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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 27 Jul 2021 at 01:33 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-07-22

Rhoades DA, Farley J, Schwartz SM, et al (2021)

Cancer mortality in a population-based cohort of American Indians - The strong heart study.

Cancer epidemiology, 74:101978 pii:S1877-7821(21)00095-3 [Epub ahead of print].

BACKGROUND: Cancer mortality among American Indian (AI) people varies widely, but factors associated with cancer mortality are infrequently assessed.

METHODS: Cancer deaths were identified from death certificate data for 3516 participants of the Strong Heart Study, a population-based cohort study of AI adults ages 45-74 years in Arizona, Oklahoma, and North and South Dakota. Cancer mortality was calculated by age, sex and region. Cox proportional hazards model was used to assess independent associations between baseline factors in 1989 and cancer death by 2010.

RESULTS: After a median follow-up of 15.3 years, the cancer death rate per 1000 person-years was 6.33 (95 % CI 5.67-7.04). Cancer mortality was highest among men in North/South Dakota (8.18; 95 % CI 6.46-10.23) and lowest among women in Arizona (4.57; 95 % CI 2.87-6.92). Factors independently associated with increased cancer mortality included age, current or former smoking, waist circumference, albuminuria, urinary cadmium, and prior cancer history. Factors associated with decreased cancer mortality included Oklahoma compared to Dakota residence, higher body mass index and total cholesterol. Sex was not associated with cancer mortality. Lung cancer was the leading cause of cancer mortality overall (1.56/1000 person-years), but no lung cancer deaths occurred among Arizona participants. Mortality from unspecified cancer was relatively high (0.48/100 person-years; 95 % CI 0.32-0.71).

CONCLUSIONS: Regional variation in AI cancer mortality persisted despite adjustment for individual risk factors. Mortality from unspecified cancer was high. Better understanding of regional differences in cancer mortality, and better classification of cancer deaths, will help healthcare programs address cancer in AI communities.

RevDate: 2021-07-22

Greninger AL (2021)

Unbiased Pandemic Pathogen Detection and the Federal Register.

While I agree with much of what was written in Dr. Kumeren Govender's commentary on how metagenomics will improve diagnostics and catch early pandemics ("Precision Pandemic Preparedness: Improving Diagnostics with Metagenomics"), significant attention to current regulatory matters is required before realizing the author's vision (1).….

RevDate: 2021-07-22

Boddicker NJ, Hu C, Weitzel JN, et al (2021)

Risk of Late-Onset Breast Cancer in Genetically Predisposed Women.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.

METHODS: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.

RESULTS: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2.

CONCLUSION: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

RevDate: 2021-07-22

Tadesse F, Asres G, Abubeker A, et al (2021)

Spectrum of BCR-ABL Mutations and Treatment Outcomes in Ethiopian Imatinib-Resistant Patients With Chronic Myeloid Leukemia.

JCO global oncology, 7:1187-1193.

PURPOSE: Despite the successes achieved in chronic myeloid leukemia (CML) with tyrosine kinase inhibitor (TKI) therapy, resistance remains an obstacle. The most common mechanism of resistance is the acquisition of a point mutation in the BCR-ABL kinase domain. Few studies have reported African patients with CML in regard to such mutations. We here report the types of BCR-ABL mutations in Ethiopian imatinib-resistant patients with CML and their outcome.

PATIENTS AND METHODS: Patients with CML with a diagnosis of imatinib resistance who were tested for BCR-ABL mutation between 2014 and September 2019 were included.

RESULTS: A total of 962 cases of CML on imatinib therapy were reviewed and 164 cases of failure were found. Of these, only 31 cases (19%) had mutation analysis performed. Most cases (94%) were secondary failures. At the time of CML diagnosis, the median age was 33 years and the majority presented with features of advanced-phase disease. Of the 31 patients, 22 mutations were found (65%). The types of mutations detected were as follows: non-P-loop mutations 36% (11), P-loop mutations 13% (four), and alternatively spliced BCR-ABL variants 23% (seven). The splice variant frequently detected was BCR-ABL35INS (20%). Twenty-six of the 31 patients (84%) were switched to second-line TKIs, whereas in four patients (13%), imatinib dose escalation was done. Overall, the outcome revealed that 16 patients (52%) were alive with complete hematologic response, whereas 12 patients (39%) had died. All patients who expressed BCR-ABL135INS were treated with second-line TKIs, and two of them (33%) had died because of disease progression.

CONCLUSION: In Ethiopia, CML affects the young and point mutations were frequently detected in imatinib-resistant patients. BCR-ABL1 35INS was also prevalent and associated with disease progression.

RevDate: 2021-07-22

Francini E, Montagnani F, Nuzzo PV, et al (2021)

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy.

JAMA network open, 4(7):e2116536 pii:2782169.

Importance: Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown.

Objective: To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy.

This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019.

Exposures: Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy.

Main Outcomes and Measures: The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used.

Results: Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001).

Conclusions and Relevance: In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

RevDate: 2021-07-22

Gooptu M, Romee R, St Martin A, et al (2021)

HLA-haploidentical vs matched unrelated donor transplants with posttransplant cyclophosphamide-based prophylaxis.

Blood, 138(3):273-282.

Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio [HR], 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.

RevDate: 2021-07-22

Advani RH, Skrypets T, Civallero M, et al (2021)

Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project.

Blood, 138(3):213-220.

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

RevDate: 2021-07-22

Leary SES, Packer RJ, Li Y, et al (2021)

Efficacy of Carboplatin and Isotretinoin in Children With High-risk Medulloblastoma: A Randomized Clinical Trial From the Children's Oncology Group.

JAMA oncology pii:2782033 [Epub ahead of print].

Importance: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed.

Objective: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma.

A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children's Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia.

Interventions: Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance.

Main Outcomes and Measures: The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array.

Results: Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P = .11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P = .047). Five-year overall survival differed by molecular subgroup (P = .006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%).

Conclusions and Relevance: In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT00392327.

RevDate: 2021-07-22

Johnson SB, Parsons M, Dorff T, et al (2021)

Cancer Misinformation and Harmful Information on Facebook and Other Social Media: A Brief Report.

Journal of the National Cancer Institute pii:6323231 [Epub ahead of print].

There are little data on the quality of cancer treatment information available on social media. Here, we quantify the accuracy of cancer treatment information on social media and its potential for harm. Two cancer experts reviewed 50 of the most popular social media articles on each of the 4 most common cancers. The proportion of misinformation and potential for harm were reported for all 200 articles, and their association with the number of social media engagements using a 2-sample Wilcoxon rank-sum test. All statistical tests were 2-sided. Of 200 total articles, 32.5% (n = 65) contained misinformation and 30.5% (n = 61) contained harmful information. Among articles containing misinformation, 76.9% (50 of 65) contained harmful information. The median number of engagements for articles with misinformation was greater than factual articles (median [IQR] = 2300 [1200-4700] vs 1600 [819-4700], P = .05). The median number of engagements for articles with harmful information was statistically significantly greater than safe articles (median [IQR] = 2300 [1400-4700] vs 1500 [810-4700], P = .007).

RevDate: 2021-07-22

Mohty R, J Gauthier (2021)

Current combinatorial CAR T cell strategies with Bruton tyrosine kinase inhibitors and immune checkpoint inhibitors.

Bone marrow transplantation [Epub ahead of print].

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown high efficacy in patients with refractory B-cell malignancies such as non-Hodgkin lymphoma and acute lymphoblastic leukemia. Despite promising results, responses are not durable in most patients. In addition, patients receiving CD19 CAR T cell therapy are at risk of developing severe, potentially life-threatening, adverse events including cytokine release syndrome and immune effector-cell associated neurotoxicity syndrome. Many combinatorial approaches are currently being investigated to improve CAR T cell in vivo function, antitumor effects, and mitigate toxicities. In this review, we discuss the use of ibrutinib and immune checkpoint inhibitors in combination with CAR T cell therapy in patients with lymphoid B-cell malignancies.

RevDate: 2021-07-21

Lind ML, Roncaioli S, Liu C, et al (2021)

Are hematopoietic cell transplant recipients with Gram-negative bacteremia spending more time outpatient while on intravenous antibiotics? Addressing trends over 10 years at a single center.

Immunity, inflammation and disease [Epub ahead of print].

INTRODUCTION: The increasing proportion of outpatient allogeneic hematopoietic cell transplants (HCTs) coupled with increased access of once-daily broad-spectrum antibiotics and evidence that outpatient antibiotic treatment may be safer and less costly than inpatient treatment, suggest that allogeneic HCT recipients with Gram-negative rod bacteremia (GNRBs) are increasingly being treated in ambulatory care settings.

METHODS: Using data from the first GNRB event that occurred within the first 100 days posttransplantation among allogeneic HCT recipients transplanted at a single center between 2007 and 2016, we estimated the temporal trends in GNRB incidence and treatment management of GNRBs and identified if patient or infection characteristics impacted observed trends.

RESULTS: A total of 11% (238/2165) of the observed allogeneic HCT recipients experienced ≥1 GNRB with available resistance data and contributed antibiotic treatment time. Patients, on average, received 55.1% of their antibiotic treatment in an outpatient setting and we observed a significant decline in the proportion of treatment time spent outpatient (crude: -3.3% [95% confidence interval: -5.0, -1.6%]). We observed similar declines in the proportion of treatment time spent outpatient among patients with similar GNRB and pretransplant complexity factors but not among patients with similar posttransplant complications (p value: .165).

CONCLUSION: These results suggest that, despite increased availability of outpatient suitable treatment options, allogeneic HCT recipients with GNRBs received less treatment in outpatient settings. However, among patients with similar posttransplant complications, the lack of significant decline suggests that treatment location decisions remained consistent for patients with similar posttransplant complications. These findings suggest the need for additional interventions targeting outpatient antibiotic treatment among allogeneic HCT recipients with GNRBs.

RevDate: 2021-07-21

Sholukh AM, Fiore-Gartland A, Ford ES, et al (2021)

Evaluation of cell-based and surrogate SARS-CoV-2 neutralization assays.

Journal of clinical microbiology [Epub ahead of print].

Determinants of protective immunity against SARS-CoV-2 infection require the development of well-standardized, reproducible antibody assays. This need has led to the emergence of a variety of neutralization assays. Head-to-head evaluation of different SARS-CoV-2 neutralization platforms could facilitate comparisons across studies and laboratories. Five neutralization assays were compared using forty plasma samples from convalescent individuals with mild-to-moderate COVID-19: four cell-based systems using either live recombinant SARS-CoV-2 or pseudotyped viral particles created with lentivirus (LV) or vesicular stomatitis virus (VSV) packaging and one surrogate ELISA-based test that measures inhibition of the spike protein receptor binding domain (RBD) binding its receptor, human angiotensin converting enzyme 2 (hACE2). Vero, Vero E6, HEK293T expressing hACE2, and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 were tested. All cell-based assays showed 50% neutralizing dilution (ND50) geometric mean titers (GMTs) that were highly correlated (Pearson r = 0.81-0.89) and ranged within 3.4-fold. The live-virus assay and LV-pseudovirus assays with HEK293T/hACE2 cells showed very similar mean titers: 141 and 178, respectively. ND50 titers positively correlated with plasma IgG targeting SARS-CoV-2 spike and RBD (r = 0.63-0.89), but moderately correlated with nucleoprotein IgG (r = 0.46-0.73). ND80 GMTs mirrored ND50 data and showed similar correlation between assays and with IgG concentrations. The VSV-pseudovirus assay and LV-pseudovirus assay with HEK293T/hACE2 cells in low and high-throughput versions were calibrated against the WHO SARS-CoV-2 IgG standard. High concordance between the outcomes of cell-based assays with live and pseudotyped virions enables valid cross-study comparison using these platforms. 249.

RevDate: 2021-07-21

Yeung C, Qu X, Sala-Torra O, et al (2021)

Mutational profiling in acute lymphoblastic leukemia by RNA sequencing and chromosomal genomic array testing.

Cancer medicine [Epub ahead of print].

BACKGROUND: Comprehensive molecular and cytogenetic profiling of acute lymphoblastic leukemia (ALL) is important and critical to the current standard of care for patients with B-acute lymphoblastic leukemia (B-ALL). Here we propose a rapid process for detecting gene fusions whereby FusionPlex RNA next-generation sequencing (NGS) and DNA chromosome genomic array testing (CGAT) are combined for a more efficient approach in the management of patients with B-ALL.

METHODS: We performed RNA NGS and CGAT on 28 B-ALL samples and, in four patients, compared fixed cell pellets to paired cryo-preserved samples as a starting material to further assess the utility of cytogenetic fixed pellets for gene expression analysis.

RESULTS: Among the fixed specimens, when using alternative techniques as references, including karyotype, fluorescence in situ hybridization, CGAT, and RT-qPCR, fusions were detected by RNA NGS with 100% sensitivity and specificity. In the four paired fixed versus fresh cryopreserved samples, fusions were also 100% concordant. Four of the 28 patients showed mutations that were detected by RNA sequencing and three of four of these mutations had well-known drug resistance implications.

CONCLUSIONS: We conclude that FusionPlex is a robust and reliable anchored multiplex RNA sequencing platform for use in the detection of fusions in both fresh cryopreserved and cytogenetic fixed pellets. Gene expression data could only be obtained from fresh samples and although limited variant data are available, critical hotspot variants can be determined in conjunction with the fusions.

RevDate: 2021-07-21

Trendowski MR, Baedke JL, Sapkota Y, et al (2021)

Clinical and genetic risk factors for radiation-associated ototoxicity: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Cancer [Epub ahead of print].

BACKGROUND: Cranial radiation therapy (CRT) is associated with ototoxicity, which manifests as hearing loss and tinnitus. The authors sought to identify clinical determinants and genetic risk factors for ototoxicity among adult survivors of pediatric cancer treated with CRT.

METHODS: Logistic regression evaluated associations of tinnitus (n = 1991) and hearing loss (n = 2198) with nongenetic risk factors and comorbidities among CRT-treated survivors in the Childhood Cancer Survivor Study. Genome-wide association studies (GWASs) of CRT-related tinnitus and hearing loss were also performed.

RESULTS: Males were more likely to report CRT-related tinnitus (9.4% vs 5.4%; P = 5.1 × 10-4) and hearing loss (14.0% vs 10.7%; P = .02) than females. Survivors with tinnitus or hearing loss were more likely to experience persistent dizziness or vertigo (tinnitus: P < 2 × 10-16 ; hearing loss: P = 6.4 × 10-9), take antidepressants (tinnitus: P = .02; hearing loss: P = .01), and report poorer overall health (tinnitus: P = 1.5 × 10-6 ; hearing loss: P = 1.7 × 10-6) in comparison with controls. GWAS of CRT-related tinnitus revealed a genome-wide significant signal in chromosome 1 led by rs203248 (P = 1.5 × 10-9), whereas GWAS of CRT-related hearing loss identified rs332013 (P = 5.8 × 10-7) in chromosome 8 and rs67522722 (P = 7.8 × 10-7) in chromosome 6 as nearly genome-wide significant. A replication analysis identified rs67522722, intronic to ATXN1, as being significantly associated with CRT-related hearing loss (P = .03) and de novo hearing loss (P = 3.6 × 10-4).

CONCLUSIONS: CRT-associated ototoxicity was associated with sex, several neuro-otological symptoms, increased antidepressant use, and poorer self-reported health. GWAS of CRT-related hearing loss identified rs67522722, which was supported in an independent cohort of survivors.

LAY SUMMARY: Hearing loss and subjective tinnitus (the perception of noise or ringing in the ear) are long-term side effects of cancer treatment and are common in children treated with radiation to the brain. These toxicities can affect childhood development and potentially contribute to serious learning and behavioral difficulties. This study's data indicate that males are at greater risk for hearing loss and tinnitus than females after radiation therapy to the brain. Those who develop these toxicities are more likely to use antidepressants and report poorer overall health. Health care providers can improve the management of survivors by informing patients and/or their parents of these risks.

RevDate: 2021-07-21

Srivatsan S, Heidl S, Pfau B, et al (2021)

SwabExpress: An end-to-end protocol for extraction-free covid-19 testing.

Clinical chemistry pii:6323225 [Epub ahead of print].

BACKGROUND: The urgent need for massively scaled clinical testing for SARS-CoV-2, along with global shortages of critical reagents and supplies, has necessitated development of streamlined laboratory testing protocols. Conventional nucleic acid testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab in transport medium, nucleic acid extraction, and quantitative reverse transcription PCR (RT-qPCR) (1). As testing has scaled across the world, the global supply chain has buckled, rendering testing reagents and materials scarce (2). To address shortages, we developed SwabExpress, an end-to-end protocol developed to employ mass produced anterior nares swabs and bypass the requirement for transport media and nucleic acid extraction.

METHODS: We evaluated anterior nares swabs, transported dry and eluted in low-TE buffer as a direct-to-RT-qPCR alternative to extraction-dependent viral transport media. We validated our protocol of using heat treatment for viral inactivation and added a proteinase K digestion step to reduce amplification interference. We tested this protocol across archived and prospectively collected swab specimens to fine-tune test performance.

RESULTS: After optimization, SwabExpress has a low limit of detection at 2-4 molecules/uL, 100% sensitivity, and 99.4% specificity when compared side-by-side with a traditional RT-qPCR protocol employing extraction. On real-world specimens, SwabExpress outperforms an automated extraction system while simultaneously reducing cost and hands-on time.

CONCLUSION: SwabExpress is a simplified workflow that facilitates scaled testing for COVID-19 without sacrificing test performance. It may serve as a template for the simplification of PCR-based clinical laboratory tests, particularly in times of critical shortages during pandemics.

RevDate: 2021-07-21

Li S, Simoni Y, Zhuang S, et al (2021)

Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies.

Proceedings of the National Academy of Sciences of the United States of America, 118(30):.

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti-PD-1 and anti-CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen-specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.

RevDate: 2021-07-20

Lee H, Nakamura K, Narayanan S, et al (2021)

Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis.

Multiple sclerosis and related disorders, 54:103149 pii:S2211-0348(21)00416-8 [Epub ahead of print].

BACKGROUND: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT.

METHODS: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up.

RESULTS: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not.

CONCLUSIONS: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level.

RevDate: 2021-07-20

Alderuccio JP, Olszewski AJ, Evens AM, et al (2021)

HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis.

Blood advances, 5(14):2852-2862.

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

RevDate: 2021-07-20

Schroeder CM, Tomlin SA, Mejia Natividad I, et al (2021)

An actin-related protein that is most highly expressed in Drosophila testes is critical for embryonic development.

eLife, 10: pii:71279.

Most actin-related proteins (Arps) are highly conserved and carry out well-defined cellular functions in eukaryotes. However, many lineages like Drosophila and mammals encode divergent non-canonical Arps whose roles remain unknown. To elucidate the function of non-canonical Arps, we focus on Arp53D, which is highly expressed in testes and retained throughout Drosophila evolution. We show that Arp53D localizes to fusomes and actin cones, two germline-specific actin structures critical for sperm maturation, via a unique N-terminal tail. Surprisingly, we find that male fertility is not impaired upon Arp53D loss, yet population cage experiments reveal that Arp53D is required for optimal fitness in Drosophila melanogaster. To reconcile these findings, we focus on Arp53D function in ovaries and embryos where it is only weakly expressed. We find that under heat stress Arp53D-knockout (KO) females lay embryos with reduced nuclear integrity and lower viability; these defects are further exacerbated in Arp53D-KO embryos. Thus, despite its relatively recent evolution and primarily testis-specific expression, non-canonical Arp53D is required for optimal embryonic development in Drosophila.

RevDate: 2021-07-20

Heffner JL, Coggeshall S, Wheat CL, et al (2021)

Receipt of Tobacco Treatment and One-Year Smoking Cessation Rates Following Lung Cancer Screening in the Veterans Health Administration.

Journal of general internal medicine [Epub ahead of print].

BACKGROUND: Implementation of effective smoking cessation interventions in lung cancer screening has been identified as a high-priority research gap, but knowledge of current practices to guide process improvement is limited due to the slow uptake of screening and dearth of data to assess cessation-related practices and outcomes under real-world conditions.

OBJECTIVE: To evaluate cessation treatment receipt and 1-year post-screening cessation outcomes within the largest integrated healthcare system in the USA-the Veterans Health Administration (VHA). Design Observational study using administrative data from electronic medical records (EMR). Patients Currently smoking Veterans who received a first lung cancer screening test using low-dose CT (LDCT) between January 2014 and June 2018. Main Outcomes Tobacco treatment received within the window of 30 days before and 30 days after LDCT; 1-year quit rates based on EMR Smoking Health Factors data 6-18 months after LDCT. Key Results Of the 47,609 current smokers screened (95.3% male), 8702 (18.3%) received pharmacotherapy and/or behavioral treatment for smoking cessation; 531 (1.1%) received both. Of those receiving pharmacotherapy, only one in four received one of the most effective medications: varenicline (12.1%) or combination nicotine replacement therapy (14.3%). Overall, 5400 Veterans quit smoking-a rate of 11.3% (missing=smoking) or 13.5% (complete case analysis). Treatment receipt and cessation were associated with numerous sociodemographic, clinical, and screening-related factors.

CONCLUSIONS: One-year quit rates for Veterans receiving lung cancer screening in VHA are similar to those reported in LDCT clinical trials and cohort studies (i.e., 10-17%). Only 1% of Veterans received the recommended combination of pharmacotherapy and counseling, and the most effective pharmacotherapies were not the most commonly received ones. The value of screening within VHA could be improved by addressing these treatment gaps, as well as the observed disparities in treatment receipt or cessation by race, rurality, and psychiatric conditions.

RevDate: 2021-07-20

Starr TN, Czudnochowski N, Zatta F, et al (2021)

Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape.

bioRxiv : the preprint server for biology.

An ideal anti-SARS-CoV-2 antibody would resist viral escape 1-3 , have activity against diverse SARS-related coronaviruses 4-7 , and be highly protective through viral neutralization 8-11 and effector functions 12,13 . Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S309 4 , the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 in vitro neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.

RevDate: 2021-07-19

Tortorici MA, Czudnochowski N, Starr TN, et al (2021)

Broad sarbecovirus neutralization by a human monoclonal antibody.

Nature pii:10.1038/s41586-021-03817-4 [Epub ahead of print].

The recent emergence of SARS-CoV-2 variants of concern (VOC)1-10 and the recurrent spillovers of coronaviruses11,12 in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1, B.1.427/B.1.429 VOC, as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile limited to the single substitution G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters against challenge with the prototypic SARS-CoV-2 and the B.1.351 VOC, suggesting this mAb is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

RevDate: 2021-07-19

Mostaghel EA (2021)

Statins and adrenal androgen levels in prostate cancer: A new twist.

EBioMedicine, 70:103494 pii:S2352-3964(21)00287-5 [Epub ahead of print].

RevDate: 2021-07-19

Ahmad K, S Henikoff (2021)

The H3.3K27M oncohistone antagonizes reprogramming in Drosophila.

PLoS genetics, 17(7):e1009225 pii:PGENETICS-D-20-01723 [Epub ahead of print].

Development proceeds by the activation of genes by transcription factors and the inactivation of others by chromatin-mediated gene silencing. In certain cases development can be reversed or redirected by mis-expression of master regulator transcription factors. This must involve the activation of previously silenced genes, and such developmental aberrations are thought to underlie a variety of cancers. Here, we express the wing-specific Vestigial master regulator to reprogram the developing eye, and test the role of silencing in reprogramming using an H3.3K27M oncohistone mutation that dominantly inhibits histone H3K27 trimethylation. We find that production of the oncohistone blocks eye-to-wing reprogramming. CUT&Tag chromatin profiling of mutant tissues shows that H3K27me3 of domains is generally reduced upon oncohistone production, suggesting that a previous developmental program must be silenced for effective transformation. Strikingly, Vg and H3.3K27M synergize to stimulate overgrowth of eye tissue, a phenotype that resembles that of mutations in Polycomb silencing components. Transcriptome profiling of elongating RNA Polymerase II implicates the mis-regulation of signaling factors in overgrowth. Our results demonstrate that growth dysregulation can result from the simple combination of crippled silencing and transcription factor mis-expression, an effect that may explain the origins of oncohistone-bearing cancers.

RevDate: 2021-07-19

Estey E, Talpaz M, H Kantarjian (2021)

Remembering Emil J. Freireich: A Portrait of Courage and Innovation in Cancer Research-March 16, 1927 to February 1, 2021.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

RevDate: 2021-07-19

Alexander S, Swami U, Kaur A, et al (2021)

Safety of immune checkpoint inhibitors in patients with cancer and pre-existing autoimmune disease.

Annals of translational medicine, 9(12):1033.

Background: Patients with pre-existing autoimmune disease (AD) have been largely excluded from clinical trials of immune checkpoint inhibitors (ICI), so data on safety of ICIs among patients with pre-existing AD are relatively limited. There is a need for deeper understanding of the type and management of complications from ICI in patients with pre-existing AD. We sought to investigate the safety of ICIs in patients with pre-existing ADs as well as factors associated with AD flare.

Methods: Consecutive patients with pre-existing AD who received monotherapy as well as combination of ICI therapies at our institution from September 2015 through September 1st, 2018 were identified. Clinical information was abstracted via manual chart review. Clinical factors associated with AD flare were determined using multivariable logistic regression.

Results: A total of 42 patients were identified of whom 12 developed AD flare. All flares were treated with oral or topical corticosteroids, while a patient with flare of rheumatoid arthritis was treated with tofacitinib and another patient with Crohn's flare was treated with infliximab. Female sex, smoking status, higher age at the start of ICI therapy, cancer type, such as melanoma and lung cancer as compared to other cancers, were not significantly associated with AD flare, however, patients with underlying rheumatologic AD were noted to have a five times greater likelihood of flare as compared to other non-rheumatologic AD. Nine patients developed new immune related adverse events (IRAEs) unrelated to underlying AD, such as inflammatory poly-arthropathy, neuropathy, hypothyroidism, diarrhea, lichenoid drug eruptions, which were managed with oral and/or topical corticosteroids. ICI was stopped in six patients due to AD flare, in four patients due to IRAE flare (out of which one resumed ICI after resolution of IRAE).

Conclusions: In patients with pre-existing AD treated with ICI, AD flare occurred in 28% of patients and were managed successfully with corticosteroids alone or with additional disease-modifying therapies. ICI could be considered in patients with AD, but with very close monitoring and preemptive multidisciplinary collaboration.

RevDate: 2021-07-19

Shin MB, Liu G, Mugo N, et al (2021)

A Framework for Cervical Cancer Elimination in Low-and-Middle-Income Countries: A Scoping Review and Roadmap for Interventions and Research Priorities.

Frontiers in public health, 9:670032.

The World Health Organization announced an ambitious call for cervical cancer elimination worldwide. With existing prevention and treatment modalities, cervical cancer elimination is now within reach for high-income countries. Despite limited financing and capacity constraints in low-and-middle-income countries (LMICs), prevention and control efforts can be supported through integrated services and new technologies. We conducted this scoping review to outline a roadmap toward cervical cancer elimination in LMICs and highlight evidence-based interventions and research priorities to accelerate cervical cancer elimination. We reviewed and synthesized literature from 2010 to 2020 on primary and secondary cervical cancer prevention strategies. In addition, we conducted expert interviews with gynecologic and infectious disease providers, researchers, and LMIC health officials. Using these data, we developed a logic model to summarize the current state of science and identified evidence gaps and priority research questions for each prevention strategy. The logic model for cervical cancer elimination maps the needs for improved collaboration between policy makers, production and supply, healthcare systems, providers, health workers, and communities. The model articulates responsibilities for stakeholders and visualizes processes to increase access to and coverage of prevention methods. We discuss the challenges of contextual factors and highlight innovation needs. Effective prevention methods include HPV vaccination, screening using visual inspection and HPV testing, and thermocoagulation. However, vaccine coverage remains low in LMICs. New strategies, including single-dose vaccination could enhance impact. Loss to follow-up and treatment delays could be addressed by improved same-day screen-and-treat technologies. We provide a practical framework to guide cervical cancer elimination in LMICs. The scoping review highlights existing and innovative strategies, unmet needs, and collaborations required to achieve elimination across implementation contexts.

RevDate: 2021-07-19

Roe D, Vierra-Green C, Pyo CW, et al (2021)

Corrigendum: A Detailed View of KIR Haplotype Structures and Gene Families as Provided by a New Motif-Based Multiple Sequence Alignment.

Frontiers in immunology, 12:724357.

[This corrects the article DOI: 10.3389/fimmu.2020.585731.].

RevDate: 2021-07-18

Hare J, Fiore-Gartland A, Gowan EM, et al (2021)

Selective HLA restriction enables the evaluation and interpretation of immunogenic breadth at comparable levels to that observed with broader HLA distribution.

Proteomics [Epub ahead of print].

Existing approaches to identifying predictive T-cell epitopes have traditionally utilized either 2-digit HLA super-families or more commonly utilizing autologous HLA alleles to facilitate the predictions. However, the use of these criteria may not consider the HLA representation within any target population. Here we propose a modification to concept of utilizing autologous HLA whereby subsets of individuals are selected for their specific HLA allele profiles and the representation they provide within a given population. Using this selective approach to HLA selection and the linkages to specific individuals may enable the design of more targeted experimental strategies. This article is protected by copyright. All rights reserved.

RevDate: 2021-07-18

Feld LD, Cleveland ER, Rabinowitz LG, et al (2021)

Analysis of Speaker Introduction Formality by Gender at the American College of Gastroenterology 2020 Annual Scientific Meeting.

Digestive diseases and sciences [Epub ahead of print].

BACKGROUND: Gender-based differences in the use of professional titles during speaker introductions have been described in other medical specialties.

AIMS: Our primary aim was to assess gender-based differences in the formality of speaker introductions at the American College of Gastroenterology 2020 Virtual Annual Scientific Meeting. Our secondary aim was to assess gender-based differences in the formality of speaker self-introductions.

METHODS: Reviewed presentations from the American College of Gastroenterology Annual Meeting for gender-based differences in professional title use during speaker introductions and self-introductions.

RESULTS: Speakers included 29 women (37.2%) and 49 men (62.8%). We found no significant gender differences in the use of professional titles by introducers (t(67) = - 0.775, p = 0.441) or in self-introductions (36.4% of women vs. 41.9% of men, t(63) = 0.422, p = 0.674).

CONCLUSION: The lack of gender differences in professional title use may represent a novel advantage of virtual meeting formats or suggest increased attention to gender bias in introductions.

RevDate: 2021-07-18

Salmon C, Song L, Muir K, et al (2021)

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

European journal of epidemiology [Epub ahead of print].

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.

RevDate: 2021-07-18

Sanft T, Harrigan M, Cartmel B, et al (2021)

Effect of healthy diet and exercise on chemotherapy completion rate in women with breast cancer: The Lifestyle, Exercise and Nutrition Early after Diagnosis (LEANer) study: Study protocol for a randomized clinical trial.

Contemporary clinical trials pii:S1551-7144(21)00244-5 [Epub ahead of print].

BACKGROUND: The World Cancer Research Fund and the American Cancer Society provide nutrition and physical activity guidelines for cancer survivors. Many women with breast cancer do not follow these guidelines and delay efforts toward following them until active treatment is complete. However, adoption of these recommended lifestyle behaviors soon after diagnosis may prevent adverse treatment-related side effects and may improve adherence to treatment, resulting in improved breast cancer prognosis. The Lifestyle, Exercise, and Nutrition Early after Diagnosis (LEANer) study is testing the effect of a nutrition and physical activity intervention on chemotherapy completion rates.

METHODS: 172 women with stage I-III breast cancer undergoing chemotherapy will be randomized 1:1 to a yearlong, 16 session, nutrition and exercise intervention or usual care control group. The intervention is delivered by registered dietitians specializing in oncology nutrition and exercise training. The intervention includes goal setting to meet nutrition and physical activity guidelines for cancer survivors. After each chemotherapy session, date and dose of each drug administered, and reason for dose-adjustments and/or dose-delays are abstracted from the electronic medical record or obtained from the treating oncologist. Chemotherapy completion rate is assessed as the average relative dose-intensity (RDI) for the originally planned regimen based on standard formulas. Secondary endpoints of endocrine therapy adherence, treatment-related side effects, and changes in inflammatory and metabolic biomarkers, body composition, and patient reported outcomes are assessed at four timepoints.

DISCUSSION: If successful, this study has the potential to make healthy lifestyle interventions a standard component of breast cancer treatment.

RevDate: 2021-07-16

Cheng Y, Gunasegaran B, Singh HD, et al (2021)

Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma.

Immunity pii:S1074-7613(21)00257-0 [Epub ahead of print].

Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.

RevDate: 2021-07-16

King G, M Javle (2021)

FGFR Inhibitors: Clinical Activity and Development in the Treatment of Cholangiocarcinoma.

Current oncology reports, 23(9):108.

PURPOSE OF REVIEW: Cholangiocarcinoma is an aggressive cancer with a poor prognosis and limited treatment. Gene sequencing studies have identified genetic alterations in fibroblast growth factor receptor (FGFR) in a significant proportion of cholangiocarcinoma (CCA) patients. This review will discuss the FGFR signaling pathway's role in CCA and highlight the development of therapeutic strategies targeting this pathway.

RECENT FINDINGS: The development of highly potent and selective FGFR inhibitors has led to the approval of pemigatinib for FGFR2 fusion or rearranged CCA. Other selective FGFR inhibitors are currently under clinical investigation and show promising activity. Despite encouraging results, the emergence of resistance is inevitable. Studies using circulating tumor DNA and on-treatment tissue biopsies have elucidated underlying mechanisms of intrinsic and acquired resistance. There is a critical need to not only develop more effective compounds, but also innovative sequencing strategies and combinations to overcome resistance to selective FGFR inhibition. Therapeutic development of precision medicine for FGFR-altered CCA is a dynamic process of involving a comprehensive understanding of tumor biology, rational clinical trial design, and therapeutic optimization. Alterations in FGFR represent a valid therapeutic target in CCA and selective FGFR inhibitors are treatment options for this patient population.

RevDate: 2021-07-16

Casto A, Seo S, Levine D, et al (2021)

Genetic Variants Associated with Cytomegalovirus Infection after Allogeneic Hematopoietic Cell Transplantation.

Blood pii:476416 [Epub ahead of print].

Human cytomegalovirus (CMV) reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Despite routine screening for CMV reactivation and early antiviral treatment, the rates of CMV-related complications after HCT remain high. Genetic variants in both the donor and recipient have been associated with the risk of CMV reactivation and disease after HCT, but these associations have not been validated and their clinical importance remains unclear. In this study, we assessed 117 candidate variants previously associated with CMV-related phenotypes for association with CMV reactivation and disease in a cohort of 2169 CMV-seropositive HCT recipients. We also carried out a genome-wide association study (GWAS) for CMV reactivation and disease in the same cohort. Both analyses used a pre-specified discovery and replication approach to control the risk of false-positive results. Among the 117 candidate variants, our analysis implicates only the donor ABCB1 rs1045642 genotype as a risk factor for CMV reactivation. This synonymous variant in P-glycoprotein may influence the risk of CMV reactivation by altering the efflux of cyclosporine and tacrolimus from donor lymphocytes. In the GWAS analysis, the donor CDC42EP3 rs11686168 genotype approached the significance threshold for association with CMV reactivation, although we could not identify a mechanism to explain this association. The results of this study suggest that most genomic variants previously associated with CMV phenotypes do not significantly alter the risk for CMV reactivation or disease after HCT.

RevDate: 2021-07-16

Huynh P, Williams J, Shannon Dorcy K, et al (2021)

Theory-Informed Models: Application to Nursing Practice.

Clinical journal of oncology nursing, 25(4):474-478.

The processes for review and confirmation of a theoretical model, its translation into current clinical practice, and the evaluation of outcomes will be presented. The authors' experience at the Seattle Cancer Care Alliance in Washington illustrates the value and relevance of theoretical models in oncology care.

RevDate: 2021-07-16

Ellis D, Brunette N, Crawford KHD, et al (2021)

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design.

Frontiers in immunology, 12:710263.

The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.

RevDate: 2021-07-16

Galsky MD, Balar AV, Black PC, et al (2021)

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer.

Journal for immunotherapy of cancer, 9(7):.

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

RevDate: 2021-07-15

Cutler CS, Lee SJ, Arai S, et al (2021)

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood pii:476399 [Epub ahead of print].

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).

RevDate: 2021-07-15

Gettinger SN, Redman MW, Bazhenova L, et al (2021)

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial.

JAMA oncology pii:2781889 [Epub ahead of print].

Importance: Nivolumab plus ipilimumab is superior to platinum-based chemotherapy in treatment-naive advanced non-small cell lung cancer (NSCLC). Nivolumab is superior to docetaxel in advanced pretreated NSCLC.

Objective: To determine whether the addition of ipilimumab to nivolumab improves survival in patients with advanced, pretreated, immunotherapy-naive squamous (Sq) NSCLC.

The Lung Cancer Master Protocol (Lung-MAP) S1400I phase 3, open-label randomized clinical trial was conducted from December 18, 2015, to April 23, 2018, randomizing patients in a 1:1 ratio to nivolumab alone or combined with ipilimumab. The median follow-up in surviving patients was 29.5 months. The trial was conducted through the National Clinical Trials Network and included patients with advanced immunotherapy-naive SqNSCLC and a Zubrod score of 0 (asymptomatic) to 1 (symptomatic but completely ambulatory) with disease progression after standard platinum-based chemotherapy. Randomization was stratified by sex and number of prior therapies (1 vs 2 or more). Data were analyzed from May 3, 2018, to February 1, 2021.

Interventions: Nivolumab, 3 mg/kg intravenously every 2 weeks, with or without ipilimumab, 1 mg/kg intravenously every 6 weeks, until disease progression or intolerable toxic effects.

Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (IA-PFS) and response per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1.

Results: Of 275 enrolled patients, 252 (mean age, 67.5 years [range 41.8-90.3 years]; 169 men [67%]; 206 White patients [82%]) were deemed eligible (125 randomized to nivolumab/ipilimumab and 127 to nivolumab). The study was closed for futility at a planned interim analysis. Overall survival was not significantly different between the groups (hazard ratio [HR], 0.87; 95% CI, 0.66-1.16; P = .34). Median survival was 10 months (95% CI, 8.0-14.4 months) in the nivolumab/ipilimumab group and 11 months (95% CI, 8.6-13.7 months) in the nivolumab group. The IA-PFS HR was 0.80 (95% CI, 0.61-1.03; P = .09); median IA-PFS was 3.8 months (95% CI, 2.7-4.4 months) in the nivolumab/ipilimumab group and 2.9 months (95% CI, 1.8-4.0 months) in the nivolumab alone group. Response rates were 18% (95% CI, 12%-25%) with nivolumab/ipilimumab and 17% (95% CI, 10%-23%) with nivolumab. Median response duration was 28.4 months (95% CI, 4.9 months to not reached) with nivolumab/ipilimumab and 9.7 months with nivolumab (95% CI, 4.2-23.1 months). Grade 3 or higher treatment-related adverse events occurred in 49 of 124 patients (39.5%) who received nivolumab/ipilimumab and in 41 of 123 (33.3%) who received nivolumab alone. Toxic effects led to discontinuation in 31 of 124 patients (25%) on nivolumab/ipilimumab and in 19 of 123 (15%) on nivolumab.

Conclusions and Relevance: In this phase 3 randomized clinical trial, ipilimumab added to nivolumab did not improve outcomes in patients with advanced, pretreated, immune checkpoint inhibitor-naive SqNSCLC.

Trial Registration: ClinicalTrials.gov Identifier: NCT02785952.

RevDate: 2021-07-15

Shipley MM, Mangala Prasad V, Doepker LE, et al (2021)

Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection.

eLife, 10: pii:68110 [Epub ahead of print].

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

RevDate: 2021-07-15

Newcomb PA, Ton M, Malen RC, et al (2021)

Cannabis use is associated with patient and clinical factors in a population-based sample of colorectal cancer survivors.

Cancer causes & control : CCC [Epub ahead of print].

PURPOSE: This study aimed to characterize patient and clinical factors associated with cannabis (marijuana) use among patients diagnosed with colorectal cancer (CRC).

METHODS: We identified CRC patients, diagnosed from 2016 to 2018, using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. CRC patients were recruited via mail and telephone, and participants completed a questionnaire eliciting information on medical history, demographics, and lifestyle factors, including cannabis use. Cancer stage was obtained from SEER registry data.

RESULTS: Of 1,433 survey respondents, 339 (24%) were current cannabis users. Current cannabis use was associated with younger age at diagnosis, lower BMI, and a higher prevalence of cigarette smoking and alcohol consumption (p-value < 0.05). Cannabis use was also associated with lower quality of life scores (FACT-C) and advanced-stage cancer (p-value < 0.05).

CONCLUSION: Cannabis use among CRC patients was common. Patients with more advanced disease were more likely to report cannabis use. Use also varied by some personal factors, consistent with patterns in the general population. Given the high prevalence of cannabis use among CRC patients, research is needed to determine the benefits and harms of cannabis use for symptom management in cancer patients.

RevDate: 2021-07-15

Gulleen EA, Adams SV, Chang BH, et al (2021)

Factors and Outcomes Related to the Use of Guideline-Recommended Antibiotics in Patients With Neutropenic Fever at the Uganda Cancer Institute.

Open forum infectious diseases, 8(7):ofab307 pii:ofab307.

Background: Neutropenic fever (NF) is associated with significant morbidity and mortality for patients receiving cancer treatment in sub-Saharan Africa (sSA). However, the antibiotic management of NF in sub-Saharan Africa has not been well described. We evaluated the timing and selection of antibiotics for patients with NF at the Uganda Cancer Institute (UCI).

Methods: We conducted a retrospective chart review of adults with acute leukemia admitted to UCI from 1 January 2016 to 31 May 2017, who developed NF. For each NF event, we evaluated the association of clinical presentation and demographics with antibiotic selection as well as time to both initial and guideline-recommended antibiotics. We also evaluated the association between ordered antibiotics and the in-hospital case fatality ratio (CFR).

Results: Forty-nine NF events occurred among 39 patients. The time to initial antibiotic order was <1 day. Guideline-recommended antibiotics were ordered for 37 (75%) NF events. The median time to guideline-recommended antibiotics was 3 days. Fever at admission, a documented physical examination, and abdominal abnormalities were associated with a shorter time to initial and guideline-recommended antibiotics. The in-hospital CFR was 43%. There was no difference in in-hospital mortality when guideline-recommended antibiotics were ordered as compared to when non-guideline or no antibiotics were ordered (hazard ratio, 0.51 [95% confidence interval {CI}, .10-2.64] and 0.78 [95% CI, .20-2.96], respectively).

Conclusions: Patients with acute leukemia and NF had delayed initiation of guideline-recommended antibiotics and a high CFR. Prospective studies are needed to determine optimal NF management in sub-Saharan Africa, including choice of antibiotics and timing of antibiotic initiation.

RevDate: 2021-07-15

Tan KT, Kim H, Carrot-Zhang J, et al (2021)

Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

Genome medicine, 13(1):114.

BACKGROUND: Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.

METHODS: We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.

RESULTS: We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events.

CONCLUSIONS: Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.

RevDate: 2021-07-14

Starr TN, Czudnochowski N, Liu Z, et al (2021)

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.

Nature pii:10.1038/s41586-021-03807-6 [Epub ahead of print].

An ideal anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse SARS-related coronaviruses (sarbecoviruses)4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

RevDate: 2021-07-14

Zeiser R, Polverelli N, Ram R, et al (2021)

Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.

The New England journal of medicine, 385(3):228-238.

BACKGROUND: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.

METHODS: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.

RESULTS: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.

CONCLUSIONS: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).

RevDate: 2021-07-14

Li A, Kuderer NM, Hsu CY, et al (2021)

The CoVID-TE Risk Assessment Model for Venous Thromboembolism in Hospitalized Patients with Cancer and COVID-19.

Journal of thrombosis and haemostasis : JTH [Epub ahead of print].

BACKGROUND: Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking.

METHODS: Among patients with cancer in the CCC19 cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19 associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.

FINDINGS: From 3/17/2020 to 11/30/2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n=1423 vs. high-risk, 3+ points, n=1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% CI 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.

INTERPRETATION: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.

RevDate: 2021-07-14

Lin DY, Gu Y, Zeng D, et al (2021)

Evaluating Vaccine Efficacy Against SARS-CoV-2 Infection.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6321290 [Epub ahead of print].

Although interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically in- fected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Ad- ditional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment of participants or crossover of placebo recipients to the vaccine arm before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, stag- gered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.

RevDate: 2021-07-14

Chawla SP, Van Tine BA, Pollack SM, et al (2021)

Phase II Randomized Study of CMB305 and Atezolizumab Compared With Atezolizumab Alone in Soft-Tissue Sarcomas Expressing NY-ESO-1.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1-specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti-programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma.

PATIENTS AND METHODS: Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed.

RESULTS: A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1-specific T cells (P = .01) and NY-ESO-1-specific antibody responses (P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02).

CONCLUSION: Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti-programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

RevDate: 2021-07-14

Ketterl TG, Ballard S, Bradford MC, et al (2021)

Feasibility and acceptability of a home-based resistance training intervention in adolescent and young adult hematopoietic cell transplant survivors.

Pediatric blood & cancer [Epub ahead of print].

BACKGROUND: Adolescent and young adult (AYA) hematopoietic cell transplantation (HCT) survivors are at increased risk of metabolic syndrome and lean body mass (LBM) deficits. Resistance training (RT) is a potential intervention to improve LBM, metabolic fitness, and reduce risk of cardiovascular disease.

PROCEDURE: Eligible participants ages 13-39 years, 80-120 days post-HCT, transfusion independent, and prednisone dose ≤1 mg/kg/day were approached. Baseline assessments of body composition (DXA), anthropometrics, and strength testing were completed and participants were taught a 12-week, home-based RT intervention with weekly remote coaching. Follow-up assessments were at day +200 (FU1) and +365 post-HCT (FU2). Feasibility targets were (a) 60% enrollment of approached patients, (b) 80% completion of weekly phone calls, and (c) 80% completion of the RT intervention and FU1 assessments. Acceptability was based on positive responses in qualitative interviews.

RESULTS: Twenty of 31 (65%) eligible AYAs enrolled. Three participants failed to complete baseline measurements (2 = scheduling barriers, 1 = passive refusal) and four participants who completed baseline assessments did not receive the intervention (1 = medical reasons, 2 = no longer interested). Of those who completed baseline assessments, 13 received the intervention, completed 88.5% of coaching calls, and 11 (65%) completed FU1. LBM (kg) increased or remained unchanged in nine of nine participants with complete body composition data at FU1 (mean 1.1 kg; 95%CI: 0.4, 1.9). All participants who completed FU1 reported they would recommend the intervention to an AYA HCT survivor.

CONCLUSIONS: A home-based RT intervention in AYA HCT survivors early post HCT is both feasible and acceptable and may maintain or increase LBM.

RevDate: 2021-07-14

Schmidt KA, Cromer G, Burhans MS, et al (2021)

Impact of low-fat and full-fat dairy foods on fasting lipid profile and blood pressure: exploratory endpoints of a randomized controlled trial.

The American journal of clinical nutrition pii:6320817 [Epub ahead of print].

BACKGROUND: Dietary guidelines traditionally recommend low-fat dairy because dairy's high saturated fat content is thought to promote cardiovascular disease (CVD). However, emerging evidence indicates that dairy fat may not negatively impact CVD risk factors when consumed in foods with a complex matrix.

OBJECTIVE: The aim was to compare the effects of diets limited in dairy or rich in either low-fat or full-fat dairy on CVD risk factors.

METHODS: In this randomized controlled trial, 72 participants with metabolic syndrome completed a 4-wk run-in period, limiting their dairy intake to ≤3 servings/wk of nonfat milk. Participants were then randomly assigned to 1 of 3 diets, either continuing the limited-dairy diet or switching to a diet containing 3.3 servings/d of either low-fat or full-fat milk, yogurt, and cheese for 12 wk. Exploratory outcome measures included changes in the fasting lipid profile and blood pressure.

RESULTS: In the per-protocol analysis (n = 66), there was no intervention effect on fasting serum total, LDL, and HDL cholesterol; triglycerides; free fatty acids; or cholesterol content in 38 isolated plasma lipoprotein fractions (P > 0.1 for all variables in repeated-measures ANOVA). There was also no intervention effect on diastolic blood pressure, but a significant intervention effect for systolic blood pressure (P = 0.048), with a trend for a decrease in the low-fat dairy diet (-1.6 ± 8.6 mm Hg) compared with the limited-dairy diet (+2.5 ± 8.2 mm Hg) in post hoc testing. Intent-to-treat results were consistent for all endpoints, with the exception that systolic blood pressure became nonsignificant (P = 0.08).

CONCLUSIONS: In men and women with metabolic syndrome, a diet rich in full-fat dairy had no effects on fasting lipid profile or blood pressure compared with diets limited in dairy or rich in low-fat dairy. Therefore, dairy fat, when consumed as part of complex whole foods, does not adversely impact these classic CVD risk factors. This trial was registered at clinicaltrials.gov as NCT02663544.

RevDate: 2021-07-14

Julián-Serrano S, Yuan F, Wheeler W, et al (2021)

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

The American journal of clinical nutrition pii:6320813 [Epub ahead of print].

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

RevDate: 2021-07-15

Mollan KR, Eron JJ, Krajewski TJ, et al (2021)

SARS-CoV-2 infectious virus, viral RNA in nasopharyngeal swabs, and serostatus of symptomatic COVID-19 outpatients in the United States.

medRxiv : the preprint server for health sciences.

Background: SARS-CoV-2 infectious virus isolation in the upper airway of COVID-19 patients is associated with higher levels of viral RNA. However, comprehensive evaluation of the relationships between host and disease factors and infectious, replication competent virus is needed.

Methods: Symptomatic COVID-19 outpatients were enrolled from the United States. Clinical symptoms were recorded via patient diary. Nasopharyngeal swabs were collected to quantitate SARS-CoV-2 RNA by reverse transcriptase polymerase chain reaction and for infectious virus isolation in Vero E6-cells. SARS-CoV-2 antibodies were measured in serum using a validated ELISA assay.

Findings: Among 204 participants within one week of reported symptom onset (median=5, IQR 4-5 days), median age was 40 (min-max: 18-82 years), median nasopharyngeal viral RNA was 6.5 (IQR 4.7-7.6 log 10 copies/mL), and 26% had detectable SARS-CoV-2 antibodies at baseline. Infectious virus was recovered in 7% of participants with antibodies compared to 58% of participants without antibodies (probability ratio (PR)=0.12, 95% CI: 0.04, 0.36; p=0.00016). Infectious virus isolation was also associated with higher levels of viral RNA (mean RNA difference +2.6 log 10 , 95% CI: 2.2, 3.0; p<0.0001) and fewer days since symptom onset (PR=0.79, 95% CI: 0.71, 0.88 per day; p<0.0001).

Interpretation: The presence of SARS-CoV-2 antibodies is strongly associated with clearance of infectious virus isolation. Seropositivity and viral RNA are likely more reliable markers of infectious virus suppression than subjective measure of COVID-19 symptoms. Virus-targeted treatment and prevention strategies should be administered as early as possible and ideally before seroconversion.

Funding: Ridgeback Biotherapeutics, LP and NIH.

ClinicalTrialsgov Identifier: NCT04405570.

Research in Context: Evidence before this study: A deeper understanding of the viral and host factors associated with infectious virus detection is essential to accurately identify and quarantine contagious individuals. Several studies have reported associations between SARS-CoV-2 virus isolation and viral RNA levels or time from symptom onset. However, little is known about which host factors (i.e. demographics, comorbidities, SARS-CoV-2 seropositivity, symptomatology etc.) are associated with infectious virus detection. A search of PubMed on 12 April 2021 using keywords "COVID-19" or "SARS-CoV-2" and "infectious virus isolation" yielded 14 publications that evaluated virus isolation from respiratory samples of SARS-CoV-2 infected individuals. Five of these studies were case reports or case series that included up to 5 individuals. Seven studies included cohorts of both outpatients and hospitalized individuals and found strong associations between virus isolation and time from symptom onset and viral RNA level. Of these seven, only two studies evaluated the association between SARS-CoV-2-specific antibodies and virus isolation, but were limited by the late timing of collection (>10 days after symptom onset) or the small number of participants included. The remaining two articles compared virus isolation with antigen and molecular based diagnostics and reviewed prior literature respectively. Collectively, these studies suggest that infectious virus isolation from nasopharyngeal swab samples is possible up to 10 days from symptom onset in individuals with mild disease and for longer in those with severe illness or an underlying immune deficiency. No study has systematically evaluated host, disease, and viral factors associated with infectious virus isolation in the same cohort.Added value of this study: To better understand the host, disease, and viral factors associated with virus isolation in ambulatory individuals with COVID-19, we analyzed demographic, symptom, virologic, and SARS-CoV-2-specific antibody data at baseline entry to outpatient care from 204 individuals enrolled in a randomized placebo-controlled study of a novel oral therapeutic. Host characteristics were self-reported and viral RNA quantitation, virus isolation, and SARS-2 specific antibody testing (IgG, IgM, IgA and total Ig) were performed at central laboratories. This represents the largest evaluation of virus isolation from symptomatic outpatients with COVID-19 reported to date, and affords an important opportunity to understand which host, virus, and disease factors are associated with the presence and clearance of infectious virus in the nasopharynx. Consistent with prior studies, we found that isolation of replication competent SARS-CoV-2 in vitro strongly correlated with both higher nasal viral qRT-PCR RNA levels and shorter time since symptom onset. Importantly, we also found that SARS-CoV-2 antibodies are strongly associated with the clearance of infectious virus, with virus isolation in 7% of seropositive individuals compared to 58% of seronegative individuals. Implications of all the available evidence: Our findings provide a comprehensive analysis of key virus, host, and disease factors associated with infectious virus isolation and suggest that antibody detection appears to be a more reliable marker of infectious virus clearance than patient-reported symptom duration.

RevDate: 2021-07-15

Cohen KW, Linderman SL, Moodie Z, et al (2021)

Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells.

medRxiv : the preprint server for health sciences.

Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. We evaluated 254 COVID-19 patients longitudinally from early infection and for eight months thereafter and found a predominant broad-based immune memory response. SARS-CoV-2 spike binding and neutralizing antibodies exhibited a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. In addition, there was a sustained IgG+ memory B cell response, which bodes well for a rapid antibody response upon virus re-exposure. Polyfunctional virus-specific CD4+ and CD8+ T cells were also generated and maintained with an estimated half-life of 200 days. Interestingly, the CD4+ T cell response equally targeted several SARS-CoV-2 proteins, whereas the CD8+ T cell response preferentially targeted the nucleoprotein, highlighting the importance of including the nucleoprotein as a potential vaccine antigen. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.

RevDate: 2021-07-15

Annavajhala MK, Mohri H, Wang P, et al (2021)

A Novel SARS-CoV-2 Variant of Concern, B.1.526, Identified in New York.

medRxiv : the preprint server for health sciences.

Recent months have seen surges of SARS-CoV-2 infection across the globe along with considerable viral evolution. Extensive mutations in the spike protein of variants B.1.1.7, B1.351, and P.1 have raised concerns that the efficacy of current vaccines and therapeutic monoclonal antibodies could be threatened. In vitro studies have shown that one mutation, E484K, plays a crucial role in the loss of neutralizing activity of some monoclonal antibodies as well as most convalescent and vaccinee sera against variant B.1.351. In fact, two vaccine trials have recently reported lower protective efficacy in South Africa, where B.1.351 is dominant. To survey for these novel variants in our patient population in New York City, PCR assays were designed to identify viruses with two signature mutations, E484K and N501Y. We observed a steady increase in the detection rate from late December to mid-February, with an alarming rise to 12.3% in the past two weeks. Whole genome sequencing further demonstrated that most of our E484K isolates (n=49/65) fell within a single lineage: NextStrain clade 20C or Pangolin lineage B.1.526. Patients with this novel variant came from diverse neighborhoods in the metropolitan area, and they were on average older and more frequently hospitalized. Phylogenetic analyses of sequences in the database further reveal that this B.1.526 variant is scattered in the Northeast of US, and its unique set of spike mutations may also pose an antigenic challenge for current interventions.

RevDate: 2021-07-15

Mayer-Blackwell K, Schattgen S, Cohen-Lavi L, et al (2020)

TCR meta-clonotypes for biomarker discovery with tcrdist3: quantification of public, HLA-restricted TCR biomarkers of SARS-CoV-2 infection.

bioRxiv : the preprint server for biology.

As the mechanistic basis of adaptive cellular antigen recognition, 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 antigen-enriched repertoires to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly quantify functionally similar TCRs in bulk repertoires. We apply the framework to TCR data from COVID-19 patients, generating 1,915 public TCR meta-clonotypes from the 18 SARS-CoV-2 antigen-enriched repertoires with the strongest evidence of HLA-restriction. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 44% (845/1915) were significantly enriched among COVID-19 patients that expressed the putative restricting HLA allele, 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 workflows for distance-based TCR repertoire analysis.

RevDate: 2021-07-15

Davis JT, Chinazzi M, Perra N, et al (2020)

Estimating the establishment of local transmission and the cryptic phase of the COVID-19 pandemic in the USA.

medRxiv : the preprint server for health sciences.

We use a global metapopulation transmission model to study the establishment of sustained and undetected community transmission of the COVID-19 epidemic in the United States. The model is calibrated on international case importations from mainland China and takes into account travel restrictions to and from international destinations. We estimate widespread community transmission of SARS-CoV-2 in February, 2020. Modeling results indicate international travel as the key driver of the introduction of SARS-CoV-2 in the West and East Coast metropolitan areas that could have been seeded as early as late-December, 2019. For most of the continental states the largest contribution of imported infections arrived through domestic travel flows.

RevDate: 2021-07-15

Srivatsan S, Heidl S, Pfau B, et al (2020)

Preliminary support for a "dry swab, extraction free" protocol for SARS-CoV-2 testing via RT-qPCR.

bioRxiv : the preprint server for biology.

The urgent need for massively scaled clinical or surveillance testing for SARS-CoV-2 has necessitated a reconsideration of the methods by which respiratory samples are collected, transported, processed and tested. Conventional testing for SARS-CoV-2 involves collection of a clinical specimen with a nasopharyngeal swab, storage of the swab during transport in universal transport medium (UTM), extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). As testing has scaled across the world, supply chain challenges have emerged across this entire workflow. Here we sought to evaluate how eliminating the UTM storage and RNA extraction steps would impact the results of molecular testing. Using paired mid-turbinate swabs self-collected by 11 individuals with previously established SARS-CoV-2 positivity, we performed a comparison of conventional (swab → UTM → RNA extraction → RT-qPCR) vs. simplified (direct elution from dry swab → RT-qPCR) protocols. Our results suggest that dry swabs eluted directly into a simple buffered solution (TE) can support molecular detection of SARS-CoV-2 via endpoint RT-qPCR without substantially compromising sensitivity. Although further confirmation with a larger sample size and variation of other parameters is necessary, these results are encouraging for the possibility of a simplified workflow that could support massively scaled testing for COVID-19 control.

RevDate: 2021-07-13

Mo J, Darke AK, Guthrie KA, et al (2021)

Association of Fatigue and Outcomes in Advanced Cancer: An Analysis of Four SWOG Treatment Trials.

JCO oncology practice [Epub ahead of print].

PURPOSE: Patient-reported outcomes may be associated with cancer outcomes. We evaluated clinically significant fatigue (CSF), overall survival, adverse events (AEs), and quality of life (QOL) during cancer treatment.

METHODS: We compared outcomes in four phase II or III chemotherapy trials, two advanced non-small-cell lung cancer and two advanced hormone-refractory prostate cancer, with or without baseline CSF. CSF was defined as a rating of two or greater on the Functional Assessment of Cancer Therapy fatigue question or a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 fatigue symptom score of 50% or greater. Survival was compared according to CSF using Kaplan-Meier estimates and Cox regression models. Differences in AE rates by CSF were assessed via chi-squared tests, and QOL changes from baseline to 3 months via linear regression.

RESULTS: Of 1,994 participants, 1,907 (median age 69 years, range: 32-91) had complete baseline QOL survey data, with 52% reporting CSF at baseline. For the two hormone-refractory prostate cancer studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios of (95% CI, P value) 1.32 (1.13 to 1.55, P < .001) and 1.31 (1.02 to 1.67, P = .03) and with increased incidence of grade 3-5 constitutional (16.5% v 9.4%, P = .002; 13.9% v 6.3%, P = .002) and neurologic (11.7% v 6.1%, P = .006; 9.0% v 3.9%, P = .01) AEs, respectively. Baseline CSF was associated with a higher mortality rate in one non-small-cell lung cancer study: hazard ratio 1.44 and 1.04 to 2.00, P = .03.

CONCLUSION: Oncology trial participants with baseline CSF had poorer survival and experienced more AEs than participants without CSF. This indicates fatigue as an important baseline prognostic factor in oncology treatment trials.

RevDate: 2021-07-13

Diab A, Tykodi SS, Daniels GA, et al (2021)

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.

METHODS: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.

RESULTS: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.

CONCLUSION: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.

RevDate: 2021-07-13

Wrenn E, Huang Y, K Cheung (2021)

Collective metastasis: coordinating the multicellular voyage.

Clinical & experimental metastasis [Epub ahead of print].

The metastatic process is arduous. Cancer cells must escape the confines of the primary tumor, make their way into and travel through the circulation, then survive and proliferate in unfavorable microenvironments. A key question is how cancer cells overcome these multiple barriers to orchestrate distant organ colonization. Accumulating evidence in human patients and animal models supports the hypothesis that clusters of tumor cells can complete the entire metastatic journey in a process referred to as collective metastasis. Here we highlight recent studies unraveling how multicellular coordination, via both physical and biochemical coupling of cells, induces cooperative properties advantageous for the completion of metastasis. We discuss conceptual challenges and unique mechanisms arising from collective dissemination that are distinct from single cell-based metastasis. Finally, we consider how the dissection of molecular transitions regulating collective metastasis could offer potential insight into cancer therapy.

RevDate: 2021-07-13

Sheth V, Potter V, de Lavallade H, et al (2021)

Mixed T cell lineage chimerism in acute leukemia/MDS using pre-emptive donor lymphocyte infusion strategy-Is it prognostic?-a single-center retrospective study.

Blood cancer journal, 11(7):128.

Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI.

RevDate: 2021-07-12

Cohen KW, Linderman SL, Moodie Z, et al (2021)

Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells.

Cell reports. Medicine pii:S2666-3791(21)00203-2 [Epub ahead of print].

Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to eight months and find durable broad-based immune responses. SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.

RevDate: 2021-07-13

Coffey DG, Cowan AJ, DeGraaff B, et al (2021)

High-Throughput Drug Screening and Multi-Omic Analysis to Guide Individualized Treatment for Multiple Myeloma.

JCO precision oncology, 5:.

Multiple myeloma (MM) is a genetically heterogeneous malignancy characterized by variable treatment responses. Although numerous drugs have been approved in recent years, the ability to predict treatment response and tailor individual therapy is limited by the absence of robust predictive biomarkers. The goal of this clinical trial was to use ex vivo, high-throughput screening (HTS) of 170 compounds to predict response among patients with relapsed or refractory MM and inform the next treatment decisions. Additionally, we integrated HTS with multi-omic analysis to uncover novel associations between in vitro drug sensitivity and gene expression and mutation profiles.

MATERIALS AND METHODS: Twenty-five patients with relapsed or refractory MM underwent a screening bone marrow or soft tissue biopsy. Sixteen patients were found to have sufficient plasma cells for HTS. Targeted next-generation sequencing was performed on plasma cell-free DNA from all patients who underwent HTS. RNA and whole-exome sequencing of bone marrow plasma cells were performed on eight and seven patients, respectively.

RESULTS: Results of HTS testing were made available to treating physicians within a median of 5 days from the biopsy. An actionable treatment result was identified in all 16 patients examined. Among the 13 patients who received assay-guided therapy, 92% achieved stable disease or better. The expression of 105 genes and mutations in 12 genes correlated with in vitro cytotoxicity.

CONCLUSION: In patients with relapsed or refractory MM, we demonstrate the feasibility of ex vivo drug sensitivity testing on isolated plasma cells from patient bone marrow biopsies or extramedullary plasmacytomas to inform the next line of therapy.

RevDate: 2021-07-13

Henikoff S, Henikoff JG, K Ahmad (2021)

Simplified Epigenome Profiling Using Antibody-tethered Tagmentation.

Bio-protocol, 11(11):e4043.

We previously introduced Cleavage Under Targets & Tagmentation (CUT&Tag), an epigenomic profiling method in which antibody tethering of the Tn5 transposase to a chromatin epitope of interest maps specific chromatin features in small samples and single cells. With CUT&Tag, intact cells or nuclei are permeabilized, followed by successive addition of a primary antibody, a secondary antibody, and a chimeric Protein A-Transposase fusion protein that binds to the antibody. Addition of Mg++ activates the transposase and inserts sequencing adapters into adjacent DNA in situ. We have since adapted CUT&Tag to also map chromatin accessibility by simply modifying the transposase activation conditions when using histone H3K4me2, H3K4me3, or Serine-5-phosphorylated RNA Polymerase II antibodies. Using these antibodies, we redirect the tagmentation of accessible DNA sites to produce chromatin accessibility maps with exceptionally high signal-to-noise and resolution. All steps from nuclei to amplified sequencing-ready libraries are performed in single PCR tubes using non-toxic reagents and inexpensive equipment, making our simplified strategy for simultaneous chromatin profiling and accessibility mapping suitable for the lab, home workbench, or classroom.

RevDate: 2021-07-12

Alzawad Z, Marcus Lewis F, Ngo L, et al (2021)

Exploratory model of parental stress during children's hospitalisation in a paediatric intensive care unit.

Intensive & critical care nursing pii:S0964-3397(21)00098-7 [Epub ahead of print].

OBJECTIVES: This exploratory study (a) examined pre-existing and peri-trauma risk factors of parental stress during a child's PICU hospitalisation using the Integrative Trajectory Model of Paediatric Medical Traumatic Stress and (b) identified the type of PICU-related stressors that predicted parental stress during the child's PICU hospitalisation.

METHODS: A cross-sectional, descriptive correlational design with 81 parents of children admitted 48 or more hours to a Paediatric Intensive Care Unit (PICU). Questionnaires measured parent's and child's demographic and clinical characteristics and parent-reported stressors using the Parental Stressors Scale (PSS:PICU). Analysis included descriptive statistics and multiple linear regression analyses with simultaneous predictor entry.

RESULTS: Male parents tended to be significantly more stressed than female parents. Parental stress was significantly increased when parents had one or more stressful life events one-month prior to PICU admission, when the child required ventilatory support, or the child had a cardiovascular diagnosis. Parental stress was also predicted by the child's appearance, procedures, child's behaviour, behaviour of staff, and parental role.

CONCLUSION: Nurses are in a prime position to identify parents at potentially high risk for psychological morbidity when they know a parent has had a stressful life event prior to admission, has a child with a cardiovascular diagnosis or requires ventilatory assistance. Nurses can diminish parental stress by interpreting the child's appearance for parents, helping parents understand the procedures being done for the child, interpreting the child's behaviour, explaining the staff's behaviour, and assisting parents to define their parental role during the child's hospitalisation.

RevDate: 2021-07-10

Pinto N, Navarro SL, Rimorin C, et al (2021)

Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with event-free survival in intermediate-risk rhabdomyosarcoma: A report from the Children's Oncology Group.

Pediatric blood & cancer [Epub ahead of print].

BACKGROUND: In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting.

PROCEDURES: We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics.

RESULTS: Eight SNPs were associated (p-value < .05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate < 0.05.

CONCLUSIONS: Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.

RevDate: 2021-07-10

Sopfe J, Marsh R, Frederick NN, et al (2021)

Adolescent and young adult childhood cancer survivors' preferences for screening and education of sexual function.

Pediatric blood & cancer [Epub ahead of print].

BACKGROUND: Sexual dysfunction (SD) is a common yet underrecognized concern among childhood cancer survivors (CCS). CCS who are now adolescent and young adult (AYA-CCS) identify SD as an unmet need. This study sought to explore AYA-CCS preferences on how, when, where, and by whom SD-focused communication should occur.

PROCEDURE: This qualitative study utilized semi-structured interviews to explore AYA-CCS (now aged 15-24 years) experiences with, and preferences for, SD conversations. Thematic analysis methodology guided interpretation; themes were clustered into categories of who, how, when, and where SD conversations should occur.

RESULTS: AYA-CCS highlighted the importance of patient-provider rapport to facilitate SD conversations, but did not have consistent preferences regarding provider type or specialty. Providers should reduce discomfort by normalizing ongoing, personalized conversations. Some AYA-CCS mentioned that notification that such a conversation is going to occur would be appreciated, and most were in favor of a screening tool to facilitate conversations. Preferences for when and where SD conversations should occur were centered on maximizing privacy.

CONCLUSIONS: SD is an inadequately addressed concern in AYA-CCS, and providers must familiarize themselves with AYA-CCS preferences for discussing SD to reduce communication barriers and address this unmet need. In addition to corroborating prior studies' findings such as normalizing ongoing SD conversations, this study demonstrated novel ideas for reducing barriers, including use of a notification to prepare them prior to SD conversations, favoring the use of a screening tool, and the importance of establishing rapport prior to the SD conversations.

RevDate: 2021-07-12

Lim Y, Arora S, Schuster SL, et al (2021)

Multiplexed functional genomic analysis of 5' untranslated region mutations across the spectrum of prostate cancer.

Nature communications, 12(1):4217.

The functional consequences of genetic variants within 5' untranslated regions (UTRs) on a genome-wide scale are poorly understood in disease. Here we develop a high-throughput multi-layer functional genomics method called PLUMAGE (Pooled full-length UTR Multiplex Assay on Gene Expression) to quantify the molecular consequences of somatic 5' UTR mutations in human prostate cancer. We show that 5' UTR mutations can control transcript levels and mRNA translation rates through the creation of DNA binding elements or RNA-based cis-regulatory motifs. We discover that point mutations can simultaneously impact transcript and translation levels of the same gene. We provide evidence that functional 5' UTR mutations in the MAP kinase signaling pathway can upregulate pathway-specific gene expression and are associated with clinical outcomes. Our study reveals the diverse mechanisms by which the mutational landscape of 5' UTRs can co-opt gene expression and demonstrates that single nucleotide alterations within 5' UTRs are functional in cancer.

RevDate: 2021-07-10

Genkinger JM, Wu K, Wang M, et al (2021)

Corrigendum to 'Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer': [Annals of Oncology Volume 31, Issue 1, January 2020, Pages 103-114].

RevDate: 2021-07-11

Hill JA, Ujjani CS, Greninger AL, et al (2021)

Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination in a lymphoma patient.

RevDate: 2021-07-08

Telenti A, Arvin A, Corey L, et al (2021)

After the pandemic: perspectives on the future trajectory of COVID-19.

Nature pii:10.1038/s41586-021-03792-w [Epub ahead of print].

There is a realistic expectation that the global effort in vaccination will bring the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic under control. Nonetheless, uncertainties remain about the type of long-term association the virus will establish with the human population, particularly whether the coronavirus disease 2019 (COVID-19) will become an endemic disease. Although the trajectory is difficult to predict, the conditions, concepts, and variables that influence this transition can be anticipated. Persistence of SARS-CoV-2 as an endemic virus, perhaps with seasonal epidemic peaks, may be fueled by pockets of susceptible individuals and waning immunity after infection or vaccination, changes in the virus through antigenic drift that diminish protection, and reentries from zoonotic reservoirs. Here, we review relevant observations from previous epidemics and discuss the potential evolution of SARS-CoV-2 as it adapts during persistent transmission in the presence of a level of population immunity. Lack of effective surveillance or adequate response could enable the emergence of new epidemic or pandemic patterns from an endemic infection of SARS-CoV-2. There are key pieces of data that are urgently needed in order to make good decisions. We outline these and propose a way forward.

RevDate: 2021-07-13

Jennewein MF, MacCamy AJ, Akins NR, et al (2021)

Isolation and characterization of cross-neutralizing coronavirus antibodies from COVID-19+ subjects.

Cell reports [Epub ahead of print].

SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier and caused widespread disease in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterize 198 antibodies isolated from four COVID-19+ subjects and identify 14 SARS-CoV-2 neutralizing antibodies. One targets the N-terminal domain (NTD), one recognizes an epitope in S2, and 11 bind the receptor-binding domain (RBD). Three anti-RBD neutralizing antibodies cross-neutralize SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs to the ACE2 receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency and antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. All four cross-neutralizing antibodies neutralize the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

RevDate: 2021-07-08

Boehmer U, Ozonoff A, Winter M, et al (2021)

Health-related quality of life among colorectal cancer survivors of diverse sexual orientations.

Cancer [Epub ahead of print].

BACKGROUND: The purpose of this study was to examine the health-related quality of life of sexual minority survivors in comparison with heterosexual survivors.

METHODS: Four hundred eighty eligible survivors participated in a telephone survey that measured survivors' outcomes, which consisted of physical and mental quality of life and self-rated fair or poor health. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of 3 years before the survey and were recruited from 4 cancer registries. Using forward selection with generalized linear models or logistic regression models, the authors considered 4 domains-personal factors, environmental factors, health condition characteristics, and body function and structure-as correlates for each survivorship outcome.

RESULTS: The authors found that unadjusted physical quality of life and self-rated fair/poor health were similar for all survivors. Sexual minority survivors had poorer unadjusted mental quality of life in comparison with heterosexual survivors. After adjustments for covariates, this difference was no longer statistically significant. Three domains (personal factors, health condition characteristics, and body function and structure) explained colorectal cancer survivors' fair/poor health and 46% of the variance in physical quality of life, whereas 56% of the variance in mental quality of life was explained by personal factors, body function and structure, and environmental factors.

CONCLUSIONS: This study has identified modifiable factors that can be used to improve cancer survivors' quality of life and are, therefore, relevant to ongoing efforts to improve the survivorship experience.

RevDate: 2021-07-08

Grieshober L, Graw S, Barnett MJ, et al (2021)

Pre-diagnosis neutrophil-to-lymphocyte ratio and mortality in individuals who develop lung cancer.

Cancer causes & control : CCC [Epub ahead of print].

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been reported to be associated with survival after chronic disease diagnoses, including lung cancer. We hypothesized that the inflammatory profile reflected by pre-diagnosis NLR, rather than the well-studied pre-treatment NLR at diagnosis, may be associated with increased mortality after lung cancer is diagnosed in high-risk heavy smokers.

METHODS: We examined associations between pre-diagnosis methylation-derived NLR (mdNLR) and lung cancer-specific and all-cause mortality in 279 non-small lung cancer (NSCLC) and 81 small cell lung cancer (SCLC) cases from the β-Carotene and Retinol Efficacy Trial (CARET). Cox proportional hazards models were adjusted for age, sex, smoking status, pack years, and time between blood draw and diagnosis, and stratified by stage of disease. Models were run separately by histotype.

RESULTS: Among SCLC cases, those with pre-diagnosis mdNLR in the highest quartile had 2.5-fold increased mortality compared to those in the lowest quartile. For each unit increase in pre-diagnosis mdNLR, we observed 22-23% increased mortality (SCLC-specific hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.02, 1.48; all-cause HR = 1.22, 95% CI 1.01, 1.46). SCLC associations were strongest for current smokers at blood draw (Interaction Ps = 0.03). Increasing mdNLR was not associated with mortality among NSCLC overall, nor within adenocarcinoma (N = 148) or squamous cell carcinoma (N = 115) case groups.

CONCLUSION: Our findings suggest that increased mdNLR, representing a systemic inflammatory profile on average 4.5 years before a SCLC diagnosis, may be associated with mortality in heavy smokers who go on to develop SCLC but not NSCLC.

RevDate: 2021-07-13

Mathsyaraja H, Catchpole J, Freie B, et al (2021)

Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness.

eLife, 10:.

MGA, a transcription factor and member of the MYC network, is mutated or deleted in a broad spectrum of malignancies. As a critical test of a tumor suppressive role, we inactivated Mga in two mouse models of non-small cell lung cancer using a CRISPR-based approach. MGA loss significantly accelerated tumor growth in both models and led to de-repression of non-canonical Polycomb ncPRC1.6 targets, including genes involved in metastasis and meiosis. Moreover, MGA deletion in human lung adenocarcinoma lines augmented invasive capabilities. We further show that MGA-MAX, E2F6, and L3MBTL2 co-occupy thousands of promoters and that MGA stabilizes these ncPRC1.6 subunits. Lastly, we report that MGA loss also induces a pro-growth effect in human colon organoids. Our studies establish MGA as a bona fide tumor suppressor in vivo and suggest a tumor suppressive mechanism in adenocarcinomas resulting from widespread transcriptional attenuation of MYC and E2F target genes mediated by MGA-MAX associated with a non-canonical Polycomb complex.

RevDate: 2021-07-09

Greaney AJ, Starr TN, Barnes CO, et al (2021)

Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies.

Nature communications, 12(1):4196.

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.

RevDate: 2021-07-11

Garzia NA, Cushing-Haugen K, Kensler TW, et al (2021)

Adolescent and early adulthood inflammation-associated dietary patterns in relation to premenopausal mammographic density.

Breast cancer research : BCR, 23(1):71.

BACKGROUND: Adolescence and early adulthood has been identified as a critical time window for establishing breast cancer risk. Mammographic density is an independent risk factor for breast cancer that may be influenced by diet, but there has been limited research conducted on the impact of diet on mammographic density. Thus, we sought to examine the association between adolescent and early adulthood inflammatory dietary patterns, which have previously been associated with breast cancer risk, and premenopausal mammographic density among women in the Nurses' Health Study II (NHSII).

METHODS: This study included control participants with premenopausal mammograms from an existing breast cancer case-control study nested within the NHSII who completed a Food Frequency Questionnaire in 1998 about their diet during high school (HS-FFQ) (n = 685) and/or a Food Frequency Questionnaire in 1991 (Adult-FFQ) when they were 27-44 years old (n = 1068). Digitized analog film mammograms were used to calculate the percent density, absolute dense, and non-dense areas. Generalized linear models were fit to evaluate the associations of a pro-inflammatory dietary pattern and the Alternative Healthy Eating Index (AHEI, an anti-inflammatory dietary pattern) with each breast density measure.

RESULTS: Significant associations were observed between an adolescent pro-inflammatory dietary pattern and mammographic density in some age-adjusted models; however, these associations did not remain after adjustment for BMI and other breast cancer risk factors. No associations were observed with the pro-inflammatory pattern or with the AHEI pattern in adolescence or early adulthood in fully adjusted models.

CONCLUSIONS: To our knowledge, this is the first study to evaluate the dietary patterns during adolescence and early adulthood in relation to mammographic density phenotypes. Our findings do not support an association between adolescent and early adulthood diet and breast density in mid-adulthood that is independent of BMI or other breast cancer risk factors.

RevDate: 2021-07-07

Hua X, Kratz M, Malen RC, et al (2021)

Association between post-treatment circulating biomarkers of inflammation and survival among stage II-III colorectal cancer patients.

British journal of cancer [Epub ahead of print].

BACKGROUND: Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival.

METHODS: We included 306 eligible incident stage II-III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models.

RESULTS: Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10-2.59), 2.72 (2.07-3.56), 1.97 (1.18-3.28) and 1.71 (1.14-2.58), respectively. IL-6 and adiponectin had a dose-response effect (Ptrend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2-2.56), IL-6 (HR = 5.02, 95% CI: 2.92-8.59), MCP-1 (HR = 3.78, 95% CI: 1.41-10.08), and adiponectin (HR = 3.16, 95% CI: 1.27-7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29-0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years.

CONCLUSION: Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II-III CRC patients.

RevDate: 2021-07-10

Huang Y, Seaton KE, Casapia M, et al (2021)

AIDSVAX protein boost improves breadth and magnitude of vaccine-induced HIV-1 envelope-specific responses after a 7-year rest period.

Vaccine pii:S0264-410X(21)00827-6 [Epub ahead of print].

BACKGROUND: Eliciting durable humoral immunity with sufficient breadth and magnitude is important for HIV-1 vaccine design. The HVTN 114 vaccine trial evaluated different boost regimens administered after a 7-year rest period in participants previously enrolled in HVTN 205, who received either three MVA/HIV62B (MMM) or two DNA and two MVA/HIV62B (DDMM) injections; both vaccines expressed multiple HIV-1 antigens in non-infectious virus-like-particles. The primary objective of HVTN 114 was to assess the impact of a heterologous gp120 protein AIDSVAX B/E boost on the magnitude, breadth and durability of vaccine-induced immune responses.

METHODS: We enrolled 27 participants from HVTN 205 into five groups. Eight participants who previously received MMM were randomized and boosted with either MVA/HIV62B alone (T1; n = 4) or MVA/HIV62B and AIDSVAX B/E (T2; n = 4). Nineteen participants who received DDMM were randomized and boosted with MVA/HIV62B alone (T3; n = 6), MVA/HIV62B and AIDSVAX B/E (T4; n = 6), or AIDSVAX B/E alone (T5; n = 7). Boosts were at months 0 and 4. Participants were followed for safety and immunogenicity for 10 months and were pooled for analysis based on the regimen: MVA-only (T1 + T3), MVA + AIDSVAX (T2 + T4), and AIDSVAX-only (T5).

RESULTS: All regimens were safe and well-tolerated. Prior to the boost vaccination, binding antibody and CD4+T-cell responses were observed 7 years after HVTN 205 vaccinations. Late boosting with AIDSVAX, with or without MVA, resulted in high binding antibody responses to gp120 and V1V2 epitopes, with increased magnitude and breadth compared to those observed in HVTN 205. Late boosting with MVA, with or without AIDSVAX, resulted in increased gp140 and gp41 antibody responses and higher CD4+T-cell responses to Env and Gag.

CONCLUSIONS: Late boosting with AIDSVAX, alone or in combination with MVA, can broaden binding antibody responses and increase T-cell responses even years following the original MVA/HIV62B with or without DNA-priming vaccine.

RevDate: 2021-07-06

Barrenäs F, Hansen SG, Law L, et al (2021)

Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy.

PLoS pathogens, 17(7):e1009278 pii:PPATHOGENS-D-21-00034 [Epub ahead of print].

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.

RevDate: 2021-07-09

Zahed H, Johansson M, Ueland PM, et al (2021)

Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults.

Scientific reports, 11(1):13805.

Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40-80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was - 0.91 standard-deviations lower in women than men (95%CI - 0.98; - 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p < 0.05) association with time since smoking cessation was observed for 8 markers, including C-reactive protein, kynurenine, choline, and total homocysteine. We conclude that most blood biomarkers show small variations across demographic characteristics. Patterns by smoking status point to normalization of multiple physiological processes after smoking cessation.

RevDate: 2021-07-05

Madewell ZJ, Pastore Y Piontti A, Zhang Q, et al (2021)

Using simulated infectious disease outbreaks to inform site selection and sample size for individually randomized vaccine trials during an ongoing epidemic.

Clinical trials (London, England) [Epub ahead of print].

BACKGROUND: Novel strategies are needed to make vaccine efficacy trials more robust given uncertain epidemiology of infectious disease outbreaks, such as arboviruses like Zika. Spatially resolved mathematical and statistical models can help investigators identify sites at highest risk of future transmission and prioritize these for inclusion in trials. Models can also characterize uncertainty in whether transmission will occur at a site, and how nearby or connected sites may have correlated outcomes. A structure is needed for how trials can use models to address key design questions, including how to prioritize sites, the optimal number of sites, and how to allocate participants across sites.

METHODS: We illustrate the added value of models using the motivating example of Zika vaccine trial planning during the 2015-2017 Zika epidemic. We used a stochastic, spatially resolved, transmission model (the Global Epidemic and Mobility model) to simulate epidemics and site-level incidence at 100 high-risk sites in the Americas. We considered several strategies for prioritizing sites (average site-level incidence of infection across epidemics, median incidence, probability of exceeding 1% incidence), selecting the number of sites, and allocating sample size across sites (equal enrollment, proportional to average incidence, proportional to rank). To evaluate each design, we stochastically simulated trials in each hypothetical epidemic by drawing observed cases from site-level incidence data.

RESULTS: When constraining overall trial size, the optimal number of sites represents a balance between prioritizing highest-risk sites and having enough sites to reduce the chance of observing too few endpoints. The optimal number of sites remained roughly constant regardless of the targeted number of events, although it is necessary to increase the sample size to achieve the desired power. Though different ranking strategies returned different site orders, they performed similarly with respect to trial power. Instead of enrolling participants equally from each site, investigators can allocate participants proportional to projected incidence, though this did not provide an advantage in our example because the top sites had similar risk profiles. Sites from the same geographic region may have similar outcomes, so optimal combinations of sites may be geographically dispersed, even when these are not the highest ranked sites.

CONCLUSION: Mathematical and statistical models may assist in designing successful vaccination trials by capturing uncertainty and correlation in future transmission. Although many factors affect site selection, such as logistical feasibility, models can help investigators optimize site selection and the number and size of participating sites. Although our study focused on trial design for an emerging arbovirus, a similar approach can be made for any infectious disease with the appropriate model for the particular disease.

RevDate: 2021-07-04

Wolff D, Fatobene G, Rocha V, et al (2021)

Steroid-refractory chronic graft-versus-host disease: treatment options and patient management.

Bone marrow transplantation [Epub ahead of print].

Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.

RevDate: 2021-07-04

Johnson AC, RA Zager (2021)

Catalytic Iron Mediated Renal Stress Responses During Experimental Cardiorenal Syndrome 1 ("CRS-1").

Translational research : the journal of laboratory and clinical medicine pii:S1931-5244(21)00145-6 [Epub ahead of print].

Cardiorenal syndrome I (CRS-1) denotes a state in which acute kidney injury occurs in the setting of acute heart failure (AHF). Isoproterenol (Iso) administration is widely used as an AHF model by transiently inducing extreme tachycardia, hypotension, and myocyte apoptosis/necrosis. To gain potential insights into renal manifestations of CRS-1, mice were subjected to the Iso-AHF model (50 mg Iso/kg), followed by renal functional and renal cortical assessments over 4 hrs. Iso induced acute azotemia (doubling of BUN, plasma creatinine) and significantly reduced renal plasma flow (prolonged plasma para-amino-hippurate clearance). Although no morphologic tubular injury was identified, marked increases in renal cortical 'stress markers' (NGAL, HO-1, IL-6, MCP-1 mRNAs) and oxidant stress (decreased glutathione, increased malondialdehyde) were observed. These changes were catalytic Fe dependent, given that the iron chelator desferrioxamine (DFO) significantly blunted, or completely reversed, these renal cortical abnormalities. Despite these acute changes, no lasting renal injury was observed (assessed over 3 days). To determine whether Iso directly impacts tubular cell integrity, cultured proximal tubule (HK-2) cells were exposed to Iso. Substantial Fe dependent cell injury (decreased MTT uptake), and Fe independent increases in HO-1/IL-6 mRNA expression were observed. We conclude that Iso-induced AHF is a useful reversible model of CRS-1. Despite its largely hemodynamic ('pre-renal') nature, Fe-mediated oxidative stress and pro-inflammatory reactions are induced. These arise, at least in part, from direct Iso- induced tubular cell toxicity, rather than simply being secondary to Iso-mediated hemodynamic events. Finally, Iso-triggered renal cytokine production can potentially contribute to 'organ cross talk' and a systemic pro-inflammatory state.

RevDate: 2021-07-04

Li A, Gupta R, Amos CI, et al (2021)

Thrombotic microangiopathy increases the risk of chronic kidney disease but not overall mortality in long-term transplant survivors.

Transplantation and cellular therapy pii:S2666-6367(21)01030-7 [Epub ahead of print].

BACKGROUND: Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined.

OBJECTIVES: To assess the risk of CKD and mortality in HCT survivors with and without history of TMA.

STUDY DESIGN: We conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1-year post-transplant. We examined the association between the history of TMA within 1-year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit (LTFU) follow-up visits. Kaplan Meier curves landmarked at 1-year were used for survival analyses.

RESULTS: Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1-year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1-year and 1094 did not have TMA. There was no pre-transplant baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% CI 1.33 to 6.03) for CKD development over 5 years post-transplant. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank p=0.122).

CONCLUSION: HCT survivors with a history of TMA had increased risk of CKD development. While TMA was associated with high risk of mortality within 1-year post-transplant, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should not only focus on short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.

RevDate: 2021-07-09

Wolff D, Radojcic V, Lafyatis R, et al (2021)

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Transplantation and cellular therapy pii:S2666-6367(21)00949-0 [Epub ahead of print].

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

RevDate: 2021-07-08
CmpDate: 2021-07-08

Croswell JM, Corley DA, Lafata JE, et al (2021)

Cancer screening in the U.S. through the COVID-19 pandemic, recovery, and beyond.

Preventive medicine, 151:106595.

COVID-19 has proved enormously disruptive to the provision of cancer screening, which does not just represent an initial test but an entire process, including risk detection, diagnostic follow-up, and treatment. Successful delivery of services at all points in the process has been negatively affected by the pandemic. There is a void in empirical high-quality evidence to support a specific strategy for administering cancer screening during a pandemic and its resolution phase, but several pragmatic considerations can help guide prioritization efforts. Targeting guideline-eligible people who have never been screened, or those who are significantly out of date with screening, has the potential to maximize benefits now and into the future. Disruptions to care due to the pandemic could represent an unparalleled opportunity to reassess early detection programs towards an explicit, thoughtful, and just prioritization of populations historically experiencing cancer disparities. By focusing screening services on populations that have the most to gain, and by careful and deliberate planning for the period following the pandemic, we can positively affect cancer outcomes for all.

RevDate: 2021-07-08
CmpDate: 2021-07-06

Sun YC, Inamoto Y, Wang RK, et al (2021)

The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease.

BMC ophthalmology, 21(1):271.

PURPOSE: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients.

METHODS: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months.

RESULTS: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD.

CONCLUSIONS: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.

RevDate: 2021-07-02

Wamalwa D, Njuguna I, Maleche-Obimbo E, et al (2021)

Cytomegalovirus viremia and clinical outcomes in Kenyan children diagnosed with HIV in hospital.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6313248 [Epub ahead of print].

BACKGROUND: Cytomegalovirus (CMV) viremia is common in HIV infection, and is associated with worse long-term outcomes. To date, no studies have assessed CMV viremia in children diagnosed with HIV in hospital.

METHODS: We studied CMV viremia and clinical outcomes in 163 Kenyan children aged 2 months-12 years, diagnosed with HIV in hospital. CMV DNA levels in plasma were measured using quantitative PCR. Regression models were used to assess associations between CMV viremia >1000 IU/mL and the risk of continued hospitalization or death at 15 days, duration of hospitalization, and 6-month mortality.

RESULTS: At enrollment, 62/114 (54%) children had CMV viremia, and 20 (32%) were >1000 IU/mL. Eleven CMV reactivations were observed after admission. The prevalence and level of CMV viremia were highest in children <2 years and lowest in children >5 years old. CMV viremia >1000 IU/mL was independently associated with age < 2 years (p=0.03), higher log10 HIV RNA level (p=0.01), and height-for-age z score <-2 (p=0.02). Adjusting for age and log10 HIV RNA, the relative risk of death or continued hospitalization at 15 days was 1.74 (95%CI=1.04, 2.90), and the hazard ratio of 6-month mortality was 1.97 (95%CI=0.57, 5.07) for children with CMV DNA ≥1000 IU/ml compared to lower-level or undetectable CMV DNA. Children with CMV DNA ≥1000 IU/ml were hospitalized a median ~5 days longer than children with lower-level or undetectable CMV DNA (p=0.002).

CONCLUSIONS: In this nested observational study, CMV viremia was common in hospitalized children with HIV, and levels ≥1000 IU/mL were associated with increased risk of mortality and longer hospitalization.

RevDate: 2021-07-06

Sarnowski C, Chen H, Biggs ML, et al (2021)

Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

PloS one, 16(7):e0253611 pii:PONE-D-20-39658.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

RevDate: 2021-07-02

Thornton AM, Fang L, Lo A, et al (2021)

eVIP2: Expression-based variant impact phenotyping to predict the function of gene variants.

PLoS computational biology, 17(7):e1009132 pii:PCOMPBIOL-D-20-00006 [Epub ahead of print].

While advancements in genome sequencing have identified millions of somatic mutations in cancer, their functional impact is poorly understood. We previously developed the expression-based variant impact phenotyping (eVIP) method to use gene expression data to characterize the function of gene variants. The eVIP method uses a decision tree-based algorithm to predict the functional impact of somatic variants by comparing gene expression signatures induced by introduction of wild-type (WT) versus mutant cDNAs in cell lines. The method distinguishes between variants that are gain-of-function, loss-of-function, change-of-function, or neutral. We present eVIP2, software that allows for pathway analysis (eVIP Pathways) and usage with RNA-seq data. To demonstrate the eVIP2 software and approach, we characterized two recurrent frameshift variants in RNF43, a negative regulator of Wnt signaling, frequently mutated in colorectal, gastric, and endometrial cancer. RNF43 WT, RNF43 R117fs, RNF43 G659fs, or GFP control cDNA were overexpressed in HEK293T cells. Analysis with eVIP2 predicted that the frameshift at position 117 was a loss-of-function mutation, as expected. The second frameshift at position 659 has been previously described as a passenger mutation that maintains the RNF43 WT function as a negative regulator of Wnt. Surprisingly, eVIP2 predicted G659fs to be a change-of-function mutation. Additional eVIP Pathways analysis of RNF43 G659fs predicted 10 pathways to be significantly altered, including TNF-α via NFκB signaling, KRAS signaling, and hypoxia, highlighting the benefit of a more comprehensive approach when determining the impact of gene variant function. To validate these predictions, we performed reporter assays and found that each pathway activated by expression of RNF43 G659fs, but not expression of RNF43 WT, was identified as impacted by eVIP2, supporting that RNF43 G659fs is a change-of-function mutation and its effect on the identified pathways. Pathway activation was further validated by Western blot analysis. Lastly, we show primary colon adenocarcinoma patient samples with R117fs and G659fs variants have transcriptional profiles similar to BRAF missense mutations with activated RAS/MAPK signaling, consistent with KRAS signaling pathways being GOF in both variants. The eVIP2 method is an important step towards overcoming the current challenge of variant interpretation in the implementation of precision medicine. eVIP2 is available at https://github.com/BrooksLabUCSC/eVIP2.

RevDate: 2021-07-02

Huang Y, Zhang L, Eaton A, et al (2021)

Prediction of serum HIV-1 neutralization titers of VRC01 in HIV-uninfected Antibody Mediated Prevention (AMP) trial participants.

Human vaccines & immunotherapeutics [Epub ahead of print].

VRC01 is being evaluated in the AMP efficacy trials, the first assessment of a passively administered broadly neutralizing monoclonal antibody (bnAb) for HIV-1 prevention. A key analysis will assess serum VRC01-mediated neutralization as a potential correlate of protection. To prepare for this analysis, we conducted a pilot study where we measured longitudinal VRC01 serum concentrations and serum VRC01-mediated neutralization in 47 and 31 HIV-1 uninfected AMP participants, respectively. We applied four different statistical approaches to predict serum VRC01-mediated neutralization titer against Env-pseudotyped viruses, including breakthrough viruses isolated from AMP placebo recipients who became HIV-1 infected during the trial, using VRC01 serum concentration and neutralization potency (IC50 or IC80) of the VRC01 clinical lot against the same virus. Approaches 3 and 4, which utilized pharmacokinetics/pharmacodynamics joint modeling of concentration and neutralization titer, generally performed the best or comparably to Approaches 1 and 2, which, respectively, utilized only measured and model-predicted concentration. For prediction of ID80 titers against breakthrough viruses, Approaches 1 and 2 rendered comparable performance to Approaches 3 and 4, and could be reasonable approaches to adopt in practice as they entail reduced assay cost and less complicated statistical analysis. Our results may be applied to future studies of other bnAbs and bnAb combinations to maximize resource efficiency in serum neutralization titer measurement.

RevDate: 2021-07-03

Young WC, Carpp LN, Chaudhury S, et al (2021)

Comprehensive Data Integration Approach to Assess Immune Responses and Correlates of RTS,S/AS01-Mediated Protection From Malaria Infection in Controlled Human Malaria Infection Trials.

Frontiers in big data, 4:672460.

RTS,S/AS01 (GSK) is the world's first malaria vaccine. However, despite initial efficacy of almost 70% over the first 6 months of follow-up, efficacy waned over time. A deeper understanding of the immune features that contribute to RTS,S/AS01-mediated protection could be beneficial for further vaccine development. In two recent controlled human malaria infection (CHMI) trials of the RTS,S/AS01 vaccine in malaria-naïve adults, MAL068 and MAL071, vaccine efficacy against patent parasitemia ranged from 44% to 87% across studies and arms (each study included a standard RTS,S/AS01 arm with three vaccine doses delivered in four-week-intervals, as well as an alternative arm with a modified version of this regimen). In each trial, RTS,S/AS01 immunogenicity was interrogated using a broad range of immunological assays, assessing cellular and humoral immune parameters as well as gene expression. Here, we used a predictive modeling framework to identify immune biomarkers measured at day-of-challenge that could predict sterile protection against malaria infection. Using cross-validation on MAL068 data (either the standard RTS,S/AS01 arm alone, or across both the standard RTS,S/AS01 arm and the alternative arm), top-performing univariate models identified variables related to Fc effector functions and titer of antibodies that bind to the central repeat region (NANP6) of CSP as the most predictive variables; all NANP6-related variables consistently associated with protection. In cross-study prediction analyses of MAL071 outcomes (the standard RTS,S/AS01 arm), top-performing univariate models again identified variables related to Fc effector functions of NANP6-targeting antibodies as highly predictive. We found little benefit-with this dataset-in terms of improved prediction accuracy in bivariate models vs. univariate models. These findings await validation in children living in malaria-endemic regions, and in vaccinees administered a fourth RTS,S/AS01 dose. Our findings support a "quality as well as quantity" hypothesis for RTS,S/AS01-elicited antibodies against NANP6, implying that malaria vaccine clinical trials should assess both titer and Fc effector functions of anti-NANP6 antibodies.

RevDate: 2021-07-02

Wang R, Gornalusse GG, Kim Y, et al (2021)

Corrigendum: Potent Restriction of Sexual Zika Virus Infection by the Lipid Fraction of Extracellular Vesicles in Semen.

Frontiers in microbiology, 12:707875.

[This corrects the article DOI: 10.3389/fmicb.2020.574054.].

RevDate: 2021-07-13
CmpDate: 2021-07-13

Srivatsan SR, Regier MC, Barkan E, et al (2021)

Embryo-scale, single-cell spatial transcriptomics.

Science (New York, N.Y.), 373(6550):111-117.

Spatial patterns of gene expression manifest at scales ranging from local (e.g., cell-cell interactions) to global (e.g., body axis patterning). However, current spatial transcriptomics methods either average local contexts or are restricted to limited fields of view. Here, we introduce sci-Space, which retains single-cell resolution while resolving spatial heterogeneity at larger scales. Applying sci-Space to developing mouse embryos, we captured approximate spatial coordinates and whole transcriptomes of about 120,000 nuclei. We identify thousands of genes exhibiting anatomically patterned expression, leverage spatial information to annotate cellular subtypes, show that cell types vary substantially in their extent of spatial patterning, and reveal correlations between pseudotime and the migratory patterns of differentiating neurons. Looking forward, we anticipate that sci-Space will facilitate the construction of spatially resolved single-cell atlases of mammalian development.

RevDate: 2021-07-11

Earle KA, Ambrosino DM, Fiore-Gartland A, et al (2021)

Evidence for antibody as a protective correlate for COVID-19 vaccines.

Vaccine [Epub ahead of print].

A correlate of protection (CoP) is urgently needed to expedite development of additional COVID-19 vaccines to meet unprecedented global demand. To assess whether antibody titers may reasonably predict efficacy and serve as the basis of a CoP, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (ρ = 0.79) and binding antibody titer and efficacy (ρ = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. Together with evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.

RevDate: 2021-07-02

Ponce DM, Politikos I, Alousi A, et al (2021)

Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation.

Transplantation and cellular therapy, 27(7):540-544.

The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.

RevDate: 2021-07-09
CmpDate: 2021-07-09

Sokolova AO, Obeid EI, HH Cheng (2021)

Genetic Contribution to Metastatic Prostate Cancer.

The Urologic clinics of North America, 48(3):349-363.

Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.

RevDate: 2021-07-10

Yu B, Roberts MB, Raffield LM, et al (2021)

Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure.

Journal of the American College of Cardiology, 78(1):42-52.

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF).

OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF.

METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses.

RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction.

CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )