients with non-small cell lung cancer following acquired resistance to first-line therapy: A systematic review and meta-analysis.}, journal = {Cancer treatment and research communications}, volume = {29}, number = {}, pages = {100470}, doi = {10.1016/j.ctarc.2021.100470}, pmid = {34628209}, issn = {2468-2942}, abstract = {MICRO ABSTRACT: Rebiopsies characterizing resistance mutations in patients with non-small cell lung cancer (NSCLC) can guide personalized medicine and improve overall survival rates. In this systematic review, we examine the suitability of percutaneous core-needle biopsy (PT-CNB) to obtain adequate samples for molecular characterization of the acquired resistance mutation T790M. This review provides evidence that PT-CNB can obtain samples with high adequacy, with a mutation detection rate that is in accordance with prior literature.<br><br>BACKGROUND: Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and has seen improved survival rates with the rise of personalized medicine. Resistance mutations to first-line therapies, such as T790M, however, render first-line therapies ineffective. Rebiopsies characterizing resistance mutations inform therapeutic decisions, which result in prolonged survival. Given the high efficacy of percutaneous core-needle biopsy (PT-CNB), we conducted the first systematic review to analyze the ability of PT-CNB to obtain samples of high adequacy in order to characterize the acquired resistance mutation T790M in patients with NSCLC.<br><br>METHODS: We performed a comprehensive literature search across PubMed, Embase, and CENTRAL. Search terms related to "NSCLC," "rebiopsy," and "PT-CNB" were used to obtain results. We included all prospective and retrospective studies that satisfied our inclusion and exclusion criteria. A random effects model was utilized to pool adequacy and detection rates of the chosen articles. We performed a systematic review, meta-analysis, and meta-regression to investigate the adequacy and T790M detection rates of samples obtained via PT-CNB.<br><br>RESULTS: Out of the 173 studies initially identified, 5 studies met the inclusion and exclusion criteria and were chosen for our final cohort of 436 patients for meta-analysis. The pooled adequacy rate of samples obtained via PT-CNB was 86.92% (95% CI: [79.31%, 92.0%]) and the pooled T790M detection rate was 46.0% (95% CI: [26.6%, 66.7%]). There was considerable heterogeneity among studies (I2 > 50%) in both adequacy and T790M detection rates.<br><br>CONCLUSION: PT-CNB can obtain adequate samples for T790M molecular characterization in NSCLC lung cancer patients. Additional prospective studies are needed to corroborate the results in this review.}, }
@article {pmid34628108, year = {2021}, author = {Madewell, ZJ and Dean, NE and Berlin, JA and Coplan, PM and Davis, KJ and Struchiner, CJ and Halloran, ME}, title = {Challenges of evaluating and modelling vaccination in emerging infectious diseases.}, journal = {Epidemics}, volume = {37}, number = {}, pages = {100506}, doi = {10.1016/j.epidem.2021.100506}, pmid = {34628108}, issn = {1878-0067}, abstract = {Outbreaks of emerging pathogens pose unique methodological and practical challenges for the design, implementation, and evaluation of vaccine efficacy trials. Lessons learned from COVID-19 highlight the need for innovative and flexible study design and application to quickly identify promising candidate vaccines. Trial design strategies should be tailored to the dynamics of the specific pathogen, location of the outbreak, and vaccine prototypes, within the regional socioeconomic constraints. Mathematical and statistical models can assist investigators in designing infectious disease clinical trials. We introduce key challenges for planning, evaluating, and modelling vaccine efficacy trials for emerging pathogens.}, }
@article {pmid34627796, year = {2021}, author = {Kim, CS and Grady, ST and Hart, JE and Laden, F and VoPham, T and Nguyen, DD and Manson, JE and James, P and Forman, JP and Rexrode, KM and Levy, JI and Peters, JL}, title = {Long-term aircraft noise exposure and risk of hypertension in the Nurses' Health Studies.}, journal = {Environmental research}, volume = {}, number = {}, pages = {112195}, doi = {10.1016/j.envres.2021.112195}, pmid = {34627796}, issn = {1096-0953}, abstract = {BACKGROUND: Aircraft noise can affect populations living near airports. Chronic exposure to aircraft noise has been associated with cardiovascular disease, including hypertension. However, previous studies have been limited in their ability to characterize noise exposures over time and to adequately control for confounders.<br><br>OBJECTIVES: The aim of this study was to examine the association between aircraft noise and incident hypertension in two cohorts of female nurses, using aircraft noise exposure estimates with high spatial resolution over a 20-year period.<br><br>METHODS: We obtained contour maps of modeled aircraft noise levels over time for 90 U.S. airports and linked them with geocoded addresses of participants in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) to assign noise exposure for 1994-2014 and 1995-2013, respectively. We used time-varying Cox proportional hazards models to estimate hypertension risk associated with time-varying noise exposure (dichotomized at 45 and 55 dB(A)), adjusting for fixed and time-varying confounders. Results from both cohorts were pooled via random effects meta-analysis.<br><br>RESULTS: and Discussion: In meta-analyses of parsimonious and fully-adjusted models with aircraft noise dichotomized at 45 dB(A), hazard ratios (HR) for hypertension incidence were 1.04 (95% CI: 1.00, 1.07) and 1.03 (95% CI: 0.99, 1.07), respectively. When dichotomized at 55 dB(A), HRs were 1.10 (95% CI: 1.01, 1.19) and 1.07 (95% CI: 0.98, 1.15), respectively. After conducting fully-adjusted sensitivity analyses limited to years in which particulate matter (PM) was obtained, we observed similar findings. In NHS, the PM-unadjusted HR was 1.01 (95% CI: 0.90, 1.14) and PM-adjusted HR was 1.01 (95% CI: 0.89, 1.14); in NHS II, the PM-unadjusted HR was 1.08 (95% CI: 0.96, 1.22) and the PM-adjusted HR was 1.08 (95% CI: 0.95, 1.21). Overall, in these cohorts, we found marginally suggestive evidence of a positive association between aircraft noise exposure and hypertension.}, }
@article {pmid34627593, year = {2021}, author = {Querfeld, C and Thompson, JA and Taylor, MH and DeSimone, JA and Zain, JM and Shustov, AR and Johns, C and McCann, S and Lin, GHY and Petrova, PS and Uger, RA and Molloy, N and Shou, Y and Akilov, OE}, title = {Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study.}, journal = {The Lancet. Haematology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3026(21)00271-4}, pmid = {34627593}, issn = {2352-3026}, abstract = {BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome.<br><br>METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621.<br><br>FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient.<br><br>INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions.<br><br>FUNDING: Trillium Therapeutics.}, }
@article {pmid34626549, year = {2021}, author = {Antia, R and Halloran, ME}, title = {Transition to endemicity: Understanding COVID-19.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, pmid = {34626549}, issn = {1097-4180}, abstract = {The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease, coronavirus disease 2019 (COVID-19), has caused a devastating pandemic worldwide. Here, we explain basic concepts underlying the transition from an epidemic to an endemic state, where a pathogen is stably maintained in a population. We discuss how the number of infections and the severity of disease change in the transition from the epidemic to the endemic phase and consider the implications of this transition in the context of COVID-19.}, }
@article {pmid34627127, year = {2021}, author = {Schumacher, BT and Bellettiere, J and LaMonte, MJ and Evenson, KR and Di, C and Lee, IM and Sleet, DA and Eaton, CB and Lewis, CE and Margolis, KL and Tinker, LF and LaCroix, AZ}, title = {Accelerometer-Measured Daily Steps, Physical Function, and Subsequent Fall Risk in Older Women: The Objective Physical Activity and Cardiovascular Disease in Older Women Study.}, journal = {Journal of aging and physical activity}, volume = {}, number = {}, pages = {1-11}, doi = {10.1123/japa.2021-0159}, pmid = {34627127}, issn = {1543-267X}, abstract = {Steps per day were measured by accelerometer for 7 days among 5,545 women aged 63-97 years between 2012 and 2014. Incident falls were ascertained from daily fall calendars for 13 months. Median steps per day were 3,216. There were 5,473 falls recorded over 61,564 fall calendar-months. The adjusted incidence rate ratio comparing women in the highest versus lowest step quartiles was 0.71 (95% confidence interval [0.54, 0.95]; ptrend across quartiles = .01). After further adjustment for physical function using the Short Physical Performance Battery, the incidence rate ratio was 0.86 ([0.64, 1.16]; ptrend = .27). Mediation analysis estimated that 63.7% of the association may be mediated by physical function (p = .03). In conclusion, higher steps per day were related to lower incident falls primarily through their beneficial association with physical functioning. Interventions that improve physical function, including those that involve stepping, could reduce falls in older adults.}, }
@article {pmid34624176, year = {2021}, author = {Anderson, LJ and Migula, D and Abay, R and Crabtree, S and Graf, SA and Matsumoto, AM and Chauncey, TR and Garcia, JM}, title = {Androgens and estrogens predict sexual function after autologous hematopoietic stem cell transplant in men.}, journal = {Andrology}, volume = {}, number = {}, pages = {}, doi = {10.1111/andr.13117}, pmid = {34624176}, issn = {2047-2927}, abstract = {BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) is associated with sexual dysfunction and hypogonadism. Androgens are associated with sexual function in healthy men, but the role of estrogens is less well-known, and the association of these sex steroids with sexual function during AHSCT has not been characterized.<br><br>OBJECTIVES: The purpose of this study was to determine the predictive value of sex hormones before and acutely after AHSCT on sexual function recovery.<br><br>MATERIALS AND METHODS: We examined sex hormones and self-reported sexual function before (PRE) and one month post-AHSCT (MONTH1; n = 19), and sexual function again one-year post-AHSCT in men (YEAR1; n = 15).<br><br>RESULTS: Sexual function decreased from PRE to MONTH1 (p≤0.05) with no differences between PRE and YEAR1. Erectile dysfunction was prevalent at PRE (68.4%) and increased at MONTH1 (100%; p≤0.05) but was not different between PRE and YEAR1 (60.0%). From PRE to MONTH1, total testosterone (TT), dihydrotestosterone (DHT), follicle-stimulating hormone, and sex-hormone binding globulin (SHBG) increased (p≤0.02) while estradiol (p≤0.026) and estrone decreased (p≤0.001). MONTH1 TT and DHT were associated with sexual function at MONTH1, while PRE SHBG, MONTH1 estradiol, and change in estrone predicted sexual function at YEAR1.<br><br>DISCUSSION: Sexual dysfunction is very prevalent prior to AHSCT and is transiently and severely worsened acutely after. AHSCT induces acute decreases in total and free estrogens, with SHBG increases leading to increases in total androgens, without changes in free androgens.<br><br>CONCLUSION: Androgens and estrogens are both adversely affected by AHSCT but may predict sexual dysfunction in this population. This supports the premise that estrogen impacts sexual function independent from androgens and that steroid hormones are associated with acute changes in sexual function in this setting. Larger, controlled trials with long-term sex hormone assessment will need to confirm the association between early changes in estrogens and long-term sexual function recovery. This article is protected by copyright. All rights reserved.}, }
@article {pmid34623638, year = {2021}, author = {Russell, HV and Chi, YY and Okcu, MF and Bernhardt, MB and Rodriguez-Galindo, C and Gupta, AA and Hawkins, DS}, title = {Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the children's oncology group.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33917}, pmid = {34623638}, issn = {1097-0142}, support = {//St Baldrick's Foundation/ ; U10CA180899/CA/NCI NIH HHS/United States ; U10CA098413/CA/NCI NIH HHS/United States ; U10CA098543/CA/NCI NIH HHS/United States ; U10CA180886/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective.<br><br>METHODS: A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs.<br><br>RESULTS: Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices.<br><br>CONCLUSIONS: Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions.<br><br>LAY SUMMARY: Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.}, }
@article {pmid34622932, year = {2021}, author = {Weinberger, AH and Steinberg, ML and Mills, SD and Dermody, SS and Heffner, JL and Kong, AY and Pang, RD and Rosen, RL}, title = {Assessing sex, gender identity, sexual orientation, race, ethnicity, socioeconomic status, and mental health concerns in tobacco use disorder treatment research: Measurement challenges and recommendations from a Society for Research on Nicotine and Tobacco (SRNT) pre-conference workshop.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntab201}, pmid = {34622932}, issn = {1469-994X}, abstract = {This paper reports on topics discussed at a Society for Research on Nicotine and Tobacco (SRNT) pre-conference workshop at the 2019 annual SRNT meeting. The goal of the preconference workshop was to help develop a shared understanding of the importance of several tobacco-related priority groups in tobacco use disorder treatment research and to highlight challenges in measurement related to these groups. The workshop focused on persons with minoritized sex, gender identity, and sexual orientation identities; persons with minoritized racial and ethnic backgrounds; persons with lower socioeconomic status (SES); and persons with mental health concerns. In addition to experiencing commercial tobacco-related health disparities, these groups are also underrepresented in tobacco research, including tobacco use disorder (TUD) treatment studies. Importantly, there is wide variation in how and whether researchers are identifying variation within these priority groups. Best practices for measuring and reporting sex, gender identity, sexual orientation, race, ethnicity, SES, and mental health concerns in TUD treatment research are needed. This paper provides information about measurement challenges when including these groups in TUD treatment research and specific recommendations about how to measure these groups and assess potential disparities in outcomes. The goal of this paper is to encourage TUD treatment researchers to use measurement best practices in these priority groups in an effort to conduct meaningful and equity-promoting research. Increasing the inclusion and visibility of these groups in TUD treatment research will help to move the field forward in decreasing tobacco-related health disparities.<br><br>IMPLICATIONS: Tobacco-related disparities exist for a number of priority groups including, among others, women, individuals with minoritized sexual and gender identities, individuals with minoritized racial and ethnic backgrounds, individuals with lower socioeconomic status, and individuals with mental health concerns. Research on tobacco use disorder (TUD) treatments for many of these subgroups is lacking. Accurate assessment and consideration of these subgroups will provide needed information about efficacious and effective TUD treatments, about potential mediators and moderators, and for accurately describing study samples, all critical elements for reducing tobacco-related disparities, and improving diversity, equity, and inclusion in TUD treatment research.}, }
@article {pmid34622145, year = {2021}, author = {Moore, A and Machiela, MJ and Machado, M and Wang, SS and Kane, E and Slager, SL and Zhou, W and Carrington, M and Lan, Q and Milne, RL and Birmann, BM and Adami, HO and Albanes, D and Arslan, AA and Becker, N and Benavente, Y and Bisanzi, S and Boffetta, P and Bracci, PM and Brennan, P and Brooks-Wilson, AR and Canzian, F and Caporaso, N and Clavel, J and Cocco, P and Conde, L and Cox, DG and Cozen, W and Curtin, K and De Vivo, I and de Sanjose, S and Foretova, L and Gapstur, SM and Ghesquières, H and Giles, GG and Glenn, M and Glimelius, B and Gao, C and Habermann, TM and Hjalgrim, H and Jackson, RD and Liebow, M and Link, BK and Maynadie, M and McKay, J and Melbye, M and Miligi, L and Molina, TJ and Monnereau, A and Nieters, A and North, KE and Offit, K and Patel, AV and Piro, S and Ravichandran, V and Riboli, E and Salles, G and Severson, RK and Skibola, CF and Smedby, KE and Southey, MC and Spinelli, JJ and Staines, A and Stewart, C and Teras, LR and Tinker, LF and Travis, RC and Vajdic, CM and Vermeulen, RCH and Vijai, J and Weiderpass, E and Weinstein, S and Doo, NW and Zhang, Y and Zheng, T and Chanock, SJ and Rothman, N and Cerhan, JR and Dean, M and Camp, NJ and Yeager, M and Berndt, SI}, title = {Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.}, journal = {Journal of translational genetics and genomics}, volume = {5}, number = {}, pages = {200-217}, doi = {10.20517/jtgg.2021.08}, pmid = {34622145}, issn = {2578-5281}, abstract = {Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.<br><br>Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.<br><br>Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.<br><br>Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.}, }
@article {pmid34621054, year = {2021}, author = {Stephenson, KE and Julg, B and Tan, CS and Zash, R and Walsh, SR and Rolle, CP and Monczor, AN and Lupo, S and Gelderblom, HC and Ansel, JL and Kanjilal, DG and Maxfield, LF and Nkolola, J and Borducchi, EN and Abbink, P and Liu, J and Peter, L and Chandrashekar, A and Nityanandam, R and Lin, Z and Setaro, A and Sapiente, J and Chen, Z and Sunner, L and Cassidy, T and Bennett, C and Sato, A and Mayer, B and Perelson, AS and deCamp, A and Priddy, FH and Wagh, K and Giorgi, EE and Yates, NL and Arduino, RC and DeJesus, E and Tomaras, GD and Seaman, MS and Korber, B and Barouch, DH}, title = {Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {34621054}, issn = {1546-170X}, support = {OPP1107669//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; OPP1146996//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; AI149670, AI145801, AI129797, AI128751, AI126603, AI124377, OD024917//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI114381//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI106408//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, abstract = {Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.}, }
@article {pmid34621011, year = {2021}, author = {Penson, DF and Armstrong, AJ and Concepcion, RS and Agarwal, N and Olsson, CA and Karsh, LI and Dunshee, CJ and Duggan, W and Shen, Q and Sugg, J and Haas, GP and Higano, CS}, title = {Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {34621011}, issn = {1476-5608}, abstract = {BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC.<br><br>METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69).<br><br>RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%).<br><br>CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.}, }
@article {pmid34619235, year = {2021}, author = {Witlox, WJA and Ramaekers, BLT and Lacas, B and Pechoux, CL and Sun, A and Wang, SY and Hu, C and Redman, M and van der Noort, V and Li, N and Guckenberger, M and van Tinteren, H and Groen, HJM and Joore, MA and De Ruysscher, DKM}, title = {Association of different fractionation schedules for prophylactic cranial irradiation with toxicity and brain metastases-free survival in locally advanced non-small cell lung cancer: a pooled analysis of individual patient data from three randomized trials.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.radonc.2021.09.029}, pmid = {34619235}, issn = {1879-0887}, abstract = {We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule.}, }
@article {pmid34619077, year = {2021}, author = {Walls, AC and Miranda, MC and Schäfer, A and Pham, MN and Greaney, A and Arunachalam, PS and Navarro, MJ and Tortorici, MA and Rogers, K and O'Connor, MA and Shirreff, L and Ferrell, DE and Bowen, J and Brunette, N and Kepl, E and Zepeda, SK and Starr, T and Hsieh, CL and Fiala, B and Wrenn, S and Pettie, D and Sydeman, C and Sprouse, KR and Johnson, M and Blackstone, A and Ravichandran, R and Ogohara, C and Carter, L and Tilles, SW and Rappuoli, R and Leist, SR and Martinez, DR and Clark, M and Tisch, R and O'Hagan, DT and Van Der Most, R and Van Voorhis, WC and Corti, D and McLellan, JS and Kleanthous, H and Sheahan, TP and Smith, KD and Fuller, DH and Villinger, F and Bloom, J and Pulendran, B and Baric, RS and King, NP and Veesler, D}, title = {Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2021.09.015}, pmid = {34619077}, issn = {1097-4172}, abstract = {Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.}, }
@article {pmid34617189, year = {2021}, author = {Long, JE and Montaño, M and Sanchez, H and Huerta, L and Calderón Garcia, D and Lama, JR and Andrasik, M and Duerr, A}, title = {Self-Identity, Beliefs, and Behavior Among Men Who Have Sex with Transgender Women: Implications for HIV Research and Interventions.}, journal = {Archives of sexual behavior}, volume = {}, number = {}, pages = {}, pmid = {34617189}, issn = {1573-2800}, support = {3R01DA040532-03S2/DA/NIDA NIH HHS/United States ; D43 TW009345/TW/FIC NIH HHS/United States ; }, abstract = {While transgender women have been identified as a global priority population for HIV prevention and treatment, little is known about the cisgender male partners of transgender women, including their sexual behavior and HIV prevalence. Previous research has suggested that these male partners have varied identities and sexual behavior, which make identifying and engaging them in research difficult. This paper describes interviews conducted with fifteen cisgender men who reported recent sexual activity with transgender women in Lima, Peru. The purpose of this research was to explore how these men reported their identities and sexual behavior, to better understand how they would interact with HIV outreach, research, and care. The major themes were sexual orientation and identity; view of transgender partners; social ties to transgender women and other men with transgender women partners; disclosure of relationships; HIV knowledge and risk perception; and attitudes toward interventions. We found that language used to assess sexual orientation was problematic in this population, due to lack of consistency between orientation and reported behavior, and unfamiliarity with terms used to describe sexual orientation. In addition, stigma, lack of knowledge of HIV prevention methods, and fear of disclosure of sexual behavior were identified as barriers that could impact engagement in HIV research, prevention, and care. However, participants reported social relationships with both transgender women and other men who have transgender partners, presenting possible avenues for recruitment into HIV research and healthcare services.}, }
@article {pmid34613812, year = {2021}, author = {Katzelnick, LC and Zambrana, JV and Elizondo, D and Collado, D and Garcia, N and Arguello, S and Mercado, JC and Miranda, T and Ampie, O and Mercado, BL and Narvaez, C and Gresh, L and Binder, RA and Ojeda, S and Sanchez, N and Plazaola, M and Latta, K and Schiller, A and Coloma, J and Carrillo, FB and Narvaez, F and Halloran, ME and Gordon, A and Kuan, G and Balmaseda, A and Harris, E}, title = {Dengue and Zika virus infections in children elicit cross-reactive protective and enhancing antibodies that persist long term.}, journal = {Science translational medicine}, volume = {13}, number = {614}, pages = {eabg9478}, doi = {10.1126/scitranslmed.abg9478}, pmid = {34613812}, issn = {1946-6242}, abstract = {[Figure: see text].}, }
@article {pmid34610317, year = {2021}, author = {Kinsella, S and Evandy, CA and Cooper, K and Iovino, L and deRoos, PC and Hopwo, KS and Granadier, DW and Smith, CW and Rafii, S and Dudakov, JA}, title = {Attenuation of apoptotic cell detection triggers thymic regeneration after damage.}, journal = {Cell reports}, volume = {37}, number = {1}, pages = {109789}, doi = {10.1016/j.celrep.2021.109789}, pmid = {34610317}, issn = {2211-1247}, abstract = {The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.}, }
@article {pmid34610086, year = {2021}, author = {Dong, X and Liu, W and Shen, Y and Houck, KL and Yang, M and Zhou, Y and Zhao, Z and Wu, X and Blevins, T and Koehne, AL and Wun, TC and Fu, X and Li, M and Zhang, J and Dong, JF}, title = {Anticoagulation Targeting Membrane-Bound Anionic Phospholipids Improved Outcomes of Traumatic Brain Injury in Mice.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2021011310}, pmid = {34610086}, issn = {1528-0020}, abstract = {Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. Phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared to EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.}, }
@article {pmid34609969, year = {2021}, author = {Greninger, AL and Rybkina, K and Lin, MJ and Drew-Bear, J and Marcink, TC and Shean, RC and Makhsous, N and Boeckh, M and Harder, O and Bovier, F and Burstein, SR and Niewiesk, S and Rima, BK and Porotto, M and Moscona, A}, title = {Human parainfluenza virus evolution during lung infection of immunocompromised humans promotes viral persistence.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI150506}, pmid = {34609969}, issn = {1558-8238}, abstract = {The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We show that intra-host evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favor viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from two immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.}, }
@article {pmid34609096, year = {2021}, author = {Manohar, PM and Davidson, NE}, title = {Updates in endocrine therapy for metastatic breast cancer.}, journal = {Cancer biology &amp; medicine}, volume = {}, number = {}, pages = {}, doi = {10.20892/j.issn.2095-3941.2021.0255}, pmid = {34609096}, issn = {2095-3941}, support = {T32 CA009515 (PM and NED)/GF/NIH HHS/United States ; P30CA015704 (NED)/GF/NIH HHS/United States ; //Breast Cancer Research Foundation/ ; }, abstract = {Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.}, }
@article {pmid34608844, year = {2021}, author = {Halpern, AB and Othus, M and Howard, NP and Hendrie, PC and Percival, MM and Hartley, GA and Welch, VL and Estey, EH and Walter, RB}, title = {Comparative analysis of infectious complications with outpatient vs. inpatient care for adults with high-risk myeloid neoplasm receiving intensive induction chemotherapy.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/10428194.2021.1984451}, pmid = {34608844}, issn = {1029-2403}, abstract = {We recently reported an early hospital discharge (EHD) care strategy following intensive acute myeloid leukemia (AML)-like chemotherapy is safe. To evaluate its impact on infectious outcomes, we compared all adults treated from 8/1/2014 to 7/31/2018 discharging within 72 h of completing chemotherapy (EHD) with hospitalized patients (controls) across 354 induction and 259 post-remission cycles. While overall outcomes were similar, gram-positive bacteremias were more common in EHD patients than control (p<.001), although they received fewer days of IV antimicrobials (p< .001). Notably, cumulative infection risks in EHD patients were similar after induction and post-remission therapy. In multivariable analysis, only EHD status was independently associated with risk for gram-positive bacteremia (p= .01), whereas the only independent risk factor for fungal infection was fluconazole (vs. posaconazole) use (p< .001). The observation of increased rates of gram-positive bacteremias with EHD identifies improvements in catheter management as one area to further increase the safety of this care approach.}, }
@article {pmid34608275, year = {2021}, author = {Pasvolsky, O and Yeshurun, M and Fraser, R and Estrada-Merly, N and Rozovski, U and Shargian-Alon, L and Assal, A and Banerjee, R and Bumma, N and Gale, RP and Hagen, P and Holmberg, L and Hossain, NM and Lazarus, HM and Lee, C and Mian, H and Miller, KC and Nathan, S and Nagler, A and Nishihori, T and Parrondo, RD and Patel, S and Schroeder, MA and Usmani, SZ and Wang, T and Wirk, B and Kumar, S and Shah, N and Qazilbash, MH and D'Souza, A}, title = {Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34608275}, issn = {1476-5365}, abstract = {The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.}, }
@article {pmid34607346, year = {2021}, author = {Deeg, HJ}, title = {All patients with AML over 60 years of age should not be offered early allogeneic stem cell transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004799}, pmid = {34607346}, issn = {2473-9537}, }
@article {pmid34607084, year = {2021}, author = {Fontenele, RS and Kraberger, S and Hadfield, J and Driver, EM and Bowes, D and Holland, LA and Faleye, TOC and Adhikari, S and Kumar, R and Inchausti, R and Holmes, WK and Deitrick, S and Brown, P and Duty, D and Smith, T and Bhatnagar, A and Yeager, RA and Holm, RH and von Reitzenstein, NH and Wheeler, E and Dixon, K and Constantine, T and Wilson, MA and Lim, ES and Jiang, X and Halden, RU and Scotch, M and Varsani, A}, title = {High-throughput sequencing of SARS-CoV-2 in wastewater provides insights into circulating variants.}, journal = {Water research}, volume = {205}, number = {}, pages = {117710}, doi = {10.1016/j.watres.2021.117710}, pmid = {34607084}, issn = {1879-2448}, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely emerged from a zoonotic spill-over event and has led to a global pandemic. The public health response has been predominantly informed by surveillance of symptomatic individuals and contact tracing, with quarantine, and other preventive measures have then been applied to mitigate further spread. Non-traditional methods of surveillance such as genomic epidemiology and wastewater-based epidemiology (WBE) have also been leveraged during this pandemic. Genomic epidemiology uses high-throughput sequencing of SARS-CoV-2 genomes to inform local and international transmission events, as well as the diversity of circulating variants. WBE uses wastewater to analyse community spread, as it is known that SARS-CoV-2 is shed through bodily excretions. Since both symptomatic and asymptomatic individuals contribute to wastewater inputs, we hypothesized that the resultant pooled sample of population-wide excreta can provide a more comprehensive picture of SARS-CoV-2 genomic diversity circulating in a community than clinical testing and sequencing alone. In this study, we analysed 91 wastewater samples from 11 states in the USA, where the majority of samples represent Maricopa County, Arizona (USA). With the objective of assessing the viral diversity at a population scale, we undertook a single-nucleotide variant (SNV) analysis on data from 52 samples with >90% SARS-CoV-2 genome coverage of sequence reads, and compared these SNVs with those detected in genomes sequenced from clinical patients. We identified 7973 SNVs, of which 548 were "novel" SNVs that had not yet been identified in the global clinical-derived data as of 17th June 2020 (the day after our last wastewater sampling date). However, between 17th of June 2020 and 20th November 2020, almost half of the novel SNVs have since been detected in clinical-derived data. Using the combination of SNVs present in each sample, we identified the more probable lineages present in that sample and compared them to lineages observed in North America prior to our sampling dates. The wastewater-derived SARS-CoV-2 sequence data indicates there were more lineages circulating across the sampled communities than represented in the clinical-derived data. Principal coordinate analyses identified patterns in population structure based on genetic variation within the sequenced samples, with clear trends associated with increased diversity likely due to a higher number of infected individuals relative to the sampling dates. We demonstrate that genetic correlation analysis combined with SNVs analysis using wastewater sampling can provide a comprehensive snapshot of the SARS-CoV-2 genetic population structure circulating within a community, which might not be observed if relying solely on clinical cases.}, }
@article {pmid34606629, year = {2021}, author = {Brandt, HM and Kepka, D and Kirchhoff, AC and Daniel, CL and Bhatt, NS}, title = {Human papillomavirus (HPV) vaccination is cancer prevention for childhood cancer survivors.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33920}, pmid = {34606629}, issn = {1097-0142}, support = {//Huntsman Cancer Foundation/ ; P30CA021765/CA/NCI NIH HHS/United States ; //American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital/ ; }, }
@article {pmid34606625, year = {2021}, author = {Henderson, TO and Fowler, BW and Hamann, HA and Nathan, PC and Whitton, J and Leisenring, WM and Oeffinger, KC and Neglia, JP and Turcotte, LM and Arnold, MA and Conces, MR and Howell, RM and Robison, LL and Armstrong, GT and Alexander, KA}, title = {Subsequent malignant neoplasms in the childhood cancer survivor study: Occurrence of cancer types in which human papillomavirus is an established etiologic risk factor.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33922}, pmid = {34606625}, issn = {1097-0142}, support = {U24 CA55727/CA/NCI NIH HHS/United States ; CA21765//Cancer Center Support (CORE)/ ; //American Lebanese-Syrian Associated Charities (ALSAC)/ ; }, abstract = {BACKGROUND: Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMNHPV) in childhood cancer survivors are poorly understood.<br><br>METHODS: The cumulative risk of SMNHPV was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMNHPV risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs).<br><br>RESULTS: In total, 46 survivors developed an SMNHPV (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMNHPV sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMNHPV (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMNHPV (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m2 (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMNHPV SIRs in multivariable analysis.<br><br>CONCLUSIONS: Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMNHPV in cancer survivors is warranted.}, }
@article {pmid34606328, year = {2021}, author = {Hui, D and Darke, AK and Guthrie, KA and Subbiah, IM and Unger, JM and Hershman, DL and Krouse, RS and Bakitas, M and O'Rourke, MA}, title = {Association Between Health-Related Quality of Life and Progression-Free Survival in Patients With Advanced Cancer: A Secondary Analysis of SWOG Clinical Trials.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2100407}, doi = {10.1200/OP.21.00407}, pmid = {34606328}, issn = {2688-1535}, abstract = {PURPOSE: Health-related quality of life (HRQOL) is an established prognostic factor for mortality; however, it is unclear if HRQOL is predictive of time to disease progression, a particularly meaningful outcome for patients. We examined the association between HRQOL and progression-free survival (PFS) in SWOG Cancer Research Network clinical trials.<br><br>METHODS: For this secondary analysis, we reviewed all completed SWOG clinical trials to identify those for patients with advanced cancer that incorporated Functional Assessment of Cancer Therapy (FACT) questionnaires at baseline. FACT-Trial Outcome Index (FACT-TOI) was the primary independent variable. Associations between FACT-TOI and other FACT subscores with PFS and overall survival were evaluated via log-rank test and multivariable Cox regression analysis.<br><br>RESULTS: Three clinical trials met our inclusion criteria: S0027 and S9509 for advanced non-small-cell lung cancer and S0421 for hormone-refractory prostate cancer. Of the 1,527 enrolled patients, 1,295 (85%) had both HRQOL and survival outcomes data available and were included in this analysis. In univariable analysis, we observed a statistically significant gradient effect in all three trials, with higher baseline FACT-TOI scores corresponding to better PFS (S0027, P < .001; S9509, P = .02; and S0421, P < .001). In multivariable analysis, FACT-TOI was significantly associated with PFS in S0027 (hazard ratio [HR] = 0.64; 95% CI, 0.42 to 1.00) but not in S9509 (HR = 0.77; 95% CI, 0.56 to 1.05) or S042 (HR = 0.86; 95% CI, 0.73 to 1.01). FACT-TOI was significantly associated with overall survival in multivariable analysis (P < .005 in all three trials).<br><br>CONCLUSION: The association between baseline FACT-TOI scores and survival underscores their potential as a stratification factor in clinical trials.}, }
@article {pmid34605915, year = {2021}, author = {Shete, S and Deng, Y and Shannon, J and Faseru, B and Middleton, D and Iachan, R and Bernardo, B and Balkrishnan, R and Kim, SJ and Huang, B and Millar, MM and Fuemmler, B and Jensen, JD and Mendoza, JA and Hu, J and Lazovich, D and Robertson, L and Demark-Wahnefried, W and Paskett, ED and , }, title = {Differences in Breast and Colorectal Cancer Screening Adherence Among Women Residing in Urban and Rural Communities in the United States.}, journal = {JAMA network open}, volume = {4}, number = {10}, pages = {e2128000}, doi = {10.1001/jamanetworkopen.2021.28000}, pmid = {34605915}, issn = {2574-3805}, abstract = {Importance: Screening for breast and colorectal cancer has resulted in reductions in mortality; however, questions remain regarding how these interventions are being diffused to all segments of the population. If an intervention is less amenable to diffusion, it could be associated with disparities in mortality rates, especially in rural vs urban areas.<br><br>Objectives: To compare the prevalence of breast and colorectal cancer screening adherence and to identify factors associated with screening adherence among women residing in rural vs urban areas in the United States.<br><br>This population-based cross-sectional study of women aged 50 to 75 years in 11 states was conducted from 2017 to 2020.<br><br>Main Outcomes and Measures: Adherence to cancer screening based on the US Preventative Services Task Force guidelines. For breast cancer screening, women who had mammograms in the past 2 years were considered adherent. For colorectal cancer screening, women who had (1) a stool test in the past year, (2) a colonoscopy in the past 10 years, or (3) a sigmoidoscopy in the past 5 years were considered adherent. Rural status was coded using Rural Urban Continuum Codes, and other variables were assessed to identify factors associated with screening.<br><br>Results: The overall sample of 2897 women included 1090 (38.4%) rural residents; 2393 (83.5%) non-Hispanic White women; 263 (9.2%) non-Hispanic Black women; 68 (2.4%) Hispanic women; 1629 women (56.2%) aged 50 to 64 years; and 712 women (24.8%) with a high school education or less. Women residing in urban areas were significantly more likely to be adherent to colorectal cancer screening compared with women residing in rural areas (1429 [82%] vs 848 [78%]; P = .01), whereas the groups were equally likely to be adherent to breast cancer screening (1347 [81%] vs 830 [81%]; P = .78). Multivariable mixed-effects logistic regression analyses confirmed that rural residence was associated with lower odds of being adherent to colorectal cancer screening (odds ratio [OR], 0.81; 95% CI, 0.66-0.99, P = .047). Non-Hispanic Black race was associated with adherence to breast cancer screening guidelines (OR, 2.85; 95% CI, 1.78-4.56; P < .001) but not colorectal cancer screening guidelines.<br><br>Conclusions and Relevance: In this cross-sectional study, women residing in rural areas were less likely to be adherent to colorectal cancer screening guidelines but were similarly adherent to breast cancer screening. This suggests that colorectal cancer screening, a more recent intervention, may not be as available in rural areas as breast cancer screening, ie, colorectal screening has lower amenability.}, }
@article {pmid34604815, year = {2021}, author = {Polfus, LM and Darst, BF and Highland, H and Sheng, X and Ng, MCY and Below, JE and Petty, L and Bien, S and Sim, X and Wang, W and Fontanillas, P and Patel, Y and ,  and ,  and ,  and Preuss, M and Schurmann, C and Du, Z and Lu, Y and Rhie, SK and Mercader, JM and Tusie-Luna, T and González-Villalpando, C and Orozco, L and Spracklen, CN and Cade, BE and Jensen, RA and Sun, M and Joo, YY and An, P and Yanek, LR and Bielak, LF and Tajuddin, S and Nicolas, A and Chen, G and Raffield, L and Guo, X and Chen, WM and Nadkarni, GN and Graff, M and Tao, R and Pankow, JS and Daviglus, M and Qi, Q and Boerwinkle, EA and Liu, S and Phillips, LS and Peters, U and Carlson, C and Wikens, LR and Marchand, LL and North, KE and Buyske, S and Kooperberg, C and Loos, RJF and Stram, DO and Haiman, CA}, title = {Genetic discovery and risk characterization in type 2 diabetes across diverse populations.}, journal = {HGG advances}, volume = {2}, number = {2}, pages = {}, doi = {10.1016/j.xhgg.2021.100029}, pmid = {34604815}, issn = {2666-2477}, abstract = {Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10-8), which replicated in independent studies of African ancestry (p = 6.26 × 10-23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10-9), which also replicated in independent studies (p = 3.45 × 10-4). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (pheterogeneity = 3.85 × 10-20). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.}, }
@article {pmid34604798, year = {2021}, author = {Carlson, LE and Watt, GP and Tonorezos, ES and Chow, EJ and Yu, AF and Woods, M and Lynch, CF and John, EM and Mellemkjӕr, L and Brooks, JD and Knight, JA and Reiner, AS and Liang, X and Smith, SA and Bernstein, L and Dauer, LT and Cerviño, LI and Howell, RM and Shore, RE and Boice, JD and Bernstein, JL and , }, title = {Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer: The WECARE Study.}, journal = {JACC. CardioOncology}, volume = {3}, number = {3}, pages = {381-392}, doi = {10.1016/j.jaccao.2021.07.008}, pmid = {34604798}, issn = {2666-0873}, abstract = {Background: Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined.<br><br>Objectives: The purpose of this study was to report CAD risk among participants in the Women's Environmental Cancer and Radiation Epidemiology Study.<br><br>Methods: A total of 1,583 women who were <55 years of age when diagnosed with breast cancer between 1985 and 2008 completed a cardiovascular health questionnaire. Risk of radiation-associated CAD was evaluated by comparing women treated with left-sided RT with women treated with right-sided RT using multivariable Cox proportional hazards models. Effect modification by treatment and cardiovascular risk factors was examined.<br><br>Results: In total, 517 women who did not receive RT and 94 women who had a pre-existing cardiovascular disease diagnosis were excluded, leaving 972 women eligible for analysis. Their median follow-up time was 14 years (range 1-29 years). The 27.5-year cumulative incidences of CAD for women receiving left- vs right-sided RT were 10.5% and 5.8%, respectively (P = 0.010). The corresponding HR of CAD for left- vs right-sided RT in the multivariable Cox model was 2.5 (95% CI: 1.3-4.7). There was no statistically significant effect modification by any factor evaluated.<br><br>Conclusions: Young women treated with RT for left-sided breast cancer had over twice the risk of CAD compared with women treated with RT for right-sided breast cancer. Laterality of RT is independently associated with an increased risk of CAD and should be considered in survivorship care of younger breast cancer patients.}, }
@article {pmid34603296, year = {2021}, author = {St Leger, AJ and Koelle, DM and Kinchington, PR and Verjans, GMGM}, title = {Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {723809}, doi = {10.3389/fimmu.2021.723809}, pmid = {34603296}, issn = {1664-3224}, abstract = {Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune cells and paracrine activity on parenchymal cells, for example via chemokines and type I interferons. In both mice and humans, HSV-1-specific CD8 and CD4 T-cells are recruited to ganglia, with mechanistic studies suggesting active roles in immune surveillance and control of reactivation. In this review we focus mainly on HSV-1 and the TG, comparing and contrasting where possible observational, interventional, and in vitro studies between humans and animal hosts.}, }
@article {pmid34601132, year = {2021}, author = {Maynard, LH and Humbert, O and Peterson, CW and Kiem, HP}, title = {Genome editing in large animal models.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2021.09.026}, pmid = {34601132}, issn = {1525-0024}, abstract = {Although genome editing technologies have the potential to revolutionize the way we treat human diseases, barriers to successful clinical implementation remain. Increasingly, preclinical large animal models are being used to overcome these barriers. In particular, the immunogenicity and long-term safety of novel gene editing therapeutics must be evaluated rigorously. However, short-lived small animal models, such as mice and rats, cannot address secondary pathologies that may arise years after a gene editing treatment. Likewise, immunodeficient mouse models by definition lack the ability to quantify the host immune response to a novel transgene or gene-edited locus. Large animal models, including dogs, pigs and non-human primates, bear greater resemblance to human anatomy, immunology and lifespan, and can be studied over longer timescales with clinical dosing regimens that are more relevant to humans. These models allow for larger scale and repeated blood and tissue sampling, enabling greater depth of study and focus on rare cellular subsets. Here, we review current progress in the development and evaluation of novel genome editing therapies in large animal models, focusing on applications in HIV-1 infection, cancer, and genetic diseases including hemoglobinopathies, Duchenne muscular dystrophy, hypercholesterolemia, and inherited retinal diseases.}, }
@article {pmid34599920, year = {2021}, author = {Silver, M and Anderson, ML and Beaber, EF and Haas, JS and Kobrin, S and Pocobelli, G and Skinner, CS and Tiro, JA and Kamineni, A}, title = {De-implementation of cervical cancer screening before age 21.}, journal = {Preventive medicine}, volume = {}, number = {}, pages = {106815}, doi = {10.1016/j.ypmed.2021.106815}, pmid = {34599920}, issn = {1096-0260}, abstract = {In 2012, United States consensus guidelines were modified to recommend that cervical cancer screening not begin before age 21 and, since 2014, the Health Effectiveness Data and Information Set (HEDIS), a health plan quality measurement too, has included a measure for non-recommended cervical cancer screening among females ages 16-20. Our goal was to describe prevalence over time of cervical cancer screening before age 21 following the 2012 guideline change, and provide information to help understand how rapidly new guidelines may be disseminated and implemented into clinical practice. We used longitudinal clinical and administrative data from three diverse healthcare systems in the Population-based Research to Optimize the Screening Process (PROSPR II) consortium to examine annual trends in screening before age 21. We identified 55,316 average-risk, screening-eligible females ages 18-20 between 2011 and 2017. For each calendar year, we estimated the proportion of females who received a Papanicolaou (Pap) test. We observed a steady decline in the proportion of females under age 21 who received a Pap test, from an average of 8.3% in 2011 to <1% in 2017 across the sites. The observed steady decline suggests growing adherence to the 2012 consensus guidelines. This trend was consistent across diverse geographic regions, healthcare systems, and patient populations, strengthening the generalizability of the results; however, since we only had 1-2 years of study data prior to the consensus guidelines, we cannot discern whether screening under age 21 was already in decline. Nonetheless, these results provide data to compare with other guideline changes to de-implement non-recommended screening practices.}, }
@article {pmid34599169, year = {2021}, author = {Cejas, P and Xie, Y and Font-Tello, A and Lim, K and Syamala, S and Qiu, X and Tewari, AK and Shah, N and Nguyen, HM and Patel, RA and Brown, L and Coleman, I and Hackeng, WM and Brosens, L and Dreijerink, KMA and Ellis, L and Alaiwi, SA and Seo, JH and Baca, S and Beltran, H and Khani, F and Pomerantz, M and Dall'Agnese, A and Crowdis, J and Van Allen, EM and Bellmunt, J and Morrisey, C and Nelson, PS and DeCaprio, J and Farago, A and Dyson, N and Drapkin, B and Liu, XS and Freedman, M and Haffner, MC and Corey, E and Brown, M and Long, HW}, title = {Subtype heterogeneity and epigenetic convergence in neuroendocrine prostate cancer.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {5775}, pmid = {34599169}, issn = {2041-1723}, support = {2P01CA163227-06A1//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.}, }
@article {pmid34599155, year = {2021}, author = {Racca, C and Britton, S and Hédouin, S and Francastel, C and Calsou, P and Larminat, F}, title = {BRCA1 prevents R-loop-associated centromeric instability.}, journal = {Cell death &amp; disease}, volume = {12}, number = {10}, pages = {896}, pmid = {34599155}, issn = {2041-4889}, abstract = {Centromeres are defined by chromatin containing the histone H3 variant CENP-A assembled onto repetitive α-satellite sequences, which are actively transcribed throughout the cell cycle. Centromeres play an essential role in chromosome inheritance and genome stability through coordinating kinetochores assembly during mitosis. Structural and functional alterations of the centromeres cause aneuploidy and chromosome aberrations which can induce cell death. In human cells, the tumor suppressor BRCA1 associates with centromeric chromatin in the absence of exogenous damage. While we previously reported that BRCA1 contributes to proper centromere homeostasis, the mechanism underlying its centromeric function and recruitment was not fully understood. Here, we show that BRCA1 association with centromeric chromatin depends on the presence of R-loops, which are non-canonical three-stranded structures harboring a DNA:RNA hybrid and are frequently formed during transcription. Subsequently, BRCA1 counteracts the accumulation of R-loops at centromeric α-satellite repeats. Strikingly, BRCA1-deficient cells show impaired localization of CENP-A, higher transcription of centromeric RNA, increased breakage at centromeres and formation of acentric micronuclei, all these features being R-loop-dependent. Finally, BRCA1 depletion reveals a Rad52-dependent hyper-recombination process between centromeric satellite repeats, associated with centromere instability and missegregation. Altogether, our findings provide molecular insights into the key function of BRCA1 in maintaining centromere stability and identity.}, }
@article {pmid34597898, year = {2021}, author = {Shutta, KH and Balasubramanian, R and Huang, T and Jha, SC and Zeleznik, OA and Kroenke, CH and Tinker, LF and Smoller, JW and Casanova, R and Tworoger, SS and Manson, JE and Clish, CB and Rexrode, KM and Hankinson, SE and Kubzansky, LD}, title = {Plasma metabolomic profiles associated with chronic distress in women.}, journal = {Psychoneuroendocrinology}, volume = {133}, number = {}, pages = {105420}, doi = {10.1016/j.psyneuen.2021.105420}, pmid = {34597898}, issn = {1873-3360}, abstract = {Several forms of chronic distress including anxiety and depression are associated with adverse cardiometabolic outcomes. Metabolic alterations may underlie these associations. Whether these forms of distress are associated with metabolic alterations even after accounting for comorbid conditions and other factors remains unclear. Using an agnostic approach, this study examines a broad range of metabolites in relation to chronic distress among women. For this cross-sectional study of chronic distress and 577 plasma metabolites, data are from different substudies within the Women's Health Initiative (WHI) and Nurses' Health Studies (NHSI, NHSII). Chronic distress was characterized by depressive symptoms and other depression indicators in the WHI and NHSII substudies, and by combined indicators of anxiety and depressive symptoms in the NHSI substudy. We used a two-phase discovery-validation framework, with WHI (N = 1317) and NHSII (N = 218) substudies in the discovery phase (identifying metabolites associated with distress) and NHSI (N = 558) substudy in the validation phase. A differential network analysis provided a systems-level assessment of metabolomic alterations under chronic distress. Analyses adjusted for potential confounders and mediators (demographics, comorbidities, medications, lifestyle factors). In the discovery phase, 46 metabolites were significantly associated with depression measures. In validation, six of these metabolites demonstrated significant associations with chronic distress after adjustment for potential confounders. Among women with high distress, we found lower gamma-aminobutyric acid (GABA), threonine, biliverdin, and serotonin and higher C16:0 ceramide and 3-methylxanthine. Our findings suggest chronic distress is associated with metabolomic alterations and provide specific targets for future study of biological pathways in chronic diseases.}, }
@article {pmid34597472, year = {2021}, author = {Makrakis, D and Talukder, R and Diamantopoulos, LN and Carril-Ajuria, L and Castellano, D and De Kouchkovsky, I and Koshkin, VS and Park, JJ and Alva, A and Bilen, MA and Stewart, TF and McKay, RR and Santos, VS and Agarwal, N and Jain, J and Zakharia, Y and Morales-Barrera, R and Devitt, ME and Grant, M and Lythgoe, MP and Pinato, DJ and Nelson, A and Hoimes, CJ and Shreck, E and Gartrell, BA and Sankin, A and Tripathi, A and Zakopoulou, R and Bamias, A and Murgic, J and Fröbe, A and Rodriguez-Vida, A and Drakaki, A and Liu, S and Kumar, V and Di Lorenzo, G and Joshi, M and Isaacsson-Velho, P and Buznego, LA and Duran, I and Moses, M and Barata, P and Sonpavde, G and Yu, EY and Wright, JL and Grivas, P and Khaki, AR}, title = {Association of prior local therapy and outcomes with PD(L)1 inhibitor in advanced urothelial cancer.}, journal = {BJU international}, volume = {}, number = {}, pages = {}, doi = {10.1111/bju.15603}, pmid = {34597472}, issn = {1464-410X}, abstract = {OBJECTIVES: To compare clinical outcomes with anti-PD(L)1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation (RT) prior to developing metastatic disease.<br><br>PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first [1st ] &amp; second or greater [2nd+ ]). Logistic regression was used to compare ORR; Kaplan-Meier analysis and Cox regression for PFS and OS. Multivariable models were adjusted for known prognostic factors.<br><br>RESULTS: We included 562 patients (1st line: 342 and 2nd+ : 220). There was no difference in outcomes based on prior locoregional treatment among those treated with 1st line ICI. In the 2nd+ line, prior RS was associated with higher ORR (adjusted odds ratio [aOR] 2.61 [95% CI 1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61 [95% CI 0.42-0.88]) and PFS (aHR 0.63 [95% CI 0.45-0.89]) vs no prior RS. This association remained significant when the type of prior locoregional treatment (RS and RT) was modeled separately.<br><br>CONCLUSION: Prior RS prior to developing advanced disease was associated with better outcomes in patients with aUC treated with ICI in the 2nd+ , but not in the 1st line setting. While further validation is needed, our findings can have implications on prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include retrospective nature, lack of randomization, possible selection and confounding biases.}, }
@article {pmid34596937, year = {2021}, author = {Elgarten, CW and Wood, AC and Li, Y and Alonzo, TA and Brodersen, LE and Gerbing, RB and Getz, KD and Huang, YV and Loken, M and Meshinchi, S and Pollard, JA and Sung, L and Woods, WG and Kolb, EA and Gamis, AS and Aplenc, R}, title = {Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e29281}, doi = {10.1002/pbc.29281}, pmid = {34596937}, issn = {1545-5017}, support = {COG NCTN Network Group Operations Centres (5U10CA180886-07)//Division of Cancer Prevention, National Cancer Institute/ ; (2U10CA180899-07).//NCTN Statistics &amp; Data Center Grant/ ; }, abstract = {BACKGROUND: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.<br><br>METHODS: Patients on AAML0531 received cytarabine (1600 mg/m2)/daunorubicin (150 mg/m2)/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m2)/cytarabine (8000 mg/m2) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.<br><br>RESULTS: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II.<br><br>CONCLUSION: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).}, }
@article {pmid34596427, year = {2021}, author = {Bauermeister, JA and Tingler, RC and Johnson, S and Macagna, N and Lucas, J and Dominguez-Islas, C and Szydlo, D and Ngo, J and Jacobson, CE and Kramzer, L and Singh, D and Dezzutti, CS and Kunjara Na Ayudhya, RP and Piper, J and Devlin, B and Hendrix, CW and Ho, K and , }, title = {Acceptability of a Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-033 Study).}, journal = {AIDS education and prevention : official publication of the International Society for AIDS Education}, volume = {33}, number = {5}, pages = {361-376}, doi = {10.1521/aeap.2021.33.5.361}, pmid = {34596427}, issn = {1943-2755}, abstract = {We triangulated quantitative and qualitative assessments to evaluate participants' acceptability of 0.05% dapivirine rectal microbicide (RM) gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) as part of a Phase I trial (N = 14) among men who have sex with men (MSM) randomized using a 1:1 ratio. Overall, participants reported favorable acceptability of the gel (n = 11; 78.6%), the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods had positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.}, }
@article {pmid34596054, year = {2021}, author = {Peterson, CW}, title = {HIV-specific CAR T cells return to the clinic.}, journal = {The Journal of clinical investigation}, volume = {131}, number = {19}, pages = {}, doi = {10.1172/JCI153204}, pmid = {34596054}, issn = {1558-8238}, abstract = {Over the past decade, chimeric antigen receptor (CAR) T cells have emerged as the prototype gene therapy for B cell leukemias. These so-called living drugs are derived from a patient's own cells, reprogrammed to recognize and destroy cancer cells, and then reintroduced into the body. The huge success of this therapy for cancer is rooted in pioneering clinical and preclinical studies, established more than three decades ago, focused on persistent HIV-1 infection. In this issue of the JCI, Bingfeng Liu et al. revisit HIV-specific CAR T cells in an important clinical study that supports broader application of this groundbreaking therapy. Although curative endpoints were not achieved, these findings lay the foundation for augmented approaches applying combinatorial technologies including antigen supplementation.}, }
@article {pmid34594330, year = {2021}, author = {Koyama, M and Hill, GR}, title = {Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {715893}, doi = {10.3389/fimmu.2021.715893}, pmid = {34594330}, issn = {1664-3224}, abstract = {Allogeneic stem cell transplantation (alloSCT) is a curative therapy for hematopoietic malignancies. The therapeutic effect relies on donor T cells and NK cells to recognize and eliminate malignant cells, known as the graft-versus-leukemia (GVL) effect. However, off target immune pathology, known as graft-versus-host disease (GVHD) remains a major complication of alloSCT that limits the broad application of this therapy. The presentation of recipient-origin alloantigen to donor T cells is the primary process initiating GVHD and GVL. Therefore, the understanding of spatial and temporal characteristics of alloantigen presentation is pivotal to attempts to separate beneficial GVL effects from detrimental GVHD. In this review, we discuss mouse models and the tools therein, that permit the quantification of alloantigen presentation after alloSCT.}, }
@article {pmid34593636, year = {2021}, author = {Bello, T and Paindelli, C and Diaz-Gomez, LA and Melchiorri, A and Mikos, AG and Nelson, PS and Dondossola, E and Gujral, TS}, title = {Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {40}, pages = {}, doi = {10.1073/pnas.2103623118}, pmid = {34593636}, issn = {1091-6490}, abstract = {Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.}, }
@article {pmid34591653, year = {2021}, author = {Cheon, IS and Li, C and Son, YM and Goplen, NP and Wu, Y and Cassmann, T and Wang, Z and Wei, X and Tang, J and Li, Y and Marlow, H and Hughes, S and Hammel, L and Cox, TM and Goddery, E and Ayasoufi, K and Weiskopf, D and Boonyaratanakornkit, J and Dong, H and Li, H and Chakraborty, R and Johnson, AJ and Edell, E and Taylor, JJ and Kaplan, MH and Sette, A and Bartholmai, BJ and Kern, R and Vassallo, R and Sun, J}, title = {Immune signatures underlying post-acute COVID-19 lung sequelae.}, journal = {Science immunology}, volume = {}, number = {}, pages = {eabk1741}, doi = {10.1126/sciimmunol.abk1741}, pmid = {34591653}, issn = {2470-9468}, abstract = {[Figure: see text].}, }
@article {pmid34590218, year = {2021}, author = {Dangerfield, DT and Kuo, I and Magnus, M and Beauchamp, G and Fields, SD and Nelson, L and Shoptaw, S and Wilton, L and Wheeler, DP}, title = {Sexual Risk Profiles Among Black Sexual Minority Men: Implications for Targeted PrEP Messaging.}, journal = {Archives of sexual behavior}, volume = {}, number = {}, pages = {}, pmid = {34590218}, issn = {1573-2800}, support = {UM1AI068619/NH/NIH HHS/United States ; }, abstract = {Black gay, bisexual, and other Black sexual minority men (BSMM) continue to experience some of the largest sexual health disparities in the U.S. Engaging BSMM in PrEP is crucial to improving sexual health outcomes and reducing disparities. However, knowledge of the profiles of sexual risk and PrEP initiation among this group is limited. This study used latent class analysis to identify HIV risk and PrEP initiation patterns among BSMM in the HPTN 073 Study (n = 226). Guided by current Centers for Disease Control screening guidelines, latent class indicators included relationship status, condom use, number of sexual partners, substance use, sexually transmitted infection (STI) history, and partner HIV status. Age and PrEP initiation were used in a multinomial regression to identify correlates of class membership. Three latent classes were identified: Single, Condomless Partners, Single, Multiple Partners, and Serodiscordant Partners. Single, Condomless Partners had the highest conditional probabilities of having greater than three male partners, substance use before sex, and receiving an STI diagnosis. Serodiscordant Partners had a 100% conditional probability of condomless sex and having a male partner living with HIV. BSMM who initiated PrEP were less likely to be classified as Single, Condomless Partners than Serodiscordant Partners (AOR = 0.07, 95% CI = 0.02, 0.66). Findings support the need for culturally relevant tailored and targeted messaging for BSMM with multiple sexual risk indicators.}, }
@article {pmid34590205, year = {2021}, author = {Syrjala, KL and Walsh, CA and Yi, JC and Leisenring, WM and Rajotte, EJ and Voutsinas, J and Ganz, PA and Jacobs, LA and Palmer, SC and Partridge, A and Baker, KS}, title = {Cancer survivorship care for young adults: a risk-stratified, multicenter randomized controlled trial to improve symptoms.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {34590205}, issn = {1932-2267}, support = {CA215134/CA/NCI NIH HHS/United States ; CA246659/CA/NCI NIH HHS/United States ; CA092408/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Young adult (YA) cancer survivors have high rates of adverse health and psychosocial outcomes. This risk-stratified, multicenter, randomized controlled trial (RCT) compared a self-management survivorship intervention to usual care in YA survivors with symptoms of cancer-related distress, insomnia, fatigue, pain, and/or depression.<br><br>METHODS: Eligibility included age 18-39 at diagnosis with an invasive malignancy in the previous 1-5 years. Baseline assessment determined "high need" participants, with 2-5 elevated targeted symptoms. We randomized high need participants to intervention or usual care and offered intervention participants a survivorship clinic visit, which included mutually decided action plans for symptoms. Follow-up calls at 1 and 3 months after the clinic visit reviewed action plan progress. Outcomes compared rates of improved symptoms for intervention vs usual care at 6 months and 12 months.<br><br>RESULTS: N = 344 completed baseline assessment, with n = 147 (43%) categorized as high need and randomized. Of n = 73 randomized to the intervention, n = 42 (58%) did not attend their survivorship clinic visit. In intent-to-treat analyses, aggregate symptom scores did not differ between arms, though distress improved for 46% in the intervention arm at 6 months compared to 18% in usual care (p = 0.03) among those with elevated distress at baseline.<br><br>CONCLUSIONS: Distress improved for YAs who received self-management survivorship care. However, the study demonstrates a need for alternative strategies for providing YA survivorship care.<br><br>TRIAL REGISTRATION: NCT02192333 IMPLICATIONS FOR CANCER SURVIVORS: While YA survivors demonstrate some improved distress when provided survivorship care, to make care accessible and effective, they require options such as remote delivery of care.}, }
@article {pmid34590125, year = {2021}, author = {Kaenkumchorn, TK and Merritt, MA and Lim, U and Le Marchand, L and Boushey, CJ and Shepard, JA and Wilkens, LR and Ernst, T and Lampe, JW}, title = {Diet and Liver Adiposity in Older Adults: The Multiethnic Cohort Adiposity Phenotype Study.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxab300}, pmid = {34590125}, issn = {1541-6100}, support = {U01 CA164973/NH/NIH HHS/United States ; P01 CA168530/CA/NCI NIH HHS/United States ; //University of Hawaii Cancer Center/ ; //University of Southern California/ ; UL1 TR000130/TR/NCATS NIH HHS/United States ; //Southern California Clinical and Translational Science Institute/ ; }, abstract = {BACKGROUND: Diet plays a key role in the pathogenesis of nonalcoholic fatty liver disease. Limited data exist regarding specific nutrients and food groups and liver fat continuously, particularly among different ethnicities.<br><br>OBJECTIVES: We aimed to determine the relationship between usual dietary intake and accurately measured liver fat content in a multiethnic population.<br><br>METHODS: Participants from the Multiethnic Cohort were recruited into the cross-sectional Adiposity Phenotype Study including women and men aged 60-77 y and 5 race/ethnic groups (African American, Japanese American, Latino, Native Hawaiian, and white). They filled out a detailed FFQ and underwent abdominal MRI for liver fat quantification and whole-body DXA for total adiposity. Intake of a priori-selected dietary factors (total and macronutrient energy, specific micronutrients, and food groups) was analyzed in relation to liver fat by estimating the mean percentage liver fat for quartiles of each dietary factor in a general linear model that adjusted for age, sex, race/ethnicity, percentage body fat, and daily energy intake (kcal/d).<br><br>RESULTS: In total, 1682 participants (mean age: 69.2 y; 51% female) were included. Mean ± SD liver fat percentage was 5.7 ± 4.6. A significant positive association with liver fat was found across quartiles of percentage energy from fat, saturated fat, cholesterol, total red meat, red meat excluding processed red meat, and coffee (Bonferroni-adjusted P-trend < 0.05). A significant inverse association was observed for dietary fiber, vitamin C, and vitamin E (Bonferroni-adjusted P-trend < 0.05).<br><br>CONCLUSIONS: This study of ethnically diverse older adults shows that certain dietary factors, in particular red meat and saturated fat from red meat, were strongly associated with liver fat, whereas dietary fiber was inversely associated with liver fat, replicating some of the previous studies conducted mostly in whites.}, }
@article {pmid34590066, year = {2021}, author = {Brewer, N and Bartholomew, K and Grant, J and Maxwell, A and McPherson, G and Wihongi, H and Bromhead, C and Scott, N and Crengle, S and Foliaki, S and Cunningham, C and Douwes, J and Potter, JD}, title = {Acceptability of human papillomavirus (HPV) self-sampling among never- and under-screened Indigenous and other minority women: a randomised three-arm community trial in Aotearoa New Zealand.}, journal = {The Lancet regional health. Western Pacific}, volume = {16}, number = {}, pages = {100265}, doi = {10.1016/j.lanwpc.2021.100265}, pmid = {34590066}, issn = {2666-6065}, abstract = {Background: Internationally, self-sampling for human papillomavirus (HPV) has been shown to increase participation in cervical-cancer screening. In Aotearoa New Zealand, there are long-standing ethnic inequalities in cervical-cancer screening, incidence, and mortality, particularly for indigenous Māori women, as well as Pacific and Asian women.<br><br>Methods: We invited never- and markedly under-screened (≥5 years overdue) 30-69-year-old Māori, Pacific, and Asian women to participate in an open-label, three-arm, community-based, randomised controlled trial, with a nested sub-study. We aimed to assess whether two specific invitation methods for self-sampling improved screening participation over usual care among the least medically served populations. Women were individually randomised 3:3:1 to: clinic-based self-sampling (CLINIC - invited to take a self-sample at their usual general practice); home-based self-sampling (HOME - mailed a kit and invited to take a self-sample at home); and usual care (USUAL - invited to attend a clinic for collection of a standard cytology sample). Neither participants nor research staff could be blinded to the intervention. In a subset of general practices, women who did not participate within three months of invitation were opportunistically invited to take a self-sample, either next time they attended a clinic or by mail.<br><br>Findings: We randomised 3,553 women: 1,574 to CLINIC, 1,467 to HOME, and 512 to USUAL. Participation was highest in HOME (14.6% among Māori, 8.8% among Pacific, and 18.5% among Asian) with CLINIC (7.0%, 5.3% and 6.9%, respectively) and USUAL (2.0%, 1.7% and 4.5%, respectively) being lower. In fully adjusted models, participation was statistically significantly more likely in HOME than USUAL: Māori OR=9.7, (95%CI 3.0-31.5); Pacific OR=6.0 (1.8-19.5); and Asian OR=5.1 (2.4-10.9). There were no adverse outcomes reported. After three months, 2,780 non-responding women were invited to participate in a non-randomised, opportunistic, follow-on substudy. After 6 months,192 (6.9%) additional women had taken a self-sample.<br><br>Interpretation: Using recruitment methods that mimic usual practice, we provide critical evidence that self-sampling increases screening among the groups of women (never and under-screened) who experience the most barriers in Aotearoa New Zealand, although the absolute level of participation through this population approach was modest. Follow-up for most women was routine but a small proportion required intensive support.<br><br>Trial registration: ANZCTR Identifier: ACTRN12618000367246 (date registered 12/3/2018) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371741&amp;isReview=true; UTN: U1111-1189-0531.<br><br>Funding: Health Research Council of New Zealand (HRC 16/405).<br><br>Protocol: http://publichealth.massey.ac.nz/assets/Uploads/Study-protocol-V2.1Self-sampling-for-HPV-screening-a-community-trial.pdf.}, }
@article {pmid34590025, year = {2021}, author = {Merkhofer, CM and Baik, CS}, title = {Durable Response of Leptomeningeal Disease With Osimertinib and Pemetrexed in EGFR-Mutated Metastatic NSCLC: A Case Report.}, journal = {JTO clinical and research reports}, volume = {2}, number = {6}, pages = {100177}, doi = {10.1016/j.jtocrr.2021.100177}, pmid = {34590025}, issn = {2666-3643}, abstract = {Optimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy.}, }
@article {pmid34588433, year = {2021}, author = {Chazot, N and Condamine, FL and Dudas, G and Peña, C and Kodandaramaiah, U and Matos-Maraví, P and Aduse-Poku, K and Elias, M and Warren, AD and Lohman, DJ and Penz, CM and DeVries, P and Fric, ZF and Nylin, S and Müller, C and Kawahara, AY and Silva-Brandão, KL and Lamas, G and Kleckova, I and Zubek, A and Ortiz-Acevedo, E and Vila, R and Vane-Wright, RI and Mullen, SP and Jiggins, CD and Wheat, CW and Freitas, AVL and Wahlberg, N}, title = {Conserved ancestral tropical niche but different continental histories explain the latitudinal diversity gradient in brush-footed butterflies.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {5717}, pmid = {34588433}, issn = {2041-1723}, support = {ANR-10-LABX-25-01//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-16-CE02-0012//Agence Nationale de la Recherche (French National Research Agency)/ ; RGP0014/2016//Human Frontier Science Program (HFSP)/ ; DEB-1541557//NSF | BIO | Division of Environmental Biology (DEB)/ ; WW-227R-17//National Geographic Society/ ; 2015-04441//Vetenskapsrådet (Swedish Research Council)/ ; }, abstract = {The global increase in species richness toward the tropics across continents and taxonomic groups, referred to as the latitudinal diversity gradient, stimulated the formulation of many hypotheses to explain the underlying mechanisms of this pattern. We evaluate several of these hypotheses to explain spatial diversity patterns in a butterfly family, the Nymphalidae, by assessing the contributions of speciation, extinction, and dispersal, and also the extent to which these processes differ among regions at the same latitude. We generate a time-calibrated phylogeny containing 2,866 nymphalid species (~45% of extant diversity). Neither speciation nor extinction rate variations consistently explain the latitudinal diversity gradient among regions because temporal diversification dynamics differ greatly across longitude. The Neotropical diversity results from low extinction rates, not high speciation rates, and biotic interchanges with other regions are rare. Southeast Asia is also characterized by a low speciation rate but, unlike the Neotropics, is the main source of dispersal events through time. Our results suggest that global climate change throughout the Cenozoic, combined with tropical niche conservatism, played a major role in generating the modern latitudinal diversity gradient of nymphalid butterflies.}, }
@article {pmid34587551, year = {2021}, author = {Singh, A and Dandoy, CE and Chen, M and Kim, S and Mulroney, CM and Kharfan-Dabaja, MA and Ganguly, S and Maziarz, RT and Kanakry, CG and Kanakry, JA and Patel, SS and Hill, JA and De Oliveira, S and Taplitz, R and Hematti, P and Lazarus, HM and Abid, MB and Goldsmith, SR and Romee, R and Komanduri, KV and Badawy, SM and Friend, BD and Beitinjaneh, A and Politikos, I and Perales, MA and Riches, M}, title = {Post-Transplant cyclophosphamide is associated with increase in Non-CMV Herpesvirus infections in Acute leukemia and MDS patients.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.09.015}, pmid = {34587551}, issn = {2666-6367}, abstract = {BACKGROUND: There is increasing use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis for both haploidentical and fully matched transplants. Published studies have reported an increased incidence of CMV infection with the use of PTCy. Limited data exist regarding the incidence and outcomes of infection with non-CMV herpes viruses (NCHV) in this setting.<br><br>OBJECTIVE: The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplant-specific outcomes in patients receiving haploidentical transplant with PTCy(HaploCy), matched sibling donor transplant with PTCy (SibCy) or matched sibling donor transplant with calcineurin inhibitor based prophylaxis (SibCNI). We hypothesized that, like CMV infection, patients receiving haploidentical transplant with PTCy will have higher risk of NCHV infections.<br><br>STUDY DESIGN: Using the CIBMTR database, we analyzed patients (HaploCy, n=757; SibCNI, n=1605; SibCy, n=403) receiving first hematopoietic stem-cell transplant between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome.<br><br>RESULTS: The cumulative incidence of non-CMV herpes virus infection at six months post-transplant in the HaploCy, SibCy and SibCNI were 13.9% (99%CI=10.8-17.3%), 10.7% (99%CI=7.1-15%), and 5.7% (99%CI=4.3-7.3%), p<0.001 respectively. This was primarily due to a higher frequency of HHV-6 viremia reported in patients receiving PTCy. Incidence of Epstein-Barr viremia was low in all groups and no cases of post-transplant lymphoproliferative disorder were seen in PTCy groups. The incidence of non-CMV herpes virus organ disease was low in all three cohorts. Development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, and disease-free survival. Patients in PTCy cohorts who did not develop non-CMV herpes virus infection had lower rates of cGVHD.<br><br>CONCLUSIONS: This study demonstrates that the use of PTCy is associated with increased risk of NCHV infection. Development of NCHV infection is associated with increased non-relapse mortality, especially in HaploCY group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for better understanding of the clinical relevance of viral reactivation in different transplant settings.}, }
@article {pmid34587382, year = {2021}, author = {Falsey, AR and Sobieszczyk, ME and Hirsch, I and Sproule, S and Robb, ML and Corey, L and Neuzil, KM and Hahn, W and Hunt, J and Mulligan, MJ and McEvoy, C and DeJesus, E and Hassman, M and Little, SJ and Pahud, BA and Durbin, A and Pickrell, P and Daar, ES and Bush, L and Solis, J and Carr, QO and Oyedele, T and Buchbinder, S and Cowden, J and Vargas, SL and Benavides, AG and Call, R and Keefer, MC and Kirkpatrick, BD and Pullman, J and Tong, T and Isaacs, MB and Benkeser, D and Janes, HE and Nason, MC and Green, JA and Kelly, EJ and Maaske, J and Mueller, N and Shoemaker, K and Takas, T and Marshall, RP and Pangalos, MN and Villafana, T and Gonzalez-Lopez, A and , }, title = {Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2105290}, pmid = {34587382}, issn = {1533-4406}, support = {Agreement No. W15QKN-20-9-1003//U.S. Department of Health and Human Services/ ; UM1 AI 148372//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 148450//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 148574//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 148684//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 148684-03//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 68614HVTN//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 68618//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 68619//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 68635//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 68636//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {BACKGROUND: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known.<br><br>METHODS: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.<br><br>RESULTS: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.<br><br>CONCLUSIONS: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).}, }
@article {pmid34584245, year = {2021}, author = {Adair, JE and Androski, L and Bayigga, L and Bazira, D and Brandon, E and Dee, L and Deeks, S and Draz, M and Dubé, K and Dybul, M and Gurkan, U and Harlow, E and Kityo, C and Louella, M and Malik, P and Mathews, V and McKemey, A and Mugerwa, H and Muyanja, D and Olayiwola, O and Orentas, RJ and Popovski, A and Sheehy, J and Ssali, F and Nsubuga, MS and Tisdale, JF and Verhoeyen, E and Dropulić, B}, title = {Correction: Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).}, journal = {Gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41434-021-00293-3}, pmid = {34584245}, issn = {1476-5462}, }
@article {pmid34583965, year = {2021}, author = {Omofuma, OO and Peterson, LL and Turner, DP and Merchant, AT and Zhang, J and Thomson, CA and Neuhouser, ML and Snetselaar, L and Caan, BJ and Shadyab, AH and Saquib, N and Banack, HR and Uribarri, J and Steck, SE}, title = {Dietary Advanced Glycation End-Products (AGEs) and Mortality After Breast Cancer in the Women's Health Initiative (WHI).}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0610}, pmid = {34583965}, issn = {1538-7755}, abstract = {BACKGROUND: Advanced glycation end-products (AGEs) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between post-diagnosis dietary NƐ-carboxymethyl-lysine (CML)-AGE intake and mortality among women diagnosed with breast cancer (BC).<br><br>METHODS: Postmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive BC during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CIs) of association between tertiles of post-diagnosis CML-AGE intake and mortality risk from all-causes, BC, and cardiovascular disease (CVD).<br><br>RESULTS: After a median 15.1 years of follow-up, 630 deaths from all-causes were reported (193 were BC-related and 129 were CVD-related). Post-diagnosis CML-AGE intake was associated with all-cause (HRT3vsT1: 1.37, 95% CI: 1.09-1.74), BC (HRT3vsT1: 1.49, 95% CI: 0.98-2.24) and CVD (HRT3vsT1: 1.91, 95% CI: 1.09-3.32) mortality.<br><br>CONCLUSIONS: Higher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with BC.<br><br>IMPACT: Our findings suggest that dietary AGEs may contribute to the risk of mortality after BC diagnosis. Further prospective studies examining dietary AGEs in BC outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.}, }
@article {pmid34582791, year = {2021}, author = {Mikhaylova, AV and McHugh, CP and Polfus, LM and Raffield, LM and Boorgula, MP and Blackwell, TW and Brody, JA and Broome, J and Chami, N and Chen, MH and Conomos, MP and Cox, C and Curran, JE and Daya, M and Ekunwe, L and Glahn, DC and Heard-Costa, N and Highland, HM and Hobbs, BD and Ilboudo, Y and Jain, D and Lange, LA and Miller-Fleming, TW and Min, N and Moon, JY and Preuss, MH and Rosen, J and Ryan, K and Smith, AV and Sun, Q and Surendran, P and de Vries, PS and Walter, K and Wang, Z and Wheeler, M and Yanek, LR and Zhong, X and Abecasis, GR and Almasy, L and Barnes, KC and Beaty, TH and Becker, LC and Blangero, J and Boerwinkle, E and Butterworth, AS and Chavan, S and Cho, MH and Choquet, H and Correa, A and Cox, N and DeMeo, DL and Faraday, N and Fornage, M and Gerszten, RE and Hou, L and Johnson, AD and Jorgenson, E and Kaplan, R and Kooperberg, C and Kundu, K and Laurie, CA and Lettre, G and Lewis, JP and Li, B and Li, Y and Lloyd-Jones, DM and Loos, RJF and Manichaikul, A and Meyers, DA and Mitchell, BD and Morrison, AC and Ngo, D and Nickerson, DA and Nongmaithem, S and North, KE and O'Connell, JR and Ortega, VE and Pankratz, N and Perry, JA and Psaty, BM and Rich, SS and Soranzo, N and Rotter, JI and Silverman, EK and Smith, NL and Tang, H and Tracy, RP and Thornton, TA and Vasan, RS and Zein, J and Mathias, RA and ,  and Reiner, AP and Auer, PL}, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2021.08.007}, pmid = {34582791}, issn = {1537-6605}, abstract = {Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.}, }
@article {pmid34581433, year = {2021}, author = {Riedell, PA and Hamadani, M and Ahn, KW and Litovich, C and Brunstein, CG and Cashen, AF and Cohen, JB and Epperla, N and Hill, BT and Im, A and Inwards, DJ and Lister, J and McCarty, JM and Ravi Kiran Pingali, S and Shadman, M and Shaughnessy, P and Solh, M and Stiff, PJ and Vose, JM and Kharfan-Dabaja, MA and Herrera, AF and Sauter, CS and Smith, SM}, title = {Effect of time to relapse on overall survival in patients with mantle cell lymphoma following autologous haematopoietic cell transplantation.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.17865}, pmid = {34581433}, issn = {1365-2141}, abstract = {In young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front-line setting. Recently, time-to-event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post-autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six-month [hazard ratio (HR) = 7·68], 12-month (HR = 6·68), and 18-month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non-relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high-risk group with inferior post-relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up-front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.}, }
@article {pmid34580401, year = {2021}, author = {Yang, S and Kay, NE and Shi, M and Ossenkoppele, G and Walter, RB and Gale, RP}, title = {Measurable residual disease testing in chronic lymphocytic leukaemia: hype, hope neither or both?.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {34580401}, issn = {1476-5551}, }
@article {pmid34580114, year = {2021}, author = {Chiorean, EG and Guthrie, KA and Philip, PA and Swisher, EM and Jalikis, F and Pishvaian, MJ and Berlin, J and Noel, MS and Suga, JM and Garrido-Laguna, I and Cardin, DB and Radke, MR and Duong, M and Bellasea, S and Lowy, AM and Hochster, HS}, title = {Randomized Phase II Study of PARP Inhibitor Veliparib with Modified FOLFIRI versus FOLFIRI as Second Line Treatment of Metastatic Pancreatic Cancer: SWOG S1513.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-21-1789}, pmid = {34580114}, issn = {1557-3265}, abstract = {PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors synergize with topoisomerase inhibitors, and veliparib plus modified (m) FOLFIRI (no 5-FU bolus) had preliminary activity in metastatic pancreatic cancers (mPC). This study evaluated the safety and efficacy of second-line treatment with veliparib and mFOLFIRI vs FOLFIRI (control) for mPC.<br><br>EXPERIMENTAL DESIGN: This randomized phase II clinical trial led by the SWOG Cancer Research Network enrolled patients between September 1, 2016 and December 13, 2017. The median follow-up was 9 months (IQR 1-27). BRCA1/2 and homologous recombination DNA damage repair (HR-DDR) genetic defects were tested in blood and tumor biopsies. Patients received veliparib 200 mg twice daily, days 1-7 with mFOLFIRI days 3-5, or FOLFIRI in 14 days-cycles.<br><br>RESULTS: After 123 of planned 143 patients were accrued, an interim futility analysis indicated the veliparib arm was unlikely to be superior to control, and the study was halted. Median survival (OS) was 5.4 vs 6.5 months (HR 1.23, p=0.28), and median progression free survival (PFS) was 2.1 vs 2.9 months (HR 1.39, p=0.09) with veliparib vs control. Grade 3/4 toxicities were more common with veliparib (69% vs 58%, p=0.23). For cancers with HR-DDR defects vs wild type, median PFS and OS were 7.3 vs 2.5 months (p=0.05), and 10.1 vs 5.9 months (p=0.17), respectively with FOLFIRI, and 2.0 vs 2.1 months (p=0.62) and 7.4 vs 5.1 months (p=0.10), respectively with veliparib plus mFOLFIRI.<br><br>CONCLUSIONS: Veliparib plus mFOLFIRI did not improve survival for mPC. FOLFIRI should be further studied in pancreatic cancers with HR-DDR defects.}, }
@article {pmid34579786, year = {2021}, author = {Barnabas, RV and Brown, ER and Onono, M and Bukusi, EA and Njoroge, B and Winer, RL and Donnell, D and Galloway, D and Cherne, S and Heller, K and Leingang, H and Morrison, S and Rechkina, E and McClelland, RS and Baeten, JM and Celum, C and Mugo, N and , }, title = {Single-dose HPV vaccination efficacy among adolescent girls and young women in Kenya (the KEN SHE Study): study protocol for a randomized controlled trial.}, journal = {Trials}, volume = {22}, number = {1}, pages = {661}, pmid = {34579786}, issn = {1745-6215}, support = {OPP1188693//Bill and Melinda Gates Foundation/ ; }, abstract = {BACKGROUND: HPV infection is the primary cause of cervical cancer, a leading cause of cancer among women in Kenya and many sub-Saharan African countries. High coverage of HPV vaccination is a World Health Organization priority to eliminate cervical cancer globally, but vaccine supply and logistics limit widespread implementation of the current two or three dose HPV vaccine schedule.<br><br>METHODS: We are conducting an individual randomized controlled trial to evaluate whether a single dose of the bivalent (HPV 16/18) or nonavalent (HPV 16/18/31/33/45/52/58/6/11) HPV vaccine prevents persistent HPV infection, a surrogate marker for precancerous lesions and cervical cancer. The primary objective is to compare the efficacy of immediate, single-dose bivalent or nonavalent vaccination with delayed HPV vaccination. Kenyan women age 15-20 years old are randomized to immediate bivalent HPV and delayed meningococcal vaccine (group 1), immediate nonavalent HPV vaccine and delayed meningococcal vaccine (group 2), or immediate meningococcal vaccine and delayed HPV vaccine (group 3) with 36 months of follow-up. The primary outcome is persistent vaccine-type HPV infection by month 18 and by month 36 for the final durability outcome. The secondary objectives include to (1) evaluate non-inferiority of antibody titers among girls and adolescents (age 9 to 14 years) from another Tanzanian study, the DoRIS Study (NCT02834637), compared to KEN SHE Study participants; (2) assess the memory B cell immune response at months 36 and 37; and (3) estimate cost-effectiveness using the trial results and health economic models.<br><br>DISCUSSION: This study will evaluate single-dose HPV vaccine efficacy in Africa and has the potential to guide public health policy and increase HPV vaccine coverage. The secondary aims will assess generalizability of the trial results by evaluating immunobridging from younger ages, durability of the immune response, and the long-term health benefits and cost of single-dose HPV vaccine delivery.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT03675256 . Registered on September 18, 2018.}, }
@article {pmid34509873, year = {2021}, author = {Giraldi, L and Collatuzzo, G and Hashim, D and Franceschi, S and Herrero, R and Chen, C and Schwartz, SM and Smith, E and Kelsey, K and McClean, M and Gillison, M and Boccia, S and Hashibe, M and Amy Lee, YC and Boffetta, P}, title = {Infection with Human Papilloma Virus (HPV) and risk of subsites within the oral cancer.}, journal = {Cancer epidemiology}, volume = {75}, number = {}, pages = {102020}, doi = {10.1016/j.canep.2021.102020}, pmid = {34509873}, issn = {1877-783X}, abstract = {BACKGROUND: The aim of this study was to investigate the relationship between high-risk genotypes of Human Papilloma Virus (HPV) and cancer of different subsites of the oral cavity.<br><br>MATERIAL AND METHODS: A pooled analysis of five studies included on the International Head and Neck Cancer Epidemiology (INHANCE) Consortium was conducted. HPV 16 and HPV 18 were considered. Adjusted odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for HPV and each oral cavity subsites were simultaneously estimated using multinomial logistic regression models.<br><br>RESULTS: The analysis included 1157 cases and 3272 controls. This study showed a slightly higher prevalence of HPV infection among oral cancer cases than controls. In particular, an increased risk of other and not otherwise specified (NOS) sites within the oral cavity, oral tongue, palate and floor of mouth cancer was observed for overall HPV16 positivity (OR = 1.66, 95 % CI: 1.01-2.72; OR = 1.97, 95 % CI: 1.36-2.85; OR = 2.48, 95 % CI: 1.50-4.11; OR = 2.71, 95 % CI: 1.06-6.95, respectively). In particular, HPV16E7 was related to cancer of floor of mouth, oral cavity NOS and palate (OR = 2.71, 95 % CI: 1.06-6.95; OR = 3.32, 95 % CI:1.53-7.19; OR = 3.34, 95 % CI:1.38-8.06). Results were inconsistent for HPV18 due to low prevalence of infection.<br><br>CONCLUSION: Our study suggests that HPV16 infection may increase the risk of developing floor of mouth, gum, tongue, and palate cancers.<br><br>CLINICAL RELEVANCE: Subjects with HPV infection have a higher risk of cancer from all sites of the oral cavity.}, }
@article {pmid34571378, year = {2021}, author = {Bardi, E and Mulder, RL and van Dalen, EC and Bhatt, NS and Ruble, KA and Burgis, J and Castellino, SM and Constine, LS and den Hoed, CM and Green, DM and Koot, BGP and Levitt, G and Szonyi, L and Wallace, WH and Skinner, R and Hudson, MM and Kremer, LCM and Effinger, KE and Bresters, D}, title = {Late hepatic toxicity surveillance for survivors of childhood, adolescent and young adult cancer: Recommendations from the international late effects of childhood cancer guideline harmonization group.}, journal = {Cancer treatment reviews}, volume = {100}, number = {}, pages = {102296}, doi = {10.1016/j.ctrv.2021.102296}, pmid = {34571378}, issn = {1532-1967}, abstract = {BACKGROUND: Survivors of childhood, adolescent and young adult (CAYA) cancer may develop treatment-induced chronic liver disease. Surveillance guidelines can improve survivors' health outcomes. However, current recommendations vary, leading to uncertainty about optimal screening. The International Late Effects of Childhood Cancer Guideline Harmonization Group has developed recommendations for the surveillance of late hepatotoxicity after CAYA cancer.<br><br>METHODS: Evidence-based methods based on the GRADE framework were used in guideline development. A multidisciplinary guideline panel performed systematic literature reviews, developed evidence summaries, appraised the evidence, and formulated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance while allowing for flexibility in implementation across different health care systems.<br><br>RESULTS: The guideline strongly recommends a physical examination and measurement of serum liver enzyme concentrations (ALT, AST, gGT, ALP) once at entry into long-term follow-up for survivors treated with radiotherapy potentially exposing the liver (moderate- to high-quality evidence). For survivors treated with busulfan, thioguanine, mercaptopurine, methotrexate, dactinomycin, hematopoietic stem cell transplantation (HSCT), or hepatic surgery, or with a history of chronic viral hepatitis or sinusoidal obstruction syndrome, similar surveillance for late hepatotoxicity once at entry into LTFU is reasonable (low-quality evidence/expert opinion, moderate recommendation). For survivors who have undergone HSCT and/or received multiple red blood cell transfusions, surveillance for iron overload with serum ferritin is strongly recommended once at long-term follow-up entry.<br><br>CONCLUSIONS: These evidence-based, internationally-harmonized recommendations for the surveillance of late hepatic toxicity in cancer survivors can inform clinical care and guide future research of health outcomes for CAYA cancer survivors.}, }
@article {pmid34571290, year = {2021}, author = {Simon, S and Bugos, G and Salter, AI and Riddell, SR}, title = {Synthetic receptors for logic gated T cell recognition and function.}, journal = {Current opinion in immunology}, volume = {74}, number = {}, pages = {9-17}, doi = {10.1016/j.coi.2021.09.003}, pmid = {34571290}, issn = {1879-0372}, abstract = {Adoptive cell therapy with T cells engineered with customized receptors that redirect antigen specificity to cancer cells has emerged as an effective therapeutic approach for many malignancies. Toxicity due to on target or off target effects, antigen heterogeneity on cancer cells, and acquired T cell dysfunction have been identified as barriers that can hinder successful therapy. This review will discuss recent advances in T cell engineering that have enabled the application of logic gates in T cells that can mimic the integration of natural signaling pathways and act in a cell intrinsic or extrinsic fashion to precisely target tumor cells and regulate effector functions, potentially overcoming these barriers to effective therapy.}, }
@article {pmid34571212, year = {2021}, author = {Dahlberg, A and Kurtzberg, J and Boelens, J and Martinez, C and Carpenter, P and , }, title = {Guidelines for Pediatric Unrelated Cord Blood Transplantation-Unique Considerations.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.09.013}, pmid = {34571212}, issn = {2666-6367}, abstract = {Cord blood (CB) is the stem cell source of choice for approximately 30% of pediatric patients undergoing hematopoietic cell transplantation. Cord blood is readily available and is a particularly appealing stem cell source for patients who lack appropriate HLA matched related or unrelated donors. Pediatric cord blood transplant (CBT) recipients have low rates of disease relapse in the malignant setting and very low rates of chronic GVHD. In addition, CB has unique properties that make it the stem cell source of choice for some non-malignant conditions such as metabolic disorders. This review provides evidence-based and experience-based pediatric specific guidelines for CBT including considerations for infectious disease management, CB unit selection and infusion, conditioning regimen selection, and GVHD management. In addition, it covers unique bedside considerations for pediatric patients and CB banking. In concert with the other topic specific CB guidelines previously published in this series, it provides a comprehensive overview of the clinical management of pediatric CBT.}, }
@article {pmid34570884, year = {2021}, author = {Liese, AD and Reboussin, BA and Kahkoska, AR and Frongillo, EA and Malik, FS and Imperatore, G and Saydah, S and Bellatorre, A and Lawrence, JM and Dabelea, D and Mendoza, JA}, title = {Inequalities in Glycemic Control in Youth with Type 1 Diabetes Over Time: Intersectionality Between Socioeconomic Position and Race and Ethnicity.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/abm/kaab086}, pmid = {34570884}, issn = {1532-4796}, support = {//Marilyn Owsley Clinical Research Center/ ; //South Carolina Clinical &amp; Translational Research Institute/ ; //Medical University of South Carolina/ ; /NH/NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; UL1 TR00423//Seattle Children's Hospital and the University of Washington/ ; UL1 TR000154/TR/NCATS NIH HHS/United States ; P30 DK57516//University of Colorado/ ; UL1 TR000077/TR/NCATS NIH HHS/United States ; //Ohio Department of Health/ ; DP-15-002/CC/CDC HHS/United States ; F30DK113728/DK/NIDDK NIH HHS/United States ; U48/CCU919219//Kaiser Permanente Southern California/ ; U48/CCU819241-3//University of Colorado Denver/ ; U48/CCU519239//Cincinnati's Children's Hospital Medical Center/ ; U48/CCU419249//University of North Carolina at Chapel Hill/ ; U58/CCU019235-4//Seattle Children's Hospital/ ; U48/CCU919219//Wake Forest University School of Medicine/ ; }, abstract = {BACKGROUND: Racial/ethnic health inequities have been well-documented among youth and young adults with type 1 diabetes (T1D), yet little is known about how socioeconomic position (SEP) intersects with the risk marker of race/ethnicity to predict inequities in longitudinal glycemic control.<br><br>PURPOSE: To identify patterns of SEP, race/ethnicity, and clinical characteristics that differentiate hemoglobin A1c (HbA1c) trajectories among youth and young adults after T1D diagnosis.<br><br>METHODS: The SEARCH for Diabetes in Youth cohort includes youth with diabetes diagnosed from 2002 to 2006 and 2008 who were followed through 2015. We analyzed data from 1,313 youth and young adults with T1D with ≥3 HbA1c measures. Classification tree analysis identified patterns of baseline demographic, SEP, and clinical characteristic that best predicted HbA1c trajectories over an average of 8.3 years using group-based trajectory modeling.<br><br>RESULTS: Two HbA1c trajectories were identified: Trajectory 1 (77%) with lower baseline HbA1c and mild increases (from mean 7.4% to 8.4%) and Trajectory 2 (23%) with higher baseline HbA1c and major increases (from 8.5% to 11.2%). Race/ethnicity intersected with different SEP characteristics among non-Hispanic white (NHW) than in non-whites. Public health insurance predicted high-risk Trajectory 2 membership in non-whites, whereas parental education, household structure, diagnosis age and glucose checking frequency predicted membership for NHW youth and young adults. Two characteristics, race/ethnicity and parental education alone identified 80% of the Trajectory 2 members.<br><br>CONCLUSIONS: Race/ethnicity intersects with multiple SEP and clinical characteristics among youth and young adults with T1D, which is associated with particularly high risk of poor long-term glycemic control.}, }
@article {pmid34568921, year = {2021}, author = {Ali, MF and Latimer, AJ and Wang, Y and Hogenmiller, L and Fontenas, L and Isabella, AJ and Moens, CB and Yu, G and Kucenas, S}, title = {Met is required for oligodendrocyte progenitor cell migration in Danio rerio.}, journal = {G3 (Bethesda, Md.)}, volume = {11}, number = {10}, pages = {}, doi = {10.1093/g3journal/jkab265}, pmid = {34568921}, issn = {2160-1836}, support = {//NIH/ ; //National Institutes of Neurological Disorders and Stroke/ ; R01NS107525/NS/NINDS NIH HHS/United States ; T32GM008715/GM/NIGMS NIH HHS/United States ; F32HD096860//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01MH11504/MH/NIMH NIH HHS/United States ; }, abstract = {During vertebrate central nervous system development, most oligodendrocyte progenitor cells (OPCs) are specified in the ventral spinal cord and must migrate throughout the neural tube until they become evenly distributed, occupying non-overlapping domains. While this process of developmental OPC migration is well characterized, the nature of the molecular mediators that govern it remain largely unknown. Here, using zebrafish as a model, we demonstrate that Met signaling is required for initial developmental migration of OPCs, and, using cell-specific knock-down of Met signaling, show that Met acts cell-autonomously in OPCs. Taken together, these findings demonstrate in vivo, the role of Met signaling in OPC migration and provide new insight into how OPC migration is regulated during development.}, }
@article {pmid34568833, year = {2021}, author = {Beauchamp, EM and Leventhal, M and Bernard, E and Hoppe, ER and Todisco, G and Creignou, M and Gallì, A and Castellano, CA and McConkey, M and Tarun, A and Wong, W and Schenone, M and Stanclift, C and Tanenbaum, B and Malolepsza, E and Nilsson, B and Bick, AG and Weinstock, JS and Miller, M and Niroula, A and Dunford, A and Taylor-Weiner, A and Wood, T and Barbera, A and Anand, S and Psaty, BM and Desai, P and Cho, MH and Johnson, AD and Loos, R and ,  and MacArthur, DG and Lek, M and ,  and Neuberg, DS and Lage, K and Carr, SA and Hellstrom-Lindberg, E and Malcovati, L and Papaemmanuil, E and Stewart, C and Getz, G and Bradley, RK and Jaiswal, S and Ebert, BL}, title = {ZBTB33 is mutated in clonal hematopoiesis and myelodysplastic syndromes and impacts RNA splicing.}, journal = {Blood cancer discovery}, volume = {2}, number = {5}, pages = {500-517}, doi = {10.1158/2643-3230.BCD-20-0224}, pmid = {34568833}, issn = {2643-3249}, abstract = {Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader, ZBTB33, as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in myelodysplastic syndrome patients. Zbtb33 edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.}, }
@article {pmid34568831, year = {2021}, author = {Abou-El-Enein, M and Elsallab, M and Feldman, SA and Fesnak, AD and Heslop, HE and Marks, P and Till, BG and Bauer, G and Savoldo, B}, title = {Scalable Manufacturing of CAR T cells for Cancer Immunotherapy.}, journal = {Blood cancer discovery}, volume = {2}, number = {5}, pages = {408-422}, doi = {10.1158/2643-3230.bcd-21-0084}, pmid = {34568831}, issn = {2643-3249}, abstract = {As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematological malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for cancer patients. In this review we describe current CAR T cells clinical manufacturing models and discuss emerging technological advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T-cell manufacturing times and highlight regulatory challenges to scaling production for clinical use.<br><br>As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development.This review provides a critical appraisal of these technologies that can be leveraged to scale and optimize the production of next generation CAR T cells.}, }
@article {pmid34561204, year = {2021}, author = {Msaouel, P and Grivas, P and Zhang, T}, title = {Adjuvant Systemic Therapies for Patients with Renal Cell Carcinoma: Choosing Treatment Based on Patient-level Characteristics.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2021.09.003}, pmid = {34561204}, issn = {2588-9311}, abstract = {Motivated by recent presentation of the KEYNOTE-564 interim results for adjuvant pembrolizumab in clear-cell renal cell carcinoma, we discuss concepts that can guide patient-specific decision-making in selecting individuals for whom adjuvant therapies should be offered.}, }
@article {pmid34560310, year = {2021}, author = {Yong, MK and Shigle, TL and Kim, YJ and Carpenter, PA and Chemaly, RF and Papanicolaou, GA}, title = {American Society of Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.09.010}, pmid = {34560310}, issn = {2666-6367}, abstract = {The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy (ASTCT) partnered with its Transplant Infectious Disease Special Interest Group (TID-SIG) to update its 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). A new approach was employed with the goal of better serving clinical providers by publishing each standalone topic in the infectious diseases series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious diseases and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The fourth topic in the series focuses on the management and treatment of cytomegalovirus (CMV) resistant and refractory infections. The diagnosis, definitions of resistant and refractory CMV, risk factors, virological genotypes and treatment algorithms are reviewed.}, }
@article {pmid34559844, year = {2021}, author = {Aljedani, SS and Liban, TJ and Tran, K and Phad, G and Singh, S and Dubrovskaya, V and Pushparaj, P and Martinez-Murillo, P and Rodarte, J and Mileant, A and Mangala Prasad, V and Kinzelman, R and O'Dell, S and Mascola, JR and Lee, KK and Karlsson Hedestam, GB and Wyatt, RT and Pancera, M}, title = {Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.}, journal = {PLoS pathogens}, volume = {17}, number = {9}, pages = {e1009543}, doi = {10.1371/journal.ppat.1009543}, pmid = {34559844}, issn = {1553-7374}, abstract = {Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.}, }
@article {pmid34559198, year = {2021}, author = {Angenendt, L and Wöste, M and Mikesch, JH and Arteaga, MF and Angenendt, A and Sandmann, S and Berdel, WE and Lenz, G and Dugas, M and Meshinchi, S and Schliemann, C and Rossig, C}, title = {Calcitonin receptor-like (CALCRL) is a marker of stemness and an independent predictor of outcome in pediatric AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005236}, pmid = {34559198}, issn = {2473-9537}, abstract = {We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.}, }
@article {pmid34558625, year = {2021}, author = {Moon, JY and Hua, S and Qi, Q and Sotres-Alvarez, D and Mattei, J and Casagrande, SS and Mossavar-Rahmani, Y and Siega-Riz, AM and Gallo, LC and Wassertheil-Smoller, S and Kaplan, R and Corsino, L}, title = {Association of Sugar-sweetened Beverage Consumption with Prediabetes and Glucose Metabolism Markers in Hispanic/Latino Adults in the United States: Results from HCHS/SOL.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/jn/nxab334}, pmid = {34558625}, issn = {1541-6100}, abstract = {BACKGROUND: Diabetes mellitus and consumption of sugar-sweetened beverages is high in the Hispanic/Latino population in the United States. The associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers in the diverse Hispanic/Latino population in the US are unknown.<br><br>OBJECTIVE: To examine the cross-sectional associations between consumption of sugar-sweetened beverages, artificially sweetened beverages, and 100% fruit juice with prediabetes and glucose metabolism markers such as fasting glucose and insulin, 2-hour oral glucose tolerance test (OGTT) glucose, HOMA index for insulin resistance (HOMA-IR), HOMA index for β-cell function (HOMA-B), and hemoglobin A1C (HbA1c) among US Hispanic/Latino adults.<br><br>METHODS: Using baseline data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL; 2008-2011), beverage consumption was ascertained using two 24-hour dietary recalls and the Food Propensity Questionnaire. Diabetes/prediabetes status was defined by self-report, antihyperglycemic medication use, and American Diabetes Association laboratory criteria. Among 9965 individuals without diabetes (5194 normoglycemia, 4771 prediabetes) aged 18-74 years, the associations of beverage consumption with prediabetes and glucose metabolism markers were analyzed using logistic and linear regressions, respectively, accounting for complex survey design.<br><br>RESULTS: Compared with individuals who consumed < 1 serving/day (<240 mL/day) of sugar-sweetened beverages, individuals who consumed > 2 servings/day (>480 mL/day) had 1.3 times greater odds of having prediabetes (95% confidence interval = 1.06-1.61) and higher glucose metabolism markers including fasting glucose, fasting insulin, HOMA-IR, and HbA1c. Consumption of artificially sweetened beverages showed an inverse association with β-cell function (HOMA-B). 100% fruit juice intake was not significantly associated with prediabetes nor with glucose metabolism markers.<br><br>CONCLUSIONS: Among US Hispanic/Latino adults, higher sugar-sweetened beverage consumption was associated with an increased odds of prediabetes and higher glucose metabolism markers. Public health initiatives to decrease sugar-sweetened beverage consumption could potentially reduce the burden of diabetes among Hispanics/Latinos in the US.}, }
@article {pmid34551388, year = {2021}, author = {Dotan, E and Walter, LC and Browner, IS and Clifton, K and Cohen, HJ and Extermann, M and Gross, C and Gupta, S and Hollis, G and Hubbard, J and Jagsi, R and Keating, NL and Kessler, E and Koll, T and Korc-Grodzicki, B and McKoy, JM and Misra, S and Moon, D and O'Connor, T and Owusu, C and Rosko, A and Russell, M and Sedrak, M and Siddiqui, F and Stella, A and Stirewalt, DL and Subbiah, IM and Tew, WP and Williams, GR and Hollinger, L and George, GV and Sundar, H}, title = {NCCN Guidelines® Insights: Older Adult Oncology, Version 1.2021.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {9}, pages = {1006-1019}, doi = {10.6004/jnccn.2021.0043}, pmid = {34551388}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.}, }
@article {pmid34551384, year = {2021}, author = {Brown, PA and Shah, B and Advani, A and Aoun, P and Boyer, MW and Burke, PW and DeAngelo, DJ and Dinner, S and Fathi, AT and Gauthier, J and Jain, N and Kirby, S and Liedtke, M and Litzow, M and Logan, A and Luger, S and Maness, LJ and Massaro, S and Mattison, RJ and May, W and Oluwole, O and Park, J and Przespolewski, A and Rangaraju, S and Rubnitz, JE and Uy, GL and Vusirikala, M and Wieduwilt, M and Lynn, B and Berardi, RA and Freedman-Cass, DA and Campbell, M}, title = {Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {9}, pages = {1079-1109}, doi = {10.6004/jnccn.2021.0042}, pmid = {34551384}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.}, }
@article {pmid34510414, year = {2021}, author = {Chan, KCG and Gao, F and Xia, F}, title = {Discussion on "Causal mediation of semicompeting risks" by Yen-Tsung Huang.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13520}, pmid = {34510414}, issn = {1541-0420}, support = {R01HL122212/HL/NHLBI NIH HHS/United States ; U01AG016976//National Institutes on Aging/ ; DMS1711952//National Science Foundation/ ; }, }
@article {pmid34554826, year = {2021}, author = {Hastie, KM and Li, H and Bedinger, D and Schendel, SL and Dennison, SM and Li, K and Rayaprolu, V and Yu, X and Mann, C and Zandonatti, M and Diaz Avalos, R and Zyla, D and Buck, T and Hui, S and Shaffer, K and Hariharan, C and Yin, J and Olmedillas, E and Enriquez, A and Parekh, D and Abraha, M and Feeney, E and Horn, GQ and ,  and Aldon, Y and Ali, H and Aracic, S and Cobb, RR and Federman, RS and Fernandez, JM and Glanville, J and Green, R and Grigoryan, G and Lujan Hernandez, AG and Ho, DD and Huang, KA and Ingraham, J and Jiang, W and Kellam, P and Kim, C and Kim, M and Kim, HM and Kong, C and Krebs, SJ and Lan, F and Lang, G and Lee, S and Leung, CL and Liu, J and Lu, Y and MacCamy, A and McGuire, AT and Palser, AL and Rabbitts, TH and Rikhtegaran Tehrani, Z and Sajadi, MM and Sanders, RW and Sato, AK and Schweizer, L and Seo, J and Shen, B and Snitselaar, JJ and Stamatatos, L and Tan, Y and Tomic, MT and van Gils, MJ and Youssef, S and Yu, J and Yuan, TZ and Zhang, Q and Peters, B and Tomaras, GD and Germann, T and Saphire, EO}, title = {Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study.}, journal = {Science (New York, N.Y.)}, volume = {}, number = {}, pages = {eabh2315}, doi = {10.1126/science.abh2315}, pmid = {34554826}, issn = {1095-9203}, abstract = {[Figure: see text].}, }
@article {pmid34554572, year = {2021}, author = {Storb, R}, title = {Commentary on the 1962 Transfusion paper by Don Thomas and Joe Ferrebee.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.16684}, pmid = {34554572}, issn = {1537-2995}, }
@article {pmid34554223, year = {2021}, author = {Wang, T and Ling, W and Plantinga, AM and Wu, MC and Zhan, X}, title = {Testing microbiome association using integrated quantile regression models.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btab668}, pmid = {34554223}, issn = {1367-4811}, abstract = {MOTIVATION: Most existing microbiome association analyses focus on the association between microbiome and conditional mean of health or disease-related outcomes, and within this vein, vast computational tools and methods have been devised for standard binary or continuous outcomes. However, these methods tend to be limited either when the underlying microbiome-outcome association occurs somewhere other than the mean level, or when distribution of the outcome variable is irregular (e.g., zero-inflated or mixtures) such that conditional outcome mean is less meaningful. We address this gap by investigating association analysis between microbiome compositions and conditional outcome quantiles.<br><br>RESULTS: We introduce a new association analysis tool named MiRKAT-IQ within the Microbiome Regression-based Kernel Association Test framework using Integrated Quantile regression models to examine the association between microbiome and the distribution of outcome. For an individual quantile, we utilize the existing kernel machine regression framework to examine the association between that conditional outcome quantile and a group of microbial features (e.g., microbiome community compositions). Then, the goal of examining microbiome association with the whole outcome distribution is achieved by integrating all outcome conditional quantiles over a process, and thus our new MiRKAT-IQ test is robust to both the location of association signals (e.g.,mean, variance, median) and the heterogeneous distribution of the outcome. Extensive numerical simulation studies have been conducted to show the validity of the new MiRKAT-IQ test. We demonstrate the potential usefulness of MiRKAT-IQ with applications to actual biological data collected from a previous microbiome study.<br><br>AVAILABILITY: R codes to implement the proposed methodology is provided in the MiRKAT package, which is available on CRAN.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid34553764, year = {2021}, author = {Little, A and Hu, Y and Sun, Q and Jain, D and Broome, J and Chen, MH and Thibord, F and McHugh, C and Surendran, P and Blackwell, TW and Brody, JA and Bhan, A and Chami, N and Vries, PS and Ekunwe, L and Heard-Costa, N and Hobbs, BD and Manichaikul, A and Moon, JY and Preuss, MH and Ryan, K and Wang, Z and Wheeler, M and Yanek, LR and Abecasis, GR and Almasy, L and Beaty, TH and Becker, LC and Blangero, J and Boerwinkle, E and Butterworth, AS and Choquet, H and Correa, A and Curran, JE and Faraday, N and Fornage, M and Glahn, DC and Hou, L and Jorgenson, E and Kooperberg, C and Lewis, JP and Lloyd-Jones, DM and Loos, RJF and Min, N and Mitchell, BD and Morrison, AC and Nickerson, D and North, KE and O'Connell, JR and Pankratz, N and Psaty, BM and Vasan, RS and Rich, SS and Rotter, JI and Smith, AV and Smith, NL and Tang, H and Tracy, RP and Conomos, MP and Laurie, CA and Mathias, RA and Li, Y and Auer, PL and ,  and Thornton, T and Reiner, AP and Johnson, AD and Raffield, LM}, title = {Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddab252}, pmid = {34553764}, issn = {1460-2083}, abstract = {Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI's Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.}, }
@article {pmid34553186, year = {2021}, author = {Bellettiere, J and Nguyen, S and Eaton, CB and Liles, S and Laddu-Patel, D and Di, C and Stefanick, ML and LaCroix, AZ and LaMonte, MJ}, title = {The short physical performance battery and incident heart failure among older women: the OPACH study.}, journal = {American journal of preventive cardiology}, volume = {8}, number = {}, pages = {100247}, doi = {10.1016/j.ajpc.2021.100247}, pmid = {34553186}, issn = {2666-6677}, abstract = {Objective: Reduced functional capacity is a hallmark of early pre-clinical stages of heart failure (HF). The Short Physical Performance Battery (SPPB) is a valid measure of lower extremity physical function, has relatively low implementation burden, and is associated with cardiovascular disease and mortality. However, the SPPB-HF association is understudied in older women among whom HF burden is high.<br><br>Methods: Women (n = 5325; mean age 79 ± 7 years; 34% Black, 18% Hispanic, and 49% White) without prior HF completed the SPPB consisting of standing balance, strength, and walking tests that were summarized as a composite score from 0 (lowest) to 12 (highest), categorized as very low (0-3), low (4-6), medium (7-9), or high (10-12). Participants were followed for up to 8 years for incident HF (306 cases identified). Cox proportional hazards regression estimated hazard ratios (HR) adjusting for age, race/ethnicity, education, smoking, alcohol, diabetes, hypertension, COPD, osteoarthritis, depression, BMI, systolic blood pressure, lipids, glucose, and accelerometer-measured moderate-vigorous physical activity (MVPA) and sedentary time.<br><br>Results: Incident HF cases (crude rate per 1000 person-years) in the four SPPB categories (very low to high) were 34 (26.0), 79 (14.5), 128 (9.3), and 65 (5.6). Corresponding multivariable-adjusted HRs (95% CIs) were 2.22 (1.34-3.66), 1.63 (1.11-2.38), 1.39 (1.00-1.94), and 1.00 (referent; P-trend<0.001). Higher HF risk was associated with lower SPPB in women with major modifiable HF risk factors including obesity (HR per 3-unit SPPB decrement: present HR = 1.41, absent HR = 1.41), hypertension (present HR = 1.45, absent HR = 1.30), diabetes (present HR = 1.32, absent HR = 1.44), and lower accelerometer-measured MVPA (<45 min/day HR = 1.29, ≥45 min/day HR = 1.60); all P-interaction>0.10.<br><br>Conclusion: Lower SPPB scores were associated with greater risk of incident HF in older women even after accounting for differences in HF risk factors and objectively measured PA. Implementing the SPPB in clinical settings could potentially enhance individual-level HF risk assessment, which should be further explored.}, }
@article {pmid34552595, year = {2021}, author = {Peng, T and Phasouk, K and Sodroski, CN and Sun, S and Hwangbo, Y and Layton, ED and Jin, L and Klock, A and Diem, K and Magaret, AS and Jing, L and Laing, K and Li, A and Huang, ML and Mertens, M and Johnston, C and Jerome, KR and Koelle, DM and Wald, A and Knipe, DM and Corey, L and Zhu, J}, title = {Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {735643}, doi = {10.3389/fimmu.2021.735643}, pmid = {34552595}, issn = {1664-3224}, abstract = {Tissue-resident-memory T cells (TRM) populate the body's barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.}, }
@article {pmid34551507, year = {2021}, author = {Verstovsek, S and Mesa, R and Talpaz, M and Kiladjian, JJ and Harrison, CN and Oh, ST and Vannucchi, AM and Rampal, R and Scott, BL and Buckley, SA and Craig, AR and Roman-Torres, K and Mascarenhas, JO}, title = {Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2021.279415}, pmid = {34551507}, issn = {1592-8721}, abstract = {Thrombocytopenia is common in patients with myelofibrosis and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (.}, }
@article {pmid34551225, year = {2021}, author = {El Sahly, HM and Baden, LR and Essink, B and Doblecki-Lewis, S and Martin, JM and Anderson, EJ and Campbell, TB and Clark, J and Jackson, LA and Fichtenbaum, CJ and Zervos, M and Rankin, B and Eder, F and Feldman, G and Kennelly, C and Han-Conrad, L and Levin, M and Neuzil, KM and Corey, L and Gilbert, P and Janes, H and Follmann, D and Marovich, M and Polakowski, L and Mascola, JR and Ledgerwood, JE and Graham, BS and August, A and Clouting, H and Deng, W and Han, S and Leav, B and Manzo, D and Pajon, R and Schödel, F and Tomassini, JE and Zhou, H and Miller, J and , }, title = {Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2113017}, pmid = {34551225}, issn = {1533-4406}, support = {UM1 AI 68614; UM1 AI 68635; UM1 AI 68618;UM1 AI 68//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.<br><br>METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.<br><br>RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.<br><br>CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).}, }
@article {pmid34551064, year = {2021}, author = {Menghrajani, K and Gomez-Arteaga, A and Madero-Marroquin, R and Zhang, MJ and Bo-Subait, K and Sanchez, J and Wang, HL and Aljurf, M and Assal, A and Bacher, U and Badawy, SM and Bejanyan, N and Bhatt, VR and Bredeson, CN and Byrne, M and Castillo, P and Cerny, J and Chhabra, S and Ciurea, SO and DeFilipp, Z and Farhadfar, N and Gadalla, SM and Gale, RP and Ganguly, S and Gowda, L and Grunwald, MR and Hashmi, S and Hildebrandt, GC and Kanakry, CG and Kansagra, A and Khimani, F and Krem, M and Lazarus, HM and Liu, H and Martino, R and Michelis, FV and Nathan, S and Nishihori, T and Olsson, RF and Reshef, R and Rizzieri, D and Rowe, JM and Savani, BN and Seo, S and Sharma, A and Solh, M and Ustun, C and Verdonck, LF and Hourigan, CS and Sandmaier, BM and Litzow, MR and Kebriaei, P and Weisdorf, DJ and Zhang, Y and Tallman, MS and Saber, W}, title = {Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004881}, pmid = {34551064}, issn = {2473-9537}, abstract = {Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes for acute myeloid leukemia (AML) patients. We evaluated 8709 AML patients from the CIBMTR database and, after selection and manual curation of cytogenetics data, 3779 patients in CR1 were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis compared to intermediate-risk patients detected an increased risk of relapse for KMT2A-rearranged and adverse-risk patients (HR 1.27, p = 0.01 and HR 1.71, p < 0.001, respectively). Leukemia-free survival (LFS) was similar for KMT2A and adverse-risk patients (HR 1.26, p = 0.002 and HR 1.47, p < 0.001), as was overall survival (OS) (HR 1.32, p < 0.001 and HR 1.45, p < 0.001). No differences in outcome could be detected when patients were stratified by KMT2A fusion partner. This is the largest study conducted to date on post-HCT outcomes in AML using manually curated cytogenetics for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A rearrangements and adverse-risk disease.}, }
@article {pmid34550860, year = {2021}, author = {Duggan, C and Yu, M and Willbanks, AR and Tapsoba, JD and Wang, CY and Grady, WM and McTiernan, A}, title = {Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women.}, journal = {Epigenetics}, volume = {}, number = {}, pages = {}, doi = {10.1080/15592294.2021.1982512}, pmid = {34550860}, issn = {1559-2308}, abstract = {Physical activity reduces risk of colon cancer persons by 20-30%. Aberrant methylation patterns are common epigenetic alterations in colorectal adenomas and cancers, and play a role in cancer initiation and progression. Alterations have been identified in normal colon tissue potentially representing a "field cancerization" process, where the normal colon is primed for carcinogenesis. Here, we investigate methylation patterns in three genes -Ena/VASP-like (EVL), (CDKN2A (p14, ARF)), and Estrogen Receptor-1 (ESR1)-in normal colon tissue collected at baseline and 12-months from 202 sedentary men and women, 40-75 years, enrolled in a randomized controlled trial testing an exercise intervention vs. control (http://clinicaltrials.gov/show/NCT00668161). Participants were randomized to moderate-to-vigorous intensity exercise, 60 minutes/day, 6 days/week for 12 months, or usual lifestyle. Sigmoid colon biopsies were obtained at baseline and 12-months, DNA extracted, and bisulphite converted. Droplet digital methylation-specific PCR was performed for EVL, p14ARF, and ESR1. Generalized estimating equations modification of linear regression were used to model relationships between intervention effects and candidate gene methylation levels, adjusting for possible confounders.There were no statistically significant differences between methylation patterns at 12-months between exercisers and controls. ESR1 methylation patterns differed by sex: women -10.58% (exercisers) +11.10% (controls); men +5.54% (exercisers), -8.16% (controls); (P=0.05), adjusting for BMI and age. There were no statistically significant changes in methylation patterns in any gene stratified by change in VO2max, or by minutes/week of exercise.While no statistically significant differences were found in gene methylation patterns comparing exercises vs. controls, 12-month exercise effects on ESR1 methylation differed by sex, warranting further study.}, }
@article {pmid34550730, year = {2021}, author = {Becht, E and Tolstrup, D and Dutertre, CA and Morawski, PA and Campbell, DJ and Ginhoux, F and Newell, EW and Gottardo, R and Headley, MB}, title = {High-throughput single-cell quantification of hundreds of proteins using conventional flow cytometry and machine learning.}, journal = {Science advances}, volume = {7}, number = {39}, pages = {eabg0505}, doi = {10.1126/sciadv.abg0505}, pmid = {34550730}, issn = {2375-2548}, abstract = {[Figure: see text].}, }
@article {pmid34550327, year = {2021}, author = {Kessler, RC and Luedtke, A}, title = {Pragmatic Precision Psychiatry-A New Direction for Optimizing Treatment Selection.}, journal = {JAMA psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamapsychiatry.2021.2500}, pmid = {34550327}, issn = {2168-6238}, abstract = {Importance: Clinical trials have identified numerous prescriptive predictors of mental disorder treatment response, ie, predictors of which treatments are best for which patients. However, none of these prescriptive predictors is strong enough alone to guide precision treatment planning. This has prompted growing interest in developing precision treatment rules (PTRs) that combine information across multiple prescriptive predictors, but this work has been much less successful in psychiatry than some other areas of medicine. Study designs and analysis schemes used in research on PTR development in other areas of medicine are reviewed, key challenges for implementing similar studies of mental disorders are highlighted, and recent methodological advances to address these challenges are described here.<br><br>Observations: Discovering prescriptive predictors requires large samples. Three approaches have been used in other areas of medicine to do this: conduct very large randomized clinical trials, pool individual-level results across multiple smaller randomized clinical trials, and develop preliminary PTRs in large observational treatment samples that are then tested in smaller randomized clinical trials. The third approach is most feasible for research on mental disorders. This approach requires working with large real-world observational electronic health record databases; carefully selecting samples to emulate trials; extracting information about prescriptive predictors from electronic health records along with other inexpensive data augmentation strategies; estimating preliminary PTRs in the observational data using appropriate methods; implementing pragmatic trials to validate the preliminary PTRs; and iterating between subsequent observational studies and quality improvement pragmatic trials to refine and expand the PTRs. New statistical methods exist to address the methodological challenges of implementing this approach.<br><br>Conclusions and Relevance: Advances in pragmatic precision psychiatry will require moving beyond the current focus on randomized clinical trials and adopting an iterative discovery-confirmation process that integrates observational and experimental studies in real-world clinical populations.}, }
@article {pmid34548634, year = {2021}, author = {Dong, J and Zost, SJ and Greaney, AJ and Starr, TN and Dingens, AS and Chen, EC and Chen, RE and Case, JB and Sutton, RE and Gilchuk, P and Rodriguez, J and Armstrong, E and Gainza, C and Nargi, RS and Binshtein, E and Xie, X and Zhang, X and Shi, PY and Logue, J and Weston, S and McGrath, ME and Frieman, MB and Brady, T and Tuffy, KM and Bright, H and Loo, YM and McTamney, PM and Esser, MT and Carnahan, RH and Diamond, MS and Bloom, JD and Crowe, JE}, title = {Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail.}, journal = {Nature microbiology}, volume = {}, number = {}, pages = {}, pmid = {34548634}, issn = {2058-5276}, support = {AI095202//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75N93019C00062/AI/NIAID NIH HHS/United States ; AI157155//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI141707//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75N93019C00074/AI/NIAID NIH HHS/United States ; AI150739//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI157155//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UL1TR001439//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; HR0011-18-3-0001//United States Department of Defense | Defense Advanced Research Projects Agency (DARPA)/ ; HR0011-18-2-0001//United States Department of Defense | Defense Advanced Research Projects Agency (DARPA)/ ; Future Insight Prize 2019//Merck KGaA/ ; DE-AC02-06CH11357//DOE | LDRD | Argonne National Laboratory (ANL)/ ; 085P1000817//Michigan Economic Development Corporation (MEDC)/ ; }, abstract = {Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.}, }
@article {pmid34548627, year = {2021}, author = {Rocha, V and Arcuri, LJ and Seber, A and Colturato, V and Zecchin, VG and Kuwahara, C and Nichele, S and Gouveia, R and Fernandes, JF and Macedo, AV and Tavares, R and Daudt, L and De Souza, MP and Darrigo-Jr, LG and Villela, NC and Mariano, LCB and Ginani, VC and Zanette, A and Loth, G and Gomes, AA and Hamerschlak, N and Flowers, ME and Bonfim, C and , }, title = {Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34548627}, issn = {1476-5365}, abstract = {Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.}, }
@article {pmid34548385, year = {2021}, author = {Zou, Q and Wang, X and Ren, D and Hu, B and Tang, G and Zhang, Y and Huang, M and Pai, RK and Buchanan, DD and Win, AK and Newcomb, PA and Grady, WM and Yu, H and Luo, Y}, title = {DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer.}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {9}, pages = {}, doi = {10.1136/jitc-2021-002671}, pmid = {34548385}, issn = {2051-1426}, abstract = {BACKGROUND: Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC).<br><br>METHODS: A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score.<br><br>RESULTS: Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts.<br><br>CONCLUSIONS: This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.}, }
@article {pmid34548329, year = {2021}, author = {Jiao, B and Gulati, R and Katki, HA and Castle, PE and Etzioni, R}, title = {A Quantitative Framework to Study Potential Benefits and Harms of Multi-cancer Early Detection Testing.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0380}, pmid = {34548329}, issn = {1538-7755}, abstract = {BACKGROUND: Multi-cancer tests offer screening for multiple cancers with one blood draw, but the potential population impact is poorly understood.<br><br>METHODS: We formulate mathematical expressions for expected numbers of (1) individuals exposed to unnecessary confirmation tests (EUC), (2) cancers detected (CD), and (3) lives saved (LS) given test performance, disease incidence and mortality, and mortality reduction. We add colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer, approximating prevalence at ages 50, 60, or 70 using incidence over the next 5 years and mortality using corresponding probabilities of cancer death over 15 years in the Surveillance, Epidemiology, and End Results registry.<br><br>RESULTS: EUC is overwhelmingly determined by specificity. For a given specificity, EUC/CD is most favorable for higher-prevalence cancers. Under 99% specificity and sensitivities as published for a 50-cancer test, EUC/CD is 1.1 for breast+lung versus 1.3 for breast+liver at age 50. Under a common mortality reduction associated with screening, EUC/LS is most favorable when the test includes higher-mortality cancers (e.g., 19.9 for breast+lung versus 30.4 for breast+liver at age 50 assuming a common 10% mortality reduction).<br><br>CONCLUSIONS: Published multi-cancer test performance suggests a favorable tradeoff of EUC to CD, yet the full burden of unnecessary confirmations will depend on the post-test work-up protocol. Harm-benefit tradeoffs will be improved if tests prioritize more prevalent and/or lethal cancers for which curative treatments exist.<br><br>IMPACT: The population impact of multi-cancer testing will depend not only on test performance but also on disease characteristics and efficacy of early treatment.}, }
@article {pmid34548310, year = {2021}, author = {Helms, EJ and Berry, MW and Chaw, RC and DuFort, CC and Sun, D and Onate, MK and Oon, C and Bhattacharyya, S and Sanford-Crane, H and Horton, W and Finan, JM and Sattler, A and Makar, R and Dawson, DW and Xia, Z and Hingorani, SR and Sherman, MH}, title = {Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-21-0601}, pmid = {34548310}, issn = {2159-8290}, abstract = {Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.}, }
@article {pmid34514868, year = {2021}, author = {Edwards, TC and Heike, CL and Kapp-Simon, KA and Jones, SM and Leroux, BG and Stueckle, LP and Bellucci, CC and Rosenberg, JM and Albert, M and Aspinall, CL and Patrick, DL}, title = {Infant with Clefts Observation Outcomes Instrument (iCOO): A New Outcome for Infants and Young Children with Orofacial Clefts.}, journal = {The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association}, volume = {}, number = {}, pages = {10556656211040307}, doi = {10.1177/10556656211040307}, pmid = {34514868}, issn = {1545-1569}, abstract = {OBJECTIVE: We evaluated the measurement properties for item and domain scores of the Infant with Clefts Observation Outcomes Instrument (iCOO).<br><br>DESIGN: Cross-sectional (before lip surgery) and longitudinal study (preoperative baseline and 2 days and 2 months after lip surgery).<br><br>SETTING: Three academic craniofacial centers and national online advertisements.<br><br>PARTICIPANTS: Primary caregivers with an infant with cleft lip with or without cleft palate (CL ± P) scheduled to undergo primary lip repair. There were 133 primary caregivers at baseline, 115 at 2 days postsurgery, and 112 at 2 months postsurgery.<br><br>MAIN OUTCOME MEASURE(S): Caregiver observation items (n = 61) and global impression of health and function items (n = 8) across eight health domains.<br><br>RESULTS: Mean age at surgery was 6.0 months (range 2.7-11.8 months). Five of eight iCOO domains have scale scores, with Cronbach's alphas ranging from 0.67 to 0.87. Except for the Facial Skin and Mouth domain, iCOO scales had acceptable intraclass correlation coefficients (ICCs) ranging from 0.76 to 0.84. The internal consistency of the Global Impression items across all domains was 0.90 and had acceptable ICCs (range 0.76-0.91). Sixteen out of 20 (nonscale) items had acceptable ICCs (range 0.66-0.96). As anticipated, iCOO scores 2 days postoperatively were generally lower than baseline and scores 2 months postsurgery were consistent with baseline or higher. The iCOO took approximately 10 min to complete.<br><br>CONCLUSIONS: The iCOO meets measurement standards and may be used for assessing the impact of cleft-related treatments in clinical research and care. More research is needed on its use in various treatment contexts.}, }
@article {pmid34547772, year = {2021}, author = {Huang, BJ and Smith, J and Wang, J and Taghizadeh, K and Leonti, AR and Ries, RE and Liu, Y and Kolekar, P and Tarlock, K and Gerbing, RB and Crowgey, E and Furlan, SN and Shaw, TI and Hagiwara, K and Wei, L and Cooper, T and Gamis, AS and Aplenc, R and Kolb, EA and Farrar, JE and Triche, TJ and Alonzo, T and Ma, X and Meshinchi, S}, title = {CBFB-MYH11 Fusion Transcripts Distinguish Acute Myeloid Leukemias with Distinct Molecular Landscapes and Outcomes.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004965}, pmid = {34547772}, issn = {2473-9537}, abstract = {Patients with inv(16)/CBFB-MYH11 AML are considered favorable risk, however, nearly one-third relapse despite intensive therapy. Despite efforts to define risk groups within this favorable risk cohort, CBFB-MYH11 AML patients continue to be treated as a uniform cohort. Through transcriptome sequencing of 186 patients with inv(16) AML, we demonstrate that fusion junction breakpoints (exon 5-exon 33 versus other) are highly associated with outcome. The presence of exon 17 KIT mutations provides additional prognostic significance. Additionally, we provide insights into the transcriptional landscapes that differentiate these distinct CBFB-MYH11 AML subtypes. Children's Oncology Group trials include CCG-2961 (registered at www.clinicaltrials.gov as NCT00002798), AAML03P1 (NCT00070174), AAML0531 (NCT00372593), and AAML1031 (NCT01371981).}, }
@article {pmid34547437, year = {2021}, author = {Shaukat, A and Marsh, TL and Crockett, SD and Syngal, S and Bresalier, RS and Brenner, DE and , }, title = {Low prevalence of screen-detected colorectal cancer in an average-risk population: the new normal.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cgh.2021.09.013}, pmid = {34547437}, issn = {1542-7714}, }
@article {pmid34546543, year = {2021}, author = {Dembitz, V and Lalic, H and Tomic, B and Smoljo, T and Batinic, J and Dubravcic, K and Batinic, D and Bedalov, A and Visnjic, D}, title = {All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16.}, journal = {International journal of hematology}, volume = {}, number = {}, pages = {}, pmid = {34546543}, issn = {1865-3774}, support = {IP-2016-06-4581//Hrvatska Zaklada za Znanost/ ; DOK-2018-01-9599//Hrvatska Zaklada za Znanost/ ; DOK-2020-01-2873//Hrvatska Zaklada za Znanost/ ; GA KK01.1.1.01.0007//Hrvatska Zaklada za Znanost/ ; }, abstract = {All-trans retinoic acid (ATRA)-based therapy for acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML), is the most successful example of differentiation therapy. Although ATRA can induce differentiation in some non-APL AML cell lines and primary blasts, clinical results of adding ATRA to standard therapy in non-APL AML patients have been inconsistent, probably due to use of different regimens and lack of diagnostic tools for identifying which patients may be sensitive to ATRA. In this study, we exposed primary blasts obtained from non-APL AML patients to ATRA to test for differentiation potential in vitro. We observed increased expression of differentiation markers, indicating a response to ATRA, in four out of fifteen primary AML samples. Three samples in which CD11b increased in response to ATRA had an inversion of chromosome 16 as well as the CBFB-MYH11 fusion gene, and the fourth sample was from a patient with KMT2A-rearranged, therapy-related AML. In conclusion, we identified a subgroup of non-APL AML patients with inv(16) and CBFB-MYH11 as the most sensitive to ATRA-mediated differentiation in vitro, and our results can help identify patients who may benefit from ATRA treatment.}, }
@article {pmid34546072, year = {2021}, author = {Flores Ramos, S and Brugger, SD and Escapa, IF and Skeete, CA and Cotton, SL and Eslami, SM and Gao, W and Bomar, L and Tran, TH and Jones, DS and Minot, S and Roberts, RJ and Johnston, CD and Lemon, KP}, title = {Genomic Stability and Genetic Defense Systems in Dolosigranulum pigrum, a Candidate Beneficial Bacterium from the Human Microbiome.}, journal = {mSystems}, volume = {}, number = {}, pages = {e0042521}, doi = {10.1128/mSystems.00425-21}, pmid = {34546072}, issn = {2379-5077}, abstract = {Dolosigranulum pigrum is positively associated with indicators of health in multiple epidemiological studies of human nasal microbiota. Knowledge of the basic biology of D. pigrum is a prerequisite for evaluating its potential for future therapeutic use; however, such data are very limited. To gain insight into D. pigrum's chromosomal structure, pangenome, and genomic stability, we compared the genomes of 28 D. pigrum strains that were collected across 20 years. Phylogenomic analysis showed closely related strains circulating over this period and closure of 19 genomes revealed highly conserved chromosomal synteny. Gene clusters involved in the mobilome and in defense against mobile genetic elements (MGEs) were enriched in the accessory genome versus the core genome. A systematic analysis for MGEs identified the first candidate D. pigrum prophage and insertion sequence. A systematic analysis for genetic elements that limit the spread of MGEs, including restriction modification (RM), CRISPR-Cas, and deity-named defense systems, revealed strain-level diversity in host defense systems that localized to specific genomic sites, including one RM system hot spot. Analysis of CRISPR spacers pointed to a wealth of MGEs against which D. pigrum defends itself. These results reveal a role for horizontal gene transfer and mobile genetic elements in strain diversification while highlighting that in D. pigrum this occurs within the context of a highly stable chromosomal organization protected by a variety of defense mechanisms. IMPORTANCE Dolosigranulum pigrum is a candidate beneficial bacterium with potential for future therapeutic use. This is based on its positive associations with characteristics of health in multiple studies of human nasal microbiota across the span of human life. For example, high levels of D. pigrum nasal colonization in adults predicts the absence of Staphylococcus aureus nasal colonization. Also, D. pigrum nasal colonization in young children is associated with healthy control groups in studies of middle ear infections. Our analysis of 28 genomes revealed a remarkable stability of D. pigrum strains colonizing people in the United States across a 20-year span. We subsequently identified factors that can influence this stability, including genomic stability, phage predators, the role of MGEs in strain-level variation, and defenses against MGEs. Finally, these D. pigrum strains also lacked predicted virulence factors. Overall, these findings add additional support to the potential for D. pigrum as a therapeutic bacterium.}, }
@article {pmid34543770, year = {2021}, author = {Bhatt, NS and Meyer, C and Mau, LW and Broglie, L and Devine, S and Choi, SW and Auletta, J and Phelan, R}, title = {Return to School Practices for Pediatric Hematopoietic Cell Transplant Recipients During COVID-19 Pandemic.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.09.007}, pmid = {34543770}, issn = {2666-6367}, abstract = {While organizations such as Centers for Disease Control and Prevention and American Academy of Pediatrics have published guidelines favoring resumption of in-person schooling during COVID-19 pandemic, there is no specific guidance on hematopoietic cell transplant (HCT) recipients' safety of returning to school. We conducted a cross-sectional survey of pediatric HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) practicing in the United States (US) to describe current return to school practices during the COVID-19 pandemic for HCT recipients. A total of 122 respondents (response rate 30.6%) from 60 transplant centers in 32 US states completed the survey. The majority of respondents (76%) recommend that HCT recipients should consider remote or hybrid school option at this time, if possible. If not possible, physicians recommended return to in-person school as long as they are at least 12 months post-transplant or off immune suppression while taking school safety measures and local COVID-19 cases into account. These results provide valuable guidance to the HCT community, patients, and caregivers, regarding important topics to consider while making return-to-school decisions.}, }
@article {pmid34543612, year = {2021}, author = {Yung, RL and Davidson, NE}, title = {Optimal adjuvant endocrine therapy for breast cancer.}, journal = {The Lancet. Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S1470-2045(21)00420-4}, pmid = {34543612}, issn = {1474-5488}, }
@article {pmid34543346, year = {2021}, author = {Pal, S and Myburgh, J and Bansil, P and Hann, A and Robertson, L and Gerth-Guyette, E and Ambler, G and Bizilj, G and Kahn, M and Zobrist, S and Manis, MR and Styke, NA and Allan, V and Ansbro, R and Akingbade, T and Bryan, A and Murphy, SC and Kublin, JG and Layton, M and Domingo, GJ}, title = {Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.}, journal = {PloS one}, volume = {16}, number = {9}, pages = {e0257560}, doi = {10.1371/journal.pone.0257560}, pmid = {34543346}, issn = {1932-6203}, abstract = {Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3-100.0)/97 (95.2-98.2) and 100 (95.7-100.0)/97.4 (95.7-98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3-99.9)/88.2 (83.9-91.7) and 82.4 (56.6-96.2)/87.6(83.3-91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.}, }
@article {pmid34539630, year = {2021}, author = {Song, Q and Kong, X and Martin, PJ and Zeng, D}, title = {Murine Models Provide New Insights Into Pathogenesis of Chronic Graft-Versus-Host Disease in Humans.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {700857}, doi = {10.3389/fimmu.2021.700857}, pmid = {34539630}, issn = {1664-3224}, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for hematologic malignancies, but its success is complicated by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic types. Acute GVHD represents an acute alloimmune inflammatory response initiated by donor T cells that recognize recipient alloantigens. Chronic GVHD has a more complex pathophysiology involving donor-derived T cells that recognize recipient-specific antigens, donor-specific antigens, and antigens shared by the recipient and donor. Antibodies produced by donor B cells contribute to the pathogenesis of chronic GVHD but not acute GVHD. Acute GVHD can often be effectively controlled by treatment with corticosteroids or other immunosuppressant for a period of weeks, but successful control of chronic GVHD requires much longer treatment. Therefore, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HCT. Murine models of allo-HCT have made great contributions to our understanding pathogenesis of acute and chronic GVHD. In this review, we summarize new mechanistic findings from murine models of chronic GVHD, and we discuss the relevance of these insights to chronic GVHD pathogenesis in humans and their potential impact on clinical prevention and treatment.}, }
@article {pmid34536584, year = {2021}, author = {Smith, SK and Somers, TJ and Kuhn, E and Laber, E and Sung, AD and Syrjala, KL and Feger, B and Kelleher, SA and Majestic, C and Gebert, R and LeBlanc, M and Owen, JE and Applebaum, AJ}, title = {A SMART approach to optimizing delivery of an mHealth intervention among cancer survivors with posttraumatic stress symptoms.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {106569}, doi = {10.1016/j.cct.2021.106569}, pmid = {34536584}, issn = {1559-2030}, abstract = {BACKGROUND/AIMS: Many cancer survivors who received intensive treatment such as hematopoietic stem cell transplantation (HCT) experience posttraumatic stress disorder (PTSD) symptoms. PTSD is associated with lower quality of life and other symptoms that require clinical treatment. The iterative treatment decisions that happen in clinical practice are not adequately represented in traditional randomized controlled trials (RCT) of PTSD treatments. The proposed stepped-care SMART design allows for evaluation of initial response to the Cancer Distress Coach mobile app; adaptive stepped-care interventions; and precision treatment strategies that tailor treatment selection to patient characteristics.<br><br>METHODS/DESIGN: HCT survivors (N = 400) reporting PTSD symptoms are being recruited at two cancer centers and randomly assigned to: 1) Cancer Distress Coach app or 2) Usual Care. The app includes educational and cognitive behavioral therapy (CBT)-based activities. Four weeks post-randomization, participants re-rate their PTSD symptoms and, based on intervention response, non-responders are re-randomized to receive video-conferenced sessions with a therapist: 3) coaching sessions in using the mobile app; or 4) CBT specific to HCT survivors. Participants complete outcome measures of PTSD, depression, and anxiety after Months 1, 3, and 6. Participant characteristics moderating intervention responses will be examined.<br><br>CONCLUSIONS: This novel adaptive trial design will afford evidence that furthers knowledge about optimizing PTSD interventions for HCT survivors. To our knowledge, this study is the first SMART design evaluating PTSD symptom management in cancer survivors. If successful, it could be used to optimize treatment among a range of cancer and other trauma survivors.}, }
@article {pmid34536571, year = {2021}, author = {Amonoo, HL and Topping, CE and Clay, MA and Reynolds, MJ and Rice, J and Harnedy, LE and Longley, RM and LeBlanc, TW and Greer, JA and Chen, YB and DeFilipp, Z and Lee, SJ and Temel, JS and El-Jawahri, A}, title = {Distress in a Pandemic - The Association of the Coronavirus Disease-2019 (COVID-19) Pandemic with Distress and Quality of Life in Hematopoietic Stem Cell Transplantation (HSCT).}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.09.001}, pmid = {34536571}, issn = {2666-6367}, abstract = {BACKGROUND: The global coronavirus disease 2019 (COVID-19) pandemic has drastically disrupted cancer care, potentially exacerbating patients' distress levels. Patients undergoing HSCT may be especially vulnerable to this pandemic stress. However, the associations of the COVID-19 pandemic with distress, fatigue, and QOL are not well understood in this population.<br><br>METHOD: In a cross-sectional analysis of data from 205 patients undergoing HSCT enrolled in a supportive care trial, we compared baseline pre-HSCT distress (depression, anxiety, and posttraumatic stress disorder [PTSD]) symptoms, fatigue, and QOL between enrollees pre- (i.e., 03/2019-01/2020) and during (i.e., 03/2020-01/2021) the COVID-19 pandemic. We used linear regression models adjusting for sociodemographics and cancer diagnosis to examine the associations between enrollment period and patient-reported outcomes. We used semi-structured qualitative interviews in 20 allogeneic HSCT recipients who were ≥3-months post-HSCT to understand the impact of the COVID-19 pandemic on their recovery post-HSCT.<br><br>RESULTS: Prior to COVID-19, 124 participants enrolled, while 81 participants enrolled during the pandemic. The cohorts had similar baseline demographics and disease risk factors. In multivariate regression models, enrollment during COVID-19 was not associated with pre-HSCT symptoms of depression, anxiety, PTSD, fatigue, or QOL impairment. COVID-19-era participants reported themes of negative (e.g., increased isolation) and positive (e.g., engagement with meaningful activities) implications of the pandemic on HSCT recovery.<br><br>CONCLUSIONS: We found no differences in pre-HSCT distress, fatigue or QOL in patients undergoing HSCT prior to or during the COVID-19 pandemic. Patients in early recovery post-HSCT, however, report both negative and positive implications of the COVID-19 pandemic on their lives.}, }
@article {pmid34536346, year = {2021}, author = {Kordahi, MC and Stanaway, IB and Avril, M and Chac, D and Blanc, MP and Ross, B and Diener, C and Jain, S and McCleary, P and Parker, A and Friedman, V and Huang, J and Burke, W and Gibbons, SM and Willis, AD and Darveau, RP and Grady, WM and Ko, CW and DePaolo, RW}, title = {Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer.}, journal = {Cell host &amp; microbe}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chom.2021.08.013}, pmid = {34536346}, issn = {1934-6069}, abstract = {Colorectal cancer is a major health concern worldwide. Growing evidence for the role of the gut microbiota in the initiation of CRC has sparked interest in approaches that target these microorganisms. However, little is known about the composition and role of the microbiota associated with precancerous polyps. Here, we found distinct microbial signatures between patients with and without polyps and between polyp subtypes using sequencing and culturing techniques. We found a correlation between Bacteroides fragilis recovered and the level of inflammatory cytokines in the mucosa adjacent to the polyp. Additional analysis revealed that B. fragilis from patients with polyps are bft-negative, activate NF-κB through Toll-like receptor 4, induce a pro-inflammatory response, and are enriched in genes associated with LPS biosynthesis. This study provides fundamental insight into the microbial microenvironment of the pre-neoplastic polyp by highlighting strain-specific genomic and proteomic differences, as well as more broad compositional differences in the microbiome.}, }
@article {pmid34535742, year = {2021}, author = {Ahuno, ST and Doebley, AL and Ahearn, TU and Yarney, J and Titiloye, N and Hamel, N and Adjei, E and Clegg-Lamptey, JN and Edusei, L and Awuah, B and Song, X and Vanderpuye, V and Abubakar, M and Duggan, M and Stover, DG and Nyarko, K and Bartlett, JMS and Aitpillah, F and Ansong, D and Gardner, KL and Boateng, FA and Bowcock, AM and Caldas, C and Foulkes, WD and Wiafe, S and Wiafe-Addai, B and Garcia-Closas, M and Kwarteng, A and Ha, G and Figueroa, JD and Polak, P and , }, title = {Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa.}, journal = {NPJ precision oncology}, volume = {5}, number = {1}, pages = {83}, pmid = {34535742}, issn = {2397-768X}, support = {P30CA196521-01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA013696//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1R01CA253368//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1R01CA161870//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; K22CA237746//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; SAC110008//Susan G. Komen (Susan G. Komen Breast Cancer Foundation)/ ; }, abstract = {Circulating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.}, }
@article {pmid34535015, year = {2021}, author = {Pidala, J and Onstad, L and Martin, PJ and Hamilton, BK and Cutler, CS and Kitko, CL and Carpenter, PA and Chen, GL and Arora, M and Flowers, ME and Arai, S and Alousi, A and White, J and Jacobsohn, DA and Pusic, I and Lee, SJ}, title = {Initial therapy of chronic graft vs. host disease: Analysis of practice variation and failure-free survival.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021005286}, pmid = {34535015}, issn = {2473-9537}, abstract = {Prior clinical trials largely considered prednisone 1mg/kg/day with or without calcineurin inhibitor as standard initial therapy for chronic graft vs. host disease (cGVHD) but uncertainty remains regarding the extent of practice variation and whether this affects subsequent outcomes. We assembled a cohort of 745 cGVHD patients treated with initial systemic immune suppressive (IS) therapy from three prior Chronic GVHD Consortium observational studies. Initial therapy was defined as first IS therapy started for cGVHD or prednisone increased to ≥ 0.4mg/kg/day from lower doses within 30 days before cGVHD diagnosis to any time afterward. Initial therapies were non-prednisone IS therapies (n=137, 18%), prednisone alone (n=411, 55%), or prednisone plus other IS therapy (n=197, 26%). In multivariate analysis, initial therapy group was not associated with FFS (failure-free survival, a composite of death, relapse, new IS therapy), overall survival (OS) or non-relapse mortality (NRM). Among the prednisone-based approaches, steroid dose (mg/kg/day) was <0.25 (9%), 0.25-0.74 (36%), 0.75-1.25 (42%), or >1.25 (13%). Prednisone dose within the steroid-treated patients was not significantly associated with FFS, OS, or NRM. No significant interactions were detected between overall cGVHD severity and either initial therapy group or prednisone dose for the outcomes of FFS, OS, or NRM. These observational data document heterogeneity in more contemporary cGVHD initial treatment practices, including prednisone dose and use of non-steroid approaches. This variation was not associated with FFS, OS, or NRM. Prospective trials are needed to verify efficacy of reduced-dose prednisone or prednisone-free initial therapy approaches.}, }
@article {pmid34535014, year = {2021}, author = {Martin, PJ and Storer, BE and Levine, DM and Hansen, JA}, title = {Genetic Variants Associated with Inflammatory Bowel Disease and Gut Graft-versus-host Disease.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004959}, pmid = {34535014}, issn = {2473-9537}, abstract = {Previous studies have identified genetic variants associated with inflammatory bowel disease (IBD). We tested the hypothesis that some of these variants are also associated with the risk of moderate to severe gut graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Associations were evaluated initially in a discovery cohort of 1980 HCT recipients of European ancestry with HLA-matched related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1294 HCT recipients. Among the 296 single nucleotide polymorphisms SNPs and 26 HLA alleles tested, we found that the recipient rs1260326 homozygous T allele in GCKR was associated with a higher risk of stage 2-4 gut GVHD. No other candidate variants were associated with stage 2-4 gut GVHD. The rs1260326 variant resides in an IBD-associated locus containing FNDC4, a gene that encodes a secreted anti-inflammatory factor that dampens macrophage activity and improves colitis in mice. Our results suggest that targeting inflammatory macrophages with recombinant FNDC4 offers an attractive avenue of clinical investigation for management of IBD and gut GVHD.}, }
@article {pmid34533286, year = {2021}, author = {Keyes-Elstein, L and Pinckney, A and Goldmuntz, E and Welch, B and Franks, JM and Martyanov, V and Wood, TA and Crofford, L and Mayes, M and McSweeney, P and Nash, R and Georges, G and Csuka, ME and Simms, R and Furst, D and Khanna, D and St Clair, EW and Whitfield, ML and Sullivan, KM}, title = {Clinical and Molecular Findings after Autologous Stem Cell Transplantation or Cyclophosphamide for Scleroderma: Handling Missing Longitudinal Data.}, journal = {Arthritis care &amp; research}, volume = {}, number = {}, pages = {}, doi = {10.1002/acr.24785}, pmid = {34533286}, issn = {2151-4658}, abstract = {OBJECTIVE: Among individuals with systemic sclerosis (SSc) randomized to cyclophosphamide (CYC, n=34) or hematopoietic stem cell transplantation (HSCT, n=33), we examined longitudinal trends of clinical, pulmonary function and quality of life measures while accounting for the influence of early failures on treatment comparisons.<br><br>METHODS: Assuming data were missing at random, mixed effects regression models were used to estimate longitudinal trends for clinical measures when comparing treatment groups. Results were compared to observed means and to longitudinal trends estimated from shared parameter models, assuming data were missing not at random. Longitudinal trends for SSc intrinsic molecular subsets defined by baseline gene expression signatures (normal-like, inflammatory and fibroproliferative signatures) were also studied.<br><br>RESULTS: Available observed means for pulmonary function tests appeared to improve over time in both arms. However, after accounting for participant loss, forced vital capacity in HSCT recipients increased by 0.77 percentage points/year but worsened by -3.70/yr for CYC (P=0.004). Similar results were found for DLCO and quality of life indicators. Results for both analytic models were consistent. HSCT recipients in the inflammatory (n=20) and fibroproliferative (n=20) subsets had superior long-term trends compared to CYC for pulmonary and quality of life measures. HSCT was also superior for Rodnan skin scores in the fibroproliferative subset. For the normal-like subset (n=22), superiority of HSCT was less apparent.<br><br>CONCLUSIONS: Longitudinal trends estimated from two statistical models affirm the efficacy of HSCT over CYC in severe SSc. Failure to account for early loss of participants may distort estimated clinical trends over the long-term.}, }
@article {pmid34533134, year = {2021}, author = {Shangguan, S and Ehrenberg, PK and Geretz, A and Yum, L and Kundu, G and May, K and Fourati, S and Nganou-Makamdop, K and Williams, LD and Sawant, S and Lewitus, E and Pitisuttithum, P and Nitayaphan, S and Chariyalertsak, S and Rerks-Ngarm, S and Rolland, M and Douek, DC and Gilbert, P and Tomaras, GD and Michael, NL and Vasan, S and Thomas, R}, title = {Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.69577}, pmid = {34533134}, issn = {2050-084X}, support = {W81XWH-07-2-0067//Henry M. Jackson Foundation/ ; }, abstract = {A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.}, }
@article {pmid34532717, year = {2020}, author = {Issaka, RB and Somsouk, M}, title = {Colorectal Cancer Screening and Prevention in the COVID-19 Era.}, journal = {JAMA health forum}, volume = {1}, number = {5}, pages = {}, doi = {10.1001/jamahealthforum.2020.0588}, pmid = {34532717}, issn = {2689-0186}, }
@article {pmid34532711, year = {2021}, author = {Hannan, M and Ricardo, AC and Cai, J and Franceschini, N and Kaplan, R and Marquez, DX and Rosas, SE and Schneiderman, N and Sotres-Alvarez, D and Talavera, GA and Daviglus, ML and Lash, JP}, title = {Sedentary Behavior and Change in Kidney Function: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Kidney360}, volume = {2}, number = {2}, pages = {245-253}, doi = {10.34067/kid.0006202020}, pmid = {34532711}, issn = {2641-7650}, abstract = {Background: There is accumulating evidence linking prolonged sedentary time to adverse health outcomes. The effect of sedentary behavior on kidney function has not been evaluated in US Hispanics/Latinos, a population disproportionately affected by CKD.<br><br>Methods: We evaluated the association between accelerometer-measured (1 week) sedentary time at baseline and kidney function among 7134 adults without CKD at entry in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who completed a baseline visit with accelerometry (2008-2011) and a follow-up visit (2014-2017). Outcomes included: (1) change in kidney function (eGFR and urine albumin-to-creatinine ratio, ACR), (2) incident low eGFR (eGFR <60 ml/min per 1.73 m2 and eGFR decline ≥1 ml/min per year), and (3) incident albuminuria (ACR ≥17 mg/g in men or ≥25 mg/g in women). Linear regression using survey procedures was used to evaluate change in kidney function (eGFR and ACR), and Poisson regression with robust variance was used to evaluate incident low eGFR and albuminuria.<br><br>Results: The median sedentary time was 12 hours/d. Over a median follow-up of 6.1 years, the mean relative change in eGFR was -0.50% per year, and there were 167 incident low eGFR events. On multivariable analysis, each 1 hour increase in sedentary time was associated with a longitudinal decline in eGFR (-0.06% per year, 95% CI, -0.10 to -0.02). There was a significant interaction with sex, and on stratified analyses, higher sedentary time was associated with eGFR decline in women but not men. There was no association between sedentary time and the other outcomes.<br><br>Conclusions: Sedentary time was associated with a small longitudinal decline in eGFR, which could have important implications in a population that experiences a disproportionate burden of CKD but further investigation is needed.}, }
@article {pmid34532060, year = {2021}, author = {Lewitus, E and Sanders-Buell, E and Bose, M and O'Sullivan, AM and Poltavee, K and Li, Y and Bai, H and Mdluli, T and Donofrio, G and Slike, B and Zhao, H and Wong, K and Chen, L and Miller, S and Lee, J and Ahani, B and Lepore, S and Muhammad, S and Grande, R and Tran, U and Dussupt, V and Mendez-Rivera, L and Nitayaphan, S and Kaewkungwal, J and Pitisuttithum, P and Rerks-Ngarm, S and O'Connell, RJ and Janes, H and Gilbert, PB and Gramzinski, R and Vasan, S and Robb, ML and Michael, NL and Krebs, SJ and Herbeck, JT and Edlefsen, PT and Mullins, JI and Kim, JH and Tovanabutra, S and Rolland, M}, title = {RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.}, journal = {Virus evolution}, volume = {7}, number = {2}, pages = {veab057}, doi = {10.1093/ve/veab057}, pmid = {34532060}, issn = {2057-1577}, abstract = {The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.}, }
@article {pmid34531936, year = {2020}, author = {Zheng, Y and Corley, DA and Doubeni, C and Halm, E and Shortreed, SM and Barlow, WE and Zauber, A and Tosteson, TD and Chubak, J}, title = {ANALYSES OF PREVENTIVE CARE MEASURES WITH INCOMPLETE HISTORICAL DATA IN ELECTRONIC MEDICAL RECORDS: AN EXAMPLE FROM COLORECTAL CANCER SCREENING.}, journal = {The annals of applied statistics}, volume = {14}, number = {2}, pages = {1030-1044}, doi = {10.1214/20-aoas1342}, pmid = {34531936}, issn = {1932-6157}, abstract = {The calculation of quality of care measures based on electronic medical records (EMRs) may be inaccurate because of incomplete capture of past services. We evaluate the influence of different statistical approaches for calculating the proportion of patients who are up-to-date for a preventive service, using the example of colorectal cancer (CRC) screening. We propose an extension of traditional mixture models to account for the uncertainty in compliance, which is further complicated by the choice of various screening modalities with different recommended screening intervals. We conducted simulation studies to compare various statistical approaches and demonstrated that the proposed method can alleviate bias when individuals with complete prior medical history information were not representative of the targeted population. The method is motivated by and applied to data from the National Cancer Institute-funded consortium Population-Based Research Optimizing Screening through Personalized Regiments (PROSPR). Findings from the application are important for the evaluation of appropriate use of preventive care and provide a novel tool for dealing with similar analytical challenges with EMR data in broad settings.}, }
@article {pmid34531859, year = {2021}, author = {Cardozo-Ojeda, EF and Perelson, AS}, title = {Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {710012}, doi = {10.3389/fimmu.2021.710012}, pmid = {34531859}, issn = {1664-3224}, abstract = {VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.}, }
@article {pmid34531249, year = {2021}, author = {Liao, JB and Gwin, WR and Urban, RR and Hitchcock-Bernhardt, KM and Coveler, AL and Higgins, DM and Childs, JS and Shakalia, HN and Swensen, RE and Stanton, SE and Tinker, AV and Wahl, TA and Ancheta, RG and McGonigle, KF and Dai, JY and Disis, ML and Goff, BA}, title = {Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates.}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {9}, pages = {}, doi = {10.1136/jitc-2021-003122}, pmid = {34531249}, issn = {2051-1426}, abstract = {BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.<br><br>PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.<br><br>RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).<br><br>CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.<br><br>TRIAL REGISTRATION NUMBER: NCT03029598.}, }
@article {pmid34527282, year = {2021}, author = {Douglas, J and Mendes, FK and Bouckaert, R and Xie, D and Jiménez-Silva, CL and Swanepoel, C and de Ligt, J and Ren, X and Storey, M and Hadfield, J and Simpson, CR and Geoghegan, JL and Drummond, AJ and Welch, D}, title = {Phylodynamics reveals the role of human travel and contact tracing in controlling the first wave of COVID-19 in four island nations.}, journal = {Virus evolution}, volume = {7}, number = {2}, pages = {veab052}, pmid = {34527282}, issn = {2057-1577}, abstract = {New Zealand, Australia, Iceland, and Taiwan all saw success in controlling their first waves of Coronavirus Disease 2019 (COVID-19). As islands, they make excellent case studies for exploring the effects of international travel and human movement on the spread of COVID-19. We employed a range of robust phylodynamic methods and genome subsampling strategies to infer the epidemiological history of Severe acute respiratory syndrome coronavirus 2 in these four countries. We compared these results to transmission clusters identified by the New Zealand Ministry of Health by contact tracing strategies. We estimated the effective reproduction number of COVID-19 as 1-1.4 during early stages of the pandemic and show that it declined below 1 as human movement was restricted. We also showed that this disease was introduced many times into each country and that introductions slowed down markedly following the reduction of international travel in mid-March 2020. Finally, we confirmed that New Zealand transmission clusters identified via standard health surveillance strategies largely agree with those defined by genomic data. We have demonstrated how the use of genomic data and computational biology methods can assist health officials in characterising the epidemiology of viral epidemics and for contact tracing.}, }
@article {pmid34526299, year = {2021}, author = {Yu, C and Jordahl, KM and Bassett, JK and Joo, JE and Wong, EM and Brinkman, MT and Schmidt, DF and Bolton, DM and Makalic, E and Brasky, TM and Shadyab, AH and Tinker, LF and Longano, A and Hopper, JL and English, DR and Milne, RL and Bhatti, P and Southey, MC and Giles, GG and Dugué, PA}, title = {Smoking methylation marks for prediction of urothelial cancer risk.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0313}, pmid = {34526299}, issn = {1538-7755}, abstract = {BACKGROUND: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.<br><br>METHODS: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Women's Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).<br><br>RESULTS: The meta-analysis identified associations (P<4.7×10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).<br><br>CONCLUSIONS: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.<br><br>IMPACT: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.}, }
@article {pmid34525376, year = {2021}, author = {Dignum, T and Varnum-Finney, B and Srivatsan, SR and Dozono, S and Waltner, O and Heck, AM and Ishida, T and Nourigat-McKay, C and Jackson, DL and Rafii, S and Trapnell, C and Bernstein, ID and Hadland, B}, title = {Multipotent progenitors and hematopoietic stem cells arise independently from hemogenic endothelium in the mouse embryo.}, journal = {Cell reports}, volume = {36}, number = {11}, pages = {109675}, doi = {10.1016/j.celrep.2021.109675}, pmid = {34525376}, issn = {2211-1247}, abstract = {During embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSCs). Although previous studies have shown that yolk-sac-derived erythromyeloid progenitors and HSCs emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSCs originate from common HE. In this study, we demonstrate by clonal assays and single-cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSCs. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Taken together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSCs arise independently from HE with distinct phenotypic and transcriptional properties.}, }
@article {pmid34524558, year = {2021}, author = {Generalova, O and Roy, M and Hall, E and Shah, SA and Cunanan, K and Fardeen, T and Velazquez, B and Chu, G and Bruzzone, B and Cabot, A and Fisher, GA and Srinivas, S and Fan, AC and Haraldsdottir, S and Wakelee, HA and Neal, JW and Padda, SK and Johnson, T and Heestand, GM and Hsieh, RW and Ramchandran, K}, title = {Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer.}, journal = {Journal of patient-reported outcomes}, volume = {5}, number = {1}, pages = {91}, pmid = {34524558}, issn = {2509-8020}, support = {VAFYZ//Varian Medical Systems (US)/ ; }, abstract = {BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.<br><br>METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.<br><br>RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.<br><br>CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.}, }
@article {pmid34523977, year = {2021}, author = {Hart, JE and Hohensee, C and Laden, F and Holland, I and Whitsel, EA and Wellenius, GA and Winkelmayer, WC and Sarto, GE and Warsinger Martin, L and Manson, JE and Greenland, P and Kaufman, J and Albert, C and Perez, MV}, title = {Long-Term Exposures to Air Pollution and the Risk of Atrial Fibrillation in the Women's Health Initiative Cohort.}, journal = {Environmental health perspectives}, volume = {129}, number = {9}, pages = {97007}, doi = {10.1289/EHP7683}, pmid = {34523977}, issn = {1552-9924}, abstract = {BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence.<br><br>OBJECTIVES: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women.<br><br>METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant.<br><br>RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure-response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=<0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50m of A3 roads, compared with ≥1,000 m, p-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, p-for-trend=<0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, p-for-trend=0.002) in sensitivity models adjusting for census region.<br><br>DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. https://doi.org/10.1289/EHP7683.}, }
@article {pmid34521116, year = {2021}, author = {DeFilipp, Z and Alousi, A and Pidala, J and Carpenter, PA and Onstad, L and Arai, S and Arora, M and Cutler, CS and Flowers, ME and Kitko, CL and Chen, GL and Lee, SJ and Hamilton, BK}, title = {Non-relapse mortality among patients diagnosed with chronic GVHD: An updated analysis from The Chronic GVHD Consortium.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004941}, pmid = {34521116}, issn = {2473-9537}, abstract = {Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for non-relapse mortality (NRM), we analyzed patient, transplant, and chronic GVHD-related variables, risk factors, and causes of non-relapse deaths in an updated cohort of 937 subjects enrolled on two prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (0.1 months - 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years and increased over time with a projected 40% (95%CI, 30-50) at 12 years. Centers reported that chronic GVHD (37.8%) was the commonest cause of NRM and was associated with organ failure, infection, or additional cause not otherwise specified. The next most frequent causes without mention of chronic GVHD were infection (17%) and respiratory failure (10%). In multivariate analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, NIH skin score 2-3, NIH lung score 1-3, worse modified HAP adjusted activity score, and decreased distance on walk test. In conclusion, chronic GVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung chronic GVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options are needed that do not predispose patients to infections.}, }
@article {pmid34521104, year = {2021}, author = {Nieuwlaat, R and Wiercioch, W and Brożek, JL and Santesso, NAM and Kunkle, R and Alonso-Coello, P and Anderson, DR and Bates, S and Cushman, M and Dahm, P and Iorio, A and Lim, W and Lyman, GH and Middeldorp, S and Monagle, P and Mustafa, RA and Neumann, I and Ortel, T and Rochwerg, B and Vesely, SK and Witt, DM and Cuker, A and Schunemann, HJ}, title = {How to write a guideline: a proposal for a manuscript template that supports the creation of trustworthy guidelines.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2020003577}, pmid = {34521104}, issn = {2473-9537}, abstract = {Trustworthy health guidelines should provide recommendations, document the development process, and highlight implementation information. Our objective was to develop a guideline manuscript template to help authors write a complete and useful report. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) centre collaborated with the American Society of Hematology (ASH) to develop guidelines for the management of venous thromboembolism. A template for reporting the guidelines was developed based on prior approaches and refined using input from other key stakeholders. The proposed guideline manuscript template includes: 1) title for guideline identification; 2) abstract, including a summary of key recommendations; 3) overview of all recommendations [executive summary]; 4) the main text, providing sufficient detail on the entire process including objectives, background, and methodological decisions from panel selection and conflict of interest management to criteria for updating, as well as supporting information such as links to online (interactive) tables. The template further allows for tailoring to the specific topic, using examples. Initial experience with the ASH guideline manuscript template was positive, and challenges included drafting descriptions of recommendations involving multiple management pathways, tailoring the template for a specific guideline, and choosing key recommendations to highlight. Feedback from a larger group of guideline authors and users will be needed to evaluate its usefulness and refine. The proposed guideline manuscript template is the first detailed template for transparent and complete reporting of guidelines. Consistent application of the template may simplify preparing an evidence-based guideline manuscript and facilitate its use.}, }
@article {pmid34520313, year = {2021}, author = {Mulenga, H and Musvosvi, M and Mendelsohn, SC and Penn-Nicholson, A and Kimbung Mbandi, S and Gartland, AF and Tameris, M and Mabwe, S and Africa, H and Bilek, N and Kafaar, F and Khader, SA and Carstens, B and Hadley, K and Hikuam, C and Erasmus, M and Jaxa, L and Raphela, R and Nombida, O and Kaskar, M and Nicol, MP and Mbhele, S and Van Heerden, J and Innes, C and Brumskine, W and Hiemstra, A and Malherbe, ST and Hassan-Moosa, R and Walzl, G and Naidoo, K and Churchyard, G and Hatherill, M and Scriba, TJ and , }, title = {Longitudinal Dynamics of a Blood Transcriptomic Signature of Tuberculosis.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1164/rccm.202103-0548OC}, pmid = {34520313}, issn = {1535-4970}, abstract = {Objectives We evaluated longitudinal kinetics of an 11-gene blood transcriptomic tuberculosis (TB) signature, RISK11, and effects of TB preventative therapy (TPT) and respiratory organisms on RISK11 signature score, in HIV-uninfected and HIV-infected individuals. Methods RISK11 was measured in a longitudinal study of RISK11-guided TPT in HIV-uninfected adults, a cross-sectional respiratory organisms cohort or a longitudinal study in people living with HIV (PLHIV). HIV-uninfected RISK11+ participants were randomised to TPT or no TPT; RISK11- participants received no TPT. PLHIV received standard-of-care ART and TPT. In the cross-sectional respiratory organisms cohort, viruses and bacteria in nasopharyngeal and oropharyngeal swabs were quantified by RT-qPCR. Measurements and Main Results RISK11+ status was transient in most of the 128 HIV-negative participants with longitudinal samples; >70% of RISK11+ participants reverted to RISK11- by 3 months, irrespective of TPT. By comparison, reversion from a RISK11-positive state was less common in 645 PLHIV (42.1%). Non-HIV viral and non-tuberculous bacterial organisms were detected in 7.2% and 38.9% of the 1,000 respiratory organisms cohort participants, respectively, and among those investigated for TB, 3.8% had prevalent disease. Median RISK11 scores (%) were higher in participants with viral organisms alone (46.7%), viral and bacterial organisms (42.8%), or prevalent TB (85.7%), than those with bacterial organisms other than TB (13.4%), or no organisms (14.2%). RISK11 could not discriminate between prevalent TB and viral organisms. Conclusions Positive RISK11 signature status is often transient, possibly due to intercurrent viral infection, highlighting potentially important challenges for implementation of these biomarkers as new tools for TB control. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).}, }
@article {pmid34519771, year = {2021}, author = {Hill, JA}, title = {Humoral Immunity After mRNA SARS-CoV-2 Vaccination in Allogeneic HCT Recipients-Room for Improvement and Much to Learn.}, journal = {JAMA network open}, volume = {4}, number = {9}, pages = {e2127454}, doi = {10.1001/jamanetworkopen.2021.27454}, pmid = {34519771}, issn = {2574-3805}, }
@article {pmid34519082, year = {2021}, author = {Boe, LA and Tinker, LF and Shaw, PA}, title = {An approximate quasi-likelihood approach for error-prone failure time outcomes and exposures.}, journal = {Statistics in medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/sim.9108}, pmid = {34519082}, issn = {1097-0258}, support = {R01 AI131771/NH/NIH HHS/United States ; R 160936207/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, abstract = {Measurement error arises commonly in clinical research settings that rely on data from electronic health records or large observational cohorts. In particular, self-reported outcomes are typical in cohort studies for chronic diseases such as diabetes in order to avoid the burden of expensive diagnostic tests. Dietary intake, which is also commonly collected by self-report and subject to measurement error, is a major factor linked to diabetes and other chronic diseases. These errors can bias exposure-disease associations that ultimately can mislead clinical decision-making. We have extended an existing semiparametric likelihood-based method for handling error-prone, discrete failure time outcomes to also address covariate error. We conduct an extensive numerical study to compare the proposed method to the naive approach that ignores measurement error in terms of bias and efficiency in the estimation of the regression parameter of interest. In all settings considered, the proposed method showed minimal bias and maintained coverage probability, thus outperforming the naive analysis which showed extreme bias and low coverage. This method is applied to data from the Women's Health Initiative to assess the association between energy and protein intake and the risk of incident diabetes mellitus. Our results show that correcting for errors in both the self-reported outcome and dietary exposures leads to considerably different hazard ratio estimates than those from analyses that ignore measurement error, which demonstrates the importance of correcting for both outcome and covariate error.}, }
@article {pmid34518674, year = {2021}, author = {Koup, RA and Donis, RO and Gilbert, PB and Li, AW and Shah, NA and Houchens, CR}, title = {A government-led effort to identify correlates of protection for COVID-19 vaccines.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {34518674}, issn = {1546-170X}, }
@article {pmid34518593, year = {2021}, author = {Buas, MF and Drescher, CW and Urban, N and Li, CI and Bettcher, L and Hait, NC and Moysich, KB and Odunsi, K and Raftery, D and Yan, L}, title = {Quantitative global lipidomics analysis of patients with ovarian cancer versus benign adnexal mass.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {18156}, pmid = {34518593}, issn = {2045-2322}, support = {P50CA159981/CA/NCI NIH HHS/United States ; U01CA152637/CA/NCI NIH HHS/United States ; P50CA083636/CA/NCI NIH HHS/United States ; U01CA152637-04S1/CA/NCI NIH HHS/United States ; P30CA016056/CA/NCI NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; S10OD021562/NH/NIH HHS/United States ; }, abstract = {Altered lipid metabolism has emerged as an important feature of ovarian cancer (OC), yet the translational potential of lipid metabolites to aid in diagnosis and triage remains unproven. We conducted a multi-level interrogation of lipid metabolic phenotypes in patients with adnexal masses, integrating quantitative lipidomics profiling of plasma and ascites with publicly-available tumor transcriptome data. Using Sciex Lipidyzer, we assessed concentrations of > 500 plasma lipids in two patient cohorts-(i) a pilot set of 100 women with OC (50) or benign tumor (50), and (ii) an independent set of 118 women with malignant (60) or benign (58) adnexal mass. 249 lipid species and several lipid classes were significantly reduced in cases versus controls in both cohorts (FDR < 0.05). 23 metabolites-triacylglycerols, phosphatidylcholines, cholesterol esters-were validated at Bonferroni significance (P < 9.16 × 10-5). Certain lipids exhibited greater alterations in early- (diacylglycerols) or late-stage (lysophospholipids) cases, and multiple lipids in plasma and ascites were positively correlated. Lipoprotein receptor gene expression differed markedly in OC versus benign tumors. Importantly, several plasma lipid species, such as DAG(16:1/18:1), improved the accuracy of CA125 in differentiating early-stage OC cases from benign controls, and conferred a 15-20% increase in specificity at 90% sensitivity in multivariate models adjusted for age and BMI. This study provides novel insight into systemic and local lipid metabolic differences between OC and benign disease, further implicating altered lipid uptake in OC biology, and advancing plasma lipid metabolites as a complementary class of circulating biomarkers for OC diagnosis and triage.}, }
@article {pmid34518311, year = {2021}, author = {Bickett, TE and Knitz, M and Darragh, LB and Bhatia, S and Van Court, B and Gadwa, J and Bhuvane, S and Piper, M and Nguyen, D and Tu, H and Lenz, L and Clambey, ET and Barry, K and Karam, SD}, title = {FLT3L release by NK cells enhances response to radioimmunotherapy in preclinical models of HNSCC.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-21-0971}, pmid = {34518311}, issn = {1557-3265}, abstract = {PURPOSE: Natural Killer (NK) cells are type 1 innate lymphoid cells that are known to secrete cytokines and for their role in killing virally infected cells or cancer cells through cytotoxicity. In addition to direct tumor cell killing, NK cells are known to play fundamental roles in the tumor microenvironment through secretion of key cytokines such as FMS-like tyrosine kinase 3 ligand (FLT3L). Although radiation therapy (RT) is the mainstay treatment most cancers, the role of radiation therapy on NK cells is not well characterized.<br><br>EXPERIMENTAL DESIGN: This study combines radiation, immunotherapies, genetic mouse models, and antibody depletion experiments to identify the role of NK cells in overcoming resistance to RT in orthotopic models of head and neck squamous cell carcinoma.<br><br>RESULTS: We have found that NK cells are a crucial component in the development of an anti-tumor response, as depleting them removes efficacy of the previously successful combination treatment of RT, anti-CD25 and anti-CD137. However, in the absence of NK cells, the effect can be rescued through treatment with FLT3L. But neither RT with FLT3L therapy alone nor RT with anti-NKG2A yields any meaningful tumor growth delay. We also identify a role for IL-2 in activating NK cells to secrete FLT3L. This activity is mediated through CD122, the intermediate affinity IL-2 receptor and can be targeted with anti-CD25.<br><br>CONCLUSIONS: These findings highlight the complexity of using radio-immunotherapies to activate NK cells within the tumor microenvironment, and the importance of NK cells in activating dendritic cells for increased tumor surveillance.}, }
@article {pmid34517814, year = {2021}, author = {Hu, Y and Bien, SA and Nishimura, KK and Haessler, J and Hodonsky, CJ and Baldassari, AR and Highland, HM and Wang, Z and Preuss, M and Sitlani, CM and Wojcik, GL and Tao, R and Graff, M and Huckins, LM and Sun, Q and Chen, MH and Mousas, A and Auer, PL and Lettre, G and ,  and Tang, W and Qi, L and Thyagarajan, B and Buyske, S and Fornage, M and Hindorff, LA and Li, Y and Lin, D and Reiner, AP and North, KE and Loos, RJF and Raffield, LM and Peters, U and Avery, CL and Kooperberg, C}, title = {Correction to: Multi-ethnic genome-wide association analyses of white blood cell and platelet traits in the Population Architecture using Genomics and Epidemiology (PAGE) Study.}, journal = {BMC genomics}, volume = {22}, number = {1}, pages = {656}, pmid = {34517814}, issn = {1471-2164}, }
@article {pmid34517754, year = {2021}, author = {Su, W and Sia, SF and Schmitz, AJ and Bricker, TL and Starr, TN and Greaney, AJ and Turner, JS and Mohammed, BM and Liu, Z and Choy, KT and Darling, TL and Joshi, A and Cheng, KM and Wong, AYL and Harastani, HH and Nicholls, JM and Whelan, SPJ and Bloom, JD and Yen, HL and Ellebedy, AH and Boon, ACM}, title = {Neutralizing Monoclonal Antibodies That Target the Spike Receptor Binding Domain Confer Fc Receptor-Independent Protection against SARS-CoV-2 Infection in Syrian Hamsters.}, journal = {mBio}, volume = {}, number = {}, pages = {e0239521}, doi = {10.1128/mBio.02395-21}, pmid = {34517754}, issn = {2150-7511}, abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action in vivo is incompletely understood. Here, we demonstrate that 2B04, an antibody with an ultrapotent neutralizing activity (50% inhibitory concentration [IC50] of 0.04 μg/ml), protects hamsters against SARS-CoV-2 in a prophylactic and therapeutic infection model. Protection is associated with reduced weight loss and viral loads in nasal turbinates and lungs after challenge. MAb 2B04 also blocked aerosol transmission of the virus to naive contacts. We next examined three additional MAbs (2C02, 2C03, and 2E06), recognizing distinct epitopes within the receptor binding domain of spike protein that possess either minimal (2C02 and 2E06, IC50 > 20 μg/ml) or weak (2C03, IC50 of 5 μg/ml) virus neutralization capacity in vitro. Only 2C03 protected Syrian hamsters from weight loss and reduced lung viral load after SARS-CoV-2 infection. Finally, we demonstrated that Fc-Fc receptor interactions were not required for protection when 2B04 and 2C03 were administered prophylactically. These findings inform the mechanism of protection and support the rational development of antibody-mediated protection against SARS-CoV-2 infections. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has resulted in the loss of millions of lives. Safe and effective vaccines are considered the ultimate remedy for the global social and economic disruption caused by the pandemic. However, a thorough understanding of the immune correlates of protection against this virus is lacking. Here, we characterized four different monoclonal antibodies and evaluated their ability to prevent or treat SARS-CoV-2 infection in Syrian hamsters. These antibodies varied in their ability to neutralize the virus in vitro. Prophylactic administration of potent and weakly neutralizing antibodies protected against SARS-CoV-2 infection, and this effect was Fc receptor independent. The potent neutralizing antibody also had therapeutic efficacy and eliminated onward aerosol transmission. In contrast, minimally neutralizing antibodies provided no protection against infection with SARS-CoV-2 in Syrian hamsters. Combined, these studies highlight the significance of weakly neutralizing antibodies in the protection against SARS-CoV-2 infection and associated disease.}, }
@article {pmid34516663, year = {2021}, author = {Sokolova, AO and Marshall, CH and Lozano, R and Gulati, R and Ledet, EM and De Sarkar, N and Grivas, P and Higano, CS and Montgomery, B and Nelson, PS and Olmos, D and Sokolov, V and Schweizer, MT and Yezefski, TA and Yu, EY and Paller, CJ and Sartor, O and Castro, E and Antonarakis, ES and Cheng, HH}, title = {Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations.}, journal = {The Prostate}, volume = {}, number = {}, pages = {}, doi = {10.1002/pros.24236}, pmid = {34516663}, issn = {1097-0045}, support = {//Center for Strategic Scientific Initiatives, National Cancer Institute/ ; //Prostate Cancer Foundation/ ; //Institute for Prostate Cancer Research/ ; //Washington State Medical Oncology Society/ ; //Advancing Cancer Treatment/ ; //Patrick Walsh Prostate Cancer Research Fund/ ; //NCI/ ; //DoD/ ; }, abstract = {BACKGROUND: Among men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).<br><br>METHODS: This is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.<br><br>RESULTS AND LIMITATIONS: The study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.<br><br>CONCLUSIONS: Conventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.}, }
@article {pmid34516660, year = {2021}, author = {Kirk, PS and Zhu, K and Zheng, Y and Newcomb, LF and Schenk, JM and Brooks, JD and Carroll, PR and Dash, A and Ellis, WJ and Filson, CP and Gleave, ME and Liss, M and Martin, F and McKenney, JK and Morgan, TM and Nelson, PS and Thompson, IM and Wagner, AA and Lin, DW and Gore, JL}, title = {Treatment in the absence of disease reclassification among men on active surveillance for prostate cancer.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33911}, pmid = {34516660}, issn = {1097-0142}, support = {U01 CA224255/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Maintaining men on active surveillance for prostate cancer can be challenging. Although most men who eventually undergo treatment have experienced clinical progression, a smaller subset elects treatment in the absence of disease reclassification. This study sought to understand factors associated with treatment in a large, contemporary, prospective cohort.<br><br>METHODS: This study identified 1789 men in the Canary Prostate Cancer Active Surveillance Study cohort enrolled as of 2020 with a median follow-up of 5.6 years. Clinical and demographic data as well as information on patient-reported quality of life and urinary symptoms were used in multivariable Cox proportional hazards regression models to identify factors associated with the time to treatment RESULTS: Within 4 years of their diagnosis, 33% of men (95% confidence interval [CI], 30%-35%) underwent treatment, and 10% (95% CI, 9%-12%) were treated in the absence of reclassification. The most significant factor associated with any treatment was an increasing Gleason grade group (adjusted hazard ratio [aHR], 14.5; 95% CI, 11.7-17.9). Urinary quality-of-life scores were associated with treatment without reclassification (aHR comparing "mostly dissatisfied/terrible" with "pleased/mixed," 2.65; 95% CI, 1.54-4.59). In a subset analysis (n = 692), married men, compared with single men, were more likely to undergo treatment in the absence of reclassification (aHR, 2.63; 95% CI, 1.04-6.66).<br><br>CONCLUSIONS: A substantial number of men with prostate cancer undergo treatment in the absence of clinical changes in their cancers, and quality-of-life changes and marital status may be important factors in these decisions.<br><br>LAY SUMMARY: This analysis of men on active surveillance for prostate cancer shows that approximately 1 in 10 men will decide to be treated within 4 years of their diagnosis even if their cancer is stable. These choices may be related in part to quality-or-life or spousal concerns.}, }
@article {pmid34515392, year = {2021}, author = {Belitškin, D and Pant, SM and Munne, P and Suleymanova, I and Belitškina, K and Hongisto, HA and Englund, J and Raatikainen, T and Klezovitch, O and Vasioukhin, V and Li, S and Wu, Q and Monni, O and Kuure, S and Laakkonen, P and Pouwels, J and Tervonen, TA and Klefström, J}, title = {Hepsin regulates TGFβ signaling via fibronectin proteolysis.}, journal = {EMBO reports}, volume = {}, number = {}, pages = {e52532}, doi = {10.15252/embr.202152532}, pmid = {34515392}, issn = {1469-3178}, support = {//Sihtasutus Archimedes (Archimedes Foundation)/ ; 1309848//Academy of Finland (Suomen Akatemia)/ ; //Ida Montinin Säätiö (Ida Montin Foundation)/ ; 4708006//Sigrid Juséliuksen Säätiö (Sigrid Jusélius Stiftelse)/ ; 440949//Business Finland/ ; //EU H2020 RESCUER/ ; //Cancer Society of Finland/ ; //Finnish Cancer Organizations/ ; //K. Albin Johanssons stiftelse/ ; //Jane and Aatos Erkko Foundation/ ; //iCAN Digital Precision Cancer Medicine Flagship/ ; //Helsinki Institute of Life Science Infrastructures (HiLIFE) of the University of Helsinki/ ; }, abstract = {Transforming growth factor-beta (TGFβ) is a multifunctional cytokine with a well-established role in mammary gland development and both oncogenic and tumor-suppressive functions. The extracellular matrix (ECM) indirectly regulates TGFβ activity by acting as a storage compartment of latent-TGFβ, but how TGFβ is released from the ECM via proteolytic mechanisms remains largely unknown. In this study, we demonstrate that hepsin, a type II transmembrane protease overexpressed in 70% of breast tumors, promotes canonical TGFβ signaling through the release of latent-TGFβ from the ECM storage compartment. Mammary glands in hepsin CRISPR knockout mice showed reduced TGFβ signaling and increased epithelial branching, accompanied by increased levels of fibronectin and latent-TGFβ1, while overexpression of hepsin in mammary tumors increased TGFβ signaling. Cell-free and cell-based experiments showed that hepsin is capable of direct proteolytic cleavage of fibronectin but not latent-TGFβ and, importantly, that the ability of hepsin to activate TGFβ signaling is dependent on fibronectin. Altogether, this study demonstrates a role for hepsin as a regulator of the TGFβ pathway in the mammary gland via a novel mechanism involving proteolytic downmodulation of fibronectin.}, }
@article {pmid34515202, year = {2021}, author = {Buonerba, C and Grivas, P and Di Lorenzo, G}, title = {Perioperative Immune Checkpoint Inhibitors in Renal Cell and Urothelial Carcinomas: An Exciting New Paradigm under Investigation?.}, journal = {Oncology}, volume = {}, number = {}, pages = {1-5}, doi = {10.1159/000518741}, pmid = {34515202}, issn = {1423-0232}, }
@article {pmid34510779, year = {2021}, author = {Alblas, M and Peterse, EFP and Du, M and Zauber, AG and Steyerberg, EW and van Leeuwen, N and Lansdorp-Vogelaar, I}, title = {Cost-effectiveness of prophylactic hysterectomy in first-degree female relatives with Lynch syndrome of patients diagnosed with colorectal cancer in the United States: a microsimulation study.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.4080}, pmid = {34510779}, issn = {2045-7634}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01-CA199335/CA/NCI NIH HHS/United States ; 634570//Horizon 2020 Framework Programme/ ; }, abstract = {BACKGROUND: To evaluate the cost-effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS).<br><br>METHODS: We developed a microsimulation model incorporating the natural history for the development of hyperplasia with and without atypia into endometrial cancer (EC) based on the MISCAN-framework. We simulated women identified as first-degree relatives (FDR) with LS of colorectal cancer patients after universal testing for LS. We estimated costs and benefits of offering this cohort PH, accounting for reduced quality of life after PH and for having EC. Three minimum ages (30/35/40) and three maximum ages (70/75/80) were compared to no PH.<br><br>RESULTS: In the absence of PH, the estimated number of EC cases was 300 per 1,000 women with LS. Total associated costs for treatment of EC were $5.9 million. Offering PH to FDRs aged 40-80 years was considered optimal. This strategy reduced the number of endometrial cancer cases to 5.4 (-98%), resulting in 516 quality-adjusted life years (QALY) gained and increasing the costs (treatment of endometrial cancer and PH) to $15.0 million (+154%) per 1,000 women. PH from earlier ages was more costly and resulted in fewer QALYs, although this finding was sensitive to disutility for PH.<br><br>CONCLUSIONS: Offering PH to 40- to 80-year-old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at a younger age, depending on their individual disutility for PH and premature menopause.}, }
@article {pmid34508031, year = {2021}, author = {Qayed, M and Bleakley, M and Shah, NN}, title = {Role of chimeric antigen receptor T-cell therapy: bridge to transplantation or stand-alone therapy in pediatric acute lymphoblastic leukemia.}, journal = {Current opinion in hematology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MOH.0000000000000685}, pmid = {34508031}, issn = {1531-7048}, abstract = {PURPOSE OF REVIEW: To discuss the curative potential for chimeric antigen receptor T-cell (CAR-T) therapy, with or without consolidative hematopoietic stem cell transplantation (HCT) in the treatment of children and young adults with B lineage acute lymphoblastic leukemia (B-ALL).<br><br>RECENT FINDINGS: CAR-T targeting CD19 can induce durable remissions and prolong life in patients with relapsed/refractory B-ALL. Whether HCT is needed to consolidate remission and cure relapse/refractory B-ALL following a CD19 CAR-T induced remission remains controversial. Preliminary evidence suggests that consolidative HCT following CAR-T in HCT-naïve children improves leukemia-free survival. However, avoiding HCT-related late effects is a desirable goal, so identification of patients at high risk of relapse is needed to appropriately direct those patients to HCT when necessary, while avoiding HCT in others. High disease burden prior to CAR-T infusion, loss of B-cell aplasia and detection of measurable residual disease by flow cytometry or next-generation sequencing following CAR-T therapy associate with a higher relapse risk and may identify patients requiring consolidative HCT for relapse prevention.<br><br>SUMMARY: There is a pressing need to determine when CD19 CAR-T alone is likely to be curative and when a consolidative HCT will be required. We discuss the current state of knowledge and future directions.}, }
@article {pmid34506832, year = {2021}, author = {Peeken, JC and Asadpour, R and Specht, K and Chen, EY and Klymenko, O and Akinkuoroye, V and Hippe, DS and Spraker, MB and Schaub, SK and Dapper, H and Knebel, C and Mayr, NA and Gersing, AS and Woodruff, HC and Lambin, P and Nyflot, MJ and Combs, SE}, title = {MRI-based Delta-Radiomics predicts pathologic complete response in high-grade soft-tissue sarcoma patients treated with neoadjuvant therapy.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.radonc.2021.08.023}, pmid = {34506832}, issn = {1879-0887}, abstract = {PURPOSE: In high-grade soft-tissue sarcomas (STS) the standard of care encompasses multimodal therapy regimens. While there is a growing body of evidence for prognostic pretreatment radiomic models, we hypothesized that temporal changes in radiomic features following neoadjuvant treatment ("delta-radiomics") may be able to predict the pathological complete response (pCR).<br><br>METHODS: MRI scans (T1-weighted with fat-saturation and contrast-enhancement (T1FSGd) and T2-weighted with fat-saturation (T2FS)) of patients with STS of the extremities and trunk treated with neoadjuvant therapy were gathered from two independent institutions (training: 103, external testing: 53 patients). pCR was defined as < 5% viable cells. After segmentation and preprocessing, 105 radiomic features were extracted. Delta-radiomic features were calculated by subtraction of features derived from MRI scans obtained before and after neoadjuvant therapy. After feature reduction, machine learning modeling was performed in 100 iterations of 3-fold nested cross-validation. Delta-radiomic models were compared with single timepoint models in the testing cohort.<br><br>RESULTS: The combined delta-radiomic models achieved the best area under the receiver operating characteristic curve (AUC) of 0.75. Pre-therapeutic tumor volume was the best conventional predictor (AUC 0.70). The T2FS-based delta-radiomic model had the most balanced classification performance with a balanced accuracy of 0.69. Delta-radiomic models achieved better reproducibility than single timepoint radiomic models, RECIST or the peri-therapeutic volume change. Delta-radiomic models were significantly associated with survival in multivariate Cox regression.<br><br>CONCLUSION: This exploratory analysis demonstrated that MRI-based delta-radiomics improves prediction of pCR over tumor volume and RECIST. Delta-radiomics may one day function as a biomarker for personalized treatment adaptations.}, }
@article {pmid34506358, year = {2021}, author = {Lemos, MP and Nandi, V and Dragavon, J and Fleming, I and Krishnan, K and Musuruana, M and Kramer, M and Glantz, H and Andrasik, M and Coombs, RW and McElrath, MJ and Tieu, HV}, title = {HIV-1 Nucleic Acids Identify Rectal HIV Exposures in Self-Collected Rectal Swabs, Whereas Y-Chromosome Single Tandem Repeat Mixtures Are Not Reliable Biomarkers of Condomless Receptive Anal Intercourse.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {88}, number = {2}, pages = {138-148}, doi = {10.1097/QAI.0000000000002748}, pmid = {34506358}, issn = {1944-7884}, abstract = {BACKGROUND: To focus interventions, biomarkers of HIV-1 exposure could help in identifying subpopulations at highest risk of acquisition. We assessed whether Y-chromosome single tandem repeat (YSTR) mixtures obtained from rectal swabs could serve as a biomarker of condomless receptive anal intercourse (CRAI) among men who have sex with men and transgender women and evaluated the feasibility of detecting HIV-1 virions to assess exposures.<br><br>METHODS: Twenty-nine sexually active HIV-seronegative men who have sex with men and one transgender woman from New York City answered on-site and mobile app sexual behavior questionnaires. They were randomized to collecting self-administered rectal swabs every morning or after receptive anal intercourse (RAI). YSTR profiles were assessed from blood sample and swabs; HIV-1 exposure was measured by conducting quantitative polymerase chain reaction in swabs.<br><br>RESULTS: After 2 months, the daily mobile survey had 135%-201% more instances of anal sex acts and 170%-193% more RAI than on-site surveys. Daily mobile reporting had 11%-35% less CRAI events than those reported on-site (Pdaily = 0.001; Pper-sex = 0.047). The daily swabbing arm reported less RAI (P < 0.001) and CRAI (P < 0.038) and had 2.95 lower odds of detecting YSTR mixtures (P = 0.021) than the per-sex-event arm. Surprisingly, YSTR detection was not significantly modified by report of bowel movements and lubricant, enema, or condom use. No participant became HIV-1 infected, yet HIV-1 total nucleic acids were detected in 6 independent episodes of CRAI in 2 participants taking pre-exposure prophylaxis.<br><br>CONCLUSIONS: YSTR mixtures demonstrated 80% specificity but only 30% sensitivity as a biomarker of CRAI in self-collected rectal swabs. However, detection of HIV-1 exposures in self-collected swabs may help in identifying those needing further HIV risk reduction strategies.}, }
@article {pmid34505128, year = {2021}, author = {Chen, J and Ali, MW and Yan, L and Dighe, SG and Dai, JY and Vaughan, TL and Casey, G and Buas, MF}, title = {Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddab259}, pmid = {34505128}, issn = {1460-2083}, abstract = {Genome-wide association studies (GWAS) have identified ~ 20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett's esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers, and typically, numerous potential candidate variants at GWAS loci require testing. We developed a systematic informatics pipeline for prioritizing candidate functional variants via integrative functional potential scores consolidated from multi-omics annotations, and used this pipeline to identify two high-scoring variants for experimental interrogation: chr9q22.32/rs11789015 and chr19p13.11/rs10423674. Minimal candidate enhancer regions spanning these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two variants tested (rs10423674) exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the putative enhancer region in EAC cell lines correlated with reduced expression of two genes-CREB-regulated transcription coactivator 1 (CRTC1) and Cartilage oligomeric matrix protein (COMP); expression of five other genes remained unchanged (CRLF1, KLHL26, TMEM59L, UBA52, RFXANK). Expression quantitative trait locus (eQTL) mapping indicated that rs10423674 genotype correlated with CRTC1 and COMP expression in normal esophagus. This study represents the first experimental effort to bridge GWAS associations to biology in BE/EAC, and supports the utility of functional potential scores to guide variant prioritization. Our findings reveal a functional variant and candidate risk enhancer at chr19p13.11, and implicate CRTC1 and COMP as putative gene targets, suggesting that altered expression of these genes may underlie the BE/EAC risk association.}, }
@article {pmid34503934, year = {2021}, author = {Curran, C and Adib, E and Kazakova, V and Grivas, P and Diamantopoulos, LN and Alva, AS and Su, C and Jain, RK and Tandon, A and Necchi, A and Marandino, L and Plastini, TM and Merchan, JR and Sonpavde, G}, title = {Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2021.08.002}, pmid = {34503934}, issn = {1938-0682}, abstract = {BACKGROUND: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue.<br><br>METHODS: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV.<br><br>RESULTS: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV.<br><br>CONCLUSION: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.}, }
@article {pmid34499366, year = {2021}, author = {Doucette, K and Percival, ME and Williams, L and Kandahari, A and Taylor, A and Wang, S and Ahn, J and Karp, JE and Lai, C}, title = {Hypoalbuminemia as a prognostic biomarker for higher mortality and treatment complications in acute myeloid leukemia.}, journal = {Hematological oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/hon.2925}, pmid = {34499366}, issn = {1099-1069}, abstract = {Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker.}, }
@article {pmid34498980, year = {2021}, author = {Cranston, RD and Brown, E and Bauermeister, J and Dunne, EF and Hoesley, C and Ho, K and Johnson, S and Lucas, J and Dominguez-Islas, C and Gundacker, H and Peda, M and Jacobson, CE and Kramzer, L and Singh, D and Dezzutti, CS and Kunjara Na Ayudhya, RP and Brand, RM and Wang, L and Marzinke, MA and Piper, J and Devlin, B and Nuttall, J and McGowan, I and Hendrix, CW}, title = {A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults (MTN-026).}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2021.0071}, pmid = {34498980}, issn = {1931-8405}, abstract = {INTRODUCTION: Dapivirine (DPV), formulated as vaginal ring, demonstrated HIV risk reduction. MTN-026 explored DPV, formulated as rectal gel, for safety, pharmacokinetics, and acceptability.<br><br>METHODS: HIV-uninfected men and women aged 18-45 years were enrolled at United States and Thailand sites and randomized 2:1 to receive DPV 0.05% or placebo gel via rectal applicator. A single dose phase was followed by 7 observed daily doses. Plasma, and fluid and tissue from both rectum and cervix were collected at baseline and after the final dose over 72 hours for pharmacokinetics, ex-vivo HIV-1 biopsy challenge, histology, and flow cytometry.<br><br>RESULTS: 28 participants were randomized; 2 terminated early; 9 were female and 19 male; 12 were white, 11 Asian, 4 black and 1 other race/ethnicity. Mean age was 28.5 and 34.2 years in the DPV and placebo arms, respectively. Thirty adverse events occurred (all Grade 1 or 2, except one unrelated Grade 3) without study arm differences. DPV rectal tissue concentrations (median [interquartile range]) 0.5-1 and 2 hours after a single dose were 256 ng/gm (below limit of quantitation [BLQ], 666) and BLQ (BLQ, 600), respectively, then BLQ (BLQ, BLQ) from 24-72 hours; concentrations following multiple doses were similar. The largest median DPV plasma concentrations were 0.33 ng/mL (0.15, 0.48) after one dose and 0.40 (0.33, 0.49) after seven doses.<br><br>CONCLUSIONS: The DPV rectal gel was acceptable and without safety concerns. While DPV plasma concentrations were similar to the vaginal ring, rectal tissue concentrations were well below vaginal ring tissue concentrations, suggesting need for reformulation.}, }
@article {pmid34497144, year = {2021}, author = {Salvucci, M and Crawford, N and Stott, K and Bullman, S and Longley, DB and Prehn, JHM}, title = {Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC).}, journal = {Gut}, volume = {}, number = {}, pages = {}, doi = {10.1136/gutjnl-2021-325193}, pmid = {34497144}, issn = {1468-3288}, abstract = {OBJECTIVES: Transcriptomic-based subtyping, consensus molecular subtyping (CMS) and colorectal cancer intrinsic subtyping (CRIS) identify a patient subpopulation with mesenchymal traits (CMS4/CRIS-B) and poorer outcome. Here, we investigated the relationship between prevalence of Fusobacterium nucleatum (Fn) and Fusobacteriales, CMS/CRIS subtyping, cell type composition, immune infiltrates and host contexture to refine patient stratification and to identify druggable context-specific vulnerabilities.<br><br>DESIGN: We coupled cell culture experiments with characterisation of Fn/Fusobacteriales prevalence and host biology/microenviroment in tumours from two independent colorectal cancer patient cohorts (Taxonomy: n=140, colon and rectal cases of The Cancer Genome Atlas (TCGA-COAD-READ) cohort: n=605).<br><br>RESULTS: In vitro, Fn infection induced inflammation via nuclear factor kappa-light-chain-enhancer of activated B cells/tumour necrosis factor alpha in HCT116 and HT29 cancer cell lines. In patients, high Fn/Fusobacteriales were found in CMS1, microsatellite unstable () tumours, with infiltration of M1 macrophages, reduced M2 macrophages, and high interleukin (IL)-6/IL-8/IL-1β signalling. Analysis of the Taxonomy cohort suggested that Fn was prognostic for CMS4/CRIS-B patients, despite having lower Fn load than CMS1 patients. In the TCGA-COAD-READ cohort, we likewise identified a differential association between Fusobacteriales relative abundance and outcome when stratifying patients in mesenchymal (either CMS4 and/or CRIS-B) versus non-mesenchymal (neither CMS4 nor CRIS-B). Patients with mesenchymal tumours and high Fusobacteriales had approximately twofold higher risk of worse outcome. These associations were null in non-mesenchymal patients. Modelling the three-way association between Fusobacteriales prevalence, molecular subtyping and host contexture with logistic models with an interaction term disentangled the pathogen-host signalling relationship and identified aberrations (including NOTCH, CSF1-3 and IL-6/IL-8) as candidate targets.<br><br>CONCLUSION: This study identifies CMS4/CRIS-B patients with high Fn/Fusobacteriales prevalence as a high-risk subpopulation that may benefit from therapeutics targeting mesenchymal biology.}, }
@article {pmid34496978, year = {2021}, author = {Leeman, J and Rohweder, C and Lee, M and Brenner, A and Dwyer, A and Ko, LK and O'Leary, MC and Ryan, G and Vu, T and Ramanadhan, S}, title = {Aligning implementation science with improvement practice: a call to action.}, journal = {Implementation science communications}, volume = {2}, number = {1}, pages = {99}, pmid = {34496978}, issn = {2662-2211}, support = {U48 DP006400/CC/CDC HHS/United States ; U48 DP006400/CC/CDC HHS/United States ; U48 DP006400/CC/CDC HHS/United States ; U48 DP006396/CC/CDC HHS/United States ; U48 DP006399/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006389/CC/CDC HHS/United States ; T32-CA-116339/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: In several recent articles, authors have called for aligning the fields of implementation and improvement science. In this paper, we call for implementation science to also align with improvement practice. Multiple implementation scholars have highlighted the importance of designing implementation strategies to fit the existing culture, infrastructure, and practice of a healthcare system. Worldwide, healthcare systems are adopting improvement models as their primary approach to improving healthcare delivery and outcomes. The prevalence of improvement models raises the question of how implementation scientists might best align their efforts with healthcare systems' existing improvement infrastructure and practice.<br><br>MAIN BODY: We describe three challenges and five benefits to aligning implementation science and improvement practice. Challenges include (1) use of different models, terminology, and methods, (2) a focus on generalizable versus local knowledge, and (3) limited evidence in support of the effectiveness of improvement tools and methods. We contend that implementation science needs to move beyond these challenges and work toward greater alignment with improvement practice. Aligning with improvement practice would benefit implementation science by (1) strengthening research/practice partnerships, (2) fostering local ownership of implementation, (3) generating practice-based evidence, (4) developing context-specific implementation strategies, and (5) building practice-level capacity to implement interventions and improve care. Each of these potential benefits is illustrated in a case study from the Centers for Disease Control and Prevention's Cancer Prevention and Control Research Network.<br><br>CONCLUSION: To effectively integrate evidence-based interventions into routine practice, implementation scientists need to align their efforts with the improvement culture and practice that is driving change within healthcare systems worldwide. This paper provides concrete examples of how researchers have aligned implementation science with improvement practice across five implementation projects.}, }
@article {pmid34493840, year = {2021}, author = {Adair, JE and Androski, L and Bayigga, L and Bazira, D and Brandon, E and Dee, L and Deeks, S and Draz, M and Dubé, K and Dybul, M and Gurkan, U and Harlow, E and Kityo, C and Louella, M and Malik, P and Mathews, V and McKemey, A and Mugerwa, H and Muyanja, D and Olayiwola, O and Orentas, RJ and Popovski, A and Sheehy, J and Ssali, F and Nsubuga, MS and Tisdale, JF and Verhoeyen, E and Dropulić, B}, title = {Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).}, journal = {Gene therapy}, volume = {}, number = {}, pages = {}, pmid = {34493840}, issn = {1476-5462}, abstract = {The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.}, }
@article {pmid34493409, year = {2021}, author = {Rane, MS and Rohani, P and Halloran, ME}, title = {Durability of protection after 5 doses of acellular pertussis vaccine among 5-9 year old children in King County, Washington.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2021.08.070}, pmid = {34493409}, issn = {1873-2518}, abstract = {PURPOSE: Waning of immunity after vaccination with the acellular Pertussis (aP) vaccine has been proposed as one of the main reasons for pertussis resurgence in the US. In this study, we estimated time-varying vaccine effectiveness after 5 doses of aP vaccine.<br><br>METHODS: We conducted a retrospective cohort study among children 5-9 years old (born between 2008 and 2012) living in King County, Washington, USA, who participated in the Washington State Immunization Information System. We estimated time-varying vaccine effectiveness after 5 doses of aP using smoothed scaled Schoenfeld residuals obtained from fitting Cox proportional hazards models to the data as well as piecewise constant Poisson regression.<br><br>RESULTS: There were 55 pertussis cases in this cohort, of whom 22 (40%) were fully-vaccinated and 33 (60%) were under-vaccinated. Vaccine effectiveness (VE) remained high for up to 42 months after the fifth dose (VE(t) = 89%; 95% CI: 64%, 97%) as estimated using survival analysis methods and up to 4 years (VE(t) = 93%; 95% CI: 67%, 98%) as estimated using Poisson regression.<br><br>CONCLUSION: We did not find evidence for waning of vaccine effectiveness for up to four years after 5 doses of aP among 5 -9 years old children in King County, WA.}, }
@article {pmid34493319, year = {2021}, author = {Maloney, DG and Kuruvilla, J and Liu, FF and Kostic, A and Kim, Y and Bonner, A and Zhang, Y and Fox, CP and Cartron, G}, title = {Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma.}, journal = {Journal of hematology &amp; oncology}, volume = {14}, number = {1}, pages = {140}, pmid = {34493319}, issn = {1756-8722}, abstract = {BACKGROUND: In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL).<br><br>METHODS: Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor.<br><br>RESULTS: The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56-3.49] and 1.21 [0.56-2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44-1.49] and 0.95 [0.58-1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01-0.07] and 0.08 [0.01-0.67], respectively) and study-specific neurological events (0.16 [0.08-0.33] and 0.05 [0.02-0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor.<br><br>CONCLUSIONS: After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL.<br><br>TRIAL REGISTRATION: NCT02631044 and NCT02348216.}, }
@article {pmid34492117, year = {2021}, author = {Janes, H and Gao, F and Luedtke, A}, title = {Discussion on "Estimating vaccine efficacy over time after a randomized study is unblinded" by Anastasios A. Tsiatis and Marie Davidian.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13542}, pmid = {34492117}, issn = {1541-0420}, support = {DP2 LM013340/NH/NIH HHS/United States ; R56AI143418/NH/NIH HHS/United States ; UM1AI068635/NH/NIH HHS/United States ; }, }
@article {pmid34492041, year = {2021}, author = {Lin, MJ and Haynes, AM and Addetia, A and Lieberman, NAP and Phung, Q and Xie, H and Nguyen, TV and Molini, BJ and Lukehart, SA and Giacani, L and Greninger, AL}, title = {Longitudinal TprK profiling of in vivo and in vitro-propagated Treponema pallidum subsp. pallidum reveals accumulation of antigenic variants in absence of immune pressure.}, journal = {PLoS neglected tropical diseases}, volume = {15}, number = {9}, pages = {e0009753}, doi = {10.1371/journal.pntd.0009753}, pmid = {34492041}, issn = {1935-2735}, abstract = {Immune evasion by Treponema pallidum subspecies pallidum (T. pallidum) has been attributed to antigenic variation of its putative outer-membrane protein TprK. In TprK, amino acid diversity is confined to seven variable (V) regions, and generation of sequence diversity within the V regions occurs via a non-reciprocal segmental gene conversion mechanism where donor cassettes recombine into the tprK expression site. Although previous studies have shown the significant role of immune selection in driving accumulation of TprK variants, the contribution of baseline gene conversion activity to variant diversity is less clear. Here, combining longitudinal tprK deep sequencing of near clonal Chicago C from immunocompetent and immunosuppressed rabbits along with the newly developed in vitro cultivation system for T. pallidum, we directly characterized TprK alleles in the presence and absence of immune selection. Our data confirm significantly greater sequence diversity over time within the V6 region during syphilis infection in immunocompetent rabbits compared to immunosuppressed rabbits, consistent with previous studies on the role of TprK in evasion of the host immune response. Compared to strains grown in immunocompetent rabbits, strains passaged in vitro displayed low level changes in allele frequencies of TprK variable region sequences similar to that of strains passaged in immunosuppressed rabbits. Notably, we found significantly increased rates of V6 allele generation relative to other variable regions in in vitro cultivated T, pallidum strains, illustrating that the diversity within these hypervariable regions occurs in the complete absence of immune selection. Together, our results demonstrate antigenic variation in T. pallidum can be studied in vitro and occurs even in the complete absence of immune pressure, allowing the T. pallidum population to continuously evade the immune system of the infected host.}, }
@article {pmid34491886, year = {2021}, author = {Hullar, MAJ and Jenkins, IC and Randolph, TW and Curtis, KR and Monroe, KR and Ernst, T and Shepherd, JA and Stram, DO and Cheng, I and Kristal, BS and Wilkens, LR and Franke, A and Le Marchand, L and Lim, U and Lampe, JW}, title = {Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study.}, journal = {Gut microbes}, volume = {13}, number = {1}, pages = {1965463}, doi = {10.1080/19490976.2021.1965463}, pmid = {34491886}, issn = {1949-0984}, abstract = {Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60-77 years, with 12-53% overall adiposity (BMI of 17.8-46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.}, }
@article {pmid34491818, year = {2021}, author = {Tagawa, ST and Grivas, P}, title = {Reply to T. Powles et al.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2101673}, doi = {10.1200/JCO.21.01673}, pmid = {34491818}, issn = {1527-7755}, }
@article {pmid34491784, year = {2021}, author = {Gooley, TA}, title = {Two Biologic-Assignment Studies Evaluating the Efficacy of Hematopoietic Cell Transplant Among Older Patients With High-Risk Myelodysplastic Syndrome.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2101594}, doi = {10.1200/JCO.21.01594}, pmid = {34491784}, issn = {1527-7755}, }
@article {pmid34491344, year = {2021}, author = {Schoenbeck, KL and Atallah, E and Lin, L and Weinfurt, KP and Cortes, J and Deininger, MWN and Kota, V and Larson, RA and Mauro, MJ and Oehler, VG and Pinilla-Ibarz, J and Radich, JP and Schiffer, CA and Shah, NP and Silver, RT and Thompson, JE and Flynn, KE}, title = {Patient-Reported Functional Outcomes in Patients with Chronic Myeloid Leukemia after Stopping Tyrosine Kinase Inhibitors.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djab184}, pmid = {34491344}, issn = {1460-2105}, abstract = {Treatment-free remission (TFR) is a goal for patients with chronic myeloid leukemia (CML). Functional outcomes after discontinuing Tyrosine Kinase Inhibitor (TKI) treatment have not been described. PROMIS patient-reported outcome measures (PROMs) of social, physical, cognitive, and sexual function were assessed over 36 months in 172 adult patients with chronic phase CML from 14 sites at baseline (on TKI) and after discontinuation. Linear mixed-effects models described the average trajectories for each PROM after discontinuation and in those who restarted TKI. Of 112 patients in TFR at 12 months, 103 (92.0%) had a ≥ 3-point improvement in social function, 80 (71.4%) in social isolation, 11 (9.8%) in satisfaction with sex life, 4 (3.6%) in physical function, and no patients had a ≥ 3-point improvement in cognitive function or interest in sexual activity. Patients' scores worsened after restarting TKI. This novel information on functional outcomes in TFR can help guide patient and clinician decision-making.}, }
@article {pmid34489966, year = {2021}, author = {Teshima, T and Hill, GR}, title = {The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {715424}, doi = {10.3389/fimmu.2021.715424}, pmid = {34489966}, issn = {1664-3224}, abstract = {Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.}, }
@article {pmid34489601, year = {2021}, author = {Lee, JW and Su, Y and Baloni, P and Chen, D and Pavlovitch-Bedzyk, AJ and Yuan, D and Duvvuri, VR and Ng, RH and Choi, J and Xie, J and Zhang, R and Murray, K and Kornilov, S and Smith, B and Magis, AT and Hoon, DSB and Hadlock, JJ and Goldman, JD and Price, ND and Gottardo, R and Davis, MM and Hood, L and Greenberg, PD and Heath, JR}, title = {Integrated analysis of plasma and single immune cells uncovers metabolic changes in individuals with COVID-19.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {34489601}, issn = {1546-1696}, abstract = {A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.}, }
@article {pmid34486806, year = {2021}, author = {Roelofs, EJ and Dengel, DR and Wang, Q and Hodges, JS and Steinberger, J and Baker, S}, title = {The role of FSH in body composition in hematopoietic cell transplant recipients.}, journal = {Pediatric transplantation}, volume = {}, number = {}, pages = {e14130}, doi = {10.1111/petr.14130}, pmid = {34486806}, issn = {1399-3046}, support = {M01-RR00400//General Clinical Research Center Program/ ; UL1TR000114//Clinical and Translational Science Institute at the University of Minnesota-Twin Cities/ ; RO1 CA112530/NH/NIH HHS/United States ; RO1 CA113930/NH/NIH HHS/United States ; 1UL1-RR033183/RR/NCRR NIH HHS/United States ; UL1TR000114//National Center for Advancing Translational Sciences of the National Institutes of Health/ ; }, abstract = {BACKGROUND: Childhood cancer survivors who received a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a significant negative impact on bone health and body composition. This study's purpose was to examine FSH and body composition in HCT recipients, non-HCT recipients and healthy controls.<br><br>METHODS: The study included HCT recipients (n = 24), non-HCT recipients (n = 309), and a control group of healthy siblings (n = 211) all aged 9-18 years. A fasting blood sample was collected to measure FSH. All participants underwent a dual X-ray absorptiometry scan to assess total and regional percent fat, lean mass (LM), fat mass (FM), bone mineral content (BMC), bone mineral density (BMD), and visceral adipose tissue (VAT) mass.<br><br>RESULTS: FSH was significantly higher in HCT recipients compared to non-HCT recipients and healthy controls. HCT recipients had significantly lower total body weight, total LM, arm and leg LM, BMC and BMD compared to non-HCT recipients and healthy controls (p < .05). Non-HCT recipients had significantly higher total, trunk, android, gynoid, arm and leg FM compared to healthy controls. Also, healthy controls had significantly lower VAT mass compared to non-HCT recipients.<br><br>CONCLUSIONS: This study's results show that HCT recipients have significant reductions in BMD, worse body composition, and abnormal FSH levels compared to non-HCT recipients and healthy controls.}, }
@article {pmid34486798, year = {2021}, author = {Chan, M and Vijay, S and McNevin, J and McElrath, MJ and Holland, EC and Gujral, TS}, title = {Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release.}, journal = {Molecular systems biology}, volume = {17}, number = {9}, pages = {e10426}, doi = {10.15252/msb.202110426}, pmid = {34486798}, issn = {1744-4292}, support = {//Fred Hutch COVID19 Pilot Fund/ ; }, abstract = {Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.}, }
@article {pmid34485852, year = {2021}, author = {Lalish, KM and Stromholt, S and Curtis, N and Chowning, JT}, title = {Explorers Virtual Internship: Fostering Rightful Presence and Sense of Belonging in an Online High School Internship Program.}, journal = {Journal of STEM outreach}, volume = {4}, number = {2}, pages = {}, doi = {10.15695/jstem/v4i2.07}, pmid = {34485852}, issn = {2576-6767}, abstract = {This paper describes the "Explorers Virtual Internship" (EVI), which was designed and presented in the 2020-21 school year by the Fred Hutchinson Cancer Research Center. Despite our initial wariness about creating a virtual internship, the shift helped us make valuable innovations to our programming. EVI paired 11 high school interns with mentors to work on individual research projects. We designed our program to foster a sense of belonging and "rightful presence" in biomedical research among the interns, all of whom came from backgrounds underrepresented in science. In addition to the research experience, we also focused on ethical issues, career awareness, community building, identity/belonging, and leadership/agency. Interns reported increases in their perceptions of the overlap of their identity and those of STEM professionals. They also reported increases in their knowledge of STEM concepts and capacity to demonstrate STEM skills (n=10). Open-ended survey responses indicated that students' uptake of scientific practices and sense of belonging were interrelated with their relationship with their mentors, and that students felt a sense of community with other students despite being in a virtual environment. We also provided programming for mentors, who indicated that learning and thinking about rightful presence and belonging was helpful for their role.}, }
@article {pmid34485613, year = {2021}, author = {Haeseleer, F and Fukazawa, Y and Park, H and Varco-Merth, B and Rust, BJ and Smedley, JV and Eichholz, K and Peterson, CW and Mason, R and Kiem, HP and Roederer, M and Picker, LJ and Okoye, AA and Corey, L}, title = {Immune inactivation of anti-simian immunodeficiency virus chimeric antigen receptor T cells in rhesus macaques.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {22}, number = {}, pages = {304-319}, doi = {10.1016/j.omtm.2021.06.008}, pmid = {34485613}, issn = {2329-0501}, abstract = {Chimeric antigen receptor (CAR) T cell therapies are being investigated as potential HIV cures and designed to target HIV reservoirs. Monoclonal antibodies (mAbs) targeting the simian immunodeficiency virus (SIV) envelope allowed us to investigate the potency of single-chain variable fragment (scFv)-based anti-SIV CAR T cells. In vitro, CAR T cells expressing the scFv to both the variable loop 1 (V1) or V3 of the SIV envelope were highly potent at eliminating SIV-infected T cells. However, in preclinical studies, in vivo infusion of these CAR T cells in rhesus macaques (RMs) resulted in lack of expansion and no detectable in vivo antiviral activity. Injection of envelope-expressing antigen-presenting cells (APCs) 1 week post-CAR T cell infusion also failed to stimulate CAR T cell expansion in vivo. To investigate this in vitro versus in vivo discrepancy, we examined host immune responses directed at CAR T cells. A humoral immune response against the CAR scFv was detected post-infusion of the anti-SIV CAR T cells; anti-SIV IgG antibodies present in plasma of SIV-infected animals were associated with inhibited CAR T cell effector functions. These data indicate that lack of in vivo expansion and efficacy of CAR T cells might be due to antibodies blocking the interaction between the CAR scFv and its epitope.}, }
@article {pmid34484202, year = {2021}, author = {Lazarus, HM and Ragsdale, CE and Gale, RP and Lyman, GH}, title = {Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {706186}, doi = {10.3389/fimmu.2021.706186}, pmid = {34484202}, issn = {1664-3224}, abstract = {Background: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans.<br><br>Objective: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings.<br><br>Methods and Results: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies.<br><br>Conclusions: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.}, }
@article {pmid34484199, year = {2021}, author = {Valadez-Cosmes, P and Maitz, K and Kindler, O and Raftopoulou, S and Kienzl, M and Santiso, A and Mihalic, ZN and Brcic, L and Lindenmann, J and Fediuk, M and Pichler, M and Schicho, R and Houghton, AM and Heinemann, A and Kargl, J}, title = {Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients.}, journal = {Frontiers in immunology}, volume = {12}, number = {}, pages = {703846}, doi = {10.3389/fimmu.2021.703846}, pmid = {34484199}, issn = {1664-3224}, abstract = {Neutrophils have been described as a phenotypically heterogeneous cell type that possess both pro- and anti-tumor properties. Recently, a subset of neutrophils isolated from the peripheral blood mononuclear cell (PBMC) fraction has been described in cancer patients. These low-density neutrophils (LDNs) show a heterogeneous maturation state and have been associated with pro-tumor properties in comparison to mature, high-density neutrophils (HDNs). However, additional studies are necessary to characterize this cell population. Here we show new surface markers that allow us to discriminate between LDNs and HDNs in non-small cell lung cancer (NSCLC) patients and assess their potential as diagnostic/prognostic tool. LDNs were highly enriched in NSCLC patients (median=20.4%, range 0.3-76.1%; n=26) but not in healthy individuals (median=0.3%, range 0.1-3.9%; n=14). Using a high-dimensional human cell surface marker screen, we identified 12 surface markers that were downregulated in LDNs when compared to HDNs, while 41 surface markers were upregulated in the LDN subset. Using flow cytometry, we confirmed overexpression of CD36, CD41, CD61 and CD226 in the LDN fraction. In summary, our data support the notion that LDNs are a unique neutrophil population and provide novel targets to clarify their role in tumor progression and their potential as diagnostic and therapeutic tool.}, }
@article {pmid34483404, year = {2021}, author = {Liang, M and Zhao, YQ}, title = {Discussion of Kallus (2020) and Mo et al (2020).}, journal = {Journal of the American Statistical Association}, volume = {116}, number = {534}, pages = {690-693}, doi = {10.1080/01621459.2020.1833887}, pmid = {34483404}, issn = {0162-1459}, abstract = {We discuss the results on improving the generalizability of individualized treatment rule following the work in Kallus [1] and Mo et al. [5]. We note that the advocated weights in Kallus [1] are connected to the efficient score of the contrast function. We further propose a likelihood-ratio-based method (LR-ITR) to accommodate covariate shifts, and compare it to the CTE-DR-ITR method proposed in Mo et al. [5]. We provide the upper-bound on the risk function of the target population when both the covariate shift and the contrast function shift are present. Numerical studies show that LR-ITR can outperform CTE-DR-ITR when there is only covariate shift.}, }
@article {pmid34481598, year = {2021}, author = {Portuguese, AJ and Long, TH and Linenberger, M}, title = {Necrobiotic Xanthogranuloma.}, journal = {Mayo Clinic proceedings}, volume = {96}, number = {9}, pages = {2432-2434}, doi = {10.1016/j.mayocp.2021.05.012}, pmid = {34481598}, issn = {1942-5546}, }
@article {pmid34481552, year = {2021}, author = {Okello, CD and Niyonzima, N and Ferraresso, M and Kadhumbula, S and Ddungu, H and Tarlock, K and Balagadde-Kambugu, J and Omoding, A and Ngendahayo, L and Karagu, A and Mwaiselage, J and Harlan, JM and Uldrick, TS and Turner, SD and Orem, J}, title = {Haematological malignancies in sub-Saharan Africa: east Africa as an example for improving care.}, journal = {The Lancet. Haematology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3026(21)00198-8}, pmid = {34481552}, issn = {2352-3026}, abstract = {Haematological malignancies account for almost 10% of all cancers diagnosed in sub-Saharan Africa, although the exact incidences and treatment outcomes are difficult to discern because population-based cancer registries in the region are still underdeveloped. More research on haematological malignancies in sub-Saharan Africa is required to establish whether these cancers have a natural history similar to those diagnosed in high-income countries, about which more is known. Several factors negatively affect the outcome of haematological malignancies in sub-Saharan Africa, showcasing a need for improved understanding of the clinicobiological profile of these cancers to facilitate prevention, early detection, diagnosis, and appropriate treatment through increased capacity building, infrastructure, community awareness, coordinated resource mobilisation, and collaboration across the world. The east African governments have pooled resources for common investments to tackle non-communicable diseases, developing the East Africa's Centres of Excellence for Skills and Tertiary Education project funded by the African Development Bank, an initiative that could be replicated for the care of haematological malignancies in other countries in sub-Saharan Africa. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.}, }
@article {pmid34480120, year = {2021}, author = {Sharma, A and Huang, S and Li, Y and Brooke, RJ and Ahmed, I and Allewelt, HB and Amrolia, P and Bertaina, A and Bhatt, NS and Bierings, MB and Bies, J and Brisset, C and Brondon, JE and Dahlberg, A and Dalle, JH and Eissa, H and Fahd, M and Gassas, A and Gloude, NJ and Goebel, WS and Goeckerman, ES and Harris, K and Ho, R and Hudspeth, MP and Huo, JS and Jacobsohn, D and Kasow, KA and Katsanis, E and Kaviany, S and Keating, AK and Kernan, NA and Ktena, YP and Lauhan, CR and López-Hernandez, G and Martin, PL and Myers, KC and Naik, S and Olaya-Vargas, A and Onishi, T and Radhi, M and Ramachandran, S and Ramos, K and Rangarajan, HG and Roehrs, PA and Sampson, ME and Shaw, PJ and Skiles, JL and Somers, K and Symons, HJ and de Tersant, M and Uber, AN and Versluys, B and Cheng, C and Triplett, BM}, title = {Outcomes of pediatric patients with therapy-related myeloid neoplasms.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {34480120}, issn = {1476-5365}, abstract = {Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.}, }
@article {pmid34479754, year = {2021}, author = {Etzioni, R and Haffner, MC and Gulati, R}, title = {Divining Harm-Benefit Tradeoffs of Magnetic Resonance Imaging-targeted Biopsy.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2021.08.009}, pmid = {34479754}, issn = {1873-7560}, }
@article {pmid34478634, year = {2021}, author = {Browning, BL and Tian, X and Zhou, Y and Browning, SR}, title = {Fast two-stage phasing of large-scale sequence data.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2021.08.005}, pmid = {34478634}, issn = {1537-6605}, abstract = {Haplotype phasing is the estimation of haplotypes from genotype data. We present a fast, accurate, and memory-efficient haplotype phasing method that scales to large-scale SNP array and sequence data. The method uses marker windowing and composite reference haplotypes to reduce memory usage and computation time. It incorporates a progressive phasing algorithm that identifies confidently phased heterozygotes in each iteration and fixes the phase of these heterozygotes in subsequent iterations. For data with many low-frequency variants, such as whole-genome sequence data, the method employs a two-stage phasing algorithm that phases high-frequency markers via progressive phasing in the first stage and phases low-frequency markers via genotype imputation in the second stage. This haplotype phasing method is implemented in the open-source Beagle 5.2 software package. We compare Beagle 5.2 and SHAPEIT 4.2.1 by using expanding subsets of 485,301 UK Biobank samples and 38,387 TOPMed samples. Both methods have very similar accuracy and computation time for UK Biobank SNP array data. However, for TOPMed sequence data, Beagle is more than 20 times faster than SHAPEIT, achieves similar accuracy, and scales to larger sample sizes.}, }
@article {pmid34477824, year = {2021}, author = {Westerterp, KR and Yamada, Y and Sagayama, H and Ainslie, PN and Andersen, LF and Anderson, LJ and Arab, L and Baddou, I and Bedu-Addo, K and Blaak, EE and Blanc, S and Bonomi, AG and Bouten, CVC and Bovet, P and Buchowski, MS and Butte, NF and Camps, SGJA and Close, GL and Cooper, JA and Das, SK and Cooper, R and Dugas, LR and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Goris, AH and Gurven, M and Hambly, C and El Hamdouchi, A and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kempen, KP and Kimura, M and Kraus, WE and Kushner, RF and Lambert, EV and Leonard, WR and Lessan, N and Martin, CK and Medin, AC and Meijer, EP and Morehen, JC and Morton, JP and Neuhouser, ML and Nicklas, TA and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Rabinovich, RA and Racette, SB and Raichlen, DA and Ravussin, E and Reynolds, RM and Roberts, SB and Schuit, AJ and Sjödin, AM and Stice, E and Urlacher, SS and Valenti, G and Van Etten, LM and Van Mil, EA and Wells, JCK and Wilson, G and Wood, BM and Yanovski, J and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Schoeller, DA and Wong, WW and Speakman, JR and , }, title = {Physical activity and fat-free mass during growth and in later life.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqab260}, pmid = {34477824}, issn = {1938-3207}, support = {BCS-1824466//National Science Foundation/ ; }, abstract = {BACKGROUND: Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass.<br><br>OBJECTIVES: A study is presented of the association between FFM and physical activity in relation to age.<br><br>METHODS: In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3-96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution.<br><br>RESULTS: PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males < 18 y old, and 32% and 47% of the variation in FFM in females and males ≥ 18 y old, respectively. In participants < 18 y old, mean FM-adjusted FFM was 1.7 kg (95% CI: 0.1, 3.2 kg) and 3.4 kg (95% CI: 1.0, 5.6 kg) higher in a very active participant with PAL = 2.0 than in a sedentary participant with PAL = 1.5, for females and males, respectively. At age 18 y, height and FM-adjusted FFM was 3.6 kg (95% CI: 2.8, 4.4 kg) and 4.4 kg (95% CI: 3.2, 5.7 kg) higher, and at age 80 y 0.7 kg (95% CI: -0.2, 1.7 kg) and 1.0 kg (95% CI: -0.1, 2.1 kg) higher, in a participant with PAL = 2.0 than in a participant with PAL = 1.5, for females and males, respectively.<br><br>CONCLUSIONS: If these associations are causal, they suggest physical activity is a major determinant of body composition as reflected in peak FFM, and that a physically active lifestyle can only partly protect against loss of FFM in aging adults.}, }
@article {pmid34474689, year = {2021}, author = {Ling, W and Zhao, N and Plantinga, AM and Launer, LJ and Fodor, AA and Meyer, KA and Wu, MC}, title = {Powerful and robust non-parametric association testing for microbiome data via a zero-inflated quantile approach (ZINQ).}, journal = {Microbiome}, volume = {9}, number = {1}, pages = {181}, pmid = {34474689}, issn = {2049-2618}, support = {R01-GM129512/NH/NIH HHS/United States ; HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I, HHSN268201800007I/HL/NHLBI NIH HHS/United States ; K01-HL127159/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Identification of bacterial taxa associated with diseases, exposures, and other variables of interest offers a more comprehensive understanding of the role of microbes in many conditions. However, despite considerable research in statistical methods for association testing with microbiome data, approaches that are generally applicable remain elusive. Classical tests often do not accommodate the realities of microbiome data, leading to power loss. Approaches tailored for microbiome data depend highly upon the normalization strategies used to handle differential read depth and other data characteristics, and they often have unacceptably high false positive rates, generally due to unsatisfied distributional assumptions. On the other hand, many non-parametric tests suffer from loss of power and may also present difficulties in adjusting for potential covariates. Most extant approaches also fail in the presence of heterogeneous effects. The field needs new non-parametric approaches that are tailored to microbiome data, robust to distributional assumptions, and powerful under heterogeneous effects, while permitting adjustment for covariates.<br><br>METHODS: As an alternative to existing approaches, we propose a zero-inflated quantile approach (ZINQ), which uses a two-part quantile regression model to accommodate the zero inflation in microbiome data. For a given taxon, ZINQ consists of a valid test in logistic regression to model the zero counts, followed by a series of quantile rank-score based tests on multiple quantiles of the non-zero part with adjustment for the zero inflation. As a regression and quantile-based approach, the method is non-parametric and robust to irregular distributions, while providing an allowance for covariate adjustment. Since no distributional assumptions are made, ZINQ can be applied to data that has been processed under any normalization strategy.<br><br>RESULTS: Thorough simulations based on real data across a range of scenarios and application to real data sets show that ZINQ often has equivalent or higher power compared to existing tests even as it offers better control of false positives.<br><br>CONCLUSIONS: We present ZINQ, a quantile-based association test between microbiota and dichotomous or quantitative clinical variables, providing a powerful and robust alternative for the current microbiome differential abundance analysis. Video Abstract.}, }
@article {pmid34474474, year = {2021}, author = {Crombie, JL and Nastoupil, LJ and Redd, RA and Tang, K and Shouse, G and Herrera, AF and Chow, VA and Shadman, M and Castaneda Puglianini, O and Saucier, A and Jacobson, CA and Armand, P and Simmons, G}, title = {Real-world outcomes of axicabtagene ciloleucel in adult patients with primary mediastinal B-cell lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2021004880}, pmid = {34474474}, issn = {2473-9537}, }
@article {pmid34473717, year = {2021}, author = {Hendelman, T and Chaudhary, A and LeClair, AC and van Leuven, K and Chee, J and Fink, SL and Welch, EJ and Berthier, E and Quist, BA and Wald, A and Wener, MH and Hoofnagle, AN and Morishima, C}, title = {Self-collection of capillary blood using Tasso-SST devices for Anti-SARS-CoV-2 IgG antibody testing.}, journal = {PloS one}, volume = {16}, number = {9}, pages = {e0255841}, doi = {10.1371/journal.pone.0255841}, pmid = {34473717}, issn = {1932-6203}, abstract = {BACKGROUND: Efforts to minimize COVID-19 exposure during the current SARS-CoV-2 pandemic have led to limitations in access to medical care and testing. The Tasso-SST kit includes all of the components necessary for remote, capillary blood self-collection. In this study, we sought to investigate the accuracy and reliability of the Tasso-SST device as a self-collection device for measurement of SARS-CoV-2 IgG antibodies.<br><br>METHODS: Capillary blood was obtained via unsupervised and supervised application of the Tasso-SST device, and venous blood was collected by standard venipuncture. Unsupervised self-collected blood samples underwent either extreme summer or winter-simulated shipping conditions prior to testing. Sera obtained by all three methods were tested concurrently using the EuroImmun anti-SARS-CoV-2 S1 IgG assay in a CLIA-certified clinical laboratory.<br><br>RESULTS: Successful Tasso-SST capillary blood collection by unsupervised and supervised administration was completed by 93.4% and 94.5% of participants, respectively. Sera from 56 participants, 55 with documented (PCR+) COVID-19, and 33 healthy controls were then tested for anti-SARS-CoV-2 IgG antibodies. Compared to venous blood results, Tasso-SST-collected (unstressed) and the summer- and winter-stressed blood samples demonstrated Deming regression slopes of 1.00 (95% CI: 0.99-1.02), 1.00 (95% CI: 0.98-1.01), and 0.99 (95% CI: 0.97-1.01), respectively, with an overall accuracy of 98.9%.<br><br>CONCLUSIONS: Capillary blood self-collection using the Tasso-SST device had a high success rate. Moreover, excellent concordance was found for anti-SARS-CoV-2 IgG results between Tasso-SST capillary and standard venous blood-derived sera. The Tasso-SST device should enable widespread collection of capillary blood for testing without medical supervision, facilitating epidemiologic studies.}, }
@article {pmid34473702, year = {2021}, author = {Foss, EJ and Sripathy, S and Gatbonton-Schwager, T and Kwak, H and Thiesen, AH and Lao, U and Bedalov, A}, title = {Chromosomal Mcm2-7 distribution and the genome replication program in species from yeast to humans.}, journal = {PLoS genetics}, volume = {17}, number = {9}, pages = {e1009714}, doi = {10.1371/journal.pgen.1009714}, pmid = {34473702}, issn = {1553-7404}, abstract = {The spatio-temporal program of genome replication across eukaryotes is thought to be driven both by the uneven loading of pre-replication complexes (pre-RCs) across the genome at the onset of S-phase, and by differences in the timing of activation of these complexes during S phase. To determine the degree to which distribution of pre-RC loading alone could account for chromosomal replication patterns, we mapped the binding sites of the Mcm2-7 helicase complex (MCM) in budding yeast, fission yeast, mouse and humans. We observed similar individual MCM double-hexamer (DH) footprints across the species, but notable differences in their distribution: Footprints in budding yeast were more sharply focused compared to the other three organisms, consistent with the relative sequence specificity of replication origins in S. cerevisiae. Nonetheless, with some clear exceptions, most notably the inactive X-chromosome, much of the fluctuation in replication timing along the chromosomes in all four organisms reflected uneven chromosomal distribution of pre-replication complexes.}, }
@article {pmid34473700, year = {2021}, author = {Pickles, M and Cori, A and Probert, WJM and Sauter, R and Hinch, R and Fidler, S and Ayles, H and Bock, P and Donnell, D and Wilson, E and Piwowar-Manning, E and Floyd, S and Hayes, RJ and Fraser, C and , }, title = {PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial.}, journal = {PLoS computational biology}, volume = {17}, number = {9}, pages = {e1009301}, doi = {10.1371/journal.pcbi.1009301}, pmid = {34473700}, issn = {1553-7358}, abstract = {Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention.}, }
@article {pmid34473400, year = {2021}, author = {Beyrer, C and Malone, J and Baral, S and Wang, Z and Rio, CD and Mayer, KH and Batey, DS and Farley, J and Gamble, T and Stanton, J and Hughes, JP and Wilson, E and Irvin, R and Guevara-Perez, O and Bocek, A and Bruce, J and Gaston, R and Cummings, V and Remien, RH and , }, title = {Comparing recruitment strategies to engage hard-to-reach men who have sex with men living with HIV with unsuppressed viral loads in four US cities: Results from HPTN 078.}, journal = {Journal of the International AIDS Society}, volume = {24}, number = {9}, pages = {e25798}, doi = {10.1002/jia2.25798}, pmid = {34473400}, issn = {1758-2652}, support = {UM1AI068619//National Institute of Allergy and Infectious Diseases/ ; UM1AI068613//National Institute of Allergy and Infectious Diseases/ ; UM1AI1068617//National Institute of Allergy and Infectious Diseases/ ; UM1 AI 068613/DA/NIDA NIH HHS/United States ; UM1 AI 068617/MH/NIMH NIH HHS/United States ; }, abstract = {INTRODUCTION: There is an urgent need to identify men who have sex with men (MSM) living with HIV with unsuppressed viral loads to prevent transmission. Though respondent-driven sampling (RDS) is traditionally used for hard-to-reach populations, we compare how RDS and direct recruitment (DR) perform in identifying MSM living with HIV with unsuppressed viral loads and identifying MSM with socio-demographics characteristic of hard-to-reach populations.<br><br>METHODS: This is a cross-sectional analysis among 1305 MSM who were recruited from March 2016 to December 2017 for a case management intervention trial (HPTN 078). We recruited participants across four cities using RDS and DR methods: Birmingham, AL; Atlanta, GA; Baltimore, MD; and Boston, MA. Participants completed a socio-demographic questionnaire and underwent HIV testing. We compare the proportion of MSM with HIV and unsuppressed viral loads (HIV RNA ≥ 1000 copies/ml) based on recruitment method using Pearson chi-square tests. We also compare differences in race, income, healthcare coverage, education, sexual orientation, hidden sexuality and comfort with participating in the LGBT community between recruitment methods and perform non-parametric trend tests to see how demographics change across RDS recruitment waves.<br><br>RESULTS: RDS recruited 721 men (55.2%) and DR yielded 584 men (44.8%). Overall, 69% were living with HIV, of whom 18% were not virally suppressed. HIV prevalence was higher among those recruited via DR (84%) compared to RDS (58%), p < 0.0001. Twenty per cent of DR recruits were not virally suppressed compared to 15% of RDS, though this was not significant. DR yielded a significantly higher proportion of Black participants and those with less than a high school diploma. The prevalence of low income, no healthcare coverage, bisexuality and hidden sexuality increased across RDS waves.<br><br>CONCLUSIONS: DR was more efficient in identifying MSM living with HIV with unsuppressed viral loads; however, there was a higher proportion of hard-to-reach MSM who were low income, lacked health coverage, were bisexual and were not open with their sexuality in deeper waves of RDS. Researchers should consider supplementing RDS recruitment with DR efforts if aiming to identify MSM with unsuppressed viral loads via RDS.}, }
@article {pmid34473192, year = {2021}, author = {Desai, A and Mohammed, TJ and Duma, N and Garassino, MC and Hicks, LK and Kuderer, NM and Lyman, GH and Mishra, S and Pinato, DJ and Rini, BI and Peters, S and Warner, JL and Whisenant, JG and Wood, WA and Thompson, MA}, title = {COVID-19 and Cancer: A Review of the Registry-Based Pandemic Response.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2021.4083}, pmid = {34473192}, issn = {2374-2445}, abstract = {Importance: The COVID-19 pandemic has had consequences for patients with cancer worldwide and has been associated with delays in diagnosis, interruption of treatment and follow-up care, and increases in overall infection rates and premature mortality.<br><br>Observations: Despite the challenges experienced during the pandemic, the global oncology community has responded with an unprecedented level of investigation, collaboration, and technological innovation through the rapid development of COVID-19 registries that have allowed an increased understanding of the natural history, risk factors, and outcomes of patients with cancer who are diagnosed with COVID-19. This review describes 14 major registries comprising more than 28 500 patients with cancer and COVID-19; these ongoing registry efforts have provided an improved understanding of the impact and outcomes of COVID-19 among patients with cancer.<br><br>Conclusions and Relevance: An initiative is needed to promote active collaboration between different registries to improve the quality and consistency of information. Well-designed prospective and randomized clinical trials are needed to collect high-level evidence to guide long-term epidemiologic, behavioral, and clinical decision-making for this and future pandemics.}, }
@article {pmid34472213, year = {2021}, author = {Getz, KD and Alonzo, TA and Sung, L and Meshinchi, S and Gerbing, RB and Raimondi, S and Hirsch, B and Loken, M and Brodersen, LE and Kahwash, S and Choi, J and Kolb, EA and Gamis, A and Aplenc, R}, title = {Cytarabine dose reduction in patients with low-risk acute myeloid leukemia: A report from the Children's Oncology Group.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e29313}, doi = {10.1002/pbc.29313}, pmid = {34472213}, issn = {1545-5017}, support = {U10CA180886//NCTN Operations Center/ ; U10CA180899//NCTN Statistics &amp; Data Center/ ; //St. Baldrick's Foundation (funding to the Children's Oncology Group)/ ; //Alex's Lemonade Stand Foundation/ ; 5K01HL143153-03//National Heart Lung and Blood Institute/ ; }, abstract = {BACKGROUND: The optimal number of chemotherapy courses for low-risk (LR) pediatric acute myeloid leukemia (AML) is not known.<br><br>OBJECTIVE: To compare outcomes for four (21.6 g/m2 cytarabine) versus five (45.6 g/m2 cytarabine) chemotherapy courses for LR-AML using data from Children's Oncology Group (COG) AAML0531 and AAML1031.<br><br>METHODS: We compared relapse risk (RR), disease-free survival (DFS), and overall survival (OS), and the differential impact in LR subgroups for patients receiving four versus five chemotherapy courses. Cox (OS and DFS) and risk (RR) regressions were used to estimate hazard ratios (HR) to compare outcomes.<br><br>RESULTS: A total of 923 LR-AML patients were included; 21% received five courses. Overall, LR-AML patients who received four courses had higher RR (40.9% vs. 31.4%; HR = 1.40, 95% confidence interval [CI]: 1.06-1.85), and worse DFS (56.0% vs. 67.0%; HR = 1.45, 95% CI: 1.10-1.91). There was a similar decrement in OS though it was not statistically significant (77.0% vs. 83.5%; HR = 1.45, 95% CI: 0.97-2.17). Stratified analyses revealed the detrimental effects of cytarabine dose de-escalation to be most pronounced in the LR-AML subgroup with uninformative cytogenetic/molecular features who were minimal residual disease (MRD) negative after the first induction course (EOI1). The absolute decrease in DFS with four courses for patients with favorable cytogenetic/molecular features and positive MRD was similar to that observed for patients with uninformative cytogenetic/molecular features and negative MRD at EOI1, though not statistically significant.<br><br>CONCLUSIONS: Our results support de-escalation of cytarabine exposure through the elimination of a fifth chemotherapy course only for LR-AML patients who have both favorable cytogenetic/molecular features and negative MRD after the first induction cycle.}, }
@article {pmid34471230, year = {2021}, author = {McLornan, DP and Hernandez-Boluda, JC and Czerw, T and Cross, N and Joachim Deeg, H and Ditschkowski, M and Moonim, MT and Polverelli, N and Robin, M and Aljurf, M and Conneally, E and Hayden, P and Yakoub-Agha, I}, title = {Correction: Allogeneic haematopoietic cell transplantation for myelofibrosis: proposed definitions and management strategies for graft failure, poor graft function and relapse: best practice recommendations of the EBMT Chronic Malignancies Working Party.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-021-01395-y}, pmid = {34471230}, issn = {1476-5551}, }
@article {pmid34469736, year = {2021}, author = {Parrish, PCR and Thomas, JD and Gabel, AM and Kamlapurkar, S and Bradley, RK and Berger, AH}, title = {Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome.}, journal = {Cell reports}, volume = {36}, number = {9}, pages = {109597}, doi = {10.1016/j.celrep.2021.109597}, pmid = {34469736}, issn = {2211-1247}, abstract = {CRISPR screens have accelerated the discovery of important cancer vulnerabilities. However, single-gene knockout phenotypes can be masked by redundancy among related genes. Paralogs constitute two-thirds of the human protein-coding genome, so existing methods are likely inadequate for assaying a large portion of gene function. Here, we develop paired guide RNAs for paralog genetic interaction mapping (pgPEN), a pooled CRISPR-Cas9 single- and double-knockout approach targeting more than 2,000 human paralogs. We apply pgPEN to two cell types and discover that 12% of human paralogs exhibit synthetic lethality in at least one context. We recover known synthetic lethal paralogs MEK1/MEK2, important drug targets CDK4/CDK6, and other synthetic lethal pairs including CCNL1/CCNL2. Additionally, we identify ten tumor suppressor paralog pairs whose compound loss promotes cell proliferation. These findings nominate drug targets and suggest that paralog genetic interactions could shape the landscape of positive and negative selection in cancer.}, }
@article {pmid34469597, year = {2021}, author = {Cole, SE and John, EM and Hines, LM and Phipps, AI and Koo, J and Ingles, SA and Baumgartner, KB and Slattery, ML and McKean-Cowden, R and Wu, AH}, title = {Cumulative menstrual months and breast cancer risk by hormone receptor status and ethnicity: The Breast Cancer Etiology in Minorities (BEM) Study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33791}, pmid = {34469597}, issn = {1097-0215}, abstract = {Reproductive and hormonal factors may influence breast cancer risk via endogenous estrogen exposure. Cumulative menstrual months (CMM) can be used as a surrogate measure of this exposure. Using harmonized data from four population-based breast cancer studies (7,284 cases and 7,242 controls), we examined ethnicity-specific associations between CMM and breast cancer risk using logistic regression, adjusting for menopausal status and other risk factors. Higher CMM was associated with increased breast cancer risk in non-Hispanic Whites, Hispanics and Asian Americans regardless of menopausal status (all FDR adjusted p trends=0.0004), but not in African Americans. In premenopausal African Americans, there was a suggestive trend of lower risk with higher CMM. Stratification by body mass index (BMI) among premenopausal African American women showed a nonsignificant positive association with CMM in non-obese (BMI <30 kg/m2) women and a significant inverse association in obese women (OR per 50 CMM=0.56, 95% CI 0.37-0.87, Ptrend =0.03). Risk patterns were similar for hormone receptor positive (HR+; ER+ or PR+) breast cancer; a positive association was found in all premenopausal and postmenopausal ethnic groups except in African Americans. HR- (ER- and PR-) breast cancer was not associated with CMM in all groups combined, except for a suggestive positive association among premenopausal Asian Americans (OR per 50 CMM=1.33, P=0.07). In summary, these results add to the accumulating evidence that established reproductive and hormonal factors impact breast cancer risk differently in African American women compared to other ethnic groups, and also differently for HR- breast cancer than HR+ breast cancer. This article is protected by copyright. All rights reserved.}, }
@article {pmid34467648, year = {2021}, author = {Krull, KR and McDonald, A and Goodman, P and Vukadinovich, C and Ford, J and Leisenring, WM and Chow, EJ and Robison, LL and Armstrong, GT}, title = {Impact of COVID-19 pandemic on a large cohort of adult survivors of childhood cancer.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e29324}, doi = {10.1002/pbc.29324}, pmid = {34467648}, issn = {1545-5017}, abstract = {Childhood cancersurvivors may be differentially impacted by coronavirus disease 2019 (COVID-19). From April to June of 2020, we examined psychosocial/health concerns in 4148 adult survivors and 571 siblings. Although more survivors reported concerns about getting sick (p = .002) and needing hospitalization (p = .003) in general, survivors and siblings were comparably concerned about being infected with and the consequences of COVID-19. Cranial radiation was associated with social isolation (relative risk [RR] = 1.3, CI = 1.1-1.7), and central nervous system (CNS) tumors were associated with unemployment due to COVID-19 (RR = 1.7, CI = 1.2-2.2). Some survivors appear more vulnerable and may require more support to meet health care and vocational needs during COVID-19, though siblings also perceive substantial risk.}, }
@article {pmid34465597, year = {2021}, author = {Schroeder, BA and LaFranzo, NA and LaFleur, BJ and Gittelman, RM and Vignali, M and Zhang, S and Flanagan, KC and Rytlewski, J and Riolobos, L and Schulte, BC and Kim, TS and Chen, E and Smythe, KS and Wagner, MJ and Mantilla, JG and Campbell, JS and Pierce, RH and Jones, RL and Cranmer, LD and Pollack, SM}, title = {CD4+ T cell and M2 macrophage infiltration predict dedifferentiated liposarcoma patient outcomes.}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {8}, pages = {}, doi = {10.1136/jitc-2021-002812}, pmid = {34465597}, issn = {2051-1426}, abstract = {BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is one of the most common soft tissue sarcoma subtypes and is devastating in the advanced/metastatic stage. Despite the observation of clinical responses to PD-1 inhibitors, little is known about the immune microenvironment in relation to patient prognosis.<br><br>METHODS: We performed a retrospective study of 61 patients with DDLPS. We completed deep sequencing of the T-cell receptor (TCR) β-chain and RNA sequencing for predictive modeling, evaluating both immune markers and tumor escape genes. Hierarchical clustering and recursive partitioning were employed to elucidate relationships of cellular infiltrates within the tumor microenvironment, while an immune score for single markers was created as a predictive tool.<br><br>RESULTS: Although many DDLPS samples had low TCR clonality, high TCR clonality combined with low T-cell fraction predicted lower 3-year overall survival (p=0.05). Higher levels of CD14+ monocytes (p=0.02) inversely correlated with 3-year recurrence-free survival (RFS), while CD4+ T-cell infiltration (p=0.05) was associated with a higher RFS. Genes associated with longer RFS included PD-1 (p=0.003), ICOS (p=0.006), BTLA (p=0.033), and CTLA4 (p=0.02). In a composite immune score, CD4+ T cells had the strongest positive predictive value, while CD14+ monocytes and M2 macrophages had the strongest negative predictive values.<br><br>CONCLUSIONS: Immune cell infiltration predicts clinical outcome in DDLPS, with CD4+ cells associated with better outcomes; CD14+ cells and M2 macrophages are associated with worse outcomes. Future checkpoint inhibitor studies in DDLPS should incorporate immunosequencing and gene expression profiling techniques that can generate immune landscape profiles.}, }
@article {pmid34462503, year = {2021}, author = {Eichholz, K and Li, AZ and Diem, K and Jensen, MC and Zhu, J and Corey, L}, title = {Author Correction: A CAR RNA FISH assay to study functional and spatial heterogeneity of chimeric antigen receptor T cells in tissue.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {17650}, doi = {10.1038/s41598-021-96979-0}, pmid = {34462503}, issn = {2045-2322}, }
@article {pmid34460935, year = {2021}, author = {Seaman, AT and Seligman, KL and Nguyen, KK and Al-Qurayshi, Z and Kendell, ND and Pagedar, NA}, title = {Characterizing head and neck cancer survivors' discontinuation of survivorship care.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33888}, pmid = {34460935}, issn = {1097-0142}, support = {P30CA086862/CA/NCI NIH HHS/United States ; KL2TR002536/TR/NCATS NIH HHS/United States ; UL1TR002537/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: Little is known about cancer survivors who discontinue survivorship care. The objective of this study was to characterize patients with head and neck cancer who discontinue survivorship care with their treating institution and identify factors associated with discontinuation.<br><br>METHODS: This was a retrospective cohort study of patients diagnosed with head and neck cancer between January 1, 2014, and December 31, 2016, who received cancer-directed therapy at the University of Iowa Hospitals and Clinics (UIHC). Eligible patients achieved a cancer-free status after curative-intent treatment and made at least 1 visit 90+ days after treatment completion. The primary outcome was discontinuation of survivorship care, which was defined as a still living survivor who had not returned to a UIHC cancer clinic for twice the expected interval. Demographic and oncologic factors were examined to identify associations with discontinuation.<br><br>RESULTS: Ninety-seven of the 426 eligible patients (22.8%) discontinued survivorship care at UIHC during the study period. The mean time in follow-up for those who discontinued treatment was 15.4 months. Factors associated with discontinuation of care included an unmarried status (P = .036), a longer driving distance to the facility (P = .0031), and a single-modality cancer treatment (P < .0001). Rurality was not associated with discontinuation (24.3% vs 21.6% for urban residence; P = .52), nor was age, gender, or payor status.<br><br>CONCLUSIONS: The study results indicate that a sizeable percentage of head and neck cancer survivors discontinue care with their treating institution. Both demographic and oncologic factors were associated with discontinuation at the treating institution, and this points to potential clinical and care delivery interventions.}, }
@article {pmid34459214, year = {2021}, author = {Lopes, RD and Higano, CS and Slovin, SF and Nelson, AJ and Bigelow, R and Sørensen, PS and Melloni, C and Goodman, SG and Evans, CP and Nilsson, J and Bhatt, DL and Clarke, NW and Olesen, TK and Doyle-Olsen, BT and Kristensen, H and Arney, L and Roe, MT and Alexander, JH}, title = {Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial.}, journal = {Circulation}, volume = {}, number = {}, pages = {}, doi = {10.1161/CIRCULATIONAHA.121.056810}, pmid = {34459214}, issn = {1524-4539}, abstract = {Background: The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. Methods: In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Results: Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). Conclusions: PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02663908.}, }
@article {pmid34458390, year = {2021}, author = {Lancaster, KE and Mollan, KR and Hanscom, BS and Shook-Sa, BE and Ha, TV and Dumchev, K and Djoerban, Z and Rose, SM and Latkin, CA and Metzger, DS and Go, VF and Dvoriak, S and Reifeis, SA and Piwowar-Manning, EM and Richardson, P and Hudgens, MG and Hamilton, EL and Eshleman, SH and Susami, H and Chu, VA and Djauzi, S and Kiriazova, T and Nhan, DT and Burns, DN and Miller, WC and Hoffman, IF}, title = {Engaging People Who Inject Drugs Living With HIV in Antiretroviral Treatment and Medication for Opioid Use Disorder: Extended Follow-up of HIV Prevention Trials Network (HPTN) 074.}, journal = {Open forum infectious diseases}, volume = {8}, number = {8}, pages = {ofab281}, doi = {10.1093/ofid/ofab281}, pmid = {34458390}, issn = {2328-8957}, abstract = {Background: People who inject drugs (PWID) living with HIV experience inadequate access to antiretroviral treatment (ART) and medication for opioid use disorders (MOUD). HPTN 074 showed that an integrated intervention increased ART use and viral suppression over 52 weeks. To examine durability of ART, MOUD, and HIV viral suppression, participants could re-enroll for an extended follow-up period, during which standard-of-care (SOC) participants in need of support were offered the intervention.<br><br>Methods: Participants were recruited from Ukraine, Indonesia and Vietnam and randomly allocated 3:1 to SOC or intervention. Eligibility criteria included: HIV-positive; active injection drug use; 18-60 years of age; ≥1 HIV-uninfected injection partner; and viral load ≥1,000 copies/mL. Re-enrollment was offered to all available intervention and SOC arm participants, and SOC participants in need of support (off-ART or off-MOUD) were offered the intervention.<br><br>Results: The intervention continuation group re-enrolled 89 participants, and from week 52 to 104, viral suppression (<40 copies/mL) declined from 41% to 29% (estimated 9.4% decrease per year, 95% CI -17.0%; -1.8%). The in need of support group re-enrolled 94 participants and had increased ART (re-enrollment: 55%, week 26: 69%) and MOUD (re-enrollment: 16%, week 26: 25%) use, and viral suppression (re-enrollment: 40%, week 26: 49%).<br><br>Conclusions: Viral suppression declined in year 2 for those who initially received the HPTN 074 intervention and improved maintenance support is warranted. Viral suppression and MOUD increased among in need participants who received intervention during the study extension. Continued efforts are needed for widespread implementation of this scalable, integrated intervention.}, }
@article {pmid34458255, year = {2021}, author = {Ray, S and Singhvi, A}, title = {Charging Up the Periphery: Glial Ionic Regulation in Sensory Perception.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {687732}, doi = {10.3389/fcell.2021.687732}, pmid = {34458255}, issn = {2296-634X}, abstract = {The peripheral nervous system (PNS) receives diverse sensory stimuli from the environment and transmits this information to the central nervous system (CNS) for subsequent processing. Thus, proper functions of cells in peripheral sense organs are a critical gate-keeper to generating appropriate animal sensory behaviors, and indeed their dysfunction tracks sensory deficits, sensorineural disorders, and aging. Like the CNS, the PNS comprises two major cell types, neurons (or sensory cells) and glia (or glia-like supporting neuroepithelial cells). One classic function of PNS glia is to modulate the ionic concentration around associated sensory cells. Here, we review current knowledge of how non-myelinating support cell glia of the PNS regulate the ionic milieu around sensory cell endings across species and systems. Molecular studies reviewed here suggest that, rather than being a passive homeostatic response, glial ionic regulation may in fact actively modulate sensory perception, implying that PNS glia may be active contributors to sensorineural information processing. This is reminiscent of emerging studies suggesting analogous roles for CNS glia in modulating neural circuit processing. We therefore suggest that deeper molecular mechanistic investigations into critical PNS glial functions like ionic regulation are essential to comprehensively understand sensorineural health, disease, and aging.}, }
@article {pmid34456224, year = {2021}, author = {Sharma, A and Bhatt, NS and Hijano, DR}, title = {Clinical experience of coronavirus disease 2019 in hematopoietic cell transplant and chimeric antigen receptor T-cell recipients.}, journal = {Current opinion in hematology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MOH.0000000000000683}, pmid = {34456224}, issn = {1531-7048}, abstract = {PURPOSE OF REVIEW: To discuss the clinical experience of coronavirus disease 2019 (COVID-19) in hematopoietic cell transplant and chimeric antigen receptor T-cell therapy recipients over the past year and to identify key knowledge gaps for future research.<br><br>RECENT FINDINGS: Immunocompromised individuals and those with chronic health conditions are especially susceptible to infections, which have had a disproportionate impact on health outcomes during the COVID-19 pandemic. Several studies have evaluated the clinical characteristics and outcomes of transplant and cellular therapy (TCT) recipients who developed COVID-19. Age, sex, comorbid conditions, and social determinants of health are important predictors of the risk of severe acute respiratory syndrome coronavirus 2 infection and of the eventual severity of the disease. Various treatment approaches have been investigated over the last year. The paradigm of management strategies continues to evolve as more experience is accumulated.<br><br>SUMMARY: In this review, we summarize some important findings as they relate to the clinical characteristics of TCT recipients who develop COVID-19. We also discuss some treatment approaches that are currently recommended and opine on vaccination in this population.}, }
@article {pmid34455067, year = {2021}, author = {Planchard, D and Besse, B and Groen, HJM and Hashemi, SMS and Mazieres, J and Kim, TM and Quoix, E and Souquet, PJ and Barlesi, F and Baik, C and Villaruz, LC and Kelly, RJ and Zhang, S and Tan, M and Gasal, E and Santarpia, L and Johnson, BE}, title = {Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic non-small cell lung cancer: Updated 5-year survival rates and genomic analysis.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtho.2021.08.011}, pmid = {34455067}, issn = {1556-1380}, abstract = {INTRODUCTION: Dabrafenib plus trametinib demonstrated robust antitumour activity in patients with BRAF V600E-mutant metastatic non-small cell lung cancer (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.<br><br>METHODS: Pretreated (cohort B) and treatment-naïve (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumours version 1.1. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety.<br><br>RESULTS: At data cut-off, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range, 0.5-78.5) and 16.3 (range, 0.4-80) months, ORR (95% CI) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median PFS (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median OS (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naïve patients, respectively. Seventeen (18%) patients were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.<br><br>CONCLUSIONS: Dabrafenib plus trametinib therapy demonstrated substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of prior treatment.}, }
@article {pmid34454975, year = {2021}, author = {Shrestha, S and Bates, JE and Liu, Q and Smith, SA and Oeffinger, KC and Chow, EJ and Gupta, AC and Owens, CA and Constine, LS and Hoppe, BS and Leisenring, WM and Qiao, Y and Weathers, RE and Court, LE and Pinnix, CC and Kry, SF and Mulrooney, DA and Armstrong, GT and Yasui, Y and Howell, RM}, title = {Radiation therapy related cardiac disease risk in childhood cancer survivors: Updated dosimetry analysis from the childhood cancer survivor study.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.radonc.2021.08.012}, pmid = {34454975}, issn = {1879-0887}, abstract = {BACKGROUND AND PURPOSE: We previously evaluated late cardiac disease in long-term survivors in the Childhood Cancer Survivor Study (CCSS) based on heart radiation therapy (RT) doses estimated from an age-scaled phantom with a simple atlas-based heart model (HAtlas). We enhanced our phantom with a high-resolution CT-based anatomically realistic and validated age-scalable cardiac model (HHybrid). We aimed to evaluate how this update would impact our prior estimates of RT-related late cardiac disease risk in the CCSS cohort.<br><br>METHODS: We evaluated 24,214 survivors from the CCSS diagnosed from 1970 to 1999. RT fields were reconstructed on an age-scaled phantom with HHybrid and mean heart dose (Dm), percent volume receiving ≥ 20 Gy (V20) and ≥ 5 Gy with V20=0 ([Formula: see text]) were calculated. We reevaluated cumulative incidences and adjusted relative rates of grade 3-5 Common Terminology Criteria for Adverse Events outcomes for any cardiac disease, coronary artery disease (CAD), and heart failure (HF) in association with Dm, V20, and [Formula: see text] (as categorical variables). Dose-response relationships were evaluated using piecewise-exponential models, adjusting for attained age, sex, cancer diagnosis age, race/ethnicity, time-dependent smoking history, diagnosis year, and chemotherapy exposure and doses. For relative rates, Dm was also considered as a continuous variable.<br><br>RESULTS: Consistent with previous findings with HAtlas, reevaluation using HHybrid dosimetry found that, Dm ≥ 10Gy, V20 ≥ 0.1%, and [Formula: see text] ≥ 50% were all associated with increased cumulative incidences and relative rates for any cardiac disease, CAD, and HF. While updated risk estimates were consistent with previous estimates overall without statistically significant changes, there were some important and significant (P< 0.05) increases in risk with updated dosimetry for Dm in the category of 20 to 29.9 Gy and V20 in the category of 30% to 79.9%. When changes in the linear dose-response relationship for Dm were assessed, the slopes of the dose response were steeper (P<0.001) with updated dosimetry. Changes were primarily observed among individuals with chest-directed RT with prescribed doses ≥ 20 Gy.<br><br>CONCLUSION: These findings present a methodological advancement in heart RT dosimetry with improved estimates of RT-related late cardiac disease risk. While results are broadly consistent with our prior study, we report that, with updated cardiac dosimetry, risks of cardiac disease are significantly higher in two dose and volume categories and slopes of the Dm-specific RT-response relationships are steeper. These data support the use of contemporary RT to achieve lower heart doses for pediatric patients, particularly those requiring chest-directed RT.}, }
@article {pmid34453886, year = {2021}, author = {Careau, V and Halsey, LG and Pontzer, H and Ainslie, PN and Andersen, LF and Anderson, LJ and Arab, L and Baddou, I and Bedu-Addo, K and Blaak, EE and Blanc, S and Bonomi, AG and Bouten, CVC and Buchowski, MS and Butte, NF and Camps, SGJA and Close, GL and Cooper, JA and Das, SK and Cooper, R and Dugas, LR and Eaton, SD and Ekelund, U and Entringer, S and Forrester, T and Fudge, BW and Goris, AH and Gurven, M and Hambly, C and El Hamdouchi, A and Hoos, MB and Hu, S and Joonas, N and Joosen, AM and Katzmarzyk, P and Kempen, KP and Kimura, M and Kraus, WE and Kushner, RF and Lambert, EV and Leonard, WR and Lessan, N and Martin, CK and Medin, AC and Meijer, EP and Morehen, JC and Morton, JP and Neuhouser, ML and Nicklas, TA and Ojiambo, RM and Pietiläinen, KH and Pitsiladis, YP and Plange-Rhule, J and Plasqui, G and Prentice, RL and Rabinovich, RA and Racette, SB and Raichlen, DA and Ravussin, E and Reilly, JJ and Reynolds, RM and Roberts, SB and Schuit, AJ and Sjödin, AM and Stice, E and Urlacher, SS and Valenti, G and Van Etten, LM and Van Mil, EA and Wells, JCK and Wilson, G and Wood, BM and Yanovski, J and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Loechl, CU and Luke, AH and Rood, J and Sagayama, H and Schoeller, DA and Wong, WW and Yamada, Y and Speakman, JR and , }, title = {Energy compensation and adiposity in humans.}, journal = {Current biology : CB}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cub.2021.08.016}, pmid = {34453886}, issn = {1879-0445}, abstract = {Understanding the impacts of activity on energy balance is crucial. Increasing levels of activity may bring diminishing returns in energy expenditure because of compensatory responses in non-activity energy expenditures.1-3 This suggestion has profound implications for both the evolution of metabolism and human health. It implies that a long-term increase in activity does not directly translate into an increase in total energy expenditure (TEE) because other components of TEE may decrease in response-energy compensation. We used the largest dataset compiled on adult TEE and basal energy expenditure (BEE) (n = 1,754) of people living normal lives to find that energy compensation by a typical human averages 28% due to reduced BEE; this suggests that only 72% of the extra calories we burn from additional activity translates into extra calories burned that day. Moreover, the degree of energy compensation varied considerably between people of different body compositions. This association between compensation and adiposity could be due to among-individual differences in compensation: people who compensate more may be more likely to accumulate body fat. Alternatively, the process might occur within individuals: as we get fatter, our body might compensate more strongly for the calories burned during activity, making losing fat progressively more difficult. Determining the causality of the relationship between energy compensation and adiposity will be key to improving public health strategies regarding obesity.}, }
@article {pmid34453768, year = {2021}, author = {Lindsay, J and Othman, J and Yong, MK and Ritchie, D and Chee, L and Tay, K and Tio, SY and Kerridge, I and Fay, K and Stevenson, W and Arthur, C and Chen, SC and Kong, DC and Greenwood, M and Pergam, SA and Liu, C and Slavin, MA}, title = {Dynamics of Epstein Barr virus on post-transplant lymphoproliferative disorders after anti-thymocyte globulin-conditioned allogeneic hematopoietic cell transplant.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/tid.13719}, pmid = {34453768}, issn = {1399-3062}, abstract = {BACKGROUND: The use of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplant (HCT) is associated with an increased risk of Epstein Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD). The dynamics and outcomes of EBV-DNAemia are not well described in this population.<br><br>METHODS: We retrospectively assessed the kinetics of EBV-DNAemia after ATG conditioned HCT recipients. Receiver operating characteristic (ROC) curves were used to assess EBV-DNAemia to predict EBV-PTLD in this group.<br><br>RESULTS: A total of 174/405 (43%) consecutive HCT recipients from 2 centers met inclusion criteria of ATG conditioned, non-B cell lymphoma patients. Of these with EBV-DNA measured using standardized IU/mL, 78.6% (92/117) developed EBV-DNAemia: 62% spontaneously resolved; 19% cleared after pre-emptive rituximab and 13% developed EBV-PTLD. ROC curve analysis using maximum pre-EBV-PTLD, EBV-DNAemia demonstrated an AUC of 0.912 with EBV-DNAemia of 9782 IU/mL, associated with 82.6% sensitivity and 94.4% specificity for development of EBV-PTLD. Median time for EBV-DNAemia to increase from initial detection to >1000 IU/mL was 7 days; to >10,000 IU/mL, 12 days; and to >100,000 IU/mL, 18 days. Median EBV-DNAemia level prior to administration of rituximab was significantly lower in patients with successful pre-emptive treatment, compared with those who developed EBV-PTLD (3.41 log10 IU/mL [3.30 - 3.67] vs. 4.34 log10 IU/mL [3.85 - 5.13], p = 0.002; i.e., 2628 IU/mL vs. 21,965 IU/mL, respectively).<br><br>CONCLUSIONS: EBV-DNAemia >10,000 IU/mL was the strongest predictor of the development of EBV-PTLD and progression to this level was rapid in ATG conditioned HCT recipients. This information may guide EBV-PTLD management strategies in these high-risk patients. This article is protected by copyright. All rights reserved.}, }
@article {pmid34452927, year = {2021}, author = {Pachynski, RK and Morishima, C and Szmulewitz, R and Harshman, L and Appleman, L and Monk, P and Bitting, RL and Kucuk, O and Millard, F and Seigne, JD and Fling, SP and Maecker, HT and Duault, C and Ramchurren, N and Hess, B and D'Amico, L and Lacroix, A and Kaiser, JC and Morre, M and Grégoire, A and Cheever, M and Yu, EY and Fong, L}, title = {IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC).}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {8}, pages = {}, doi = {10.1136/jitc-2021-002903}, pmid = {34452927}, issn = {2051-1426}, abstract = {BACKGROUND: Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP).<br><br>METHODS: Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γ ELISpot, 3H-thymidine incorporation, and ELISA.<br><br>RESULTS: Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γ ELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γ expression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group.<br><br>CONCLUSIONS: Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.}, }
@article {pmid34452722, year = {2021}, author = {Munshi, PN and Hamadani, M and Kumar, A and Dreger, P and Friedberg, JW and Dreyling, M and Kahl, B and Jerkeman, M and Kharfan-Dabaja, MA and Locke, FL and Shadman, M and Hill, BT and Ahmed, S and Herrera, AF and Sauter, CS and Bachanova, V and Ghosh, N and Lunning, M and Kenkre, VP and Aljurf, M and Wang, M and Maddocks, KJ and Leonard, JP and Kamdar, M and Phillips, T and Cashen, AF and Inwards, DJ and Sureda, A and Cohen, JB and Smith, SM and Carlo-Stella, C and Savani, B and Robinson, SP and Fenske, TS}, title = {American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma.}, journal = {Transplantation and cellular therapy}, volume = {27}, number = {9}, pages = {720-728}, doi = {10.1016/j.jtct.2021.03.001}, pmid = {34452722}, issn = {2666-6367}, abstract = {Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton's tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.}, }
@article {pmid34452721, year = {2021}, author = {Hakki, M and Aitken, SL and Danziger-Isakov, L and Michaels, MG and Carpenter, PA and Chemaly, RF and Papanicolaou, GA and Boeckh, M and Marty, FM}, title = {American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {27}, number = {9}, pages = {707-719}, doi = {10.1016/j.jtct.2021.05.001}, pmid = {34452721}, issn = {2666-6367}, abstract = {The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Disease Special Interest Group to update its 2009 compendium-style infectious diseases guidelines for the care of hematopoietic cell transplant (HCT) recipients. A new approach was taken with the goal of better serving clinical providers by publishing each standalone topic in the infectious disease series as a concise format of frequently asked questions (FAQ), tables, and figures. Adult and pediatric infectious disease and HCT content experts developed and answered FAQs. Topics were finalized with harmonized recommendations that were made by assigning an A through E strength of recommendation paired with a level of supporting evidence graded I through III. The third topic in the series focuses on the prevention of cytomegalovirus infection and disease in HCT recipients by reviewing prophylaxis and preemptive therapy approaches; key definitions, relevant risk factors, and diagnostic monitoring considerations are also reviewed.}, }
@article {pmid34452474, year = {2021}, author = {O'Connor, MA and Munson, PV and Dross, SE and Tunggal, HC and Lewis, TB and Osborn, J and Peterson, CW and Huang, MW and Moats, C and Smedley, J and Jerome, KR and Kiem, HP and Bagley, KC and Mullins, JI and Fuller, DH}, title = {A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART.}, journal = {Viruses}, volume = {13}, number = {8}, pages = {}, doi = {10.3390/v13081609}, pmid = {34452474}, issn = {1999-4915}, support = {RO1 AI104679/NH/NIH HHS/United States ; UM1 AI126623/NH/NIH HHS/United States ; R44 AI110315/NH/NIH HHS/United States ; T32-AI007140/NH/NIH HHS/United States ; }, abstract = {Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies.}, }
@article {pmid34452338, year = {2021}, author = {Gornalusse, GG and Vojtech, LN and Levy, CN and Hughes, SM and Kim, Y and Valdez, R and Pandey, U and Ochsenbauer, C and Astronomo, R and McElrath, J and Hladik, F}, title = {Buprenorphine Increases HIV-1 Infection In Vitro but Does Not Reactivate HIV-1 from Latency.}, journal = {Viruses}, volume = {13}, number = {8}, pages = {}, doi = {10.3390/v13081472}, pmid = {34452338}, issn = {1999-4915}, support = {R01 DA040386/DA/NIDA NIH HHS/United States ; R01 AI116292/AI/NIAID NIH HHS/United States ; 1032144//Bill &amp; Melinda Gates Foundation's Collaboration for AIDS Vaccine Discovery/ Comprehensive Antibody Vaccine Immune Monitoring Consortium (CAVIMC)/ ; UM1AI068618/NH/NIH HHS/United States ; OPP1099507//Bill and Melinda Gates Foundation/ ; }, abstract = {BACKGROUND: medication-assisted treatment (MAT) with buprenorphine is now widely prescribed to treat addiction to heroin and other illicit opioids. There is some evidence that illicit opioids enhance HIV-1 replication and accelerate AIDS pathogenesis, but the effect of buprenorphine is unknown.<br><br>METHODS: we obtained peripheral blood mononuclear cells (PBMCs) from healthy volunteers and cultured them in the presence of morphine, buprenorphine, or methadone. We infected the cells with a replication-competent CCR5-tropic HIV-1 reporter virus encoding a secreted nanoluciferase gene, and measured infection by luciferase activity in the supernatants over time. We also surveyed opioid receptor expression in PBMC, genital epithelial cells and other leukocytes by qPCR and western blotting. Reactivation from latency was assessed in J-Lat 11.1 and U1 cell lines.<br><br>RESULTS: we did not detect expression of classical opioid receptors in leukocytes, but did find nociception/orphanin FQ receptor (NOP) expression in blood and vaginal lymphocytes as well as genital epithelial cells. In PBMCs, we found that at physiological doses, morphine, and methadone had a variable or no effect on HIV infection, but buprenorphine treatment significantly increased HIV-1 infectivity (median: 8.797-fold increase with 20 nM buprenorphine, eight experiments, range: 3.570-691.9, p = 0.0078). Using latently infected cell lines, we did not detect reactivation of latent HIV following treatment with any of the opioid drugs.<br><br>CONCLUSIONS: our results suggest that buprenorphine, in contrast to morphine or methadone, increases the in vitro susceptibility of leukocytes to HIV-1 infection but has no effect on in vitro HIV reactivation. These findings contribute to our understanding how opioids, including those used for MAT, affect HIV infection and reactivation, and can help to inform the choice of MAT for people living with HIV or who are at risk of HIV infection.}, }
@article {pmid34452330, year = {2021}, author = {Bhattacharya, T and Rice, DW and Crawford, JM and Hardy, RW and Newton, ILG}, title = {Evidence of Adaptive Evolution in Wolbachia-Regulated Gene DNMT2 and Its Role in the Dipteran Immune Response and Pathogen Blocking.}, journal = {Viruses}, volume = {13}, number = {8}, pages = {}, doi = {10.3390/v13081464}, pmid = {34452330}, issn = {1999-4915}, support = {MTM2025389//National Science Foundation/ ; R01AI144430//National Institute of Allergy and Infectious Diseases/ ; R21AI153785//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Eukaryotic nucleic acid methyltransferase (MTase) proteins are essential mediators of epigenetic and epitranscriptomic regulation. DNMT2 belongs to a large, conserved family of DNA MTases found in many organisms, including holometabolous insects such as fruit flies and mosquitoes, where it is the lone MTase. Interestingly, despite its nomenclature, DNMT2 is not a DNA MTase, but instead targets and methylates RNA species. A growing body of literature suggests that DNMT2 mediates the host immune response against a wide range of pathogens, including RNA viruses. Curiously, although DNMT2 is antiviral in Drosophila, its expression promotes virus replication in mosquito species. We, therefore, sought to understand the divergent regulation, function, and evolution of these orthologs. We describe the role of the Drosophila-specific host protein IPOD in regulating the expression and function of fruit fly DNMT2. Heterologous expression of these orthologs suggests that DNMT2's role as an antiviral is host-dependent, indicating a requirement for additional host-specific factors. Finally, we identify and describe potential evidence of positive selection at different times throughout DNMT2 evolution within dipteran insects. We identify specific codons within each ortholog that are under positive selection and find that they are restricted to four distinct protein domains, which likely influence substrate binding, target recognition, and adaptation of unique intermolecular interactions. Collectively, our findings highlight the evolution of DNMT2 in Dipteran insects and point to structural, regulatory, and functional differences between mosquito and fruit fly homologs.}, }
@article {pmid34450655, year = {2021}, author = {Etzioni, R and Gulati, R and Weiss, NS}, title = {Multi-Cancer Early Detection: Learning from the past to Meet the Future.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djab168}, pmid = {34450655}, issn = {1460-2105}, abstract = {Multi-cancer early detection (MCED) tests may soon be available to screen for many cancers using a single blood test, yet little is known about these tests beyond their diagnostic performance. Taking lessons from the history of cancer early detection, we highlight three factors that influence how performance of early detection tests translates into benefit and benefit-harm tradeoffs: the ability to readily confirm a cancer signal, the population testing strategy, and the natural histories of the targeted cancers. We explain why critical gaps in our current knowledge about each factor prevent reliably projecting the expected clinical impact of MCED testing at this point in time. Our goal is to communicate how much uncertainty there is about the possible effects of MCED tests on population health so that patients, providers, regulatory agencies, and the public are well informed about what is reasonable to expect from this potentially important technological advance. We also urge the community to invest in a coordinated effort to collect data on MCED test dissemination and outcomes so that these can be tracked and studied while the tests are rigorously evaluated for benefit, harm, and cost.}, }
@article {pmid34450188, year = {2021}, author = {Pinsky, P and Goodman, P and Parnes, H and Ford, L and Minasian, L}, title = {Adherence with protocol medication use and mortality from unrelated causes in a prevention trial.}, journal = {Preventive medicine}, volume = {}, number = {}, pages = {106778}, doi = {10.1016/j.ypmed.2021.106778}, pmid = {34450188}, issn = {1096-0260}, abstract = {Several studies have shown that non-adherence to medication use is associated with lower use of preventive services and increased mortality. We aimed to study the relationship between initial adherence to medication use and mortality in the Prostate Cancer Prevention Trial (PCPT). The PCPT randomized men age 55 and over to a finasteride or placebo arm. Duration of treatment was seven years, followed by end-of-study prostate biopsy. Extended follow-up for mortality was performed by linkage to the National Death Index. Non-adherence was defined as taking under 80% of required pills during the first or second 6-month trial period. Proportional hazards models were used to assess the relationship between adherence and all-cause mortality (excluding prostate cancer deaths). Three models were developed as follows: Model I (controlling for demographics and trial arm), Model II (Model I factors plus specific medical conditions), Model III (Model II factors plus lifestyle factors). Of 18,667 men included in the analysis, 3082 (16.5%) were non-adherent. The most common reasons for non-adherence were side effects (33.9%) and forgetting to take pills (22%). Through 5 and 10 years of follow-up, 178 (5.9%) and 483 (15.7%) non-adherent men died versus 581 (3.7%) and 1887 (12.1%) adherent men. Hazard ratios (HRs) at 5 years were 1.62 (95% CI: 1.37-1.91), 1.55 (95% CI: 1.30-1.83) and 1.49 (95% CI: 1.25-1.76) for Models I-III. HRs at ten years were lower but still statistically significant. Non-adherence to taking protocol medications was associated with increased mortality from unrelated conditions.}, }
@article {pmid34448873, year = {2021}, author = {Peters, BA and Moon, JY and Hanna, DB and Kutsch, O and Fischl, M and Moran, CA and Adimora, AA and Gange, S and Roan, NR and Michel, KG and Augenbraun, M and Sharma, A and Landay, A and Desai, S and Kaplan, RC}, title = {T-cell immune dysregulation and mortality in women with HIV.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiab433}, pmid = {34448873}, issn = {1537-6613}, abstract = {BACKGROUND: Dysregulation of adaptive immunity is a hallmark of HIV infection that persists on antiretroviral therapy (ART). Few long-term prospective studies have related adaptive immunity impairments to mortality in HIV, particularly in women.<br><br>METHODS: Among 606 women with HIV in the Women's Interagency HIV Study, peripheral blood mononuclear cells collected from 2002-2005 underwent multiparameter flow cytometry. Underlying cause of death was ascertained from the National Death Index up to 2018. We examined associations of CD4+ and CD8+ T-cell activation (%CD38+HLADR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and non-activation/normal function (%CD57-CD28+) with natural-cause, HIV-related, and non-HIV-related mortality.<br><br>RESULTS: At baseline, median participant age was 41, and 67% were on ART. Among 100 deaths during median 13.3 years follow-up, 90 were natural-cause (53 non-HIV-related, 37 HIV-related). Higher activation and exhaustion of CD4+ T-cells were associated with risk of natural-cause and non-HIV-related mortality, adjusting for age, demographic, behavioral, HIV-related, and cardiometabolic factors at baseline. Additional adjustment for time-varying viral load and CD4+ T-cell count did not attenuate these associations. CD8+ T-cell markers were not associated with any outcomes adjusting for baseline factors.<br><br>CONCLUSIONS: Persistent CD4+ T-cell activation and exhaustion may contribute to excess long-term mortality risk in women with HIV, independent of HIV disease progression.}, }
@article {pmid34448865, year = {2021}, author = {Madewell, ZJ and Yang, Y and Longini, IM and Halloran, ME and Dean, NE}, title = {Factors Associated With Household Transmission of SARS-CoV-2: An Updated Systematic Review and Meta-analysis.}, journal = {JAMA network open}, volume = {4}, number = {8}, pages = {e2122240}, doi = {10.1001/jamanetworkopen.2021.22240}, pmid = {34448865}, issn = {2574-3805}, abstract = {Importance: A previous systematic review and meta-analysis of household transmission of SARS-CoV-2 that summarized 54 published studies through October 19, 2020, found an overall secondary attack rate (SAR) of 16.6% (95% CI, 14.0%-19.3%). However, the understanding of household secondary attack rates for SARS-CoV-2 is still evolving, and updated analysis is needed.<br><br>Objective: To use newly published data to further the understanding of SARS-CoV-2 transmission in the household.<br><br>Data Sources: PubMed and reference lists of eligible articles were used to search for records published between October 20, 2020, and June 17, 2021. No restrictions on language, study design, time, or place of publication were applied. Studies published as preprints were included.<br><br>Study Selection: Articles with original data that reported at least 2 of the following factors were included: number of household contacts with infection, total number of household contacts, and secondary attack rates among household contacts. Studies that reported household infection prevalence (which includes index cases), that tested contacts using antibody tests only, and that included populations overlapping with another included study were excluded. Search terms were SARS-CoV-2 or COVID-19 with secondary attack rate, household, close contacts, contact transmission, contact attack rate, or family transmission.<br><br>Data Extraction and Synthesis: Meta-analyses were performed using generalized linear mixed models to obtain SAR estimates and 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.<br><br>Main Outcomes and Measures: Overall household SAR for SARS-CoV-2, SAR by covariates (contact age, sex, ethnicity, comorbidities, and relationship; index case age, sex, symptom status, presence of fever, and presence of cough; number of contacts; study location; and variant), and SAR by index case identification period.<br><br>Results: A total of 2722 records (2710 records from database searches and 12 records from the reference lists of eligible articles) published between October 20, 2020, and June 17, 2021, were identified. Of those, 93 full-text articles reporting household transmission of SARS-CoV-2 were assessed for eligibility, and 37 studies were included. These 37 new studies were combined with 50 of the 54 studies (published through October 19, 2020) from our previous review (4 studies from Wuhan, China, were excluded because their study populations overlapped with another recent study), resulting in a total of 87 studies representing 1 249 163 household contacts from 30 countries. The estimated household SAR for all 87 studies was 18.9% (95% CI, 16.2%-22.0%). Compared with studies from January to February 2020, the SAR for studies from July 2020 to March 2021 was higher (13.4% [95% CI, 10.7%-16.7%] vs 31.1% [95% CI, 22.6%-41.1%], respectively). Results from subgroup analyses were similar to those reported in a previous systematic review and meta-analysis; however, the SAR was higher to contacts with comorbidities (3 studies; 50.0% [95% CI, 41.4%-58.6%]) compared with previous findings, and the estimated household SAR for the B.1.1.7 (α) variant was 24.5% (3 studies; 95% CI, 10.9%-46.2%).<br><br>Conclusions and Relevance: The findings of this study suggest that the household remains an important site of SARS-CoV-2 transmission, and recent studies have higher household SAR estimates compared with the earliest reports. More transmissible variants and vaccines may be associated with further changes.}, }
@article {pmid34446472, year = {2021}, author = {Oh, H and Wild, RA and Manson, JE and Bea, JW and Shadyab, AH and Pfeiffer, RM and Saquib, N and Underland, L and Anderson, GL and Xu, X and Trabert, B}, title = {Obesity, height, and serum androgen metabolism among postmenopausal women in the Women's Health Initiative Observational Study.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-21-0604}, pmid = {34446472}, issn = {1538-7755}, abstract = {BACKGROUND: Anthropometric measures, including obesity, are important risk factors for breast and endometrial cancers in postmenopausal women. It is unknown whether these risk factors are associated with androgen metabolism, another risk factor for these cancers.<br><br>METHODS: Using baseline data from 1,765 postmenopausal women in the Women's Health Initiative Observational Study, we conducted a cross-sectional analysis examining associations between anthropometric measures (current body mass index [BMI], waist-to-hip ratio [WHR], height, and recalled BMI at age 18) and serum androgen metabolites. Twelve androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Geometric means of androgen/androgen metabolite concentrations were estimated using linear regression, adjusting for potential confounders and stratified by hormone therapy (HT) use.<br><br>RESULTS: Regardless of HT use, higher current BMI (>30 vs. <25 kg/m2) was associated with higher serum concentrations of DHEAS, 5α-reduced glucuronide metabolites (ADT-G, 3α-diol-3G, 3α-diol-17G), and DHEAS:DHEA ratio (all p-trend<0.02). BMI was also positively associated with unconjugated estrone:androstenedione and unconjugated estradiol:testosterone ratios among never/former HT users (all p-trend<0.001) but not in current users (p-int<0.001). WHR was positively associated with adrenal androgens and 5α-reduced glucuronide metabolites in obese women only (BMI>30 kg/m2; all p-trend<0.01). BMI at age 18 was inversely associated with adrenal androgens (DHEA, DHEAS, androstenedione, testosterone) and 5α-reduced glucuronide metabolites in never/former HT users (all p-trend<0.06). Height was not associated with androgen metabolites.<br><br>CONCLUSIONS: Current BMI is associated with androgen metabolism among postmenopausal women.<br><br>IMPACT: This study contributes to our understanding of the link between obesity and cancer risk in postmenopausal women.}, }
@article {pmid34445891, year = {2021}, author = {D'Andrea, D and Black, PC and Zargar, H and Dinney, CP and Soria, F and Cookson, MS and Montgomery, JS and Kassouf, W and Dall'Era, MA and Sridhar, SS and McGrath, JS and Wright, JL and Thorpe, AC and Holzbeierlein, JM and Carrión, DM and Di Trapani, E and Bivalacqua, TJ and North, S and Barocas, DA and Lotan, Y and Grivas, P and Stephenson, AJ and van Rhijn, BW and Daneshmand, S and Spiess, PE and Shariat, SF and Zargar-Shoshtar, K and Mertens, LS and Fairey, AS and Mir, MC and Krabbe, LM and Jacobsen, NE and Vasdev, N and Yu, EY and Xylinas, E and Pradere, B and Pichler, R and Campain, NJ and Seah, JA and Ercole, CE and Horenblas, S and Aning, J and Morgan, TM and Shah, JB and Moschini, M}, title = {Identifying the Optimal Number of Neoadjuvant Chemotherapy Cycles in Patients with Muscle-Invasive Bladder Cancer.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000002190}, doi = {10.1097/JU.0000000000002190}, pmid = {34445891}, issn = {1527-3792}, abstract = {PURPOSE: To investigate the pathologic response rates and survival associated with 3 versus 4 cycles of cisplatin-based NAC in patients with cT2-4N0M0 MIBC.<br><br>MATERIAL AND METHODS: In this cohort study we analyzed clinical data of 828 patients treated with NAC and RC between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathologic objective response (pOR; ypT0-Ta-Tis-T1 N0), pathologic complete response (pCR; ypT0 N0), cancer-specific survival (CSS) and overall survival (OS) were investigated.<br><br>RESULTS: pOR and pCR were achieved in 378 (45%; 95%CI 42, 49) and 207 (25%; 95%CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57,p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with OS (HR 0.68; 95%CI 0.49, 0.94; p=0.02) but not with CSS (HR 0.72; 95%CI 0.50, 1.04; p=0.08).<br><br>CONCLUSIONS: 4 cycles of NAC achieved better pathologic response and survival compared to 3 cycles. These findings may aid clinicians in counselling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.}, }
@article {pmid34444002, year = {2021}, author = {Lacourt-Ventura, MY and Vilanova-Cuevas, B and Rivera-Rodríguez, D and Rosario-Acevedo, R and Miranda, C and Maldonado-Martínez, G and Maysonet, J and Vargas, D and Ruiz, Y and Hunter-Mellado, R and Cubano, LA and Dharmawardhane, S and Lampe, JW and Baerga-Ortiz, A and Godoy-Vitorino, F and Martínez-Montemayor, MM}, title = {Soy and Frequent Dairy Consumption with Subsequent Equol Production Reveals Decreased Gut Health in a Cohort of Healthy Puerto Rican Women.}, journal = {International journal of environmental research and public health}, volume = {18}, number = {16}, pages = {}, doi = {10.3390/ijerph18168254}, pmid = {34444002}, issn = {1660-4601}, support = {SC3GM111171/GM/NIGMS NIH HHS/United States ; 8G12MD007583/MD/NIMHD NIH HHS/United States ; 8U54MD007587/MD/NIMHD NIH HHS/United States ; U54MD007600/MD/NIMHD NIH HHS/United States ; U54MD007587/MD/NIMHD NIH HHS/United States ; P031S160068//U.S. Department of Education/ ; P20GM103475/GM/NIGMS NIH HHS/United States ; U54GM133807/GM/NIGMS NIH HHS/United States ; }, abstract = {The U.S. Hispanic female population has one of the highest breast cancer (BC) incidence and mortality rates, while BC is the leading cause of cancer death in Puerto Rican women. Certain foods may predispose to carcinogenesis. Our previous studies indicate that consuming combined soy isoflavones (genistein, daidzein, and glycitein) promotes tumor metastasis possibly through increased protein synthesis activated by equol, a secondary dietary metabolite. Equol is a bacterial metabolite produced in about 20-60% of the population that harbor and exhibit specific gut microbiota capable of producing it from daidzein. The aim of the current study was to investigate the prevalence of equol production in Puerto Rican women and identify the equol producing microbiota in this understudied population. Herein, we conducted a cross-sectional characterization of equol production in a clinically based sample of eighty healthy 25-50 year old Puerto Rican women. Urine samples were collected and evaluated by GCMS for the presence of soy isoflavones and metabolites to determine the ratio of equol producers to equol non-producers. Furthermore, fecal samples were collected for gut microbiota characterization on a subset of women using next generation sequencing (NGS). We report that 25% of the participants were classified as equol producers. Importantly, the gut microbiota from equol non-producers demonstrated a higher diversity. Our results suggest that healthy women with soy and high dairy consumption with subsequent equol production may result in gut dysbiosis by having reduced quantities (diversity) of healthy bacterial biomarkers, which might be associated to increased diseased outcomes (e.g., cancer, and other diseases).}, }
@article {pmid34437913, year = {2021}, author = {Parayath, NN and Hao, S and Stephan, SB and Koehne, AL and Watson, CE and Stephan, MT}, title = {Genetic in situ engineering of myeloid regulatory cells: Controls inflammation in autoimmunity.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jconrel.2021.08.040}, pmid = {34437913}, issn = {1873-4995}, abstract = {The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis.}, }
@article {pmid34436864, year = {2021}, author = {Neto, FC and Raftery, D}, title = {Expanding Urinary Metabolite Annotation through Integrated Mass Spectral Similarity Networking.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.1c02041}, pmid = {34436864}, issn = {1520-6882}, abstract = {The urine metabolome constitutes a rich source of functional information reflecting physiological states that are influenced by distinct conditions and biological stresses, such as responses to drug treatments or disease manifestations. Although global liquid chromatography-mass spectrometry (MS) profiling provides the most comprehensive measurement of metabolites in complex biological samples, annotation remains a challenge, and computational approaches are necessary to translate the molecular composition into biological knowledge. Here, we investigated the use of tandem MS-based enhanced molecular networks (MolNetEnhancer) to improve the metabolite annotation of urine extracts. The samples (n = 10) were analyzed by hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry in both electrospray ionization (ESI) modes. Consistent with other common data preprocessing software, the use of Progenesis QI led to the annotation of up to 20 metabolites based on MS2 library searches, showing a high fragmentation score (cosine similarity ≥ 0.7), that is, ∼2% of mass features containing MS2 spectra. Molecular networking based on library matching resulted in the annotation of up to 62 urinary compounds. Using a combination of unsupervised substructure discovery (MS2LDA), the in silico tool network annotation propagation (NAP), and ClassyFire chemical ontology, embedded in a multilayered molecular network by MolNetEnhancer, we were able to expand the chemical characterization to ∼50% of the data set. The integrative approach led to the annotation of 275 compounds at the metabolomics standards initiative (MSI) confidence level 2, as well as 459 and 578 urinary metabolites (MSI level 3) in both negative and positive ESI modes, respectively. The exhaustive MS2-based annotation outperformed similar studies applied to larger cohorts while offering the discovery of metabolites not identified by the MS2 library search. This is the first work that effectively integrates orthogonal annotation methods and MS2-based fragmentation studies to improve metabolite annotation in urine samples.}, }
@article {pmid34436524, year = {2021}, author = {Henden, AS and Koyama, M and Robb, RJ and Forero, A and Kuns, RD and Chang, K and Ensbey, KS and Varelias, A and Kazakoff, SH and Waddell, N and Clouston, AD and Giri, R and Begun, J and Blazar, BR and Degli-Esposti, MA and Kotenko, SV and Lane, SW and Bowerman, KL and Savan, R and Hugenholtz, P and Gartlan, KH and Hill, GR}, title = {IFN-λ therapy prevents severe gastrointestinal graft-versus-host disease.}, journal = {Blood}, volume = {138}, number = {8}, pages = {722-737}, doi = {10.1182/blood.2020006375}, pmid = {34436524}, issn = {1528-0020}, abstract = {Immunopathology and intestinal stem cell (ISC) loss in the gastrointestinal (GI) tract is the prima facie manifestation of graft-versus-host disease (GVHD) and is responsible for significant mortality after allogeneic bone marrow transplantation (BMT). Approaches to prevent GVHD to date focus on immune suppression. Here, we identify interferon-λ (IFN-λ; interleukin-28 [IL-28]/IL-29) as a key protector of GI GVHD immunopathology, notably within the ISC compartment. Ifnlr1-/- mice displayed exaggerated GI GVHD and mortality independent of Paneth cells and alterations to the microbiome. Ifnlr1-/- intestinal organoid growth was significantly impaired, and targeted Ifnlr1 deficiency exhibited effects intrinsic to recipient Lgr5+ ISCs and natural killer cells. PEGylated recombinant IL-29 (PEG-rIL-29) treatment of naive mice enhanced Lgr5+ ISC numbers and organoid growth independent of both IL-22 and type I IFN and modulated proliferative and apoptosis gene sets in Lgr5+ ISCs. PEG-rIL-29 treatment improved survival, reduced GVHD severity, and enhanced epithelial proliferation and ISC-derived organoid growth after BMT. The preservation of ISC numbers in response to PEG-rIL-29 after BMT occurred both in the presence and absence of IFN-λ-signaling in recipient natural killer cells. IFN-λ is therefore an attractive and rapidly testable approach to prevent ISC loss and immunopathology during GVHD.}, }
@article {pmid34433860, year = {2021}, author = {Dwyer, AJ and Ritz, JM and Mitchell, JS and Martinov, T and Alkhatib, M and Silva, N and Tucker, CG and Fife, BT}, title = {Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {17142}, pmid = {34433860}, issn = {2045-2322}, support = {P01 AI35296/GF/NIH HHS/United States ; T32 AI007313/GF/NIH HHS/United States ; MNP#18.01//Minnesota Partnership for Biotechnology and Medical Genomics/ ; }, abstract = {The notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.}, }
@article {pmid34433588, year = {2021}, author = {Giraldo, NA and Berry, S and Becht, E and Ates, D and Schenk, KM and Engle, EL and Green, B and Nguyen, P and Soni, A and Stein, JE and Succaria, F and Ogurtsova, A and Xu, H and Gottardo, R and Anders, RA and Lipson, EJ and Danilova, L and Baras, AS and Taube, JM}, title = {Spatial UMAP and image-cytometry for topographic immuno-oncology biomarker discovery.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-21-0015}, pmid = {34433588}, issn = {2326-6074}, abstract = {Multiplex immunofluorescence (mIF) can detail spatial relationships and complex cell phenotypes in the tumor microenvironment (TME). However, the analysis and visualization of mIF data can be complex and time-consuming. Here, we used tumor specimens from 93 patients with metastatic melanoma to develop and validate a mIF data-analysis pipeline using established flow cytometry workflows (image-cytometry). Unlike flow cytometry, spatial information from the TME was conserved at single-cell resolution. A spatial Uniform Manifold Approximation and Projection (UMAP) was constructed using the image cytometry output. Spatial UMAP subtraction analysis (survivors vs. non-survivors at 5 years) was used to identify topographic and co-expression signatures with positive or negative prognostic impact. Cell densities and proportions identified by image cytometry showed strong correlations when compared to those obtained using gold-standard, digital pathology software (R2 > 0.8). The associated spatial UMAP highlighted 'immune neighborhoods' and associated topographic immunoactive protein expression patterns. We found that PD-L1 and PD-1 expression intensity was spatially encoded-the highest PD-L1 expression intensity was observed on CD163+ cells in neighborhoods with high CD8+ cell density and the highest PD-1 expression intensity was observed on CD8+ cells in neighborhoods with dense arrangements of tumor cells. Spatial UMAP subtraction analysis revealed numerous spatial clusters associated with clinical outcome. The variables represented in the key clusters from the unsupervised UMAP analysis were validated using established, supervised approaches. In conclusion, image cytometry and the spatial UMAPs presented herein are powerful tools for the visualization and interpretation of single-cell, spatially-resolved mIF data and associated topographic biomarker development.}, }
@article {pmid34433507, year = {2021}, author = {Karazurna, NA and Porter, CM and Aytur, S and Scott, T and Mattei, J and Noel, SE and Gonzalez, HM and Mossavar-Rahmani, Y and Sotres-Alvarez, D and Gallo, LC and Daviglus, ML and Van Horn, L and Elfassy, T and Gellman, MD and Moncrieft, AE and Tucker, KL and Kaplan, RC and Bigornia, SJ}, title = {Associations between dietary fatty acid patterns and cognitive function in the Hispanic Community Health Study/Study of Latinos.}, journal = {The British journal of nutrition}, volume = {}, number = {}, pages = {1-35}, doi = {10.1017/S0007114521003275}, pmid = {34433507}, issn = {1475-2662}, abstract = {Our objective was to quantify the cross-sectional associations between dietary fatty acid (DFA) patterns and cognitive function among Hispanic/Latino adults. This study included data from 8,942 participants of the Hispanic Community Health Study/Study of Latinos, a population-based cohort study (weighted age 56.2 y and proportion female 55.2%). The NCI (National Cancer Institute) method was used to estimate dietary intake from two 24-hr recalls. We derived DFA patterns using principal components analysis with 26 fatty acid and total plant and animal monounsaturated fatty acid (MUFA) input variables. Global cognitive function was calculated as the average z-score of 4 neurocognitive tests. Survey linear regression models included multiple potential confounders such as age, sex, education, depressive symptoms, physical activity, energy intake, and cardiovascular disease. DFA patterns were characterized by consumption of long-chain saturated fatty acids (SFA), animal-based MUFA, and trans fatty acids (Factor 1); short to medium-chain SFA (Factor 2); very-long-chain omega-3 polyunsaturated fatty acids (PUFA) (Factor 3); very-long-chain SFA and plant-based MUFA and PUFA (Factor 4). Factor 2 was associated with greater scores for global cognitive function (β=0.037 ± 0.012) and the Digit Symbol Substitution (DSS) (β=0.56±0.17), Brief Spanish English Verbal Learning-Sum (B-SEVLT) (β=0.23 ± 0.11), and B-SEVLT-Recall (β=0.11 ± 0.05) tests (P<0.05 for all). Factors 1 (β=0.04 ± 0.01) and 4 (β=0.70 ± 0.18) were associated with the DSS test (P<0.05 for all). Consumption of short to medium-chain SFA may be associated with higher cognitive function among U.S.-residing Hispanic/Latino adults. Prospective studies are necessary to confirm these findings.}, }
@article {pmid34432014, year = {2021}, author = {Issaka, RB and Dominitz, JA}, title = {Financial Incentives to Improve Colorectal Cancer Screening-Time to Cut Our Losses.}, journal = {JAMA network open}, volume = {4}, number = {8}, pages = {e2122661}, doi = {10.1001/jamanetworkopen.2021.22661}, pmid = {34432014}, issn = {2574-3805}, }
@article {pmid34429382, year = {2021}, author = {Salter, AI and Rajan, A and Kennedy, JJ and Ivey, RG and Shelby, SA and Leung, I and Templeton, ML and Muhunthan, V and Voillet, V and Sommermeyer, D and Whiteaker, JR and Gottardo, R and Veatch, SL and Paulovich, AG and Riddell, SR}, title = {Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.}, journal = {Science signaling}, volume = {14}, number = {697}, pages = {}, doi = {10.1126/scisignal.abe2606}, pmid = {34429382}, issn = {1937-9145}, abstract = {Chimeric antigen receptor (CAR)-modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells express high amounts of target antigen. However, achieving durable remission for these hematological malignancies and extending CAR T cell therapy to patients with solid tumors will require receptors that can recognize and eliminate tumor cells with a low density of target antigen. Although CARs were designed to mimic T cell receptor (TCR) signaling, TCRs are at least 100-fold more sensitive to antigen. To design a CAR with improved antigen sensitivity, we directly compared TCR and CAR signaling in primary human T cells. Global phosphoproteomic analysis revealed that key T cell signaling proteins-such as CD3δ, CD3ε, and CD3γ, which comprise a portion of the T cell co-receptor, as well as the TCR adaptor protein LAT-were either not phosphorylated or were only weakly phosphorylated by CAR stimulation. Modifying a commonplace 4-1BB/CD3ζ CAR sequence to better engage CD3ε and LAT using embedded CD3ε or GRB2 domains resulted in enhanced T cell activation in vitro in settings of a low density of antigen, and improved efficacy in in vivo models of lymphoma, leukemia, and breast cancer. These CARs represent examples of alterations in receptor design that were guided by in-depth interrogation of T cell signaling.}, }
@article {pmid34429332, year = {2021}, author = {Leighl, NB and Redman, MW and Rizvi, N and Hirsch, FR and Mack, PC and Schwartz, LH and Wade, JL and Irvin, WJ and Reddy, SC and Crawford, J and Bradley, JD and Stinchcombe, TE and Ramalingam, SS and Miao, J and Minichiello, K and Herbst, RS and Papadimitrakopoulou, VA and Kelly, K and Gandara, DR}, title = {Phase II study of durvalumab plus tremelimumab as therapy for patients with previously treated anti-PD-1/PD-L1 resistant stage IV squamous cell lung cancer (Lung-MAP substudy S1400F, NCT03373760).}, journal = {Journal for immunotherapy of cancer}, volume = {9}, number = {8}, pages = {}, doi = {10.1136/jitc-2021-002973}, pmid = {34429332}, issn = {2051-1426}, abstract = {INTRODUCTION: S1400F is a non-match substudy of Lung Cancer Master Protocol (Lung-MAP) evaluating the immunotherapy combination of durvalumab and tremelimumab to overcome resistance to anti-programmed death ligand 1 (PD-(L)1) therapy in patients with advanced squamous lung carcinoma (sq non-small-cell lung cancer (NSCLC)).<br><br>METHODS: Patients with previously treated sqNSCLC with disease progression after anti-PD-(L)1 monotherapy, who did not qualify for any active molecularly targeted Lung-MAP substudies, were eligible. Patients received tremelimumab 75 mg plus durvalumab 1500 mg once every 28 days for four cycles then durvalumab alone every 28 days until disease progression. The primary endpoint was the objective response rate (RECIST V.1.1). Primary and acquired resistance cohorts, defined as disease progression within 24 weeks versus ≥24 weeks of starting prior anti-PD-(L)1 therapy, were analyzed separately and an interim analysis for futility was planned after 20 patients in each cohort were evaluable for response.<br><br>RESULTS: A total of 58 eligible patients received drug, 28 with primary resistance and 30 with acquired resistance to anti-PD-(L)1 monotherapy. Grade ≥3 adverse events at least possibly related to treatment were seen in 20 (34%) patients. The response rate in the primary resistance cohort was 7% (95% CI 0% to 17%), with one complete and one partial response. No responses were seen in the acquired resistance cohort. In the primary and resistance cohorts the median progression-free survival was 2.0 months (95% CI 1.6 to 3.0) and 2.1 months (95% CI 1.6 to 3.2), respectively, and overall survival was 7.7 months (95% CI 4.0 to 12.0) and 7.6 months (95% CI 5.3 to 10.2), respectively.<br><br>CONCLUSION: Durvalumab plus tremelimumab had minimal activity in patients with advanced sqNSCLC progressing on prior anti-PD-1 therapy.Trial registration numberNCT03373760.}, }
@article {pmid34429228, year = {2021}, author = {Laird, DW and Lampe, PD}, title = {Cellular mechanisms of connexin-based inherited diseases.}, journal = {Trends in cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tcb.2021.07.007}, pmid = {34429228}, issn = {1879-3088}, abstract = {The 21-member connexin gene family exhibits distinct tissue expression patterns that can cause a diverse array of over 30 inherited connexin-linked diseases ranging from deafness to skin defects and blindness. Intriguingly, germline mutations can cause disease in one tissue while other tissues that abundantly express the mutant connexin remain disease free, highlighting the importance of the cellular context of mutant expression. Modeling connexin pathologies in genetically modified mice and tissue-relevant cells has informed extensively on no less than a dozen gain- and loss-of-function mechanisms that underpin disease. This review focuses on how a deeper molecular understanding of the over 930 mutations in 11 connexin-encoding genes is foundational for creating a framework for therapeutic interventions.}, }
@article {pmid34428777, year = {2021}, author = {Annavajhala, MK and Mohri, H and Wang, P and Nair, M and Zucker, JE and Sheng, Z and Gomez-Simmonds, A and Kelley, AL and Tagliavia, M and Huang, Y and Bedford, T and Ho, DD and Uhlemann, AC}, title = {Emergence and expansion of SARS-CoV-2 B.1.526 after identification in New York.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41586-021-03908-2}, pmid = {34428777}, issn = {1476-4687}, abstract = {Recent months have seen surges of SARS-CoV-2 infection across the globe with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten the efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature mutations of concern are E484K, which plays a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here we report the emergence of variant lineage B.1.526 that contains E484K and its alarming rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies in clinical use and less susceptible to neutralization by convalescent plasma or vaccinee sera, posing a modest antigenic challenge. The B.1.526 lineage has now been reported from all 50 states in the United States and numerous other countries. B.1.526 rapidly replaced earlier lineages in New York upon its emergence, with an estimated transmission advantage of 35%. Such transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, probably contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrent with the rise of B.1.1.7 and ensuing variants.}, }
@article {pmid34428556, year = {2021}, author = {Metheny, L and Callander, NS and Hall, AC and Zhang, MJ and Bo-Subait, K and Wang, HL and Agrawal, V and Al-Homsi, AS and Assal, A and Bacher, U and Beitinjaneh, A and Bejanyan, N and Bhatt, VR and Bredeson, C and Byrne, M and Cairo, M and Cerny, J and DeFilipp, Z and Perez, MAD and Freytes, CO and Ganguly, S and Grunwald, MR and Hashmi, S and Hildebrandt, GC and Inamoto, Y and Kanakry, CG and Kharfan-Dabaja, MA and Lazarus, HM and Lee, JW and Nathan, S and Nishihori, T and Olsson, RF and Ringdén, O and Rizzieri, D and Savani, BN and Savoie, ML and Seo, S and van der Poel, M and Verdonck, LF and Wagner, JL and Yared, JA and Hourigan, CS and Kebriaei, P and Litzow, M and Sandmaier, BM and Saber, W and Weisdorf, D and de Lima, M}, title = {Allogeneic Transplantation to Treat Therapy Related MDS and AML in Adults.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2021.08.010}, pmid = {34428556}, issn = {2666-6367}, abstract = {Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) have a poor prognosis. An earlier CIBMTR analysis of allogeneic hematopoietic cell therapy (allo-HCT) (n=868, 1990-2004) showed 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%. Modern supportive care, graft versus host disease (GVHD) prophylaxis and reduced intensity conditioning (RIC) regimens have improved outcomes. Therefore, the Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 1531 allo-HCT for adults with t-MDS (n = 759) or t-AML (n = 772) performed from 2000 to 2014. Median age was 59 years (18-74) for t-MDS and 52 years (18-77) for t-AML. 24% of patient with t-MDS and 11% of patients with t-AML and had a prior autologous transplant. A myeloablative regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Non-relapse mortality (NRM) at five years was 34% (95% confidence interval (CI) 30-37) and 34% (30-37) for t-MDS and t-AML, respectively. Relapse rates at five years were 46% (43-50) and 43% (40-47), respectively. 5-year OS and DFS was 27% (23-31) and 19% (16-23) for patients with t-MDS and 25% (22-28) and 23% (20-26) for patients with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low risk t-MDS and those receiving MAC HCT during first complete remission (CR1) t-AML, but worse for those with prior autologous HCT, higher risk cytogenetics or IPSS-R score and partially matched unrelated donors (URD). Relapse remains the major cause of treatment failure with little improvement over the past two decades. These data indicate caution in recommending allo-HCT in these conditions and more effective anti-neoplastic approaches before and after allo-HCT.<br><br>BACKGROUND: Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) have a poor prognosis. An earlier CIBMTR analysis of allogeneic hematopoietic cell therapy (allo-HCT) (n=868, 1990-2004) showed 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%. Modern supportive care, graft versus host disease (GVHD) prophylaxis and reduced intensity conditioning (RIC) regimens have improved outcomes.<br><br>OBJECTIVES: The primary objectives are OS and DFS. The secondary objectives are non-relapse mortality (NRM), relapse, GVHD rates and identifying prognostic factors for outcomes after allo-HCT.<br><br>STUDY DESIGN: The Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 1531 allo-HCT for adults with t-MDS (n = 759) or t-AML (n = 772) performed from 2000 to 2014. Cumulative incidence function was used to estimate relapse, NRM, acute and chronic GVHD. Kaplan-Meier estimate was used to calculate probabilities of OS and DFS. Cox proportional hazards regression model was used to estimate hazard ratio (HR) of patient / disease / transplant related factors for outcomes of interest.<br><br>RESULTS: The median age was 59 years (18-74) for t-MDS and 52 years (18-77) for t-AML. 24% of patient with t-MDS and 11% of patients with t-AML and had a prior autologous transplant. A myeloablative regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Non-relapse mortality (NRM) at five years was 34% (95% confidence interval (CI) 30-37) and 34% (30-37) for t-MDS and t-AML, respectively. Relapse rates at five years were 46% (43-50) and 43% (40-47), respectively. 5-year OS and DFS was 27% (23-31) and 19% (16-23) for patients with t-MDS and 25% (22-28) and 23% (20-26) for patients with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low risk t-MDS and those receiving MAC HCT during first complete remission (CR1) t-AML, but worse for those with prior autologous HCT, higher risk cytogenetics or IPSS-R score and partially matched unrelated donors (URD).<br><br>CONCLUSIONS: Relapse remains the major cause of treatment failure with little improvement over the past two decades. These data indicate caution in recommending allo-HCT in these conditions. Through better patient optimization, more effective conditioning and studies of post-HCT interventions, outcomes for patients with t-MDS and t-AML may improve.}, }
@article {pmid34428453, year = {2021}, author = {Li, H and Hart, JE and Mahalingaiah, S and Nethery, RC and VoPham, T and Bertone-Johnson, E and Laden, F}, title = {Ultraviolet radiation and age at natural menopause in a nationwide, prospective US cohort.}, journal = {Environmental research}, volume = {}, number = {}, pages = {111929}, doi = {10.1016/j.envres.2021.111929}, pmid = {34428453}, issn = {1096-0953}, abstract = {BACKGROUND: Solar ultraviolet radiation (UV) is a critical environmental factor for dermal conversion of vitamin D, which is suggested to support reproductive health. However, current epidemiological studies have reported conflicting results on the associations between vitamin D levels and ovarian reserve. Further, few studies have considered UV exposure and reproductive aging, which is closely related to declined ovarian reserve.<br><br>OBJECTIVES: We sought to examine the associations of long-term UV exposure and age at natural menopause in a large, nationwide, prospective cohort.<br><br>METHODS: Participants in the Nurses' Health Study II (NHS II) who were premenopausal at age 40 were included and followed through 2015. Erythemal UV radiation from a high-resolution geospatial model was linked to the participants' residential histories. Early-life UV was estimated using the reported state of residence at birth, age 15, and age 30. We used time-varying Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for natural menopause, adjusting for potential confounders and predictors of menopause.<br><br>RESULTS: A total of 63,801 women reported natural menopause across the 1,051,185 person-years of follow-up among 105,631 eligible participants. We found very modest associations with delayed menopause for long-term UV exposure (adjusted HR comparing highest to lowest quartile of cumulative average UV: 0.96, 95% CI: 0.94, 0.99). There was a suggestive inverse association between UV at age 30 with menopause (adjusted HR comparing highest to lowest quartile: 0.97, 95% CI: 0.95, 1.00) but not with UV at birth and age 15.<br><br>CONCLUSIONS: Solar UV exposure in adulthood was modestly associated with later onset of menopause. Although consistent with previous findings on vitamin D intake and menopause in the same population, these weak associations found in this study may not be of clinical relevance.}, }
@article {pmid34427805, year = {2021}, author = {Jones, SMW and Gaffney, A and Unger, JM}, title = {A comparison of oncologist versus mental health provider attitudes towards standardized and tailored patient-reported outcomes.}, journal = {Journal of patient-reported outcomes}, volume = {5}, number = {1}, pages = {76}, pmid = {34427805}, issn = {2509-8020}, abstract = {BACKGROUND: Patient-reported outcomes (PROs) can be used to monitor patients during treatment. Healthcare provider preferences for individualized vs. standardized PROs have been understudied.<br><br>METHODS: This study surveyed oncology and mental health providers to compare attitudes towards individualized and standardized PROs. We have developed a method for individualizing PROs, called precision PROs, and the survey specifically assessed preferences for this method. We compared attitudes and preferences by provider type and by whether respondents were current or never users of PROs.<br><br>RESULTS: Oncology providers expressed more positive attitudes for standardized PROs in treatment planning compared to mental health providers (F(1,440) = 5.978, p = 0.015). The interaction between provider type (oncology vs. mental health) and type of PRO (individualized vs. standardized) was not significant for the attitudes about the clinical utility of PROs (p = 0.709). When directly asked about the precision PRO approach, oncologists were less likely to prefer standardized items (OR = 0.478, p = 0.001) or have no preference (OR = 0.445, p = 0.007) to the precision PRO approach when compared to mental health providers. Qualitative analyses suggested standardized PROs may be simpler or easier to understand whereas individualized PROs better capture patient variability and the unique aspects of each patient's condition. Some mental health providers expressed reticence about letting patients choose how to tailor PROs. Never users of PROs reported more positive attitudes towards individualized measures than standardized measures whereas current users of PROs did not have a difference in attitudes (p = 0.010). User status was mostly unrelated to preferences.<br><br>CONCLUSION: Results suggest that healthcare provider preference for individualized PROs may differ by medical specialty. How PROs are tailored may need to differ by discipline. This is particularly important given that previous research showing a preference for individualized PROs over standardized was conducted with psychotherapists. Further research on patient preferences for individualized and standardized PROs is warranted as is research on the clinical utility of individualized PROs such as the precision PRO approach.}, }
@article {pmid34427308, year = {2021}, author = {Isabella, AJ and Stonick, JA and Dubrulle, J and Moens, CB}, title = {Intrinsic positional memory guides target-specific axon regeneration in the zebrafish vagus nerve.}, journal = {Development (Cambridge, England)}, volume = {}, number = {}, pages = {}, doi = {10.1242/dev.199706}, pmid = {34427308}, issn = {1477-9129}, support = {R01 NS109425/NH/NIH HHS/United States ; }, abstract = {Regeneration after peripheral nerve damage requires that axons re-grow to the correct target tissues in a process called target-specific regeneration. While much is known about the mechanisms that promote axon re-growth, re-growing axons often fail to reach the correct targets, resulting in impaired nerve function. We know very little about how axons achieve target-specific regeneration, particularly in branched nerves that require distinct targeting decisions at branch points. The zebrafish vagus motor nerve is a branched nerve with a well-defined topographic organization. Here, we track regeneration of individual vagus axons after whole-nerve laser severing and find a robust capacity for target-specific, functional regrowth. We then develop a new single-cell chimera injury model for precise manipulation of axon-environment interactions and find that 1) the guidance mechanism used during regeneration is distinct from the nerve's developmental guidance mechanism, 2) target selection is specified by neurons' intrinsic memory of their position within the brain, and 3) targeting to a branch requires its pre-existing innervation. This work establishes the zebrafish vagus nerve as a tractable regeneration model and reveals the mechanistic basis of target-specific regeneration.}, }
@article {pmid34426798, year = {2021}, author = {Plymate, LC and Pepper, G and Krist, MP and Koelle, DM}, title = {Immunogenicity of repeat COVID-19 mRNA vaccinations in a patient with myasthenia gravis receiving mycophenolate, prednisone, and eculizumab.}, journal = {Journal of translational autoimmunity}, volume = {4}, number = {}, pages = {100114}, doi = {10.1016/j.jtauto.2021.100114}, pmid = {34426798}, issn = {2589-9090}, abstract = {Vaccination can prevent infection and disease due to SARS-CoV-2. Early reports indicate that immune suppressed or immune compromised populations have reduced immune responses to US emergency use authorized (EUA) vaccines. Patients with autoimmune disorders are at risk for severe COVID-19, and are frequently immune suppressed related to therapy, the underlying disease, or both. Myasthenia gravis (MG) is an autoimmune disorder characterized by antibodies that interrupt neuromuscular transmission. Chronic immune suppressive therapy is typically required. We report the case of a 74 year old woman with MG receiving mycophenolate, prednisone, and eculizumab in whom mRNA vaccination failed to elicit detectable circulating vaccine-specific IgG or IFN-γ T cell responses. Eculizumab was discontinued, and repeat vaccination with two doses of an alternative EUA mRNA vaccine led to circulating IgG specific for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein, and to detectable S-specific T cell responses. While it is not known if these responses will protect against SARS-CoV-2 infection or disease, a repeat course of mRNA vaccination appears to be safe and was broadly immunogenic in this individual.}, }
@article {pmid34426704, year = {2021}, author = {Schattgen, SA and Guion, K and Crawford, JC and Souquette, A and Barrio, AM and Stubbington, MJT and Thomas, PG and Bradley, P}, title = {Integrating T cell receptor sequences and transcriptional profiles by clonotype neighbor graph analysis (CoNGA).}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {34426704}, issn = {1546-1696}, support = {R01 AI136514/AI/NIAID NIH HHS/United States ; }, abstract = {Links between T cell clonotypes, as defined by T cell receptor (TCR) sequences, and phenotype, as reflected in gene expression (GEX) profiles, surface protein expression and peptide:major histocompatibility complex binding, can reveal functional relationships beyond the features shared by clonally related cells. Here we present clonotype neighbor graph analysis (CoNGA), a graph theoretic approach that identifies correlations between GEX profile and TCR sequence through statistical analysis of GEX and TCR similarity graphs. Using CoNGA, we uncovered associations between TCR sequence and GEX profiles that include a previously undescribed 'natural lymphocyte' population of human circulating CD8+ T cells and a set of TCR sequence determinants of differentiation in thymocytes. These examples show that CoNGA might help elucidate complex relationships between TCR sequence and T cell phenotype in large, heterogeneous, single-cell datasets.}, }
@article {pmid34425749, year = {2021}, author = {Reddy, S and Hung, LH and Sala-Torra, O and Radich, JP and Yeung, CC and Yeung, KY}, title = {A graphical, interactive and GPU-enabled workflow to process long-read sequencing data.}, journal = {BMC genomics}, volume = {22}, number = {1}, pages = {626}, pmid = {34425749}, issn = {1471-2164}, support = {R01GM126019/NH/NIH HHS/United States ; R01 CA175008/NH/NIH HHS/United States ; UG1 CA233338/NH/NIH HHS/United States ; Young Investigator Award//Natioonal Comprehensive Cancer Network/ ; Hyundai Hope on Wheel Scholars Hope Grant//Hyuandai/ ; }, abstract = {BACKGROUND: Long-read sequencing has great promise in enabling portable, rapid molecular-assisted cancer diagnoses. A key challenge in democratizing long-read sequencing technology in the biomedical and clinical community is the lack of graphical bioinformatics software tools which can efficiently process the raw nanopore reads, support graphical output and interactive visualizations for interpretations of results. Another obstacle is that high performance software tools for long-read sequencing data analyses often leverage graphics processing units (GPU), which is challenging and time-consuming to configure, especially on the cloud.<br><br>RESULTS: We present a graphical cloud-enabled workflow for fast, interactive analysis of nanopore sequencing data using GPUs. Users customize parameters, monitor execution and visualize results through an accessible graphical interface. The workflow and its components are completely containerized to ensure reproducibility and facilitate installation of the GPU-enabled software. We also provide an Amazon Machine Image (AMI) with all software and drivers pre-installed for GPU computing on the cloud. Most importantly, we demonstrate the potential of applying our software tools to reduce the turnaround time of cancer diagnostics by generating blood cancer (NB4, K562, ME1, 238 MV4;11) cell line Nanopore data using the Flongle adapter. We observe a 29x speedup and a 93x reduction in costs for the rate-limiting basecalling step in the analysis of blood cancer cell line data.<br><br>CONCLUSIONS: Our interactive and efficient software tools will make analyses of Nanopore data using GPU and cloud computing accessible to biomedical and clinical scientists, thus facilitating the adoption of cost effective, fast, portable and real-time long-read sequencing.}, }
@article {pmid34417459, year = {2021}, author = {Mao, N and Zhang, Z and Lee, YS and Choi, D and Rivera, AA and Li, D and Lee, C and Haywood, S and Chen, X and Chang, Q and Xu, G and Chen, HA and de Stanchina, E and Sawyers, C and Rosen, N and Hsieh, AC and Chen, Y and Carver, BS}, title = {Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {5053}, pmid = {34417459}, issn = {2041-1723}, support = {R37 CA230617/CA/NCI NIH HHS/United States ; P50 CA092629/CA/NCI NIH HHS/United States ; U54 CA224079/CA/NCI NIH HHS/United States ; R01 CA182503/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; F99 CA223063/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, abstract = {Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.}, }
@article {pmid34416707, year = {2021}, author = {Balis, F and Green, DM and Anderson, C and Cook, S and Dhillon, J and Gow, K and Hiniker, S and Jasty-Rao, R and Lin, C and Lovvorn, H and MacEwan, I and Martinez-Agosto, J and Mullen, E and Murphy, ES and Ranalli, M and Rhee, D and Rokitka, D and Tracy, EL and Vern-Gross, T and Walsh, MF and Walz, A and Wickiser, J and Zapala, M and Berardi, RA and Hughes, M}, title = {Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {8}, pages = {945-977}, doi = {10.6004/jnccn.2021.0037}, pmid = {34416707}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.}, }
@article {pmid34424945, year = {2021}, author = {Braun, KM and Moreno, GK and Wagner, C and Accola, MA and Rehrauer, WM and Baker, DA and Koelle, K and O'Connor, DH and Bedford, T and Friedrich, TC and Moncla, LH}, title = {Acute SARS-CoV-2 infections harbor limited within-host diversity and transmit via tight transmission bottlenecks.}, journal = {PLoS pathogens}, volume = {17}, number = {8}, pages = {e1009849}, doi = {10.1371/journal.ppat.1009849}, pmid = {34424945}, issn = {1553-7374}, abstract = {The emergence of divergent SARS-CoV-2 lineages has raised concern that novel variants eliciting immune escape or the ability to displace circulating lineages could emerge within individual hosts. Though growing evidence suggests that novel variants arise during prolonged infections, most infections are acute. Understanding how efficiently variants emerge and transmit among acutely-infected hosts is therefore critical for predicting the pace of long-term SARS-CoV-2 evolution. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to 133 SARS-CoV-2 genomes from acutely-infected individuals. We find that within-host diversity is low and transmission bottlenecks are narrow, with very few viruses founding most infections. Within-host variants are rarely transmitted, even among individuals within the same household, and are rarely detected along phylogenetically linked infections in the broader community. These findings suggest that most variation generated within-host is lost during transmission.}, }
@article {pmid34424782, year = {2021}, author = {Long, JE and Sanchez, H and Dasgupta, S and Huerta, L and Calderón Garcia, D and Lama, JR and Duerr, A}, title = {Exploring HIV risk behavior and sexual/gender identities among transgender women and their sexual partners in Peru using respondent-driven sampling.}, journal = {AIDS care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/09540121.2021.1967855}, pmid = {34424782}, issn = {1360-0451}, abstract = {HIV prevalence is high among transgender women, but little is known about cisgender men who have sex with transgender women (MSTW). The objective of this study was to investigate characteristics and behavior of MSTW compared to transgender women and men who have sex with men (MSM) using a modified respondent-driven sampling design. Seed participants completed a survey and invited up to three sex partners. Forward recruitment continued in waves through the referral of sex partners. Cross-sectional data were assessed using mixed effects models. From February to July 2018, 479 participants in Lima, Peru enrolled (n = 199 transgender women, n = 196 MSTW, and n = 45 MSM). MSTW behavior and identity differed significantly from that of transgender women and MSM. MSTW primarily identified as bisexual (69%) or heterosexual (15%) and only 6% reported male partners. Insertive condomless anal intercourse was reported by 61% of MSTW; 46% did not know their HIV serostatus. Compared to MSTW without male partners, those with recent male partners were more likely to sell sex (OR 15.7, 95% CI 4.1-60.5), and report condomless receptive anal intercourse (OR 89.0, 95% CI 19.1-414.8). This evidence suggests that MSTW are a distinct population from MSM, and highlights the critical need to include MSTW in HIV research and interventions.}, }
@article {pmid34420417, year = {2021}, author = {Selukar, S and May, S and Law, D and Othus, M}, title = {Stratified randomization for platform trials with differing experimental arm eligibility.}, journal = {Clinical trials (London, England)}, volume = {}, number = {}, pages = {17407745211028872}, doi = {10.1177/17407745211028872}, pmid = {34420417}, issn = {1740-7753}, abstract = {BACKGROUND: Platform trials facilitate efficient use of resources by comparing multiple experimental agents to a common standard of care arm. They can accommodate a changing scientific paradigm within a single trial protocol by adding or dropping experimental arms-critical features for trials in rapidly developing disease areas such as COVID-19 or cancer therapeutics. However, in these trials, efficacy and safety issues may render certain participant subgroups ineligible to some experimental arms, and methods for stratified randomization do not readily apply to this setting.<br><br>METHODS: We propose extensions for conventional methods of stratified randomization for platform trials whose experimental arms may differ in eligibility criteria. These methods balance on a prespecified set of stratification variables observable prior to arm assignment that remains the same across experimental arms. To do so, we suggest modifying block randomization by including experimental arm eligibility as a stratifying variable, and we suggest modifying the imbalance score calculation in dynamic balancing by performing pairwise comparisons between each eligible experimental arm and standard of care arm participants eligible to that experimental arm.<br><br>RESULTS: We provide worked examples to illustrate the proposed extensions. In addition, we also provide a formula to quantify the relative efficiency loss of platform trials with varying eligibility compared with trials with non-varying eligibility as measured by the size of the common standard of care arm.<br><br>CONCLUSIONS: This article presents important extensions to conventional methods for stratified randomization in order to facilitate the implementation of platform trials with differing experimental arm eligibility.}, }
@article {pmid34420223, year = {2021}, author = {Halloran, ME}, title = {Discussion on "Estimating vaccine efficacy over time after a randomized study is unblinded" by Anastasios A. Tsiatis and Marie Davidian.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13540}, pmid = {34420223}, issn = {1541-0420}, support = {R37 AI032042/AI/NIAID NIH HHS/United States ; }, }
@article {pmid34420195, year = {2021}, author = {Jones, LM and Tarlock, K and Cooper, T}, title = {Targeted Therapy in Pediatric AML: An Evolving Landscape.}, journal = {Paediatric drugs}, volume = {}, number = {}, pages = {}, pmid = {34420195}, issn = {1179-2019}, abstract = {The outcomes associated with pediatric acute myeloid leukemia (AML) have improved over the last few decades, with the implementation of intensive chemotherapy, hematopoietic stem cell transplant, and improved supportive care. However, even with intensive therapy and the use of HSCT, both of which carry significant risks of short- and long-term side effects, approximately 30% of children are not able to be cured. The characterization of AML in pediatrics has evolved over time and it currently involves use of a variety of diagnostic tools, including flow cytometry and comprehensive genomic sequencing. Given the adverse effects of chemotherapy and the need for additional therapeutic options to improve outcomes in these patients, the genomic and molecular architecture is being utilized to inform selection of targeted therapies in pediatric AML. This review provides a summary of current, targeted therapy options in pediatric AML.}, }
@article {pmid34418057, year = {2021}, author = {Pietrosanu, M and Shu, H and Jiang, B and Kong, L and Heo, G and He, Q and Gilmore, J and Zhu, H}, title = {Estimation for the bivariate quantile varying coefficient model with application to diffusion tensor imaging data analysis.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxab031}, pmid = {34418057}, issn = {1468-4357}, support = {//Natural Sciences and Engineering Research Council of Canada/ ; //Canadian Statistical Sciences Institute/ ; //McIntyre Memorial Fund/ ; //Orthodontics Division, School of Dentistry, University of Alberta/ ; MH086633 and MH116527/NH/NIH HHS/United States ; }, abstract = {Despite interest in the joint modeling of multiple functional responses such as diffusion properties in neuroimaging, robust statistical methods appropriate for this task are lacking. To address this need, we propose a varying coefficient quantile regression model able to handle bivariate functional responses. Our work supports innovative insights into biomedical data by modeling the joint distribution of functional variables over their domains and across clinical covariates. We propose an estimation procedure based on the alternating direction method of multipliers and propagation separation algorithms to estimate varying coefficients using a B-spline basis and an $L_2$ smoothness penalty that encourages interpretability. A simulation study and an application to a real-world neurodevelopmental data set demonstrates the performance of our model and the insights provided by modeling functional fractional anisotropy and mean diffusivity jointly and their association with gestational age and sex.}, }
@article {pmid34416167, year = {2021}, author = {Wang, Y and Liu, S and Yang, Z and Algazi, AP and Lomeli, SH and Wang, Y and Othus, M and Hong, A and Wang, X and Randolph, CE and Jones, AM and Bosenberg, MW and Byrum, SD and Tackett, AJ and Lopez, H and Yates, C and Solit, DB and Ribas, A and Piva, M and Moriceau, G and Lo, RS}, title = {Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2021.07.023}, pmid = {34416167}, issn = {1878-3686}, abstract = {Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.}, }
@article {pmid34415308, year = {2021}, author = {Wang, P and Castellani, CA and Yao, J and Huan, T and Bielak, LF and Zhao, W and Haessler, J and Roby, J and Sun, X and Guo, X and Longchamps, RJ and Manson, JE and Grove, ML and Bressler, J and Taylor, KD and Lappalainen, T and Kasela, S and Van Den Berg, DJ and Hou, L and Reiner, A and Liu, Y and Boerwinkle, E and Smith, JA and Peyser, PA and Fornage, M and Rich, SS and Rotter, JI and Kooperberg, C and Arking, DE and Levy, D and Liu, C and , }, title = {Epigenome-wide association study of mitochondrial genome copy number.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddab240}, pmid = {34415308}, issn = {1460-2083}, abstract = {We conducted cohort- and race-specific epigenome-wide association analyses of mtDNA copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated CpG sites (p < 1 x 10-7), with a 0.7 to 3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes (PRDM16, NR1H3, XRCC3, POLK, and PDSS2), which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, p = 4 x 10-8) and positively associated with the NR1H3 expression level (effect size = 0.43, p = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor, and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.}, }
@article {pmid34408140, year = {2021}, author = {Singh, P and Fragoza, R and Blengini, CS and Tran, TN and Pannafino, G and Al-Sweel, N and Schimenti, KJ and Schindler, K and Alani, EA and Yu, H and Schimenti, JC}, title = {Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {5005}, pmid = {34408140}, issn = {2041-1723}, support = {R01 HD082568/HD/NICHD NIH HHS/United States ; R01 HD091331/HD/NICHD NIH HHS/United States ; R35 GM134872/GM/NIGMS NIH HHS/United States ; }, abstract = {Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.}, }
@article {pmid34407973, year = {2021}, author = {Mostaghel, EA and Marck, BT and Kolokythas, O and Chew, F and Yu, EY and Schweizer, MT and Cheng, HH and Kantoff, PW and Balk, SP and Taplin, ME and Sharifi, N and Matsumoto, AM and Nelson, PS and Montgomery, RB}, title = {Circulating and intra-tumoral adrenal androgens correlate with response to abiraterone in men with castration resistant prostate cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-21-1819}, pmid = {34407973}, issn = {1557-3265}, abstract = {PURPOSE: In metastatic castration resistant prostate cancer (mCRPC) low serum androgens prior to starting Abiraterone Acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in CRPC metastases and associations of intratumoral androgens with response.<br><br>EXPERIMENTAL DESIGN: We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2000mg at progression.<br><br>RESULTS: 29 of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (p<0.001). Serum and tissue DHEAS remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pre-treatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on therapy) associated with rapid progression (20 vs 48 weeks p=0.0018; 20 vs 52 weeks p=0.0003; 14 vs 40 weeks p=0.0001; 20 vs 56 weeks p=0.02, respectively). One of 16 men escalating to 2000mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild type PTEN status associated with longer response (61 vs 33 weeks; p=0.02).<br><br>CONCLUSION: Low circulating adrenal androgens levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. CRPC patients with higher serum DHEAS levels may benefit from dual-AR pathway inhibition, while those in the lowest quartile may require combinations with non-AR directed therapy.}, }
@article {pmid34407971, year = {2021}, author = {Vyas, A and Harbison, RA and Faden, DL and Kubik, M and Palmer, D and Zhang, Q and Osmanbeyoglu, HU and Duvvuri, U and Méndez, E}, title = {Recurrent human papillomavirus-related head and neck cancer undergoes metabolic re-programming and is driven by oxidative phosphorylation.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-20-4789}, pmid = {34407971}, issn = {1557-3265}, abstract = {PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck cancer squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, ~10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear.<br><br>EXPERIMENTAL DESIGN: We performed RNA seq on tissues from matched primary (pOPSCC) and metachronous recurrent cancers (rOPSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (1) NRF2 overexpression on growth in vitro and in vivo (2) OXPHOS inhibition using IACS-010759 on NRF2 dependent cells (3) combination of cisplatin and OXPHOS inhibition.<br><br>RESULTS: The oxidative phosphorylation (OXPHOS) pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from the Cancer Genome Atlas with enrichment in OXPHOS, fatty acid metabolism, Myc, Mtor, ROS, and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells.<br><br>CONCLUSIONS: These results unveil a paradigm shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.}, }
@article {pmid34407845, year = {2021}, author = {Morra, A and Escala-Garcia, M and Beesley, J and Keeman, R and Canisius, S and Ahearn, TU and Andrulis, IL and Anton-Culver, H and Arndt, V and Auer, PL and Augustinsson, A and Beane Freeman, LE and Becher, H and Beckmann, MW and Behrens, S and Bojesen, SE and Bolla, MK and Brenner, H and Brüning, T and Buys, SS and Caan, B and Campa, D and Canzian, F and Castelao, JE and Chang-Claude, J and Chanock, SJ and Cheng, TD and Clarke, CL and ,  and Colonna, SV and Couch, FJ and Cox, A and Cross, SS and Czene, K and Daly, MB and Dennis, J and Dörk, T and Dossus, L and Dunning, AM and Dwek, M and Eccles, DM and Ekici, AB and Eliassen, AH and Eriksson, M and Evans, DG and Fasching, PA and Flyger, H and Fritschi, L and Gago-Dominguez, M and García-Sáenz, JA and Giles, GG and Grip, M and Guénel, P and Gündert, M and Hahnen, E and Haiman, CA and Håkansson, N and Hall, P and Hamann, U and Hart, SN and Hartikainen, JM and Hartmann, A and He, W and Hooning, MJ and Hoppe, R and Hopper, JL and Howell, A and Hunter, DJ and ,  and ,  and Jager, A and Jakubowska, A and Janni, W and John, EM and Jung, AY and Kaaks, R and Keupers, M and Kitahara, CM and Koutros, S and Kraft, P and Kristensen, VN and Kurian, AW and Lacey, JV and Lambrechts, D and Le Marchand, L and Lindblom, A and Linet, M and Luben, RN and Lubiński, J and Lush, M and Mannermaa, A and Manoochehri, M and Margolin, S and Martens, JWM and Martinez, ME and Mavroudis, D and Michailidou, K and Milne, RL and Mulligan, AM and Muranen, TA and Nevanlinna, H and Newman, WG and Nielsen, SF and Nordestgaard, BG and Olshan, AF and Olsson, H and Orr, N and Park-Simon, TW and Patel, AV and Peissel, B and Peterlongo, P and Plaseska-Karanfilska, D and Prajzendanc, K and Prentice, R and Presneau, N and Rack, B and Rennert, G and Rennert, HS and Rhenius, V and Romero, A and Roylance, R and Ruebner, M and Saloustros, E and Sawyer, EJ and Schmutzler, RK and Schneeweiss, A and Scott, C and Shah, M and Smichkoska, S and Southey, MC and Stone, J and Surowy, H and Swerdlow, AJ and Tamimi, RM and Tapper, WJ and Teras, LR and Terry, MB and Tollenaar, RAEM and Tomlinson, I and Troester, MA and Truong, T and Vachon, CM and Wang, Q and Hurson, AN and Winqvist, R and Wolk, A and Ziogas, A and Brauch, H and García-Closas, M and Pharoah, PDP and Easton, DF and Chenevix-Trench, G and Schmidt, MK}, title = {Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.}, journal = {Breast cancer research : BCR}, volume = {23}, number = {1}, pages = {86}, pmid = {34407845}, issn = {1465-542X}, support = {C1287/A16563/CRUK_/Cancer Research UK/United Kingdom ; C1287/A16563/CRUK_/Cancer Research UK/United Kingdom ; C1287/A10118/CRUK_/Cancer Research UK/United Kingdom ; C1287/A10710/CRUK_/Cancer Research UK/United Kingdom ; C12292/A11174/CRUK_/Cancer Research UK/United Kingdom ; C1281/A12014/CRUK_/Cancer Research UK/United Kingdom ; C5047/A8384/CRUK_/Cancer Research UK/United Kingdom ; C5047/A15007/CRUK_/Cancer Research UK/United Kingdom ; C5047/A10692/CRUK_/Cancer Research UK/United Kingdom ; C8197/A16565/CRUK_/Cancer Research UK/United Kingdom ; 634935//Horizon 2020 Research and Innovation Programme/ ; 633784//Horizon 2020 Research and Innovation Programme/ ; HEALTH-F2-2009-223175//FP7 Ideas: European Research Council/ ; U19 CA148065/NH/NIH HHS/United States ; CA128978/NH/NIH HHS/United States ; GPH-129344/CAPMC/CIHR/Canada ; PSRSIIRI-701//Ministère de l'Économie, de la Science et de l'Innovation - Québec/ ; 1U19 CA148537//Post-Cancer GWAS/ ; 1U19 CA148065//Post-Cancer GWAS/ ; 1U19 CA148112//GAME-ON/ ; W81XWH-10-1-0341//U.S. Department of Defense/ ; }, abstract = {BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.<br><br>METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer