@article {pmid33472027, year = {2021}, author = {Rabinowitch, I and Upadhyaya, B and Pant, A and Galski, D and Kreines, L and Bai, J}, title = {Circumventing Neural Damage in a C. elegans Chemosensory Circuit Using Genetically Engineered Synapses.}, journal = {Cell systems}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cels.2020.12.003}, pmid = {33472027}, issn = {2405-4720}, abstract = {Neuronal loss can considerably diminish neural circuit function, impairing normal behavior by disrupting information flow in the circuit. Here, we use genetically engineered electrical synapses to reroute the flow of information in a C. elegans damaged chemosensory circuit in order to restore organism behavior. We impaired chemotaxis by removing one pair of interneurons from the circuit then artificially coupled two other adjacent neuron pairs by ectopically expressing the gap junction protein, connexin, in them. This restored chemotaxis in the animals. We expected to observe linear and direct information flow between the connexin-coupled neurons in the recovered circuit but also revealed the formation of new potent left-right lateral electrical connections within the connexin-expressing neuron pairs. Our analysis suggests that these additional electrical synapses help restore circuit function by amplifying weakened neuronal signals in the damaged circuit in addition to emulating the wild-type circuit. A record of this paper's transparent peer review process is included in the Supplemental Information.}, }
@article {pmid33471974, year = {2021}, author = {Hu, C and Hart, SN and Gnanaolivu, R and Huang, H and Lee, KY and Na, J and Gao, C and Lilyquist, J and Yadav, S and Boddicker, NJ and Samara, R and Klebba, J and Ambrosone, CB and Anton-Culver, H and Auer, P and Bandera, EV and Bernstein, L and Bertrand, KA and Burnside, ES and Carter, BD and Eliassen, H and Gapstur, SM and Gaudet, M and Haiman, C and Hodge, JM and Hunter, DJ and Jacobs, EJ and John, EM and Kooperberg, C and Kurian, AW and Le Marchand, L and Lindstroem, S and Lindstrom, T and Ma, H and Neuhausen, S and Newcomb, PA and O'Brien, KM and Olson, JE and Ong, IM and Pal, T and Palmer, JR and Patel, AV and Reid, S and Rosenberg, L and Sandler, DP and Scott, C and Tamimi, R and Taylor, JA and Trentham-Dietz, A and Vachon, CM and Weinberg, C and Yao, S and Ziogas, A and Weitzel, JN and Goldgar, DE and Domchek, SM and Nathanson, KL and Kraft, P and Polley, EC and Couch, FJ}, title = {A Population-Based Study of Genes Previously Implicated in Breast Cancer.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2005936}, pmid = {33471974}, issn = {1533-4406}, support = {97-10500/US/United States/United States ; LVS39420/US/United States/United States ; P01CA151135/CA/NCI NIH HHS/United States ; P01CA87969/CA/NCI NIH HHS/United States ; P30CA014520/CA/NCI NIH HHS/United States ; P30CA16056/CA/NCI NIH HHS/United States ; P50116201/CA/NCI NIH HHS/United States ; R01CA047147/CA/NCI NIH HHS/United States ; R01CA067264/CA/NCI NIH HHS/United States ; R01CA097396/CA/NCI NIH HHS/United States ; R01CA098663/CA/NCI NIH HHS/United States ; R01CA100598/CA/NCI NIH HHS/United States ; R01CA185623/CA/NCI NIH HHS/United States ; R01CA192393/CA/NCI NIH HHS/United States ; R01CA204819/CA/NCI NIH HHS/United States ; R01CA225662/CA/NCI NIH HHS/United States ; R01CA49449/CA/NCI NIH HHS/United States ; R01CA58860/CA/NCI NIH HHS/United States ; R01CA67262/CA/NCI NIH HHS/United States ; R01CA77398/CA/NCI NIH HHS/United States ; R01CA92044/CA/NCI NIH HHS/United States ; R35CA253187/CA/NCI NIH HHS/United States ; U01CA164920/CA/NCI NIH HHS/United States ; U01CA164973/CA/NCI NIH HHS/United States ; U01CA164974/CA/NCI NIH HHS/United States ; U01CA176726/CA/NCI NIH HHS/United States ; U01CA199277/CA/NCI NIH HHS/United States ; U01CA82004/CA/NCI NIH HHS/United States ; UM1CA186107/CA/NCI NIH HHS/United States ; Z01-ES044005/ES/NIEHS NIH HHS/United States ; Z01-ES049033/ES/NIEHS NIH HHS/United States ; Z01-ES102245/ES/NIEHS NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.<br><br>METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.<br><br>RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.<br><br>CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).}, }
@article {pmid33471819, year = {2021}, author = {Labrecque, MP and Brown, LG and Coleman, IM and Nguyen, HM and Lin, DW and Corey, E and Nelson, PS and Morrissey, C}, title = {Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature.}, journal = {PloS one}, volume = {16}, number = {1}, pages = {e0245602}, doi = {10.1371/journal.pone.0245602}, pmid = {33471819}, issn = {1932-6203}, abstract = {With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits VEGFR2, MET and RET on SCNPC. Transcriptome analysis of the University of Washington rapid autopsy and SU2C mCRPC datasets revealed upregulated MET and RET expression in SCNPCs relative to adenocarcinomas. Additionally, increased MET expression correlated with attenuated AR expression and activity. In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1. Notably, MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumor volumes were significantly decreased with cabozantinib treatment in vivo, and this activity was independent of MET or RET expression in LuCaP 173.1. Tissue analysis indicated that cabozantinib did not inhibit tumor cell proliferation (Ki67), but significantly decreased microvessel density (CD31) and increased hypoxic stress and glycolysis (HK2) in LuCaP 93 and LuCaP 173.1 tumors. RNA-Seq and gene set enrichment analysis revealed that hypoxia and glycolysis pathways were increased in cabozantinib-treated tumors relative to control tumors. Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.}, }
@article {pmid33469762, year = {2021}, author = {Jones, SMW and Banegas, MP and Steiner, JF and De Marchis, EH and Gottlieb, LM and Sharp, AL}, title = {Association of Financial Worry and Material Financial Risk with Short-Term Ambulatory Healthcare Utilization in a Sample of Subsidized Exchange Patients.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, pmid = {33469762}, issn = {1525-1497}, support = {N/A//Kaiser Permanente National Community Health/ ; }, abstract = {BACKGROUND: Financial burden can affect healthcare utilization. Few studies have assessed the short-term associations between material (debt, trouble paying rent) and psychological (worry or distress about affording future healthcare) financial risks, and subsequent outpatient and emergency healthcare use. Worry was defined as concerns about affording future healthcare.<br><br>OBJECTIVE: Examine whether worry about affording healthcare is associated with healthcare utilization when controlling for material risk and general anxiety DESIGN: Longitudinal observational study PARTICIPANTS: Kaiser Permanente members with exchange-based federally subsidized health insurance (n = 450, 45% response rate) MAIN MEASURES: Survey measures of financial risks (material difficulty paying for medical care and worry about affording healthcare) and general anxiety. Healthcare use (primary care, urgent care, emergency department, and outpatient specialty visits) in the 6 months following survey completion.<br><br>KEY RESULTS: Emergency department and primary care visits were not associated with material risk, worry about affording care, or general anxiety in individual and pooled analyses (all 95% confidence intervals (CI) for relative risk (RR) included 1). Although no individual predictor was associated with urgent care use (all 95% CIs for RR included 1), worry about affording prescriptions (relative risk (RR) = 2.01; 95% CI 1.14, 3.55) and general anxiety (RR = 0.38; 95% CI 0.15, 0.95) were significant when included in the same model, suggesting the two confounded each other. Worry about affording healthcare services was associated with fewer specialty care visits (RR = 0.40; 95% CI 0.25, 0.64) even when controlling for material risk and general anxiety, although general anxiety was also associated with more specialty care visits (RR = 1.98; 95% CI, 1.23, 3.18).<br><br>CONCLUSIONS: Screening for both general anxiety and financial worry may assist with specialty care utilization. Identifying these concerns may provide more opportunities to assist patients. Future research should examine interventions to reduce worry about cost of care.}, }
@article {pmid33468571, year = {2021}, author = {Raiders, S and Han, T and Scott-Hewitt, N and Kucenas, S and Lew, D and Logan, MA and Singhvi, A}, title = {Engulfed by Glia: Glial Pruning in Development, Function, and Injury across Species.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.1660-20.2020}, pmid = {33468571}, issn = {1529-2401}, abstract = {Phagocytic activity of glial cells is essential for proper nervous system sculpting, maintenance of circuitry, and long-term brain health. Glial engulfment of apoptotic cells and superfluous connections ensures that neuronal connections are appropriately refined, while clearance of damaged projections and neurotoxic proteins in the mature brain protects against inflammatory insults. Comparative work across species and cell types in recent years highlights the striking conservation of pathways that govern glial engulfment. Many signaling cascades used during developmental pruning are re-employed in the mature brain to &quot;fine tune&quot; synaptic architecture and even clear neuronal debris following traumatic events. Moreover, the neuron-glia signaling events required to trigger and perform phagocytic responses are impressively conserved between invertebrates and vertebrates. This review offers a compare-and-contrast portrayal of recent findings that underscore the value of investigating glial engulfment mechanisms in a wide range of species and contexts.}, }
@article {pmid33468558, year = {2021}, author = {Maurice, NJ and Taber, AK and Prlic, M}, title = {The Ugly Duckling Turned to Swan: A Change in Perception of Bystander-Activated Memory CD8 T Cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {206}, number = {3}, pages = {455-462}, doi = {10.4049/jimmunol.2000937}, pmid = {33468558}, issn = {1550-6606}, abstract = {Memory T cells (Tmem) rapidly mount Ag-specific responses during pathogen reencounter. However, Tmem also respond to inflammatory cues in the absence of an activating TCR signal, a phenomenon termed bystander activation. Although bystander activation was first described over 20 years ago, the physiological relevance and the consequences of T cell bystander activation have only become more evident in recent years. In this review, we discuss the scenarios that trigger CD8 Tmem bystander activation including acute and chronic infections that are either systemic or localized, as well as evidence for bystander CD8 Tmem within tumors and following vaccination. We summarize the possible consequences of bystander activation for the T cell itself, the subsequent immune response, and the host. We highlight when T cell bystander activation appears to benefit or harm the host and briefly discuss our current knowledge gaps regarding regulatory signals that can control bystander activation.}, }
@article {pmid33465248, year = {2021}, author = {Wolfson, JA and Bhatia, S and Ginsberg, J and Becker, LK and Bernstein, D and Henk, HJ and Lyman, GH and Nathan, PC and Puccetti, D and Wilkes, JJ and Winestone, LE and Kenzik, KM}, title = {Expenditures among young adults with acute lymphoblastic leukemia by site of care.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33413}, pmid = {33465248}, issn = {1097-0142}, support = {SU2C-AACR-SUPHOP01//Stand Up To Cancer/ ; MRSG-18-020-10-CPPB//American Cancer Society/ ; }, abstract = {BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures.<br><br>METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled.<br><br>RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable.<br><br>CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings.<br><br>LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.}, }
@article {pmid33465157, year = {2021}, author = {Bacchus-Souffan, C and Fitch, M and Symons, J and Abdel-Mohsen, M and Reeves, DB and Hoh, R and Stone, M and Hiatt, J and Kim, P and Chopra, A and Ahn, H and York, VA and Cameron, DL and Hecht, FM and Martin, JN and Yukl, SA and Mallal, S and Cameron, PU and Deeks, SG and Schiffer, JT and Lewin, SR and Hellerstein, MK and McCune, JM and Hunt, PW}, title = {Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.}, journal = {PLoS pathogens}, volume = {17}, number = {1}, pages = {e1009214}, doi = {10.1371/journal.ppat.1009214}, pmid = {33465157}, issn = {1553-7374}, abstract = {The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.}, }
@article {pmid33465147, year = {2021}, author = {Santiago, JC and Goldman, JD and Zhao, H and Pankow, AP and Okuku, F and Schmitt, MW and Chen, LH and Hill, CA and Casper, C and Phipps, WT and Mullins, JI}, title = {Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma.}, journal = {PLoS pathogens}, volume = {17}, number = {1}, pages = {e1008594}, doi = {10.1371/journal.ppat.1008594}, pmid = {33465147}, issn = {1553-7374}, abstract = {Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that introduce errors possibly greater than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors from 2 individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.}, }
@article {pmid33463525, year = {2021}, author = {Kistler, KE and Bedford, T}, title = {Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.64509}, pmid = {33463525}, issn = {2050-084X}, support = {Graduation Research Fellowship Program,DGE-1762114//National Science Foundation/ ; Pew Biomedical Scholar,NIH R35 GM119774-01//Pew Charitable Trusts/ ; }, abstract = {Seasonal coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here, we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively-selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.}, }
@article {pmid33462536, year = {2020}, author = {Bellach, A and Kosorok, MR and Gilbert, PB and Fine, JP}, title = {General regression model for the subdistribution of a competing risk under left-truncation and right-censoring.}, journal = {Biometrika}, volume = {107}, number = {4}, pages = {949-964}, pmid = {33462536}, issn = {0006-3444}, abstract = {Left-truncation poses extra challenges for the analysis of complex time-to-event data. We propose a general semiparametric regression model for left-truncated and right-censored competing risks data that is based on a novel weighted conditional likelihood function. Targeting the subdistribution hazard, our parameter estimates are directly interpretable with regard to the cumulative incidence function. We compare different weights from recent literature and develop a heuristic interpretation from a cure model perspective that is based on pseudo risk sets. Our approach accommodates external time-dependent covariate effects on the subdistribution hazard. We establish consistency and asymptotic normality of the estimators and propose a sandwich estimator of the variance. In comprehensive simulation studies we demonstrate solid performance of the proposed method. Comparing the sandwich estimator with the inverse Fisher information matrix, we observe a bias for the inverse Fisher information matrix and diminished coverage probabilities in settings with a higher percentage of left-truncation. To illustrate the practical utility of the proposed method, we study its application to a large HIV vaccine efficacy trial dataset.}, }
@article {pmid33462485, year = {2021}, author = {Kurilshikov, A and Medina-Gomez, C and Bacigalupe, R and Radjabzadeh, D and Wang, J and Demirkan, A and Le Roy, CI and Raygoza Garay, JA and Finnicum, CT and Liu, X and Zhernakova, DV and Bonder, MJ and Hansen, TH and Frost, F and Rühlemann, MC and Turpin, W and Moon, JY and Kim, HN and Lüll, K and Barkan, E and Shah, SA and Fornage, M and Szopinska-Tokov, J and Wallen, ZD and Borisevich, D and Agreus, L and Andreasson, A and Bang, C and Bedrani, L and Bell, JT and Bisgaard, H and Boehnke, M and Boomsma, DI and Burk, RD and Claringbould, A and Croitoru, K and Davies, GE and van Duijn, CM and Duijts, L and Falony, G and Fu, J and van der Graaf, A and Hansen, T and Homuth, G and Hughes, DA and Ijzerman, RG and Jackson, MA and Jaddoe, VWV and Joossens, M and Jørgensen, T and Keszthelyi, D and Knight, R and Laakso, M and Laudes, M and Launer, LJ and Lieb, W and Lusis, AJ and Masclee, AAM and Moll, HA and Mujagic, Z and Qibin, Q and Rothschild, D and Shin, H and Sørensen, SJ and Steves, CJ and Thorsen, J and Timpson, NJ and Tito, RY and Vieira-Silva, S and Völker, U and Völzke, H and Võsa, U and Wade, KH and Walter, S and Watanabe, K and Weiss, S and Weiss, FU and Weissbrod, O and Westra, HJ and Willemsen, G and Payami, H and Jonkers, DMAE and Arias Vasquez, A and de Geus, EJC and Meyer, KA and Stokholm, J and Segal, E and Org, E and Wijmenga, C and Kim, HL and Kaplan, RC and Spector, TD and Uitterlinden, AG and Rivadeneira, F and Franke, A and Lerch, MM and Franke, L and Sanna, S and D'Amato, M and Pedersen, O and Paterson, AD and Kraaij, R and Raes, J and Zhernakova, A}, title = {Large-scale association analyses identify host factors influencing human gut microbiome composition.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {33462485}, issn = {1546-1718}, support = {024.004.017//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; 024.004.017//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; }, abstract = {To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.}, }
@article {pmid33461591, year = {2021}, author = {Wright, M and Smed, MK and Nelson, JL and Olsen, J and Hetland, ML and Zoffmann, V and Jawaheer, D}, title = {Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?.}, journal = {Arthritis research &amp; therapy}, volume = {23}, number = {1}, pages = {30}, pmid = {33461591}, issn = {1478-6362}, support = {R21AR057931/AR/NIAMS NIH HHS/United States ; R87-A1477-B512//Gigtforeningen/ ; N/A//Rigshospitalet/ ; }, abstract = {BACKGROUND: To evaluate our hypotheses that, when rheumatoid arthritis (RA) flares postpartum, gene expression patterns are altered compared to (a) healthy women, (b) RA women whose disease activity is low or in remission postpartum, and (c) pre-pregnancy expression profiles.<br><br>METHODS: Twelve women with RA and five healthy women were included in this pilot study. RA disease activity and postpartum flare were assessed using the Clinical Disease Activity Index (CDAI). Total RNA from frozen whole blood was used for RNA sequencing. Differential gene expression within the same women (within-group) over time, i.e., postpartum vs. third trimester (T3) or pre-pregnancy (T0), were examined, using a significance threshold of q < 0.05 and fold-change ≥ 2.<br><br>RESULTS: Nine of the women with RA experienced a flare postpartum (RAFlare), while three had low disease activity or were in remission (RANoFlare) during that time frame. Numerous immune-related genes were differentially expressed postpartum (vs. T3) during a flare. Fold-changes in expression from T3 to postpartum were mostly comparable between the RAFlare and healthy groups. At 3 months postpartum, compared to healthy women, several genes were significantly differentially expressed only among the RAFlare women, and not among the RANoFlare women. Some of these genes were among those whose &quot;normal&quot; expression was significantly modulated postpartum, and the postpartum expression patterns were significantly altered during the RA flare. There were also some genes that were significantly differentially expressed in RAFlare compared to both healthy and RANoFlare women, even though their expression was not significantly modulated postpartum. Furthermore, while postpartum expression profiles were similar to those at pre-pregnancy among healthy women, significant differences were found between those time points among the RAFlare women.<br><br>CONCLUSIONS: The large majority of gene expression changes between T3 and 3 months postpartum among RA women who flared postpartum reflected normal postpartum changes also seen among healthy women. Nonetheless, during a postpartum flare, a set of immune-related genes showed dysregulated expression compared to healthy women and women with RA whose disease activity was low or in remission during the same time frame, while other genes demonstrated significant differences in expression compared to RA pre-pregnancy levels.}, }
@article {pmid33461574, year = {2021}, author = {Filice, D and Dhahri, W and Solan, JL and Lampe, PD and Steele, E and Milani, N and Van Biber, B and Zhu, WZ and Valdman, TS and Romagnuolo, R and Otero-Cruz, JD and Hauch, KD and Kay, MW and Sarvazyan, N and Laflamme, MA}, title = {Correction to: Optical mapping of human embryonic stem cell-derived cardiomyocyte graft electrical activity in injured hearts.}, journal = {Stem cell research &amp; therapy}, volume = {12}, number = {1}, pages = {66}, pmid = {33461574}, issn = {1757-6512}, }
@article {pmid33454198, year = {2021}, author = {Lange, PH and Cookson, MS and Schellhammer, PF and Droller, MJ}, title = {A history of the Society of Urologic Oncology.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2020.12.018}, pmid = {33454198}, issn = {1873-2496}, abstract = {This narrative of the history of the Society of Urologic Oncology (SUO) presents the story of the founding and development of this organization and the creation and establishment of its initiatives and programs. It includes a description of how &quot;Urologic Oncology: Seminars and Original Investigations&quot; came to be designated as its &quot;official journal&quot;, thus commemorating the anniversary of the Journal's twenty-five years of publication.}, }
@article {pmid33460572, year = {2021}, author = {Leisman, DE and Ronner, L and Pinotti, R and Taylor, MD and Sinha, P and Calfee, CS and Hirayama, AV and Mastroianni, F and Turtle, CJ and Harhay, MO and Legrand, M and Deutschman, CS}, title = {Assessing the importance of interleukin-6 in COVID-19 - Authors' reply.}, journal = {The Lancet. Respiratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2213-2600(20)30603-2}, pmid = {33460572}, issn = {2213-2619}, }
@article {pmid33458808, year = {2021}, author = {Walsh, CA and Al Achkar, M}, title = {A qualitative study of online support communities for lung cancer survivors on targeted therapies.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {}, number = {}, pages = {}, pmid = {33458808}, issn = {1433-7339}, support = {5T32 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Due to recent treatment advances, people who have non-small cell lung cancer with oncogenic alterations are an important new group of cancer survivors. Little is known about lung cancer online support communities. This research was guided by two primary questions: (1) How do these lung cancer survivors engage in online support communities? and (2) What are the psychological, social, and physical impacts of such engagement?<br><br>METHODS: Qualitative in-depth interviews were conducted with patients with advanced lung cancer (N = 40) to learn about their experiences with the illness. We used qualitative thematic analysis, inductive and deductive, as outlined by Carspecken. We adapted the framework for studying online communities developed by Zhang and colleagues to examine engagement with and impacts of involvement in online lung cancer support communities.<br><br>RESULTS: Participants described engaging in the online community through (1) initializing communication through asking questions or sharing resources, (2) responding to others comments or inquiries, or (3) simply observing/reading others posts. Participation had physical, psychological, or social impacts, with benefits (e.g., empowerment) and risks (e.g., feelings of jealousy or misinformation) in each domain. Participants used various strategies to mitigate negative impacts, such as distancing oneself as needed.<br><br>CONCLUSIONS: Online lung cancer support communities provide support, camaraderie, and specialized health information. However, there are also risks of online engagement, such as social comparison or accessing misinformation. Understanding the utility of online support communities for lung cancer survivors on targeted therapies and further addressing their risks are urgent tasks, especially in the post-COVID era.}, }
@article {pmid33453189, year = {2021}, author = {Tomko, EJ and Luyties, O and Rimel, JK and Tsai, CL and Fuss, JO and Fishburn, J and Hahn, S and Tsutakawa, SE and Taatjes, DJ and Galburt, EA}, title = {The role of XPB/Ssl2 dsDNA translocation processivity in transcription-start-site scanning.}, journal = {Journal of molecular biology}, volume = {}, number = {}, pages = {166813}, doi = {10.1016/j.jmb.2021.166813}, pmid = {33453189}, issn = {1089-8638}, abstract = {The general transcription factor TFIIH contains three ATP-dependent catalytic activities. TFIIH functions in nucleotide excision repair primarily as a DNA helicase and in Pol II transcription initiation as a dsDNA translocase and protein kinase. During initiation, the XPB/Ssl2 subunit of TFIIH couples ATP hydrolysis to dsDNA translocation facilitating promoter opening and the kinase module phosphorylates Pol II to facilitate the transition to elongation. These functions are conserved between metazoans and yeast; however, yeast TFIIH also drives transcription start-site scanning in which Pol II scans downstream DNA to locate productive start-sites. The ten-subunit holo-TFIIH from S. cerevisiae has a processive dsDNA translocase activity required for scanning and a structural role in scanning has been ascribed to the three-subunit TFIIH kinase module. Here, we assess the dsDNA translocase activity of ten-subunit holo- and core-TFIIH complexes (i.e. seven subunits, lacking the kinase module) from both S. cerevisiae and H. sapiens. We find that neither holo nor core human TFIIH exhibit processive translocation, consistent with the lack of start-site scanning in humans. Furthermore, in contrast to holo-TFIIH, the S. cerevisiae core-TFIIH also lacks processive translocation and its dsDNA-stimulated ATPase activity was reduced ∼5-fold to a level comparable to the human complexes, potentially explaining the reported upstream shift in start-site observed in vitro in the absence of the S. cerevisiae kinase module. These results suggest that neither human nor S. cerevisiae core-TFIIH can translocate efficiently, and that the S. cerevisiae kinase module functions as a processivity factor to allow for robust transcription start-site scanning.}, }
@article {pmid33451977, year = {2021}, author = {Ansell, SM and Maris, M and Lesokhin, AM and Chen, R and Flinn, IW and Sawas, A and Minden, MD and Villa, D and Percival, MM and Advani, AS and Foran, JM and Horwitz, S and Mei, M and Zain, J and Savage, KJ and Querfeld, C and Akilov, OE and Johnson, LD and Catalano, T and Petrova, PS and Uger, RA and Sievers, EL and Milea, A and Roberge, K and Shou, Y and O'Connor, OA}, title = {Phase 1 Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-20-3706}, pmid = {33451977}, issn = {1557-3265}, abstract = {PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 &quot;don't eat me&quot; signal. This first-in-human phase 1 study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.<br><br>EXPERIMENTAL DESIGN: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI‑621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL) or nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoints included overall response rate (ORR).<br><br>RESULTS: Overall, 164 patients received TTI‑621: 18 in escalation and 146 in expansion (rituximab combination, n=35; nivolumab combination, n=4). Based on transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20% grade {greater than or equal to}3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI‑621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.<br><br>CONCLUSIONS: TTI-621 was well tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.}, }
@article {pmid33451499, year = {2019}, author = {Ma, W and Chen, LS and Özbek, U and Han, SW and Lin, C and Paulovich, AG and Zhong, H and Wang, P}, title = {Integrative Proteo-genomic Analysis to Construct CNA-protein Regulatory Map in Breast and Ovarian Tumors.}, journal = {Molecular &amp; cellular proteomics : MCP}, volume = {18}, number = {8S1}, pages = {S66-S81}, doi = {10.1074/mcp.RA118.001229}, pmid = {33451499}, issn = {1535-9484}, abstract = {Recent development in high throughput proteomics and genomics profiling enable one to study regulations of genome alterations on protein activities in a systematic manner. In this article, we propose a new statistical method, ProMAP, to systematically characterize the regulatory relationships between proteins and DNA copy number alterations (CNA) in breast and ovarian tumors based on proteogenomic data from the CPTAC-TCGA studies. Because of the dynamic nature of mass spectrometry instruments, proteomics data from labeled mass spectrometry experiments usually have non-ignorable batch effects. Moreover, mass spectrometry based proteomic data often possesses high percentages of missing values and non-ignorable missing-data patterns. Thus, we use a linear mixed effects model to account for the batch structure and explicitly incorporate the abundance-dependent-missing-data mechanism of proteomic data in ProMAP. In addition, we employ a multivariate regression framework to characterize the multiple-to-multiple regulatory relationships between CNA and proteins. Further, we use proper statistical regularization to facilitate the detection of master genetic regulators, which affect the activities of many proteins and often play important roles in genetic regulatory networks. Improved performance of ProMAP over existing methods were illustrated through extensive simulation studies and real data examples. Applying ProMAP to the CPTAC-TCGA breast and ovarian cancer data sets, we identified many genome regions, including a few novel ones, whose CNA were associated with protein and or phosphoprotein abundances. For example, in breast tumors, a small region in 8p11.21 was recognized as the second biggest hub in the CNA-phosphoprotein regulatory map, and further investigation of the regulatory targets suggests the potential role of 8p11.21 CNA in perturbing oxygen binding and transport activities in tumor cells. This and other findings from our analyses help to characterize the impacts of CNAs on protein activity landscapes and cast light on the genetic regulation mechanisms underlying these tumors.}, }
@article {pmid33449816, year = {2021}, author = {Watkins, B and Qayed, M and McCracken, C and Bratrude, B and Betz, K and Suessmuth, Y and Yu, A and Sinclair, S and Furlan, S and Bosinger, S and Tkachev, V and Rhodes, J and Tumlin, AG and Narayan, A and Cribbin, K and Gillespie, S and Gooley, TA and Pasquini, MC and Hebert, K and Kapoor, U and Rogatko, A and Tighiouart, M and Kim, S and Bresee, C and Choi, SW and Davis, J and Duncan, C and Giller, R and Grimley, M and Harris, AC and Jacobsohn, D and Lalefar, N and Norkin, M and Farhadfar, N and Pulsipher, MA and Shenoy, S and Petrovic, A and Schultz, KR and Yanik, GA and Waller, EK and Levine, JE and Ferrara, JL and Blazar, BR and Langston, A and Horan, JT and Kean, LS}, title = {Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2001086}, doi = {10.1200/JCO.20.01086}, pmid = {33449816}, issn = {1527-7755}, abstract = {PURPOSE: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.<br><br>METHODS: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).<br><br>RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.<br><br>CONCLUSION: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.}, }
@article {pmid33449804, year = {2021}, author = {Menon, MP and Niyonzima, N and Gralow, J and Orem, J}, title = {Breast Cancer Clinical Trials: The Landscape at the Uganda Cancer Institute and Lessons Learned.}, journal = {JCO global oncology}, volume = {7}, number = {}, pages = {127-132}, doi = {10.1200/GO.20.00185}, pmid = {33449804}, issn = {2687-8941}, abstract = {The Uganda Cancer Institute, the sole national comprehensive cancer center in Uganda, has a long and rich history of clinical investigation and locally relevant cancer research. Given the increasing burden of breast cancer in Uganda and elsewhere in sub-Saharan Africa (SSA) and driven by the limited availability of immunohistochemistry (IHC), we launched a clinical trial aimed at evaluating locally available diagnostics to detect the presence of hormone receptors (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2. Preliminary data from 32 women in the diagnostic component of the study reveal high sensitivity and specificity for estrogen receptor and progesterone receptor and high specificity for human epidermal growth factor receptor 2 when comparing reverse transcriptase polymerase chain reaction with the gold standard (IHC). Innovative diagnostic and treatment strategies are required to address the burden of breast cancer that is increasing throughout SSA. Given the costs, infrastructure, and trained personnel associated with IHC, alternative testing options (including reverse transcriptase polymerase chain reaction as tested in our study) may provide an expedited and cost-effective method to determine receptor testing in breast cancer. Clinical trials conducted in the local setting are critical to determining optimal strategies for effective breast cancer management in SSA.}, }
@article {pmid33447851, year = {2021}, author = {Jang, SH and Brown, EVR and Lee, EJ and Ko, LK}, title = {&quot;Blood pressure monitoring should be a habit&quot;: adaptation of the Check. Change. Control. program for Asian American older adults, from group-based in-person to one-on-one telephone delivery.}, journal = {Translational behavioral medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/tbm/ibaa142}, pmid = {33447851}, issn = {1613-9860}, abstract = {Asian Americans have the lowest rate of awareness about hypertension, including controlled hypertension, among all racial/ethnic groups in the USA. A high proportion of Asian American older adults have limited English proficiency (LEP) and hypertension. This study adapted the Check. Change. Control. (CCC) program, a community-based intervention for hypertension control delivered in a face-to-face group setting, to phone-based delivery and evaluated the acceptability of the program among Asian American older adults with LEP. Thirteen participants received phone-based educational sessions on hypertension control over 4 months. After 4 months of interventions, we interviewed the 13 Asian American older adults and 4 counselors to examine the acceptability of the adapted CCC program. Both Asian American older adults and counselors found the phone-based delivery of the CCC program to be acceptable, and some participants recommended holding an in-person meeting before telephone delivery to review the program content and clarify information. Future study needs to explore the effectiveness of the phone-based delivery of the program on blood pressure management among larger groups of Asian American older adults.}, }
@article {pmid33443562, year = {2021}, author = {Shadman, M and Ujjani, C}, title = {Vaccinations in CLL: implications for COVID-19.}, journal = {Blood}, volume = {137}, number = {2}, pages = {144-146}, doi = {10.1182/blood.2020009966}, pmid = {33443562}, issn = {1528-0020}, }
@article {pmid33442662, year = {2021}, author = {Nyame, YA and Gulati, R and Tsodikov, A and Gore, JL and Etzioni, R}, title = {Prostate-Specific Antigen Screening and Recent Increases in Advanced Prostate Cancer.}, journal = {JNCI cancer spectrum}, volume = {5}, number = {1}, pages = {pkaa098}, doi = {10.1093/jncics/pkaa098}, pmid = {33442662}, issn = {2515-5091}, abstract = {Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet, whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by 2 models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.}, }
@article {pmid33441422, year = {2021}, author = {Tkachev, V and Kaminski, J and Potter, EL and Furlan, SN and Yu, A and Hunt, DJ and McGuckin, C and Zheng, H and Colonna, L and Gerdemann, U and Carlson, J and Hoffman, M and Olvera, J and English, C and Baldessari, A and Panoskaltsis-Mortari, A and Watkins, B and Qayed, M and Suessmuth, Y and Betz, K and Bratrude, B and Langston, A and Horan, JT and Ordovas-Montanes, J and Shalek, AK and Blazar, BR and Roederer, M and Kean, LS}, title = {Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease.}, journal = {Science translational medicine}, volume = {13}, number = {576}, pages = {}, doi = {10.1126/scitranslmed.abc0227}, pmid = {33441422}, issn = {1946-6242}, abstract = {Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.}, }
@article {pmid33440260, year = {2021}, author = {Palumbo, PJ and Zhang, Y and Clarke, W and Breaud, A and Sivay, M and Cummings, V and Hamilton, EL and Guo, X and Ogendo, A and Kayange, N and Panchia, R and Dominguez, K and Chen, YQ and Sandfort, TGM and Eshleman, SH}, title = {Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075.}, journal = {International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijid.2020.12.085}, pmid = {33440260}, issn = {1878-3511}, abstract = {OBJECTIVES: HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period.<br><br>METHODS: Assessments included 64 participants with HIV (39 MSM, 24 TGW, one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays.<br><br>RESULTS: Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up.<br><br>CONCLUSIONS: Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly three-fold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.}, }
@article {pmid33440088, year = {2021}, author = {Sadoff, J and Le Gars, M and Shukarev, G and Heerwegh, D and Truyers, C and de Groot, AM and Stoop, J and Tete, S and Van Damme, W and Leroux-Roels, I and Berghmans, PJ and Kimmel, M and Van Damme, P and de Hoon, J and Smith, W and Stephenson, KE and De Rosa, SC and Cohen, KW and McElrath, MJ and Cormier, E and Scheper, G and Barouch, DH and Hendriks, J and Struyf, F and Douoguih, M and Van Hoof, J and Schuitemaker, H}, title = {Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2034201}, pmid = {33440088}, issn = {1533-4406}, support = {HHS0100201700018C/US/United States/United States ; }, abstract = {BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein.<br><br>METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule.<br><br>RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354) and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488), regardless of vaccine dose or age group. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 14, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3.<br><br>CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson &amp; Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).}, }
@article {pmid33438892, year = {2021}, author = {Peters, BA and Xue, X and Wang, Z and Usyk, M and Santoro, N and Sharma, A and Anastos, K and Tien, PC and Golub, ET and Weber, KM and Gustafson, D and Kaplan, RC and Burk, R and Qi, Q}, title = {Menopausal status and observed differences in the gut microbiome in women with and without HIV infection.}, journal = {Menopause (New York, N.Y.)}, volume = {Publish Ahead of Print}, number = {}, pages = {}, doi = {10.1097/GME.0000000000001730}, pmid = {33438892}, issn = {1530-0374}, abstract = {OBJECTIVE: Gut microbiota respond to host physiological phenomena, yet little is known regarding shifts in the gut microbiome due to menopausal hormonal and metabolic changes in women. HIV infection impacts menopause and may also cause gut dysbiosis. We therefore sought to determine the association between menopausal status and gut microbiome composition in women with and without HIV.<br><br>METHODS: Gut microbiome composition was assessed in stool from 432 women (99 premenopausal HIV+, 71 premenopausal HIV-, 182 postmenopausal HIV+, 80 postmenopausal HIV-) via 16S rRNA gene sequencing. We examined cross-sectional associations of menopause with gut microbiota overall diversity and composition, and taxon and inferred metagenomic pathway abundance. Models were stratified by HIV serostatus and adjusted for age, HIV-related variables, and other potential confounders.<br><br>RESULTS: Menopause, ie post- versus premenopausal status, was associated with overall microbial composition only in women with HIV (permutational MANOVA of Jensen Shannon Divergence: P = 0.01). In women with HIV, menopause was associated with enrichment of gram-negative order Enterobacteriales, depletion of highly abundant taxa within Prevotella copri, and alterations in other low-abundance taxa. Additionally, menopause in women with HIV was associated with enrichment of metagenomic pathways related to Enterobacteriales, including degradation of amino acids and phenolic compounds, biosynthesis of enterobactin, and energy metabolism pathways. Menopause-related differences in some low-abundance taxa were also observed in women without HIV.<br><br>CONCLUSIONS: A changing gut microbiome may be an overlooked phenomenon of reproductive aging in women with HIV. Longitudinal assessments across all reproductive stages are necessary to confirm these findings and identify health implications.}, }
@article {pmid33438580, year = {2021}, author = {Dingens, AS and Pratap, P and Malone, KD and Hilton, SK and Ketas, T and Cottrell, CA and Overbaugh, JM and Moore, JP and Klasse, PJ and Ward, AB and Bloom, JD}, title = {High-resolution mapping of the neutralizing and binding specificities of polyclonal sera post HIV Env trimer vaccination.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.64281}, pmid = {33438580}, issn = {2050-084X}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; P01 AI110657/AI/NIAID NIH HHS/United States ; R01 AI12096//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Mapping polyclonal serum responses is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual antibodies, which incompletely defines the polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. We used mutational antigenic profiling to determine how all mutations in Env affected viral neutralization and electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize serum Fabs bound to Env trimers. The dominant neutralizing specificities were generally only a subset of the more diverse binding specificities. Additional differences between binding and neutralization reflected antigenicity differences between virus and soluble Env trimer. Further, we refined residue-level epitope specificity directly from sera, revealing subtle differences across sera. Together, mutational antigenic profiling and EMPEM yield a holistic view of the binding and neutralizing specificity of polyclonal sera.}, }
@article {pmid33436609, year = {2021}, author = {Mistry, D and Litvinova, M and Pastore Y Piontti, A and Chinazzi, M and Fumanelli, L and Gomes, MFC and Haque, SA and Liu, QH and Mu, K and Xiong, X and Halloran, ME and Longini, IM and Merler, S and Ajelli, M and Vespignani, A}, title = {Inferring high-resolution human mixing patterns for disease modeling.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {323}, pmid = {33436609}, issn = {2041-1723}, support = {U54 GM111274/GM/NIGMS NIH HHS/United States ; }, abstract = {Mathematical and computational modeling approaches are increasingly used as quantitative tools in the analysis and forecasting of infectious disease epidemics. The growing need for realism in addressing complex public health questions is, however, calling for accurate models of the human contact patterns that govern the disease transmission processes. Here we present a data-driven approach to generate effective population-level contact matrices by using highly detailed macro (census) and micro (survey) data on key socio-demographic features. We produce age-stratified contact matrices for 35 countries, including 277 sub-national administratvie regions of 8 of those countries, covering approximately 3.5 billion people and reflecting the high degree of cultural and societal diversity of the focus countries. We use the derived contact matrices to model the spread of airborne infectious diseases and show that sub-national heterogeneities in human mixing patterns have a marked impact on epidemic indicators such as the reproduction number and overall attack rate of epidemics of the same etiology. The contact patterns derived here are made publicly available as a modeling tool to study the impact of socio-economic differences and demographic heterogeneities across populations on the epidemiology of infectious diseases.}, }
@article {pmid33436523, year = {2021}, author = {Lemmers, RJLF and van der Vliet, PJ and Blatnik, A and Balog, J and Zidar, J and Henderson, D and Goselink, R and Tapscott, SJ and Voermans, NC and Tawil, R and Padberg, GWAM and van Engelen, BG and van der Maarel, SM}, title = {Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene.}, journal = {Journal of medical genetics}, volume = {}, number = {}, pages = {}, doi = {10.1136/jmedgenet-2020-107041}, pmid = {33436523}, issn = {1468-6244}, abstract = {BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.<br><br>METHOD: Detailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.<br><br>RESULTS: Identification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.<br><br>CONCLUSION: This study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.}, }
@article {pmid33436325, year = {2021}, author = {Karlsson, Q and Brook, MN and Dadaev, T and Wakerell, S and Saunders, EJ and Muir, K and Neal, DE and Giles, GG and MacInnis, RJ and Thibodeau, SN and McDonnell, SK and Cannon-Albright, L and Teixeira, MR and Paulo, P and Cardoso, M and Huff, C and Li, D and Yao, Y and Scheet, P and Permuth, JB and Stanford, JL and Dai, JY and Ostrander, EA and Cussenot, O and Cancel-Tassin, G and Hoegel, J and Herkommer, K and Schleutker, J and Tammela, TLJ and Rathinakannan, V and Sipeky, C and Wiklund, F and Grönberg, H and Aly, M and Isaacs, WB and Dickinson, JL and FitzGerald, LM and Chua, MLK and Nguyen-Dumont, T and ,  and Schaid, DJ and Southey, MC and Eeles, RA and Kote-Jarai, Z}, title = {Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2020.12.001}, pmid = {33436325}, issn = {2588-9311}, abstract = {BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.<br><br>OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk.<br><br>We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.<br><br>Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.<br><br>RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).<br><br>CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.<br><br>PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.}, }
@article {pmid33435981, year = {2021}, author = {Sanchez, JI and Briant, KJ and Wu-Georges, S and Gonzalez, V and Galvan, A and Cole, S and Thompson, B}, title = {Eat Healthy, Be Active Community Workshops implemented with rural Hispanic women.}, journal = {BMC women's health}, volume = {21}, number = {1}, pages = {24}, pmid = {33435981}, issn = {1472-6874}, support = {U54 CA153502/CA/NCI NIH HHS/United States ; P30 CA015704-37S5/CA/NCI NIH HHS/United States ; UL1 RR025014/RR/NCRR NIH HHS/United States ; }, abstract = {BACKGROUND: In the U.S., obesity disproportionately affects some racial/ethnic groups more than others; 42.5% of Hispanic adults are obese, compared to 32.6% of non-Hispanic whites (NHW). Research also shows that Mexican American women are 40% more likely to be overweight, as compared to NHW women. With high obesity rates among Hispanics, improving healthier lifestyle practices is an important step for reducing health disparities. The Eat Healthy, Be Active (EHBA) community workshops were developed to assist individuals in translating national nutrition and physical activity recommendations into action. Promotora-led EHBA workshops could be used to promote obesity-related health behavior lifestyle changes among Hispanics.<br><br>METHODS: Hispanic women from rural communities in Washington state were recruited to participate in a six-week Promotora-led workshop series. This pilot study used a pre- and post-test study design to examine differences in healthy lifestyle knowledge and practices.<br><br>RESULTS: A total of 49 Hispanic women participated in the workshops, of whom 45% were obese. Six-weeks after implementation of EHBA, women had improvements in healthy lifestyle practices, including an increase in nutrition label literacy, decrease in consumption of food eaten in restaurants, and an increase in the number of times a woman performed physical activity long enough to make them sweat.<br><br>CONCLUSION: The findings from this pilot study indicate that delivering EHBA workshops through promotoras is a feasible culturally relevant approach to promoting healthier lifestyle practices among Hispanic women. Further, focusing on females, who do the food shopping and preparation in their homes, may help increase awareness among whole families.}, }
@article {pmid33434318, year = {2021}, author = {Hua, S and Qi, Q and Kizer, JR and Williams-Nguyen, J and Strickler, HD and Thyagarajan, B and Daviglus, M and Talavera, GA and Schneiderman, N and Cotler, SJ and Cai, J and Kaplan, R and Isasi, CR}, title = {Association of liver enzymes with incident diabetes in US Hispanic/Latino adults.}, journal = {Diabetic medicine : a journal of the British Diabetic Association}, volume = {}, number = {}, pages = {e14522}, doi = {10.1111/dme.14522}, pmid = {33434318}, issn = {1464-5491}, abstract = {INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD.<br><br>METHODS: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)).<br><br>RESULTS: A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], P-trend=0.006; RR for GGT: 2.39 [1.60-3.55], P-trend=0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (P for interaction<0.05). The association of AST with incident diabetes was found only among light-to-moderate alcohol drinkers (RR=1.50 [1.20-1.86]) but not abstainers (RR=0.91 [0.69-1.20], P for interaction=0.006).<br><br>CONCLUSION: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high risk individuals.}, }
@article {pmid33433939, year = {2021}, author = {O'Brien, KM and Tworoger, SS and Harris, HR and Trabert, B and Weinberg, CR and Fortner, RT and D'Aloisio, AA and Kaunitz, AM and Wentzensen, N and Sandler, DP}, title = {Genital powder use and risk of uterine cancer: A pooled analysis of prospective studies.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33470}, pmid = {33433939}, issn = {1097-0215}, abstract = {When powder is applied to the genital area, it has the potential to reach internal reproductive organs and promote carcinogenesis by irritating and inflaming exposed tissues. While many studies have considered the association between genital powder use and ovarian cancer risk, the relationship between genital powder use and uterine cancer is less well-studied. We pooled data from four large, prospective cohorts (the Nurses' Health Study, the Nurses' Health Study II, the Sister Study, and the Women's Health Initiative - Observational Study). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI), adjusting for pre-specified confounders. In total, 209 185 women were included, with 37% reporting ever genital powder use. Over a mean 14.5 years of follow-up, 3272 invasive uterine cancers were diagnosed. There was no overall association between ever genital powder use and uterine cancer (HR = 1.01, 95% CI: 0.94-1.09), with little difference observed for frequent (≥1 times/week) vs never use (HR = 1.05, 95% CI: 0.95-1.16; p-for-trend = 0.46). Long-term use (>20 years; HR = 1.12, 95% CI: 0.96-1.31; p-for-trend = 0.14) was associated with a small, but not statistically significant, increase in risk, compared to never use. There were not clear differences by uterine cancer histologic subtypes or across strata of relevant covariates, including race/ethnicity, follow-up time, menopausal status and body mass index. The results of this large, pooled analysis do not support a relationship between use of genital powder and uterine cancer, though the positive associations observed for long-term use may merit further consideration. This article is protected by copyright. All rights reserved.}, }
@article {pmid33433743, year = {2021}, author = {Wong, RL and Yu, EY}, title = {Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations.}, journal = {Current treatment options in oncology}, volume = {22}, number = {2}, pages = {13}, pmid = {33433743}, issn = {1534-6277}, abstract = {OPINION STATEMENT: Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in CDK12. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of &quot;precision medicine&quot; in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.}, }
@article {pmid33433609, year = {2021}, author = {Perski, O and Watson, NL and Mull, KE and Bricker, JB}, title = {Identifying content-based engagement patterns in a smoking cessation website and associations with user characteristics and cessation outcomes: A sequence and cluster analysis.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntab008}, pmid = {33433609}, issn = {1469-994X}, abstract = {INTRODUCTION: Using WebQuit as a case study, a smoking cessation website grounded in Acceptance and Commitment Therapy, we aimed to identify sequence clusters of content usage and examine their associations with baseline characteristics, change to a key mechanism of action, and smoking cessation.<br><br>METHODS: Participants were adult smokers allocated to the WebQuit arm in a randomized controlled trial (n=1,313). WebQuit contains theory-informed content including goal setting, self-monitoring and feedback, and values- and acceptance-based exercises. Sequence analysis was used to temporally order 30-second website usage segments for each participant. Similarities between sequences were assessed with the optimal matching distance algorithm and used as input in an agglomerative hierarchical clustering analysis. Associations between sequence clusters and baseline characteristics, acceptance of cravings at 3 months and self-reported 30-day point prevalence abstinence at 12 months were examined with linear and logistic regression.<br><br>RESULTS: Three qualitatively different sequence clusters were identified. 'Disengagers' (576/1,313) almost exclusively used the goal setting feature. 'Tryers' (375/1,313) used goal setting and two of the values- and acceptance-based components ('Be Aware', 'Be Willing'). 'Committers' (362/1,313) primarily used two of the values- and acceptance-based components ('Be Willing', 'Be Inspired'), goal setting, and self-monitoring and feedback. Compared with Disengagers, Committers demonstrated greater increases in acceptance of cravings (p=.01) and 64% greater odds of quit success (ORadj=1.64, 95% CI=1.18, 2.29, p=.003).<br><br>DISCUSSION: WebQuit users were categorised into Disengagers, Tryers and Committers based on their qualitatively different content usage patterns. Committers saw increases in a key mechanism of action and greater odds of quit success.<br><br>IMPLICATIONS: This case study demonstrates how employing sequence and cluster analysis of usage data can help researchers and practitioners gain a better understanding of how users engage with a given eHealth intervention over time and use findings to test theory and/or to improve future iterations to the intervention. Future WebQuit users may benefit from being directed to the values- and acceptance-based and the self-monitoring and feedback components via reminders over the course of the program.}, }
@article {pmid33433559, year = {2021}, author = {Stefanick, ML and King, AC and Mackey, S and Tinker, LF and Hlatky, MA and LaMonte, MJ and Bellettiere, J and Larson, JC and Anderson, G and Kooperberg, CL and LaCroix, AZ}, title = {Women's Health Initiative Strong and Healthy (WHISH) Pragmatic Physical Activity Intervention Trial for Cardiovascular Disease Prevention: Design and Baseline Characteristics.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glaa325}, pmid = {33433559}, issn = {1758-535X}, abstract = {BACKGROUND: National guidelines promote physical activity to prevent cardiovascular disease (CVD), yet no randomized controlled trial has tested whether physical activity reduces prevent CVD.<br><br>METHODS: The Women's Health Initiative (WHI) Strong and Healthy (WHISH) pragmatic trial used a randomized consent design to assign women for whom cardiovascular outcomes were available through WHI data collection (N=18,985) or linkage to the Centers for Medicare and Medicaid Services (N30,346), to a physical activity intervention or &quot;usual activity&quot; comparison, stratified by ages 68-99 years (in tertiles), U.S. geographic region, and outcomes data source. Women assigned to the intervention could &quot;opt out&quot; after receiving initial physical activity materials. Intervention materials applied evidence-based behavioral science principles to promote current national recommendations for older Americans The intervention was adapted to participant input regarding preferences, resources, barriers and motivational drivers and was targetted for three categories of women at lower, middle or higher levels of self-reported physical functioning and physical activity. Physical activity was assessed in both arms through annual questionnaires. The primary outcome is major cardiovascular events, specifically myocardial infarction, stroke, or CVD death; primary safety outcomes are hip fracture and non-CVD death. The trial is monitored annually by an independent Data Safety and Monitoring Board. Final analyses will be based on intention-to-treat in all randomized participants, regardless of intervention engagement.<br><br>RESULTS: The 49,331 randomized participants had a mean baseline age of 79.7 years; 84.3% were white, 9.2% black, 3.3% Hispanic, 1.9% Asian/Pacific Islander, 0.3% Native American, and 1% were of unknown race/ethnicity. The mean baseline RAND-36 physical function score was 71.6 (± 25.2 SD). There were no differences between Intervention (N=24,657) and Control (N=24,674) at baseline for age, race/ethnicity, current smoking (2.5%), use of blood pressure or lipid-lowering medications, body mass index, physical function, physical activity, or prior CVD (10.1%).<br><br>CONCLUSION: The WHISH trial is rigorously testing whether a physical activity intervention reduces major CV events in a large, diverse cohort of older women.}, }
@article {pmid33432929, year = {2021}, author = {Cardozo-Ojeda, EF and Duke, ER and Peterson, CW and Reeves, DB and Mayer, BT and Kiem, HP and Schiffer, JT}, title = {Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.57646}, pmid = {33432929}, issn = {2050-084X}, support = {UM1 AI126623/AI/NIAID NIH HHS/United States ; R01 AI150500/AI/NIAID NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; New Investigator Award P30 AI027757//Center for AIDS Research/ ; Postdoctoral Fellowship//Washington Research Foundation/ ; P51 OD010425/NH/NIH HHS/United States ; }, abstract = {Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be edited ex vivo to provide protection against infection. To project the thresholds of CCR5-edition necessary for HIV remission, we developed a mathematical model that recapitulates blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted HSPCs are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76-94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur.}, }
@article {pmid33432329, year = {2021}, author = {Farland, LV and Degnan, WJ and Harris, HR and Han, J and Cho, E and VoPham, T and Kvaskoff, M and Missmer, SA}, title = {Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study.}, journal = {Human reproduction (Oxford, England)}, volume = {36}, number = {1}, pages = {199-210}, doi = {10.1093/humrep/deaa280}, pmid = {33432329}, issn = {1460-2350}, abstract = {STUDY QUESTION: Is recreational and residential sun exposure associated with risk of endometriosis?<br><br>SUMMARY ANSWER: Tanning bed use in early adulthood, sunscreen use and history of sunburns were associated with a greater risk of endometriosis; however, higher residential UV exposure was associated with a lower endometriosis risk.<br><br>WHAT IS KNOWN ALREADY: Previous research has reported an association between endometriosis and skin cancer, with evidence of shared risk factors between the two diseases. We investigated the potential associations between ultraviolet radiation and endometriosis risk.<br><br>STUDY DESIGN, SIZE, DURATION: The Nurses' Health Study II is a prospective cohort of 116 429 female US nurses aged 25-42 years at enrolment in 1989. Participants completed self-administered biennial questionnaires through June 2015.<br><br>We investigated self-reported measures of recreational sun-exposure and geocoded residential UV exposure in childhood and adulthood in relation to risk of laparoscopically confirmed endometriosis among premenopausal white women. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs.<br><br>During follow-up, 4791 incident cases of laparoscopically confirmed endometriosis were reported among 1 252 248 person-years. Tanning bed use during high school/college (≥6 times per year vs. never use: HR = 1.19, 95% CI = 1.01-1.40; Ptrend = 0.04) and at ages 25-35 (HR = 1.24, 95% CI = 1.12-1.39; Ptrend ≤ 0.0001), number of sunburns during adolescence (Ptrend = 0.03) and percentage of time using sunscreen in adulthood (Ptrend = 0.002) were positively associated with risk of endometriosis. In contrast, residential UV level at birth (highest vs. lowest quintile: HR = 0.81, 95% CI = 0.72-0.92; Ptrend = 0.0001), at age 15 (HR = 0.79, 95% CI = 0.70-0.88; Ptrend ≤ 0.0001) and at age 30 (HR = 0.90, 95% CI = 0.82-0.99; Ptrend = 0.21) were associated with a decreased risk of endometriosis.<br><br>Self-reported endometriosis diagnosis may be prone to misclassification; however, we restricted our definition to laparoscopically confirmed endometriosis, which has been shown to have high validity compared to medical records.<br><br>Our results suggest that tanning bed use in early adulthood increases endometriosis risk, potentially through a harmful effect of ultraviolet A wavelengths, and that residential UV exposure reduces risk, possibly via optimal vitamin D synthesis. These findings should be investigated further to enhance our understanding of endometriosis aetiology.<br><br>This project was supported by NICHD grants HD48544 and HD52473, HD57210, NIH grant CA50385, CA176726. M.K. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. H.R.H. is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). The authors have nothing to disclose.<br><br>TRIAL REGISTRATION NUMBER: N/A.}, }
@article {pmid33431603, year = {2021}, author = {Carbone, LD and Johnson, K and Larson, JC and Thomas, F and Wactawski-Wende, J and Bollinger, K and Chen, Z and Watsky, M}, title = {Association of vitamin D with incident glaucoma: findings from the Women's Health Initiative.}, journal = {Journal of investigative medicine : the official publication of the American Federation for Clinical Research}, volume = {}, number = {}, pages = {}, doi = {10.1136/jim-2020-001645}, pmid = {33431603}, issn = {1708-8267}, abstract = {The relationship between vitamin D and glaucoma is controversial. The objective of this study was to examine women from the Women's Health Initiative (WHI) to determine if there is an association between vitamin D and incident glaucoma in postmenopausal women. We examined the association between dietary vitamin D intake, vitamin D supplements and serum 25 hydroxyvitamin D (25(OH)D) levels and the risk of developing glaucoma. 143,389 postmenopausal women from the WHI including a subset with serum 25(OH) D measurements were examined to determine the association of dietary, supplemental and serum levels of vitamin D to the development of glaucoma. Dietary intakes of vitamin D, use of vitamin D supplements and serum levels of 25(OH) D were predictors examined for the main outcome of incident glaucoma. In multivariable models adjusted for demographic, clinical variables and medication use, dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and serum 25 (OH) D measurements were not significantly associated with incident glaucoma. In the CaD placebo-controlled intervention clinical trial, there was also no association in the active intervention arm with glaucoma. We conclude that dietary vitamin D intake, supplements and serum levels are not significantly related to the risk of developing glaucoma in postmenopausal women.}, }
@article {pmid33431309, year = {2020}, author = {Smith, SD and Lopedote, P and Samara, Y and Mei, M and Herrera, AF and Winter, AM and Hill, BT and Shadman, M and Ujjani, C and Lynch, RC and Jacobson, CA and Kim, AI and Caimi, P and Milano, F and Gopal, AK}, title = {Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2020.12.013}, pmid = {33431309}, issn = {2152-2669}, abstract = {INTRODUCTION: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown.<br><br>PATIENTS AND METHODS: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity.<br><br>RESULTS: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%.<br><br>CONCLUSIONS: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.}, }
@article {pmid33406488, year = {2021}, author = {Pollyea, DA and Bixby, D and Perl, A and Bhatt, VR and Altman, JK and Appelbaum, FR and de Lima, M and Fathi, AT and Foran, JM and Gojo, I and Hall, AC and Jacoby, M and Lancet, J and Mannis, G and Marcucci, G and Martin, MG and Mims, A and Neff, J and Nejati, R and Olin, R and Percival, ME and Prebet, T and Przespolewski, A and Rao, D and Ravandi-Kashani, F and Shami, PJ and Stone, RM and Strickland, SA and Sweet, K and Vachhani, P and Wieduwilt, M and Gregory, KM and Ogba, N and Tallman, MS}, title = {NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {1}, pages = {16-27}, doi = {10.6004/jnccn.2021.0002}, pmid = {33406488}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.}, }
@article {pmid33406487, year = {2021}, author = {Daly, MB and Pal, T and Berry, MP and Buys, SS and Dickson, P and Domchek, SM and Elkhanany, A and Friedman, S and Goggins, M and Hutton, ML and ,  and Karlan, BY and Khan, S and Klein, C and Kohlmann, W and ,  and Kurian, AW and Laronga, C and Litton, JK and Mak, JS and ,  and Menendez, CS and Merajver, SD and Norquist, BS and Offit, K and Pederson, HJ and Reiser, G and ,  and Senter-Jamieson, L and ,  and Shannon, KM and Shatsky, R and Visvanathan, K and Weitzel, JN and Wick, MJ and Wisinski, KB and Yurgelun, MB and Darlow, SD and Dwyer, MA}, title = {Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {1}, pages = {77-102}, doi = {10.6004/jnccn.2021.0001}, pmid = {33406487}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.}, }
@article {pmid33181788, year = {2021}, author = {Bhattacharya, D and Guo, R and Tseng, CH and Emel, L and Sun, R and Chiu, SH and Stranix-Chibanda, L and Chipato, T and Mohtashemi, NZ and Kintu, K and Manji, KP and Moodley, D and Thio, CL and Maldonado, Y and Currier, JS}, title = {Maternal HBV Viremia and Association With Adverse Infant Outcomes in Women Living With HIV and HBV.}, journal = {The Pediatric infectious disease journal}, volume = {40}, number = {2}, pages = {e56-e61}, doi = {10.1097/INF.0000000000002980}, pmid = {33181788}, issn = {1532-0987}, abstract = {BACKGROUND: There is limited information on perinatal outcomes in HIV-hepatitis B virus (HBV) coinfection.<br><br>METHODS: HIV Prevention Trials Network (HPTN) 046 was a randomized double-blind placebo-controlled trial of perinatal transmission that evaluated 6 months of infant nevirapine versus placebo among breast-fed infants. Women living with HIV and their infants enrolled in sub-Saharan Africa from 2007 to 2010; 78% received antiretroviral therapy (ART). Maternal samples were tested for hepatitis B surface antigen (HBsAg). High and low HBV viral load (VL) was defined as ≥106 IU/mL and <106 IU/mL. The association between HIV-HBV coinfection and maternal and infant outcomes was assessed using multivariate (MV) logistic and Cox regression.<br><br>RESULTS: Among 2025 women, 88 (4.3%) had HBV. HIV-HBV women with high HBV VL had lower median CD4, versus HIV alone or HIV-HBV women with low HBV VL [320, 490 and 434 cells/mm3, respectively (P < 0.007)]. In MV analysis, adjusted for maternal CD4, age and maternal ART, infants born to women with high HBV VL were more likely to be low birth weight (LBW), versus HIV+/HBV- and low HBV VL women: [30% (3/10) vs. 10% (194/1953) vs. 6% (5/78), respectively, P = 0.03). High HBV VL was associated with HIV perinatal transmission [(hazard ratio 6.75 (95% confidence interval (CI): 1.86 - 24.50)]. There was no impact on infant mortality or maternal outcomes at 18 months.<br><br>CONCLUSIONS: In HIV-HBV women, high HBV viral loads increase the risk of LBW and potentially HIV perinatal transmission. Reduction of antepartum HBV viremia may have beneficial effects beyond the prevention of HBV perinatal transmission.}, }
@article {pmid21907493, year = {2011}, author = {Lu, Q and Krull, KR and Leisenring, W and Owen, JE and Kawashima, T and Tsao, JCI and Zebrack, B and Mertens, A and Armstrong, GT and Stovall, M and Robison, LL and Zeltzer, LK}, title = {Pain in long-term adult survivors of childhood cancers and their siblings: a report from the Childhood Cancer Survivor Study.}, journal = {Pain}, volume = {152}, number = {11}, pages = {2616-2624}, doi = {10.1016/j.pain.2011.08.006}, pmid = {21907493}, issn = {1872-6623}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U24 CA55727/CA/NCI NIH HHS/United States ; CA21765/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727-10/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Chronic Pain/drug therapy/*epidemiology/*psychology ; Female ; Humans ; Male ; Neoplasms/*epidemiology/therapy ; Siblings/*psychology ; Survivors/*psychology/*statistics &amp; numerical data ; Time ; Young Adult ; }, abstract = {Little is known about pain among long-term adult survivors of childhood cancers. The study investigated pain prevalence in this population compared with sibling controls and examined pain-related risk factors. Three self-reported pain outcomes including pain conditions, prescription analgesics used, and pain attributed to cancer and treatment were assessed among 10,397 cancer survivors and 3034 sibling controls from the Childhood Cancer Survivor Study. Pain conditions (pain/abnormal sensation, migraines, and other headaches) were reported by 12.3%, 15.5%, and 20.5% of survivors, respectively; 16.7% of survivors reported use of prescription analgesics, and 21% attributed pain to cancer and treatment. Risks of reporting pain conditions and using prescription analgesics were higher among survivors than siblings, adjusting for sociodemographic factors. Younger age at diagnosis and a history of non-Hodgkin lymphoma, Wilms tumor, or neuroblastoma (compared to leukemia) were associated with greater risk of reporting pain conditions. A history of bone cancer or soft tissue sarcoma (compared to leukemia) was associated with greater risks of using prescription analgesics and cancer-related pain attribution. Non-brain-directed scatter irradiation was associated with elevated risk for migraines and cancer-related pain attribution. Female gender and lower educational attainment were associated with increased reports of all 3 pain outcomes; minority status, unemployment, and being single were associated with greater risks for reporting pain conditions. These findings contribute to the understanding of pain and associated risk factors among adult survivors of childhood cancer and suggest areas of focus for pain intervention.}, }
@article {pmid19300331, year = {2009}, author = {Reed, SD and Voigt, LF and Newton, KM and Garcia, RH and Allison, HK and Epplein, M and Jordan, D and Swisher, E and Weiss, NS}, title = {Progestin therapy of complex endometrial hyperplasia with and without atypia.}, journal = {Obstetrics and gynecology}, volume = {113}, number = {3}, pages = {655-662}, pmid = {19300331}, issn = {0029-7844}, support = {R01 HD044813/HD/NICHD NIH HHS/United States ; R01 HD044813-04/HD/NICHD NIH HHS/United States ; 5 R01 HD44813-02/HD/NICHD NIH HHS/United States ; }, mesh = {Adult ; Aged ; Disease Progression ; Endometrial Hyperplasia/*drug therapy/pathology ; Female ; Humans ; Middle Aged ; Progestins/*therapeutic use ; Treatment Outcome ; }, abstract = {OBJECTIVE: To assess the likelihood of histologic persistence/progression of complex hyperplasia and atypical hyperplasia among women treated with progestin compared with those not treated, with attention to type, dose, and duration.<br><br>METHODS: This was a cohort study at an integrated health plan of women, ages 18-85 years, with complex or atypical hyperplasia on independent pathology review with a second endometrial specimen in the 2-6 months after the index diagnosis. Progestin therapy between index diagnosis and follow-up biopsy was determined from the pharmacy database. Medical record abstraction was performed. Relative risks (RRs), adjusted for age and body mass index, were calculated.<br><br>RESULTS: Among 185 women, average age 55.9 years, follow-up 16.1 weeks, 115 had complex and 70 had atypical hyperplasia. Among women with complex hyperplasia, 28.4% of those treated with progestin and 30.0% of those not treated had persistence/progression (RR 1.20, 95% confidence interval [CI] 0.53-2.72). Among women with atypical hyperplasia, 26.9% of those treated with progestin and 66.7% of those not treated had persistence/progression (RR 0.39, 95% CI 0.21-0.70); there was a suggestion that use of at least a medium dose, or a duration of at least 3 months, was associated with a particularly low probability of persistence/progression.<br><br>CONCLUSION: Although progestin treatment of women with atypical hyperplasia was associated with a substantial increase in the likelihood of regression of the lesion during the ensuing 2-6 months, persistence/progression was nonetheless present in more than one quarter of treated women. Regression of complex hyperplasia without atypia was common whether progestin had or had not been used.}, }
@article {pmid19104363, year = {2009}, author = {Kudish, BI and Iglesia, CB and Sokol, RJ and Cochrane, B and Richter, HE and Larson, J and Hendrix, SL and Howard, BV}, title = {Effect of weight change on natural history of pelvic organ prolapse.}, journal = {Obstetrics and gynecology}, volume = {113}, number = {1}, pages = {81-88}, pmid = {19104363}, issn = {0029-7844}, support = {32105-6//PHS HHS/United States ; 42107-26//PHS HHS/United States ; 32115//PHS HHS/United States ; 32100-2//PHS HHS/United States ; 24152//PHS HHS/United States ; K24 DK068389/DK/NIDDK NIH HHS/United States ; 42129-32//PHS HHS/United States ; 32118-32119//PHS HHS/United States ; 32108-9//PHS HHS/United States ; 32122//PHS HHS/United States ; N01 WH022110-024/WH/WHI NIH HHS/United States ; 44221//PHS HHS/United States ; 32111-13//PHS HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; }, mesh = {Aged ; Body Mass Index ; Cystocele/*etiology ; Disease Progression ; Female ; Humans ; Middle Aged ; Obesity/complications ; *Postmenopause ; Rectocele/*etiology ; Remission, Spontaneous ; Risk Factors ; Uterine Prolapse/*etiology ; *Weight Gain ; Weight Loss ; }, abstract = {OBJECTIVE: To evaluate the relationship between change in weight and pelvic organ prolapse (POP) progression/regression in women during a 5-year period.<br><br>METHODS: Postmenopausal women with uteri (N=16,608), ages 50 to 79, who were enrolled in the Women's Health Initiative (WHI) Estrogen plus Progestin Clinical Trial between 1993 and 1998 were included in this secondary analysis. Baseline pelvic examination, repeated annually, assessed uterine prolapse, cystocele, and rectocele using the WHI Prolapse Classification System. Statistical analyses included univariate and multiple logistic regression methods.<br><br>RESULTS: During the 5-year time period, the majority of women (9,251, 55.7%) gained weight (mean 4.43 kg, +/-5.95 kg), and the overall rate of prolapse (WHI Prolapse Classification System: grades 1-3) increased from 40.9% at baseline to 43.8% at year 5 of evaluation. Controlling for age, parity, race, and other health/physical variables, being overweight (body mass index [BMI] between 25 and 29.9) or obese (BMI of at least 30) at baseline was associated with progression in cystocele, rectocele, and uterine prolapse compared with women with healthy BMIs (BMI is calculated as weight (kg)/[height (m)]). Specifically, the risk of prolapse progression in overweight and obese women as compared with the participants with healthy BMIs increased by 32% and 48% for cystocele, by 37% and 58% for rectocele, and by 43% and 69% for uterine prolapse, respectively. Adjusting for women with prolapse at baseline and baseline BMI, a 10% weight change was associated with minimal change in overall POP. Specifically, a 10% weight loss was associated with a borderline worsening of uterine prolapse (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.88-0.97) and a minimal regression of cystocele (OR 1.03, 95% CI 1.00-1.05) and rectocele (OR 1.04, 95% CI 1.01-1.07).<br><br>CONCLUSION: Being overweight or obese is associated with progression of POP. Weight loss does not appear to be significantly associated with regression of POP, suggesting that damage to the pelvic floor related to weight gain might be irreversible.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid19104356, year = {2009}, author = {Paramsothy, P and Jamieson, DJ and Heilig, CM and Schuman, PC and Klein, RS and Shah, KV and Rompalo, AM and Cu-Uvin, S and Duerr, A}, title = {The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cytology.}, journal = {Obstetrics and gynecology}, volume = {113}, number = {1}, pages = {26-31}, doi = {10.1097/AOG.0b013e31819225cb}, pmid = {19104356}, issn = {0029-7844}, support = {U64/CC506831/CC/ODCDC CDC HHS/United States ; U64/CCU106795//PHS HHS/United States ; U64/CCU206798//PHS HHS/United States ; U64/CCU306802//PHS HHS/United States ; }, mesh = {AIDS-Related Opportunistic Infections/*virology ; Adult ; *Antiretroviral Therapy, Highly Active ; CD4 Lymphocyte Count ; Cervical Intraepithelial Neoplasia/complications/pathology/*virology ; Cervix Uteri/*pathology ; Disease Progression ; Female ; HIV Infections/*complications/drug therapy/virology ; Humans ; Papillomaviridae/*isolation &amp; purification ; Papillomavirus Infections/complications/*virology ; Remission Induction ; Vaginal Smears ; }, abstract = {OBJECTIVE: To examine the association of highly active antiretroviral therapy (HAART) with human papillomavirus (HPV) clearance and progression or regression of cervical cytological abnormalities in women with human immunodeficiency virus (HIV).<br><br>METHODS: Five hundred thirty-seven women with HIV participating in the HIV Epidemiology Research Study, an observational, multisite cohort study, were evaluated semiannually from 1996 to 2000. Cervical Pap tests were collected for cervical cytology. Testing for HPV was conducted by polymerase chain reaction. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals (CIs). Number needed to treat (NNT) at 2 years was calculated for HAART.<br><br>RESULTS: Among women with cervical squamous intraepithelial lesions, HAART was associated with an increased likelihood of HPV clearance (hazard ratio 4.5, 95% CI 1.2-16.3, NNT 22.4). Use of HAART was not associated with an increased likelihood of HPV clearance among women with normal cervical cytology (hazard ratio 1.7, 95% CI 0.9-3.1, NNT 6.5) or atypical squamous cells of undetermined significance cytology (hazard ratio 1.0, 95% CI 0.4-2.5, NNT 174.0). Use of HAART was not significantly associated with an increased likelihood of cervical cytologic regression (hazard ratio 1.3, 95% CI 1.0-1.7, NNT 10.9) or cervical cytologic progression (hazard ratio 0.7, 95% CI 0.6-1.0, NNT 12.8).<br><br>CONCLUSION: Among women with preexisting abnormal cervical cytology, HAART was associated with enhanced HPV clearance but not with Pap test regression. Close monitoring of women with HIV for cervical cytologic abnormalities, regardless of HAART treatment status, is warranted.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid33428889, year = {2021}, author = {Szulzewsky, F and Holland, EC and Vasioukhin, V}, title = {YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance.}, journal = {Developmental biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ydbio.2020.12.018}, pmid = {33428889}, issn = {1095-564X}, abstract = {YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.}, }
@article {pmid33428454, year = {2021}, author = {Hill, GR and Betts, BC and Tkachev, V and Kean, LS and Blazar, BR}, title = {Current Concepts and Advances in Graft-Versus-Host Disease Immunology.}, journal = {Annual review of immunology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-immunol-102119-073227}, pmid = {33428454}, issn = {1545-3278}, abstract = {Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, }
@article {pmid33427749, year = {2021}, author = {Kared, H and Redd, AD and Bloch, EM and Bonny, TS and Sumatoh, HR and Kairi, F and Carbajo, D and Abel, B and Newell, EW and Bettinotti, M and Benner, SE and Patel, EU and Littlefield, K and Laeyendecker, O and Shoham, S and Sullivan, D and Casadevall, A and Pekosz, A and Nardin, A and Fehlings, M and Tobian, AA and Quinn, TC}, title = {SARS-CoV-2-specific CD8+ T cell responses in convalescent COVID-19 individuals.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI145476}, pmid = {33427749}, issn = {1558-8238}, abstract = {Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understand its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across six different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and non-structural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.}, }
@article {pmid33427210, year = {2021}, author = {Barber-Axthelm, IM and Barber-Axthelm, V and Sze, KY and Zhen, A and Suryawanshi, GW and Chen, IS and Zack, JA and Kitchen, SG and Kiem, HP and Peterson, CW}, title = {Stem cell-derived CAR T cells traffic to HIV reservoirs in macaques.}, journal = {JCI insight}, volume = {6}, number = {1}, pages = {}, doi = {10.1172/jci.insight.141502}, pmid = {33427210}, issn = {2379-3708}, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5- donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell-mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.}, }
@article {pmid33427196, year = {2021}, author = {Doepker, LE and Danon, S and Harkins, E and Ralph, DK and Yaffe, Z and Garrett, ME and Dhar, A and Wagner, C and Stumpf, MM and Arenz, D and Williams, JA and Jaoko, W and Mandaliya, K and Lee, KK and Matsen, FA and Overbaugh, JM}, title = {Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.63444}, pmid = {33427196}, issn = {2050-084X}, support = {R37 AI038518/NH/NIH HHS/United States ; R01 HD103571/NH/NIH HHS/United States ; R01 GM113246/NH/NIH HHS/United States ; R01 AI146028/NH/NIH HHS/United States ; T32 AI07140/NH/NIH HHS/United States ; T32 AI083203/NH/NIH HHS/United States ; P30 AI027757/NH/NIH HHS/United States ; Faculty Scholar grant/HHMI/Howard Hughes Medical Institute/United States ; Faculty Scholar grant//Simons Foundation/ ; }, abstract = {A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naïve antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity.}, }
@article {pmid33427035, year = {2021}, author = {Cannon, P and Asokan, A and Czechowicz, A and Hammond, P and Kohn, DB and Lieber, A and Malik, P and Marks, P and Porteus, M and Verhoeyen, E and Weissman, D and Weissman, I and Kiem, HP}, title = {Safe and Effective In Vivo Targeting and Gene Editing in Hematopoietic Stem Cells: Strategies for Accelerating Development National Institutes of Health/Bill &amp; Melinda Gates Foundation Expert Scientific Roundtable Webinar Meeting.}, journal = {Human gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.1089/hum.2020.263}, pmid = {33427035}, issn = {1557-7422}, abstract = {Introduction On May 11, 2020, the National Institutes of Health (NIH) and the Bill &amp; Melinda Gates Foundation (Gates Foundation) held an exploratory expert scientific roundtable to inform an NIH-Gates Foundation collaboration on the development of scalable, sustainable, and accessible HIV and sickle cell disease (SCD) therapies based on in vivo gene editing of hematopoietic stem cells (HSC). A particular emphasis was on how such therapies could be developed for low-resource settings in sub-Saharan Africa. Paula Cannon, Ph.D., of the University of Southern California and Hans-Peter Kiem, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center served as roundtable co-chairs. Welcoming remarks were provided by the leadership of NIH, NHLBI, and BMGF, who cited the importance of assessing the state of the science and charting a path toward finding safe, effective, and durable gene-based therapies for HIV and sickle cell disease. These remarks were followed by three sessions in which participants heard presentations on and discussed the therapeutic potential of modified HSCs, leveraging HSC biology and differentiation, and in vivo HSC targeting approaches. This roundtable serves as the beginning of an ongoing discussion among NIH, the Gates Foundation, research and patient communities, and the public at large. As this collaboration progresses, these communities will be engaged as we collectively navigate the complex scientific and ethical issues surrounding in vivo HSC targeting and editing. Summarized excerpts from each of the presentations are below, reflecting the individual views and perspectives of each presenter.}, }
@article {pmid33426127, year = {2020}, author = {Moralez, EA and Thompson, B and Englund, K and Drennan, M and Mandall, N and Loest, H}, title = {The Health Disparities Field Experience: College students and community health workers in the field.}, journal = {Journal of education and health promotion}, volume = {9}, number = {}, pages = {323}, doi = {10.4103/jehp.jehp_510_20}, pmid = {33426127}, issn = {2277-9531}, abstract = {CONTEXT: Immersing students studying health promotion and disease prevention into community settings facing health disparities is an essential supplement to their academic experience. As part of many public health professions, these students will likely need to understand the values and beliefs of different cultures so that decisions of appropriate health promotion and treatment can be made equitably. This paper evaluates an education immersion program that was part of a National Cancer Institute funded collaboration supporting the recruitment and training of university students in cancer research. The primary aim of the Health Disparities Field Experience (HDFE) was to facilitate an experience for students pursuing a health-related degree to understand the conceptual issues in border/rural health and the cultural contexts related to health disparities among medically and financially indigent populations in the region.<br><br>SUBJECTS AND METHODS: This study was conducted using qualitative research methods using a variation of the content analysis approach using open codes to categorize the data. Six students were selected to participate in the HDFE (five graduate students and one undergraduate) and all six of the participants completed pre- and post-test surveys.<br><br>RESULTS: From the analysis of the data, posttest qualitative responses indicated that three participants saw racism as a primary cause of cancer-related disparities, a change from their pretest responses. When asked about the personal impact of the HDFE, respondents mentioned the importance of the experiential component.<br><br>CONCLUSIONS: Participants learned about health disparities from the HDFE and expressed high satisfaction with this approach to education.}, }
@article {pmid33423945, year = {2021}, author = {Khaki, AR and Li, A and Diamantopoulos, LN and Miller, NJ and Carril-Ajuria, L and Castellano, D and De Kouchkovsky, I and Koshkin, V and Park, J and Alva, A and Bilen, MA and Stewart, T and Santos, V and Agarwal, N and Jain, J and Zakharia, Y and Morales-Barrera, R and Devitt, M and Nelson, A and Hoimes, CJ and Shreck, E and Gartrell, BA and Sankin, A and Tripathi, A and Zakopoulou, R and Bamias, A and Rodriguez-Vida, A and Drakaki, A and Liu, S and Kumar, V and Lythgoe, MP and Pinato, DJ and Murgic, J and Fröbe, A and Joshi, M and Isaacsson Velho, P and Hahn, N and Alonso Buznego, L and Duran, I and Moses, M and Barata, P and Galsky, MD and Sonpavde, G and Yu, EY and Shankaran, V and Lyman, GH and Grivas, P}, title = {A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2020.12.006}, pmid = {33423945}, issn = {2588-9311}, abstract = {BACKGROUND: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).<br><br>OBJECTIVE: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.<br><br>Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.<br><br>We used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.<br><br>RESULTS AND LIMITATIONS: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.<br><br>CONCLUSIONS: We developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.<br><br>PATIENT SUMMARY: With multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival.}, }
@article {pmid33422300, year = {2021}, author = {Lees, B and Hampton, JM and Trentham-Dietz, A and Newcomb, P and Spencer, R}, title = {A population-based study of causes of death after endometrial cancer according to major risk factors.}, journal = {Gynecologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ygyno.2020.12.020}, pmid = {33422300}, issn = {1095-6859}, abstract = {OBJECTIVE: To identify the most common causes of death and potentially modifiable risk factors in endometrial cancer patients.<br><br>METHODS: 745 women diagnosed with incident endometrial cancer were enrolled in a population-based study from 1991 to 1994. Participants completed structured interviews about 1 year after diagnosis. Study files were linked with the National Death Index to identify dates and causes of death through 2016. Proportional hazards regression was used to estimate hazard rate ratios for cause of death adjusting for age and stage of disease. Hazard ratios were also examined according to comorbidities.<br><br>RESULTS: Of the 745 women, 450 were deceased after a median of 19.9 years. The two most common causes of death were cardiovascular disease (N = 145, 32%) and any cancer (N = 135, 30%), with only 10% of women dying from endometrial cancer (N = 46). Obesity, diabetes and smoking increased risk of all-cause mortality (HRR 1.77, 95%CI 1.36-2.31; HRR 1.74, 95%CI 1.34-2.27; HRR 1.59, 95%CI 1.16-2.17). Diabetes also increased risk of cardiovascular disease-specific mortality (HRR 1.98, 95%CI 1.38-3.08), but not endometrial cancer mortality (HRR 0.55, 95%CI 0.21-1.48). Neither obesity nor smoking was associated with increased risk of cardiovascular disease-specific mortality (HRR 1.46, 95%CI 0.92-2.32; HRR 1.21, 95%CI 0.67-2.18) nor endometrial-cancer specific mortality (HRR 1.81, 95%CI 0.83-3.93; HRR 0.61, 95%CI 0.17-2.15).<br><br>CONCLUSIONS: Endometrial cancer patients were 3 times more likely to die of cardiovascular disease than endometrial cancer. Obesity, smoking and diabetes increase the risk of death in these patients and are potentially modifiable. Clinical trials should be developed that incorporate counseling regarding these risk factors into survivorship care to determine impact on mortality.}, }
@article {pmid33421735, year = {2020}, author = {Aapro, M and Lyman, GH and Bokemeyer, C and Rapoport, BL and Mathieson, N and Koptelova, N and Cornes, P and Anderson, R and Gascón, P and Kuderer, NM}, title = {Supportive care in patients with cancer during the COVID-19 pandemic.}, journal = {ESMO open}, volume = {6}, number = {1}, pages = {100038}, doi = {10.1016/j.esmoop.2020.100038}, pmid = {33421735}, issn = {2059-7029}, abstract = {Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.}, }
@article {pmid33420905, year = {2021}, author = {Nørskov, KH and Yi, JC and Crouch, ML and Fiscalini, AS and Flowers, MED and Syrjala, KL}, title = {Social support as a moderator of healthcare adherence and distress in long-term hematopoietic cell transplantation survivors.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {33420905}, issn = {1932-2267}, support = {R01CA112631//National Institutes of Health (US)/ ; R01 CA215134/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Treatment with hematopoietic cell transplantation (HCT) has potentially severe effects on physical and psychosocial functioning. Poor social support has been linked with physical morbidity and mortality as well as psychological distress in HCT survivors. This study tested a theory-driven hypothesis that social support buffers adverse effects of health stressors of comorbidities and graft-versus-host disease (cGVHD) on distress and adherence to recommended healthcare among long-term HCT survivors.<br><br>METHODS: This cross-sectional study analyzed baseline data from a randomized controlled trial in adult survivors 3-18 years post-HCT. Data included medical records and patient-reported outcomes including cancer and treatment distress (CTXD), healthcare adherence (HCA), comorbidity index, cGVHD, ENRICHD Social Support Instrument (ESSI), Social Activity Log, and Health Self-Efficacy. We tested hypothesized models for HCA and CTXD using blocked hierarchical linear regressions.<br><br>RESULTS: Among the 781 HCT survivors completing baseline assessment, 38% had > 3 comorbidities, 8% had moderate-severe cGVHD, 30% reported low social support, 30% reported elevated distress, and 49% reported low healthcare adherence. Social support and self-efficacy were directly related to both adherence and distress. Regression models supported the hypothesized moderated relationships for distress but not for healthcare adherence.<br><br>CONCLUSIONS: The two tested models confirm that the health stressors of comorbidities and cGVHD are moderated by better social support and self-efficacy in their associations with lower distress but without moderating effects for healthcare adherence.<br><br>Social support and self-efficacy confer protective benefits on healthcare adherence and psychological distress. Interventions are needed that focus on maintaining social networks or finding new networks if necessary.<br><br>NCT00799461.}, }
@article {pmid33420793, year = {2021}, author = {Zhang, E and Chai, JC and Deik, AA and Hua, S and Sharma, A and Schneider, MF and Gustafson, D and Hanna, DB and Lake, JE and Rubin, LH and Post, WS and Anastos, K and Brown, T and Clish, CB and Kaplan, RC and Qi, Q}, title = {Plasma lipidomic profiles and risk of diabetes: two prospective cohorts of HIV-infected and HIV-uninfected individuals.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgab011}, pmid = {33420793}, issn = {1945-7197}, abstract = {OBJECTIVES: Antiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV-infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection.<br><br>RESEARCH DESIGN AND METHODS: We profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35-55 years from the Women's Interagency HIV study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years).<br><br>RESULTS: We identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (P<0.05 after FDR correction). After adjustment for multiple covariates, cholesteryl ester (CE)(22:4), lysophosphatidylcholine (LPC)(18:2), phosphatidylcholine (PC)(36:4), phosphatidylcholine-plasmalogen(34:3), and phosphatidylethanolamine (PE)(38:2) were associated with decreased risk of diabetes (HRs=0.70 to 0.82 per SD increment), while diacylglycerol(32:0), LPC(14:0), PC(38:3), PE(36:1), and triacylglycerol(50:1) were associated with increased risk of diabetes (HRs=1.26 to 1.56 per SD increment). HIV serostatus did not modify any lipid-diabetes associations; however, most of these lipid species were positively associated with HIV and/or ART use, including 3 diabetes-decreased (CE(22:4), LPC(18:2), PE(38:2)) and all 5 diabetes-increased lipid species.<br><br>CONCLUSIONS: This study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV-infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.}, }
@article {pmid33420416, year = {2021}, author = {Karunamuni, RA and Huynh-Le, MP and Fan, CC and Thompson, W and Eeles, RA and Kote-Jarai, Z and Muir, K and Lophatananon, A and ,  and Schleutker, J and Pashayan, N and Batra, J and ,  and Grönberg, H and Walsh, EI and Turner, EL and Lane, A and Martin, RM and Neal, DE and Donovan, JL and Hamdy, FC and Nordestgaard, BG and Tangen, CM and MacInnis, RJ and Wolk, A and Albanes, D and Haiman, CA and Travis, RC and Stanford, JL and Mucci, LA and West, CML and Nielsen, SF and Kibel, AS and Wiklund, F and Cussenot, O and Berndt, SI and Koutros, S and Sørensen, KD and Cybulski, C and Grindedal, EM and Park, JY and Ingles, SA and Maier, C and Hamilton, RJ and Rosenstein, BS and Vega, A and ,  and Kogevinas, M and Penney, KL and Teixeira, MR and Brenner, H and John, EM and Kaneva, R and Logothetis, CJ and Neuhausen, SL and Razack, A and Newcomb, LF and ,  and Gamulin, M and Usmani, N and Claessens, F and Gago-Dominguez, M and Townsend, PA and Roobol, MJ and Zheng, W and ,  and Mills, IG and Andreassen, OA and Dale, AM and Seibert, TM and , }, title = {Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {33420416}, issn = {1476-5608}, support = {K08EB026503//U.S. Department of Health &amp; Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (NIBIB)/ ; }, abstract = {BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).<br><br>MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.<br><br>RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.<br><br>CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.}, }
@article {pmid33419931, year = {2021}, author = {Jin, Q and Shi, N and Aroke, D and Lee, DH and Joseph, JJ and Donneyong, M and Conwell, DL and Hart, PA and Zhang, X and Clinton, SK and Cruz-Monserrate, Z and Brasky, TM and Jackson, R and Tinker, LF and Liu, S and Phillips, LS and Shadyab, AH and Nassir, R and Bao, W and Tabung, FK}, title = {Insulinemic and Inflammatory Dietary Patterns Show Enhanced Predictive Potential for Type 2 Diabetes Risk in Postmenopausal Women.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc20-2216}, pmid = {33419931}, issn = {1935-5548}, abstract = {OBJECTIVE: The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk.<br><br>RESEARCH DESIGN AND METHODS: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 73,495 postmenopausal women in the Women's Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes.<br><br>RESULTS: During a median 13.3 years of follow-up, 11,009 case subjects with incident type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were: EDIH 1.49 (1.32-1.68; Ptrend < 0.0001) and EDIP 1.45 (1.29-1.63; Ptrend < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) case subjects per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88-1.12; Ptrend = 0.46) and GL 1.01 (0.89-1.16; Ptrend = 0.30).<br><br>CONCLUSIONS: Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.}, }
@article {pmid33419791, year = {2021}, author = {Son, YM and Cheon, IS and Wu, Y and Li, C and Wang, Z and Gao, X and Chen, Y and Takahashi, Y and Fu, YX and Dent, AL and Kaplan, MH and Taylor, JJ and Cui, W and Sun, J}, title = {Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses.}, journal = {Science immunology}, volume = {6}, number = {55}, pages = {}, doi = {10.1126/sciimmunol.abb6852}, pmid = {33419791}, issn = {2470-9468}, abstract = {Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.}, }
@article {pmid30608446, year = {2019}, author = {Jones, SMW and Chennupati, S and Nguyen, T and Fedorenko, C and Ramsey, SD}, title = {Comorbidity is associated with higher risk of financial burden in Medicare beneficiaries with cancer but not heart disease or diabetes.}, journal = {Medicine}, volume = {98}, number = {1}, pages = {e14004}, doi = {10.1097/MD.0000000000014004}, pmid = {30608446}, issn = {1536-5964}, support = {U01 AG032947/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Comorbidity/*trends ; Cost of Illness ; Cross-Sectional Studies ; Diabetes Mellitus/*economics/epidemiology ; Female ; Heart Diseases/*economics/epidemiology ; Humans ; Male ; Medicare/*economics ; Neoplasms/*economics/epidemiology ; Prevalence ; Prospective Studies ; United States/epidemiology ; }, abstract = {The aim of the study was to examine how multimorbidity influences the prevalence of financial burden among older adults with heart disease, diabetes, or cancer.The study was a cross-sectional analysis of prospective observational cohort survey study.Older adults (age 65 or older) who did not report 1/6 major chronic illnesses (n = 2773; reference group), reported 1/3 major chronic illnesses without comorbidity (heart disease n = 206; diabetes n = 460; cancer n = 417), and reported 1/3 major chronic illnesses with comorbidity (heart disease n = 232; diabetes n = 202; cancer n = 109).The measures were presence of chronic diseases (heart disease, diabetes, cancer), comorbid chronic diseases (stroke, lung disease, dementia), medical-related financial burden (credit card debt due to medical costs, paying medical bills over time), and overall financial burden (financial help from family, credit card debt, help with food, utilities, and other necessities).The proportion reporting financial burden ranged from 15% to 27% across samples. Heart disease was unrelated to medical or overall financial burden, regardless of comorbidity. Diabetes was unrelated to financial burden except diabetes without comorbidity was associated with lower odds of overall financial burden compared to healthy older adults (odds ratio [OR] = 0.655, 95% confidence interval [CI]: 0.468-0.917). Cancer with comorbidity, but not cancer without comorbidity, was associated with greater odds of medical related (OR = 1.678, 95% CI: 1.057-2.664) and overall financial burden (OR = 1.748, 95% CI: 1.064-2.872).The association of multimorbidity with financial burden likely varies based on specific diseases. Future research on financial burden should focus on specific disease combinations such as cancer with comorbidity.}, }
@article {pmid33418499, year = {2021}, author = {Lin, BM and Grinde, KE and Brody, JA and Breeze, CE and Raffield, LM and Mychaleckyj, JC and Thornton, TA and Perry, JA and Baier, LJ and de Las Fuentes, L and Guo, X and Heavner, BD and Hanson, RL and Hung, YJ and Qian, H and Hsiung, CA and Hwang, SJ and Irvin, MR and Jain, D and Kelly, TN and Kobes, S and Lange, L and Lash, JP and Li, Y and Liu, X and Mi, X and Musani, SK and Papanicolaou, GJ and Parsa, A and Reiner, AP and Salimi, S and Sheu, WH and Shuldiner, AR and Taylor, KD and Smith, AV and Smith, JA and Tin, A and Vaidya, D and Wallace, RB and Yamamoto, K and Sakaue, S and Matsuda, K and Kamatani, Y and Momozawa, Y and Yanek, LR and Young, BA and Zhao, W and Okada, Y and Abecasis, G and Psaty, BM and Arnett, DK and Boerwinkle, E and Cai, J and Yii-Der Chen, I and Correa, A and Cupples, LA and He, J and Kardia, SL and Kooperberg, C and Mathias, RA and Mitchell, BD and Nickerson, DA and Turner, ST and Ramachandran, VS and Rotter, JI and Levy, D and Kramer, HJ and Köttgen, A and Nhlbi Trans-Omics For Precision Medicine TOPMed Consortium,  and TOPMed Kidney Working Group,  and Rich, SS and Lin, DY and Browning, SR and Franceschini, N}, title = {Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.}, journal = {EBioMedicine}, volume = {63}, number = {}, pages = {103157}, doi = {10.1016/j.ebiom.2020.103157}, pmid = {33418499}, issn = {2352-3964}, abstract = {BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.<br><br>METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.<br><br>FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.<br><br>INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.}, }
@article {pmid33416828, year = {2021}, author = {Liu, M and Liu, Y and Wu, MC and Hsu, L and He, Q}, title = {A Method for Subtype Analysis with Somatic Mutations.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btaa1090}, pmid = {33416828}, issn = {1367-4811}, abstract = {MOTIVATION: Cancer is a highly heterogeneous disease, and virtually all types of cancer have subtypes. Understanding the association between cancers subtypes and genetic variations is fundamental to the development of targeted therapies for patients. Somatic mutation plays important roles in tumor development and has emerged as a new type of genetic variations for studying the association with cancer subtypes. However, the low prevalence of individual mutations poses a tremendous challenge to the related statistical analysis.<br><br>RESULTS: In this article, we propose an approach, SASOM, for the association analysis of cancer subtypes with somatic mutations. Our approach tests the association between a set of somatic mutations (from a genetic pathway) and subtypes, while incorporating functional information of the mutations into the analysis. We further propose a robust p-value combination procedure, DAPC, to synthesize statistical significance from different sources. Simulation studies show that the proposed approach has correct type I error and tends to be more powerful than possible alternative methods. In a real data application, we examine the somatic mutations from a cutaneous melanoma dataset, and identify a genetic pathway that is associated with immune-related subtypes.<br><br>The SASOM R package is available at https://github.com/rksyouyou/SASOM-pkg. R scripts and data are available at https://github.com/rksyouyou/SASOM-analysis.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid33411070, year = {2021}, author = {Wu, NL and Hingorani, S}, title = {Outcomes of kidney injury including dialysis and kidney transplantation in pediatric oncology and hematopoietic cell transplant patients.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {}, number = {}, pages = {}, pmid = {33411070}, issn = {1432-198X}, support = {5T32CA009351-41/NH/NIH HHS/United States ; }, abstract = {Pediatric oncology and hematopoietic cell transplant (HCT) patients are susceptible to both acute kidney injury (AKI) and chronic kidney disease (CKD). The etiologies of AKI vary but include tumor infiltration, radiation, drug-induced toxicity, and fluid and electrolyte abnormalities including tumor lysis syndrome. HCT patients can also have additional complications such as sinusoidal obstructive syndrome, graft-versus-host disease, or thrombotic microangiopathy. For patients with severe AKI requiring dialysis, multiple modalities can be used successfully, although continuous kidney replacement therapy (CKRT) is often the principal modality for critically ill patients. While increasing numbers of pediatric cancer and HCT patients are now surviving long term, they remain at risk for a number of chronic medical conditions, including CKD. Certain high-risk patients, due to underlying risk factors or treatment-related complications, eventually develop kidney failure and may require kidney replacement therapies. Management of co-morbidities and complications associated with kidney failure, including use of erythropoietin for anemia and potential need for ongoing cancer-related treatment while on dialysis, is an additional consideration in this patient population. Kidney transplantation can be successfully performed in pediatric cancer survivors, although additional features such as specific cancer diagnosis and duration of remission should be considered.}, }
@article {pmid33410359, year = {2021}, author = {Carlson, DS and Grivas, P and Wei, W and Dhillon, PK and Abraksia, S}, title = {The Effectiveness of Shared Compared to Informed Decision Making for Prostate Cancer Screening in a High-Risk African American Population: A Randomized Control Trial.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07357907.2020.1855441}, pmid = {33410359}, issn = {1532-4192}, abstract = {BACKGROUND: Prostate cancer incidence and mortality in the United States in African Americans (AA) are higher than in Caucasians. Eastern Cuyahoga County in Ohio is majority AA and is considered an underserved population particularly vulnerable to healthcare disparities. There is a paucity of data about shared decision making among high-risk AA men with regard to prostate cancer screening. This study aims to examine shared versus informed decision making (SDM versus IDM) in a randomized, control trial among a large, high-risk AA population.<br><br>METHODS: Patients were included in annual one-day outreach events, each held over 3 years (2017-2019), and were randomized at each event into IDM (control) and SDM (investigational) groups and then were offered screening via prostate specific antigen (PSA) and digital rectal exam (DRE). The primary endpoints were proportion of participants over 40 who did not demonstrate decisional conflict about prostate cancer screening measured by the SURE score, as well as change of knowledge score about prostate cancer screening.<br><br>RESULTS: Overall, 175 patients were enrolled in the trial; 79 in the SDM arm and 96 in the IDM arm. The investigational (SDM) arm had 3/79 (3.9%) conflict versus 6/96 (6.4%) in the control (IDM) arm (p = 0.74). With regard to knowledge improvement, the SDM cohort demonstrated improvement following educational tools for 66/79 (81%) of participants versus 76/96 (79%) in the IDM cohort (p = 0.85). There was no difference in the proportion (63%) of participants in either group who found the information very helpful (using a Likert scale).<br><br>CONCLUSIONS: Our education-based study showed no significant difference between SDM and IDM with regard to decisional conflict about prostate cancer screening. The study also demonstrated significant improvement in knowledge about prostate cancer screening in a high-risk AA population in both groups. Our results should be interpreted with caution due to several limitations; however, the study can serve as a benchmark for future studies in this very important topic.}, }
@article {pmid33408242, year = {2021}, author = {McLeod, C and Gout, AM and Zhou, X and Thrasher, A and Rahbarinia, D and Brady, SW and Macias, M and Birch, K and Finkelstein, D and Sunny, J and Mudunuri, R and Orr, BA and Treadway, M and Davidson, B and Ard, TK and Chiao, A and Swistak, A and Wiggins, S and Foy, S and Wang, J and Sioson, E and Wang, S and Michael, JR and Liu, Y and Ma, X and Patel, A and Edmonson, MN and Wilkinson, MR and Frantz, AM and Chang, TC and Tian, L and Lei, S and Islam, SMA and Meyer, C and Thangaraj, N and Tater, P and Kandali, V and Ma, S and Nguyen, T and Serang, OA and McGuire, I and Robison, N and Gentry, D and Tang, X and Palmer, LE and Wu, G and Suh, E and Tanner, L and McMurry, J and Lear, M and Pappo, AS and Wang, Z and Wilson, CL and Cheng, Y and Meshinchi, S and Alexandrov, LB and Weiss, MJ and Armstrong, GT and Robison, LL and Yasui, Y and Nichols, KE and Ellison, DW and Bangur, C and Mullighan, CG and Baker, SJ and Dyer, MA and Miller, G and Newman, S and Rusch, M and Daly, R and Perry, K and Downing, JR and Zhang, J}, title = {St. Jude Cloud-a Pediatric Cancer Genomic Data Sharing Ecosystem.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-20-1230}, pmid = {33408242}, issn = {2159-8290}, abstract = {Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes. The resource is expanding rapidly with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes.}, }
@article {pmid33406495, year = {2021}, author = {Sun, J and Mathias, BJ and Laronga, C and Sun, W and Zhou, JM and Fulp, WJ and Kiluk, JV and Lee, MC}, title = {Impact of Axillary Dissection Among Patients With Sentinel Node-Positive Breast Cancer Undergoing Mastectomy.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {19}, number = {1}, pages = {40-47}, doi = {10.6004/jnccn.2020.7597}, pmid = {33406495}, issn = {1540-1413}, abstract = {BACKGROUND: Results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial supports omission of completion axillary lymph node dissection (CLND) after breast-conservation surgery with a positive sentinel lymph node biopsy (SLNB). We hypothesized that CLND also does not impact outcomes in women with clinically node-negative (cN0), pathologically node-positive breast cancer undergoing mastectomy.<br><br>MATERIALS AND METHODS: A single-institution retrospective review was performed of patients with SLN-positive breast cancer treated from July 1999 through May 2018. Clinicopathologic and outcome data were collected. Patients with SLNBs were compared with those receiving SLNB and CLND. The Kruskal-Wallis, chi-square, and Fisher exact tests were used to assess for differences between continuous and categorical variables. The log-rank test was used for time-to-event analyses, and Cox proportional hazards models were fit for locoregional and distant recurrence and overall survival (OS).<br><br>RESULTS: Of 329 patients with SLN-positive breast cancer undergoing mastectomy, 60% had CLND (n=201). Median age at diagnosis was 53 years (interquartile range [IQR], 46-62 years). The median number of SLNs sampled was 3 (IQR, 2-4), and the median number of positive SLNs was 1 (IQR, 1-2). Patients receiving CLND had higher tumor grades (P=.02) and a higher proportion of hormone receptor negativity (estrogen receptor, 19%; progesterone receptor, 27%; both P=.007). A total of 44 patients (22%) had increased N stage after CLND. Median follow-up was 51 months (IQR, 29-83 months). No association was found between CLND and change in OS and locoregional or distant recurrence. Completion of postmastectomy radiotherapy was associated with improved OS (P=.04).<br><br>CONCLUSIONS: CLND is not significantly correlated with reduced recurrence or improved OS among patients who have cN0, SLN-positive breast cancer treated with mastectomy. CLND was significantly correlated with receipt of adjuvant systemic therapy. Completion of postmastectomy radiotherapy was associated with improved OS.}, }
@article {pmid33406333, year = {2021}, author = {Martin, PJ}, title = {Sitagliptin to Prevent Acute Graft-versus-Host Disease.}, journal = {The New England journal of medicine}, volume = {384}, number = {1}, pages = {70-71}, doi = {10.1056/NEJMe2032581}, pmid = {33406333}, issn = {1533-4406}, }
@article {pmid33404013, year = {2021}, author = {Polaski, JT and Udy, DB and Escobar-Hoyos, LF and Askan, G and D Leach, SD and Ventura, A and Kannan, R and Bradley, RK}, title = {The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.62209}, pmid = {33404013}, issn = {2050-084X}, support = {T32 CA009657/CA/NCI NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; T32 CA160001/CA/NCI NIH HHS/United States ; R01 CA204228/CA/NCI NIH HHS/United States ; 1344-18//Leukemia &amp; Lymphoma Society/ ; }, abstract = {Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.}, }
@article {pmid33403483, year = {2021}, author = {Petrick, JL and Pfeiffer, RM and Liao, LM and Abnet, CC and Wu, X and Gammon, MD and Vaughan, TL and Cook, MB}, title = {Circulating MicroRNAs in Relation to Esophageal Adenocarcinoma Diagnosis and Survival.}, journal = {Digestive diseases and sciences}, volume = {}, number = {}, pages = {}, pmid = {33403483}, issn = {1573-2568}, support = {Intramural//Division of Cancer Epidemiology and Genetics, National Cancer Institute (US)/ ; }, abstract = {BACKGROUND AND AIMS: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival.<br><br>METHODS: We used all 62 EA cases from the US Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. MiRNAs (n = 2064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross-validation.<br><br>RESULTS: Sixty-eight distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2-3p fold change = 1.74, BH-adjusted P = 0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238-5p were associated with risk of mortality after EA diagnosis (HR = 4.85, 95% CI: 2.30-10.23, BH-adjusted P = 0.04 and HR = 3.81, 95% CI: 2.02-7.19, BH-adjusted P = 0.04, respectively).<br><br>CONCLUSIONS: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.}, }
@article {pmid33398111, year = {2021}, author = {Dowsett, IT and Sneeden, JL and Olson, BJ and McKay-Fleisch, J and McAuley, E and Kennedy, SR and Herr, AJ}, title = {Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles.}, journal = {Communications biology}, volume = {4}, number = {1}, pages = {21}, pmid = {33398111}, issn = {2399-3642}, support = {R01GM118854//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {Mutations that compromise mismatch repair (MMR) or DNA polymerase ε or δ exonuclease domains produce mutator phenotypes capable of fueling cancer evolution. Here, we investigate how combined defects in these pathways expands genetic heterogeneity in cells of the budding yeast, Saccharomyces cerevisiae, using a single-cell resolution approach that tallies all mutations arising from individual divisions. The distribution of replication errors present in mother cells after the initial S-phase was broader than expected for a single uniform mutation rate across all cell divisions, consistent with volatility of the mutator phenotype. The number of mismatches that then segregated to the mother and daughter cells co-varied, suggesting that each division is governed by a different underlying genome-wide mutation rate. The distribution of mutations that individual cells inherit after the second S-phase is further broadened by the sequential actions of semiconservative replication and mitotic segregation of chromosomes. Modeling suggests that this asymmetric segregation may diversify mutation burden in mutator-driven tumors.}, }
@article {pmid33397134, year = {2021}, author = {Sillah, A and Tykodi, SS and Hall, ET and Thompson, JA and Watson, NF and Lee, SM and Bhatia, S and Veatch, J and Warner, J and Peters, U and Malen, RC and Silverman, A and Phipps, AI}, title = {Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.2217/fon-2020-0730}, pmid = {33397134}, issn = {1744-8301}, support = {Pilot funding provided by the Public Health Science//Fred Hutchinson Cancer Research Center/ ; T32CA094880//National Institutes of Health Clinical Center/ ; }, abstract = {Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.}, }
@article {pmid27054934, year = {2016}, author = {Lee, AW and Ness, RB and Roman, LD and Terry, KL and Schildkraut, JM and Chang-Claude, J and Doherty, JA and Menon, U and Cramer, DW and Gayther, SA and Risch, H and Gentry-Maharaj, A and Goodman, MT and Modugno, F and Eilber, U and Moysich, KB and Berchuck, A and Rossing, MA and Jensen, A and Wicklund, KG and Cushing-Haugen, KL and Hogdall, E and Rudolph, A and Thompson, PJ and Wilkens, LR and Kjaer, SK and Carney, ME and Stram, DO and Ramus, SJ and Wu, AH and Pike, MC and Pearce, CL and , }, title = {Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk.}, journal = {Obstetrics and gynecology}, volume = {127}, number = {5}, pages = {828-836}, doi = {10.1097/AOG.0000000000001387}, pmid = {27054934}, issn = {1873-233X}, support = {R01 CA136891/CA/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; P50 CA159981/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; M01 RR000056/RR/NCRR NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; R03 CA113148/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; R01 CA080742/CA/NCI NIH HHS/United States ; R01 CA074850/CA/NCI NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; R01 CA141154/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R03 CA115195/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; P30 CA071789/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; R01 CA126841/CA/NCI NIH HHS/United States ; }, mesh = {Carcinoma, Endometrioid/*epidemiology/etiology ; Cystadenocarcinoma, Serous/*epidemiology/etiology ; Estrogen Replacement Therapy/*adverse effects ; Estrogens/therapeutic use ; Female ; Humans ; *Menopause ; Ovarian Neoplasms/*epidemiology/etiology ; Risk Assessment ; Surveys and Questionnaires ; United States/epidemiology ; }, abstract = {OBJECTIVE: To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use.<br><br>METHODS: We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations.<br><br>RESULTS: Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49).<br><br>CONCLUSION: We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.}, }
@article {pmid21422863, year = {2011}, author = {Win, AK and Dowty, JG and Antill, YC and English, DR and Baron, JA and Young, JP and Giles, GG and Southey, MC and Winship, I and Lipton, L and Parry, S and Thibodeau, SN and Haile, RW and Gallinger, S and Le Marchand, L and Lindor, NM and Newcomb, PA and Hopper, JL and Jenkins, MA}, title = {Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers.}, journal = {Obstetrics and gynecology}, volume = {117}, number = {4}, pages = {899-905}, doi = {10.1097/AOG.0b013e3182110ea3}, pmid = {21422863}, issn = {1873-233X}, support = {U01 CA074799-03/CA/NCI NIH HHS/United States ; U01 CA074783-06/CA/NCI NIH HHS/United States ; U01 CA074794-10/CA/NCI NIH HHS/United States ; U01 CA074799-07/CA/NCI NIH HHS/United States ; U01 CA074799/CA/NCI NIH HHS/United States ; U01 CA074800-09S1/CA/NCI NIH HHS/United States ; U01 CA074800-06/CA/NCI NIH HHS/United States ; U01 CA074783-09/CA/NCI NIH HHS/United States ; U01 CA097735-05S1/CA/NCI NIH HHS/United States ; U01 CA074799-04S1/CA/NCI NIH HHS/United States ; U01 CA074806-05/CA/NCI NIH HHS/United States ; U01 CA074799-03S1/CA/NCI NIH HHS/United States ; U01 CA097735-05/CA/NCI NIH HHS/United States ; U01 CA074800-05/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; U01 CA074800-04/CA/NCI NIH HHS/United States ; U01 CA074800-04S3/CA/NCI NIH HHS/United States ; U01 CA074783-04S1/CA/NCI NIH HHS/United States ; U01 CA074783-03/CA/NCI NIH HHS/United States ; U01 CA074799-09S2/CA/NCI NIH HHS/United States ; U01 CA074800-09/CA/NCI NIH HHS/United States ; U01 CA074799-06/CA/NCI NIH HHS/United States ; U01 CA074783-05/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA074794-10S1/CA/NCI NIH HHS/United States ; U01 CA074806-09S1/CA/NCI NIH HHS/United States ; U01 CA097735-04/CA/NCI NIH HHS/United States ; U24 CA074806/CA/NCI NIH HHS/United States ; U01 CA074800-03S2/CA/NCI NIH HHS/United States ; U24 CA097735/CA/NCI NIH HHS/United States ; U01 CA074799-04S2/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; U01 CA074783-09S2/CA/NCI NIH HHS/United States ; U01 CA074806-03/CA/NCI NIH HHS/United States ; U01 CA074806-04S1/CA/NCI NIH HHS/United States ; U01 CA074799-09/CA/NCI NIH HHS/United States ; U01 CA074800-07/CA/NCI NIH HHS/United States ; U01 CA074799-09S1/CA/NCI NIH HHS/United States ; U01 CA074783-08/CA/NCI NIH HHS/United States ; U01 CA074783-04S2/CA/NCI NIH HHS/United States ; U01 CA097735-03/CA/NCI NIH HHS/United States ; U01 CA074783-04/CA/NCI NIH HHS/United States ; U01 CA074783-07/CA/NCI NIH HHS/United States ; U01 CA074800-03/CA/NCI NIH HHS/United States ; U01 CA074800-04S2/CA/NCI NIH HHS/United States ; U01 CA097735/CA/NCI NIH HHS/United States ; U01 CA074806-09/CA/NCI NIH HHS/United States ; U01 CA074806-06/CA/NCI NIH HHS/United States ; U01 CA074800-08/CA/NCI NIH HHS/United States ; U01 CA074799-08/CA/NCI NIH HHS/United States ; U01 CA074800-04S1/CA/NCI NIH HHS/United States ; CA-95-011/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U01 CA074799-04/CA/NCI NIH HHS/United States ; U01 CA074806-07/CA/NCI NIH HHS/United States ; U01 CA097735-02/CA/NCI NIH HHS/United States ; U01 CA074806-04S2/CA/NCI NIH HHS/United States ; U01 CA074806-08/CA/NCI NIH HHS/United States ; U24 CA074799/CA/NCI NIH HHS/United States ; U01 CA074806/CA/NCI NIH HHS/United States ; U24 CA074800/CA/NCI NIH HHS/United States ; U01 CA074783-09S1/CA/NCI NIH HHS/United States ; U01 CA074799-05/CA/NCI NIH HHS/United States ; U01 CA097735-01/CA/NCI NIH HHS/United States ; U01 CA074806-04/CA/NCI NIH HHS/United States ; U01 CA074800/CA/NCI NIH HHS/United States ; U01 CA074806-09S2/CA/NCI NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/*genetics ; Adolescent ; Age Factors ; *Body Mass Index ; Cohort Studies ; Confidence Intervals ; DNA Mismatch Repair/genetics ; DNA Repair Enzymes/*genetics ; DNA-Binding Proteins/*genetics ; Endometrial Neoplasms/*epidemiology/*genetics/physiopathology ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease/*epidemiology ; Germ-Line Mutation ; Heterozygote ; Humans ; Incidence ; Mismatch Repair Endonuclease PMS2 ; Prognosis ; Reference Values ; Risk Assessment ; Victoria ; Young Adult ; }, abstract = {OBJECTIVE: To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene.<br><br>METHODS: We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression.<br><br>RESULTS: During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers. For carriers, there was no evidence of an association between BMI at age 20 years and endometrial cancer (adjusted hazard ratio 0.73 per 5 kg/m²; 95% confidence interval [CI], 0.40-1.34; P=.31). For noncarriers, endometrial cancer risk increased by 74% for each 5-kg/m² increment in BMI (adjusted hazard ratio 1.74; 95% CI 1.27-2.37; P<.001). The hazard ratio for BMI and endometrial cancer for noncarriers was greater than for carriers (P=.04).<br><br>CONCLUSION: The effect of body mass on endometrial cancer risk depends on the woman's mismatch repair gene mutation carrier status, suggesting obesity-independent endometrial carcinogenesis for carriers.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid20502292, year = {2010}, author = {Gardella, C and Huang, ML and Wald, A and Magaret, A and Selke, S and Morrow, R and Corey, L}, title = {Rapid polymerase chain reaction assay to detect herpes simplex virus in the genital tract of women in labor.}, journal = {Obstetrics and gynecology}, volume = {115}, number = {6}, pages = {1209-1216}, doi = {10.1097/AOG.0b013e3181e01415}, pmid = {20502292}, issn = {1873-233X}, support = {P01 AI030731-18/AI/NIAID NIH HHS/United States ; P01 AI030731/AI/NIAID NIH HHS/United States ; K24 AI 071113/AI/NIAID NIH HHS/United States ; AI-30731/AI/NIAID NIH HHS/United States ; K24 AI071113/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Herpes Genitalis/*diagnosis ; Humans ; Labor, Obstetric ; Polymerase Chain Reaction ; Pregnancy ; Pregnancy Complications, Infectious/*diagnosis/*virology ; ROC Curve ; Simplexvirus/genetics/*isolation &amp; purification ; Young Adult ; }, abstract = {OBJECTIVE: To develop a rapid quantitative real-time polymerase chain reaction (PCR) to detect herpes simplex virus (HSV) in the genital secretions of women that may be used in labor.<br><br>METHODS: Samples of genital secretions from women in labor, swabs of active genital lesions, and swabs of buffer solution were analyzed using a newly developed rapid HSV PCR assay to detect HSV glycoprotein B gene and quantitate virion copy number. A previously validated TaqMan PCR to detect HSV glycoprotein B gene was performed as the comparator gold standard. Positivity determination that optimized sensitivity and specificity was determined with receiver operating characteristic curves.<br><br>RESULTS: The median time to result for rapid HSV PCR was 2 hours (range 1.5-3.5 hours). A positivity determination rule that required both wells of the rapid test to detect 150 copies or greater of HSV per milliliter maximized specificity (96.7%) without appreciable loss of sensitivity (99.6%). Among positive samples, the correlation between the rapid test and TaqMan for the quantity of HSV isolated was excellent (R=0.96, P<.001). The rapid test had a positive predictive value of 96.7% and a negative predictive value of 99.6% in a population with HSV shedding prevalence of 10.8%, based on the prevalence of genital HSV previously found among HSV-2 seropositive women in labor.<br><br>CONCLUSION: Rapid HSV PCR provides results with excellent sensitivity and specificity within a timeframe that could inform clinical decision making for identifying neonates at risk of neonatal HSV infection.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid20502284, year = {2010}, author = {Theiler, RN and Farr, SL and Karon, JM and Paramsothy, P and Viscidi, R and Duerr, A and Cu-Uvin, S and Sobel, J and Shah, K and Klein, RS and Jamieson, DJ}, title = {High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: risk factors for cervical viral shedding.}, journal = {Obstetrics and gynecology}, volume = {115}, number = {6}, pages = {1150-1158}, doi = {10.1097/AOG.0b013e3181e00927}, pmid = {20502284}, issn = {1873-233X}, support = {U64/CCU106795//PHS HHS/United States ; U64/CCU206798//PHS HHS/United States ; U64/CCU306802//PHS HHS/United States ; U64/CCU506831//PHS HHS/United States ; }, mesh = {Adult ; Age Factors ; Alphapapillomavirus/*physiology ; CD4 Lymphocyte Count ; Case-Control Studies ; Cervix Uteri/*virology ; Female ; HIV Infections/*complications/immunology ; Humans ; Longitudinal Studies ; Middle Aged ; Papillomavirus Infections/epidemiology/immunology/*virology ; Prevalence ; Risk Factors ; Seroepidemiologic Studies ; United States/epidemiology ; Virus Activation/*immunology ; *Virus Shedding ; }, abstract = {OBJECTIVE: To evaluate the presence of and estimate risk factors for reactivation of latent high-risk human papillomavirus (HPV) cervical infection in human immunodeficiency virus (HIV)-infected and HIV-uninfected women.<br><br>METHODS: Data from 898 women in the HIV Epidemiology Research Study (HERS) were used to evaluate cervical HPV latency and reactivation. Prior exposure to HPV types (16, 18, 31, 35, and 45) was determined by serologic testing at enrollment, and cervical shedding of HPV was detected by polymerase chain reaction at 6-month intervals. Human papillomavirus cervical shedding and sexual history were used to estimate rates of reactivation and recurrence. Repeated measures survival analysis was used to estimate hazard ratios and 95% confidence intervals for reactivation and recurrence. Rates of total HPV shedding (recurrence and reactivation) during follow-up were assessed by HIV status and rate ratios were calculated.<br><br>RESULTS: Reactivation of latent HPV infections was observed in HIV-infected women, but few reactivation events were identified in HIV-uninfected women. Factors consistently associated with reactivation in HIV-infected women included CD4 count less than 200/mm and age younger than 35 years. Women infected with HIV had 1.8 to 8.2 times higher rates of viral shedding (reactivation plus recurrence) compared with HIV-uninfected women.<br><br>CONCLUSION: Women with a history of cervical HPV infection may be at risk of reactivation of latent viral infection even in the absence of sexual activity, and this risk is higher in women with HIV infection.<br><br>LEVEL OF EVIDENCE: II.}, }
@article {pmid19384118, year = {2009}, author = {Shah, CA and Goff, BA and Lowe, K and Peters, WA and Li, CI}, title = {Factors affecting risk of mortality in women with vaginal cancer.}, journal = {Obstetrics and gynecology}, volume = {113}, number = {5}, pages = {1038-1045}, doi = {10.1097/AOG.0b013e31819fe844}, pmid = {19384118}, issn = {0029-7844}, support = {P50 CA083636/CA/NCI NIH HHS/United States ; P50 CA083636-01/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; 5 T32 CA09515-22/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Carcinoma/*mortality/pathology/therapy ; Cohort Studies ; Disease-Free Survival ; Female ; Humans ; Middle Aged ; Neoplasm Staging ; Retrospective Studies ; Risk Factors ; SEER Program ; Socioeconomic Factors ; Survival Rate ; United States/epidemiology ; Vaginal Neoplasms/*mortality/pathology/therapy ; Young Adult ; }, abstract = {OBJECTIVE: To estimate the current effect of demographics, pathology, and treatment on mortality among women with vaginal cancer.<br><br>METHODS: Using data from 17 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results program, 2,149 women diagnosed with primary vaginal cancer between 1990 and 2004 were identified. The association between various demographic factors, tumor characteristics, and treatments and risk of vaginal cancer mortality were evaluated using Cox proportional hazards modeling.<br><br>RESULTS: The mean age+/-standard deviation at diagnosis was 65.7+/-14.3 years. Approximately 66% of all cases were non-Hispanic whites. Incidence was highest among African-American women (1.24 per 100,000 person-years). The 5-year disease-specific survival was 84% (stage I), 75% (stage II), and 57% (stage III/IV). In a multivariate adjusted model, women with tumors greater than 4 cm and advanced disease had elevated risks of mortality (hazard ratios 1.71 and 4.67, respectively). Compared with women with squamous cell carcinomas, patients with vaginal melanoma had a 1.51-fold (95% confidence interval 1.07-2.41) increased risk of mortality. Surgery alone as a treatment modality had the lowest risk of mortality. The risk of mortality has decreased over time, as women diagnosed after 2000 had an adjusted 17% decrease in their risk of death compared with women from 1990-1994.<br><br>CONCLUSION: Stage, tumor size, histology, and treatment modality significantly affect a woman's risk of mortality from vaginal cancer. There seems to be a survival advantage that is temporally related to the advent of chemoradiation.}, }
@article {pmid19384111, year = {2009}, author = {Schwarz, EB and Ray, RM and Stuebe, AM and Allison, MA and Ness, RB and Freiberg, MS and Cauley, JA}, title = {Duration of lactation and risk factors for maternal cardiovascular disease.}, journal = {Obstetrics and gynecology}, volume = {113}, number = {5}, pages = {974-982}, doi = {10.1097/01.AOG.0000346884.67796.ca}, pmid = {19384111}, issn = {0029-7844}, support = {N01WH32100-2/WH/WHI NIH HHS/United States ; N01WH32108-9/WH/WHI NIH HHS/United States ; K23 HD051585-03/HD/NICHD NIH HHS/United States ; N01WH42107-26/WH/WHI NIH HHS/United States ; K23 HD051585/HD/NICHD NIH HHS/United States ; N01WH32122/WH/WHI NIH HHS/United States ; N01WH32105-6/WH/WHI NIH HHS/United States ; N01WH32111-13/WH/WHI NIH HHS/United States ; N01WH32118-9/WH/WHI NIH HHS/United States ; N01WH32115/WH/WHI NIH HHS/United States ; N01WH22110/WH/WHI NIH HHS/United States ; N01WH24152/WH/WHI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Breast Feeding/*epidemiology ; Cardiovascular Diseases/*epidemiology/prevention &amp; control ; Cohort Studies ; Diabetes Mellitus/epidemiology ; Female ; Humans ; Lactation/*physiology ; Life Style ; Middle Aged ; Obesity/epidemiology ; Postmenopause ; Prevalence ; Risk Factors ; Socioeconomic Factors ; Young Adult ; }, abstract = {OBJECTIVE: To examine dose-response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease.<br><br>METHODS: We examined data from 139,681 postmenopausal women (median age 63 years) who reported at least one live birth on enrolling in the Women's Health Initiative observational study or controlled trials. Multivariable models were used to control for sociodemographic (age, parity, race, education, income, age at menopause), lifestyle, and family history variables when examining the effect of duration of lactation on risk factors for cardiovascular disease, including obesity (body mass index [BMI] at or above 30), hypertension, self-reported diabetes, hyperlipidemia, and prevalent and incident cardiovascular disease.<br><br>RESULTS: Dose-response relationships were seen; in fully adjusted models, women who reported a lifetime history of more than 12 months of lactation were less likely to have hypertension (odds ratio [OR] 0.88, P<.001), diabetes (OR 0.80, P<.001), hyperlipidemia (OR 0.81, P<.001), or cardiovascular disease (OR 0.91, P=.008) than women who never breast-fed, but they were not less likely to be obese. In models adjusted for all above variables and BMI, similar relationships were seen. Using multivariate adjusted prevalence ratios from generalized linear models, we estimate that among parous women who did not breast-feed compared with those who breast-fed for more than 12 months, 42.1% versus 38.6% would have hypertension, 5.3% versus 4.3% would have diabetes, 14.8% versus 12.3% would have hyperlipidemia, and 9.9% versus 9.1% would have developed cardiovascular disease when postmenopausal. Over an average of 7.9 years of postmenopausal participation in the Women's Health Initiative, women with a single live birth who breast-fed for 7-12 months were significantly less likely to develop cardiovascular disease (hazard ratio 0.72, 95% confidence interval 0.53-0.97) than women who never breast-fed.<br><br>CONCLUSION: Among postmenopausal women, increased duration of lactation was associated with a lower prevalence of hypertension, diabetes, hyperlipidemia, and cardiovascular disease.}, }
@article {pmid33399910, year = {2021}, author = {Farland, LV and Degnan, WJ and Harris, HR and Tobias, DK and Missmer, SA}, title = {A prospective study of endometriosis and risk of type 2 diabetes.}, journal = {Diabetologia}, volume = {}, number = {}, pages = {}, pmid = {33399910}, issn = {1432-0428}, support = {U01 CA176726/CA/NCI NIH HHS/United States ; HD57210//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, abstract = {AIMS/HYPOTHESIS: The objective of this study was to investigate the association between laparoscopically confirmed endometriosis and risk of type 2 diabetes.<br><br>METHODS: We used data from the Nurses' Health Study II, a prospective cohort of female nurses followed for >25 years (N = 112,037). We used Cox proportional hazards models to estimate the HRs and 95% CIs of incident, confirmed type 2 diabetes (n = 8496 participants) adjusted a priori for confounding factors. We additionally investigated differences in the relationship between endometriosis and type 2 diabetes by age (<50 or ≥50 years), BMI (<30 or ≥30 kg/m2), infertility history, menopausal status and history of gestational diabetes mellitus (GDM; restricted to parous women).<br><br>RESULTS: We saw no association between laparoscopically confirmed endometriosis and risk of type 2 diabetes in multivariable confounder-adjusted models (HR 1.06 [95% CI 0.98, 1.13]) or models accounting for potential mediating factors (HR 0.94 [95% CI 0.87, 1.00]). However, we observed modest differences in the association between endometriosis and type 2 diabetes by BMI group, history of infertility and history of GDM. Among non-obese women (HR 1.17 [95% CI 1.02, 1.35]), women who never experienced infertility (HR 1.14 [95% CI 1.04, 1.25]) and women who never experienced GDM (HR 1.11 [95% CI 1.01, 1.22]), endometriosis was associated with greater risk of type 2 diabetes.<br><br>CONCLUSIONS/INTERPRETATION: Overall, women with endometriosis were not at increased risk of type 2 diabetes. However, among subgroups at low risk for type 2 diabetes (i.e. non-obese women and women with no prior history of infertility or GDM), endometriosis was associated with a modest increased risk of type 2 diabetes.}, }
@article {pmid33399855, year = {2021}, author = {Hyacinth, HI and Franceschini, N and Seals, SR and Irvin, MR and Chaudhary, N and Naik, RP and Alonso, A and Carty, CL and Burke, GL and Zakai, NA and Winkler, CA and David, VA and Kopp, JB and Judd, SE and Adams, RJ and Gee, BE and Longstreth, WT and Egede, L and Lackland, DT and Greenberg, CS and Taylor, H and Manson, JE and Key, NS and Derebail, VK and Kshirsagar, AV and Folsom, AR and Konety, SH and Howard, V and Allison, M and Wilson, JG and Correa, A and Zhi, D and Arnett, DK and Howard, G and Reiner, AP and Cushman, M and Safford, MM}, title = {Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.}, journal = {JAMA network open}, volume = {4}, number = {1}, pages = {e2030435}, doi = {10.1001/jamanetworkopen.2020.30435}, pmid = {33399855}, issn = {2574-3805}, abstract = {Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).<br><br>Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.<br><br>This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.<br><br>Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.<br><br>Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).<br><br>Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).<br><br>Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.}, }
@article {pmid33398532, year = {2021}, author = {Bonm, AV and Gibson, AW and Holmberg, LA and Mielcarek, M and McGranahan, T and Taylor, LP and Graber, JJ}, title = {A single-center retrospective analysis of outcome measures and consolidation strategies for relapsed and refractory primary CNS lymphoma.}, journal = {Journal of neuro-oncology}, volume = {}, number = {}, pages = {}, pmid = {33398532}, issn = {1573-7373}, support = {NS079200/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management.<br><br>METHODS: We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded.<br><br>RESULTS: During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS.<br><br>CONCLUSIONS: PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.}, }
@article {pmid33398198, year = {2021}, author = {Conti, DV and Darst, BF and Moss, LC and Saunders, EJ and Sheng, X and Chou, A and Schumacher, FR and Olama, AAA and Benlloch, S and Dadaev, T and Brook, MN and Sahimi, A and Hoffmann, TJ and Takahashi, A and Matsuda, K and Momozawa, Y and Fujita, M and Muir, K and Lophatananon, A and Wan, P and Le Marchand, L and Wilkens, LR and Stevens, VL and Gapstur, SM and Carter, BD and Schleutker, J and Tammela, TLJ and Sipeky, C and Auvinen, A and Giles, GG and Southey, MC and MacInnis, RJ and Cybulski, C and Wokołorczyk, D and Lubiński, J and Neal, DE and Donovan, JL and Hamdy, FC and Martin, RM and Nordestgaard, BG and Nielsen, SF and Weischer, M and Bojesen, SE and Røder, MA and Iversen, P and Batra, J and Chambers, S and Moya, L and Horvath, L and Clements, JA and Tilley, W and Risbridger, GP and Gronberg, H and Aly, M and Szulkin, R and Eklund, M and Nordström, T and Pashayan, N and Dunning, AM and Ghoussaini, M and Travis, RC and Key, TJ and Riboli, E and Park, JY and Sellers, TA and Lin, HY and Albanes, D and Weinstein, SJ and Mucci, LA and Giovannucci, E and Lindstrom, S and Kraft, P and Hunter, DJ and Penney, KL and Turman, C and Tangen, CM and Goodman, PJ and Thompson, IM and Hamilton, RJ and Fleshner, NE and Finelli, A and Parent, MÉ and Stanford, JL and Ostrander, EA and Geybels, MS and Koutros, S and Freeman, LEB and Stampfer, M and Wolk, A and Håkansson, N and Andriole, GL and Hoover, RN and Machiela, MJ and Sørensen, KD and Borre, M and Blot, WJ and Zheng, W and Yeboah, ED and Mensah, JE and Lu, YJ and Zhang, HW and Feng, N and Mao, X and Wu, Y and Zhao, SC and Sun, Z and Thibodeau, SN and McDonnell, SK and Schaid, DJ and West, CML and Burnet, N and Barnett, G and Maier, C and Schnoeller, T and Luedeke, M and Kibel, AS and Drake, BF and Cussenot, O and Cancel-Tassin, G and Menegaux, F and Truong, T and Koudou, YA and John, EM and Grindedal, EM and Maehle, L and Khaw, KT and Ingles, SA and Stern, MC and Vega, A and Gómez-Caamaño, A and Fachal, L and Rosenstein, BS and Kerns, SL and Ostrer, H and Teixeira, MR and Paulo, P and Brandão, A and Watya, S and Lubwama, A and Bensen, JT and Fontham, ETH and Mohler, J and Taylor, JA and Kogevinas, M and Llorca, J and Castaño-Vinyals, G and Cannon-Albright, L and Teerlink, CC and Huff, CD and Strom, SS and Multigner, L and Blanchet, P and Brureau, L and Kaneva, R and Slavov, C and Mitev, V and Leach, RJ and Weaver, B and Brenner, H and Cuk, K and Holleczek, B and Saum, KU and Klein, EA and Hsing, AW and Kittles, RA and Murphy, AB and Logothetis, CJ and Kim, J and Neuhausen, SL and Steele, L and Ding, YC and Isaacs, WB and Nemesure, B and Hennis, AJM and Carpten, J and Pandha, H and Michael, A and De Ruyck, K and De Meerleer, G and Ost, P and Xu, J and Razack, A and Lim, J and Teo, SH and Newcomb, LF and Lin, DW and Fowke, JH and Neslund-Dudas, C and Rybicki, BA and Gamulin, M and Lessel, D and Kulis, T and Usmani, N and Singhal, S and Parliament, M and Claessens, F and Joniau, S and Van den Broeck, T and Gago-Dominguez, M and Castelao, JE and Martinez, ME and Larkin, S and Townsend, PA and Aukim-Hastie, C and Bush, WS and Aldrich, MC and Crawford, DC and Srivastava, S and Cullen, JC and Petrovics, G and Casey, G and Roobol, MJ and Jenster, G and van Schaik, RHN and Hu, JJ and Sanderson, M and Varma, R and McKean-Cowdin, R and Torres, M and Mancuso, N and Berndt, SI and Van Den Eeden, SK and Easton, DF and Chanock, SJ and Cook, MB and Wiklund, F and Nakagawa, H and Witte, JS and Eeles, RA and Kote-Jarai, Z and Haiman, CA}, title = {Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.}, journal = {Nature genetics}, volume = {}, number = {}, pages = {}, pmid = {33398198}, issn = {1546-1718}, support = {U19CA148537//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K99CA246063//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U01CA194393//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; NA//Achievement Rewards for College Scientists Foundation (ARCS Foundation)/ ; }, abstract = {Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.}, }
@article {pmid33395339, year = {2021}, author = {Barnabas, RV and Wald, A}, title = {A Public Health COVID-19 Vaccination Strategy to Maximize the Health Gains for Every Single Vaccine Dose.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/M20-8060}, pmid = {33395339}, issn = {1539-3704}, }
@article {pmid33393476, year = {2020}, author = {Sundaram, V and Gould, MK and Nair, VS}, title = {A Comparison of the PanCan Model and Lung-RADS to Assess Cancer Probability Among People With Screening-Detected, Solid Lung Nodules.}, journal = {Chest}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chest.2020.10.040}, pmid = {33393476}, issn = {1931-3543}, abstract = {BACKGROUND: The Pan-Canadian Early Detection of Lung Cancer (PanCan) risk model and the Lung CT Screening Reporting &amp; Data System (Lung-RADS) estimate cancer probability for screening-detected nodules. The accuracy and agreement of these models require further study.<br><br>RESEARCH QUESTION: What is the performance of the PanCan model and Lung-RADS to estimate the probability of cancer in screening-detected solid nodules?<br><br>STUDY DESIGN AND METHODS: We analyzed data for newly identified, solid nodules detected on any screening round in the low-dose CT arm of the National Lung Screening Trial to assign a PanCan risk and Lung-RADS score. We compared PanCan risk with the corresponding Lung-RADS category according to the expected prevalence of cancer and examined accuracy using logistic regression and between-test agreement. We also analyzed baseline screen-detected nodules only, high (defined as ≥ 5% probability of cancer) vs low-risk nodules, &quot;risk-gap&quot; nodules with a 3% to 5% PanCan probability and no equivalent Lung-RADS category, and procedure use by model.<br><br>RESULTS: Participants with solid nodules (6,956) had a calculable PanCan risk and Lung-RADS score. PanCan accuracy by cancer probabilities < 1%, 1% to 2%, 5% to 15%, and > 15% was similar to corresponding Lung-RADS categories 2, 3, 4A, and 4B for any solid nodule (area under the curve, 0.84 vs 0.84; P = .95) and for nodules identified at baseline (area under the curve, 0.85 vs 0.84; P = .17). When dichotomized by high/low risk, PanCan and Lung-RADS were discordant (P < .001). Participants with risk-gap nodules (n = 543) were distributed across Lung-RADS categories 2 through 4; 41 (8%) had invasive procedures with 23 (4%) having unnecessary invasive procedure use for solid, benign nodules.<br><br>INTERPRETATION: PanCan and Lung-RADS had similar overall accuracy for assessing cancer in screening-detected, solid lung nodules with evidence of discordance by subgroup. The existence of Lung-RADS category 4 nodules with a ≥ 3% to 5% PanCan risk may result in unnecessary procedures.}, }
@article {pmid33393458, year = {2021}, author = {Sandoval, M and Ying, Z and Beronja, S}, title = {Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium.}, journal = {eLife}, volume = {10}, number = {}, pages = {}, doi = {10.7554/eLife.54618}, pmid = {33393458}, issn = {2050-084X}, support = {AR070780/AR/NIAMS NIH HHS/United States ; Graduate Student Fellowship//Cell and Molecular Biology Training Grant/ ; }, abstract = {Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long-term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intra-clonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo, and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.}, }
@article {pmid33392445, year = {2020}, author = {Pan, K and Larson, JC and Prentice, RL and Mortimer, JE and Neuhouser, ML and Manson, JE and Van Horn, L and Rohan, TE and Lane, D and Chlebowski, RT}, title = {Protein Intake by Source and Breast Cancer Incidence and Mortality: The Women's Health Initiative.}, journal = {JNCI cancer spectrum}, volume = {4}, number = {6}, pages = {pkaa101}, doi = {10.1093/jncics/pkaa101}, pmid = {33392445}, issn = {2515-5091}, abstract = {Background: Prior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.<br><br>Methods: Biomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women's Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.<br><br>Results: After 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.<br><br>Conclusions: Calibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.}, }
@article {pmid33391257, year = {2020}, author = {Gust, J and Ponce, R and Liles, WC and Garden, GA and Turtle, CJ}, title = {Cytokines in CAR T Cell-Associated Neurotoxicity.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {577027}, doi = {10.3389/fimmu.2020.577027}, pmid = {33391257}, issn = {1664-3224}, abstract = {Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.}, }
@article {pmid33390282, year = {2020}, author = {Hamilton, RJ and Ding, K and Crook, JM and O'Callaghan, CJ and Higano, CS and Dearnaley, DP and Horwitz, EM and Goldenberg, SL and Gospodarowicz, MK and Klotz, L}, title = {The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2020.12.031}, pmid = {33390282}, issn = {1873-7560}, abstract = {BACKGROUND: Studies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT).<br><br>OBJECTIVE: To perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes.<br><br>Patients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate.<br><br>The primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT.<br><br>RESULTS AND LIMITATIONS: Of 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53-0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48-0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication.<br><br>CONCLUSIONS: In men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted.<br><br>PATIENT SUMMARY: We found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.}, }
@article {pmid33390213, year = {2021}, author = {Simons, ECG and Nyame, Y}, title = {EDITORIAL COMMENT.}, journal = {Urology}, volume = {147}, number = {}, pages = {62-63}, doi = {10.1016/j.urology.2020.08.078}, pmid = {33390213}, issn = {1527-9995}, }
@article {pmid32931481, year = {2021}, author = {Kong, X and Zeng, D and Wu, X and Wang, B and Yang, S and Song, Q and Zhu, Y and Salas, M and Qin, H and Nasri, U and Haas, KM and Riggs, AD and Nakamura, R and Martin, PJ and Huang, A and Zeng, D}, title = {Tissue-resident PSGL1loCD4+ T cells promote B cell differentiation and chronic graft-versus-host disease-associated autoimmunity.}, journal = {The Journal of clinical investigation}, volume = {131}, number = {1}, pages = {}, doi = {10.1172/JCI135468}, pmid = {32931481}, issn = {1558-8238}, support = {P30 CA033572/CA/NCI NIH HHS/United States ; R01 AI066008/AI/NIAID NIH HHS/United States ; R01 CA228465/CA/NCI NIH HHS/United States ; }, abstract = {CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted.}, }
@article {pmid33388760, year = {2021}, author = {Wolf, J and Abzug, MJ and Wattier, RL and Sue, PK and Vora, SB and Zachariah, P and Dulek, DE and Waghmare, A and Olivero, R and Downes, KJ and James, SH and Pinninti, SG and Yarbrough, A and Aldrich, ML and MacBrayne, CE and Soma, VL and Grapentine, SP and Oliveira, CR and Hayes, M and Kimberlin, DW and Jones, SB and Bio, LL and Morton, TH and Hankins, JS and Marόn-Alfaro, GM and Timberlake, K and Young, JL and Orscheln, RC and Schwenk, HT and Goldman, DL and Groves, HE and Huskins, WC and Rajapakse, NS and Lamb, GS and Tribble, AC and Lloyd, EE and Hersh, AL and Thorell, EA and Ratner, AJ and Chiotos, K and Nakamura, MM}, title = {Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of COVID-19 in Children and Adolescents.}, journal = {Journal of the Pediatric Infectious Diseases Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/jpids/piaa175}, pmid = {33388760}, issn = {2048-7207}, abstract = {BACKGROUND: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for two novel virus-neutralizing monoclonal antibody therapies, bamlanivimab, and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate COVID-19 in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.<br><br>METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.<br><br>RESULTS: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.<br><br>CONCLUSIONS: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence, and ensure implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.}, }
@article {pmid33388329, year = {2020}, author = {Malone, C and Buist, DSM and Tiro, J and Barlow, W and Gao, H and Lin, J and Winer, RL}, title = {Out of reach? Correlates of cervical cancer underscreening in women with varying levels of healthcare interactions in a United States integrated delivery system.}, journal = {Preventive medicine}, volume = {}, number = {}, pages = {106410}, doi = {10.1016/j.ypmed.2020.106410}, pmid = {33388329}, issn = {1096-0260}, abstract = {One in five U.S. women with health insurance are underscreened for cervical cancer. We sought to identify whether underscreening correlates differed among women with different levels of health care interaction. Among women age 30-64 years who were members of an integrated U.S. health system, we used 2014-2015 electronic health record data to identify underscreened cases (≥3.4 years since last Papanicolaou (Pap) test, n=3352) and screening-adherent controls (<3.4 years since last Pap test, n=45,359) and extracted data on potential underscreening correlates (demographics, health history, and healthcare utilization). We calculated the odds of underscreening in the total population and by subgroups defined by healthcare visits and online health portal usage in the prior 12 months. Underscreening was associated with older age (50-64 vs. 30-39; odds ratio (OR)=1.6; 95%CI=1.5-1.8), current tobacco use (vs. never use; OR=2.1; 95%CI=1.8-2.3), higher BMI (≥35 kg/m2 vs <25 kg/m2, OR=2.0; 95%CI=1.8-2.3), screening non-adherence for breast cancer (OR=5.1; 95%CI=4.6-5.7) and colorectal cancer (OR=8.1, 95%CI=7.3-9.0), and having no recent visit with their primary care provider (PCP) nor recent health portal use (vs. recent PCP visit and portal use; OR=8.4, 95%CI=7.6-9.4). Underscreening correlates were similar between the total study population and within all healthcare interaction groups. Interaction with the healthcare system is associated with lower odds of underscreening, but sociodemographic and health status correlates are similar regardless of primary care visits or online portal use. These data support the need for additional interventions to reach insured women who remain underscreened for cervical cancer.}, }
@article {pmid33387684, year = {2020}, author = {Cleland, SC and Domalpally, A and Liu, Z and Pak, JW and Blodi, BA and Bailey, S and Gehrs, K and Wallace, R and Tinker, L and Mares, JA and , }, title = {Reticular Pseudodrusen Characteristics and Associations in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2).}, journal = {Ophthalmology. Retina}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.oret.2020.12.019}, pmid = {33387684}, issn = {2468-6530}, abstract = {PURPOSE: To determine the prevalence and morphological features of reticular pseudodrusen (RPD) and their association with participant demographics and AMD status in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2) sample, an ancillary study of the Women's Health Initiative Observational Study.<br><br>DESIGN: Cross-sectional, multicenter, natural history study.<br><br>PARTICIPANTS: 946 eyes from 473 female postmenopausal participants aged 69 to 101 years old METHODS: Multimodal imaging including spectral domain optical coherence tomography (SD OCT) and infrared reflectance (IR) were used to identify RPD characteristics, such as location (within or outside the 6 mm diameter circle centered at the macula), presence of peripapillary RPD, pattern of RPD, and RPD area. AMD features from SD OCT, IR, and color photographs were also assessed and AMD severity was categorized.<br><br>MAIN OUTCOME MEASURES: RPD prevalence using SD OCT and IR imaging, and AMD status.<br><br>RESULTS: RPD were present in 130 eyes (14% of eyes, 16% of participants), with increasing prevalence with age; 7% in < 78 years, 14% in 78-83 years and 30% in > 83 years. Using clinical classification of AMD with color photography, RPD were seen in 2.4% of eyes with no AMD/ aging changes, 11.5% in early AMD, 25.1% in intermediate AMD and 51.1% in late AMD. Mean RPD area was 17.4 (14.7) mm2. Ribbon morphology (53%) was more common than dot morphology RPD (36%). RPD were mostly located both within and outside the 6 mm circle with primarily superior retinal distribution. RPD were visualized with corresponding color fundus photography in only 38 eyes (4% of total eyes). Participants with and without RPD had a visual acuity ± standard error of 77.9 (1.4) and 81.3 (0.4) letters, respectively (P = 0.02).<br><br>CONCLUSION: The prevalence of RPD in CAREDS2 increased with age and was associated with AMD severity. RPD was detected in eyes without other features of AMD and could represent an earlier disease state. Multimodal imaging with SD OCT and IR has significantly greater sensitivity for visualizing RPD than color fundus photography.}, }
@article {pmid33387523, year = {2020}, author = {VanWagner, LB and Issaka, RB}, title = {The Path to Gastroenterology &amp; Hepatology Leadership: Inadvertently Perpetuating the Glass Ceiling and Sticky Floor.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2020.09.063}, pmid = {33387523}, issn = {1528-0012}, }
@article {pmid33384279, year = {2020}, author = {Schiff, MA and Doody, DR and Crane, DA and Mueller, BA}, title = {Pregnancy outcomes among visually impaired women in Washington State, 1987-2014.}, journal = {Disability and health journal}, volume = {}, number = {}, pages = {101057}, doi = {10.1016/j.dhjo.2020.101057}, pmid = {33384279}, issn = {1876-7583}, abstract = {BACKGROUND: Women with visual impairment may have reduced ability to access standard care resources, however, information on their pregnancy and neonatal outcomes is limited.<br><br>OBJECTIVE: To assess risk of adverse pregnancy and neonatal outcomes among visually impaired women in Washington State from 1987 to 2014.<br><br>METHODS: We conducted a retrospective cohort study using linked Washington State birth/fetal death hospital discharge records to compare outcomes among women with and without visual impairment noted at their delivery hospitalization. Pregnancy conditions and outcomes evaluated included gestational diabetes, pre-eclampsia, labor induction and cesarean delivery. Neonatal outcomes included preterm delivery and birth weight <2500 g. We assessed length of maternal and infant delivery hospitalization. We performed Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CIs) for each outcome, adjusting for year of delivery, maternal age, and parity.<br><br>RESULTS: Most adverse pregnancy and neonatal outcomes were similar for visually impaired (N = 232) and comparison women (N = 2362). However, visually impaired women had increased risks of severe pre-eclampsia (RR 3.77, 95% CI 1.69-8.43), labor induction (RR 1.33, 95% CI 1.10-1.61) and preterm delivery (RR 1.60, 95% CI 1.06-2.42). They were also more likely to have delivery hospitalizations of 3 or more days following a vaginal (RR 1.86, 95% CI 1.41-2.47). Among cesarean deliveries, infants of visually impaired women had increased risk (RR 1.24, 95% CI 1.02-1.51) of hospitalization for 3 or more days postpartum.<br><br>CONCLUSION: Our findings may be useful for obstetric providers in counseling their visually impaired patients.}, }
@article {pmid33383062, year = {2020}, author = {Wright, JH and Huang, LY and Weaver, S and Archila, LD and McAfee, MS and Hirayama, AV and Chapuis, AG and Bleakley, M and Rongvaux, A and Turtle, CJ and Chanthaphavong, S and Campbell, JS and Pierce, RH}, title = {Detection of engineered T cells in FFPE tissue by multiplex in situ hybridization and immunohistochemistry.}, journal = {Journal of immunological methods}, volume = {}, number = {}, pages = {112955}, doi = {10.1016/j.jim.2020.112955}, pmid = {33383062}, issn = {1872-7905}, abstract = {Identifying engineered T cells in situ is important to understand the location, persistence, and phenotype of these cells in patients after adoptive T cell therapy. While engineered cells are routinely characterized in fresh tissue or blood from patients by flow cytometry, it is difficult to distinguish them from endogenous cells in formalin-fixed, paraffin-embedded (FFPE) tissue biopsies. To overcome this limitation, we have developed a method for characterizing engineered T cells in fixed tissue using in situ hybridization (ISH) to the woodchuck hepatitis post-transcriptional regulatory element (WPRE) common in many lentiviral vectors used to transduce chimeric antigen receptor T (CAR-T) and T cell receptor T (TCR-T) cells, coupled with alternative permeabilization conditions that allows subsequent multiplex immunohistochemical (mIHC) staining within the same image. This new method provides the ability to mark the cells by ISH, and simultaneously stain for cell-associated proteins to immunophenotype CAR/TCR modified T cells within tumors, as well as assess potential roles of these cells in on-target/off-tumor toxicity in other tissue.}, }
@article {pmid33382985, year = {2020}, author = {Luengo, A and Li, Z and Gui, DY and Sullivan, LB and Zagorulya, M and Do, BT and Ferreira, R and Naamati, A and Ali, A and Lewis, CA and Thomas, CJ and Spranger, S and Matheson, NJ and Vander Heiden, MG}, title = {Increased demand for NAD+ relative to ATP drives aerobic glycolysis.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2020.12.012}, pmid = {33382985}, issn = {1097-4164}, abstract = {Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.}, }
@article {pmid33381804, year = {2020}, author = {Vasbinder, A and Tinker, LF and Neuhouser, ML and Pettinger, M and Hale, L and Di, C and Zaslavsky, O and Hayman, LL and Lin, X and Eaton, C and Wang, D and Scherman, A and Stefanick, ML and Barrington, WE and Reding, KW}, title = {Risk of metabolic syndrome and metabolic phenotypes in relation to biomarker-calibrated estimates of energy and protein intakes: an investigation from the Women's Health Initiative.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqaa334}, pmid = {33381804}, issn = {1938-3207}, abstract = {BACKGROUND: Metabolic syndrome (MetS) is associated with increased mortality independent of BMI, resulting in discordant metabolic phenotypes, such as metabolically healthy obese and metabolically unhealthy normal-weight individuals. Studies investigating dietary intake in MetS have reported mixed results, due in part to the limitations of self-reported measures.<br><br>OBJECTIVES: To investigate the role of biomarker-calibrated estimates of energy and protein in MetS and metabolic phenotypes.<br><br>METHODS: Postmenopausal participants from the Women's Health Initiative (WHI) study who were free of MetS at baseline, had available data from FFQs at baseline, and had components of MetS at Year 3 (n = 3963) were included. Dietary energy and protein intakes were estimated using biomarker calibration methods. MetS was defined as 3 or more of the following: elevated serum triglycerides (≥150 mg/dL), low HDL cholesterol (<50 mg/dL), hypertension [systolic blood pressure (BP) ≥130 or diastolic BP ≥85 mmHg], elevated serum glucose (>100 mg/dL), and abdominal adiposity (waist circumference > 89 cm). Models were adjusted for age, WHI study component, race/ethnicity, education, income, smoking, recreational physical activity, disease history, and parity.<br><br>RESULTS: For every 10% increment in total calibrated energy intake, women were at a 1.37-fold elevated risk of MetS (95% CI, 1.15-1.63); a 10% increment in calibrated total protein intake was associated with a 1.21-fold elevated risk of MetS (95% CI, 1.00-1.47). Specifically, animal protein intake was associated with MetS (OR, 1.08; 95% CI, 1.02-1.14), whereas vegetable protein intake was not (OR, 0.99; 95% CI, 0.95-1.03). No differences were seen when examining metabolic phenotypes.<br><br>CONCLUSIONS: We found that higher calibrated total energy, total protein, and total animal protein intakes were strongly associated with MetS. If replicated in clinical trials, these results will have implications for the promotion of energy and animal protein restrictions for the reduction of MetS risks.}, }
@article {pmid33381677, year = {2020}, author = {Burhans, MS and Balu, N and Schmidt, KA and Cromer, G and Utzschneider, KM and Schur, EA and Holte, SE and Randolph, TW and Kratz, M}, title = {Impact of the Analytical Approach on the Reliability of MRI-Based Assessment of Hepatic Fat Content.}, journal = {Current developments in nutrition}, volume = {4}, number = {12}, pages = {nzaa171}, pmid = {33381677}, issn = {2475-2991}, abstract = {MRI is a popular noninvasive method for the assessment of liver fat content. After MRI scan acquisition, there is currently no standardized image analysis procedure for the most accurate estimate of liver fat content. We determined intraindividual reliability of MRI-based liver fat measurement using 10 different MRI slice analysis methods in normal-weight, overweight, and obese individuals who underwent 2 same-day abdominal MRI scans. We also compared the agreement in liver fat content between analytical methods and assessed the variability in fat content across the entire liver. Our results indicate that liver fat content varies across the liver, with some slices averaging 54% lower and others 75% higher fat content than the mean of all slices (gold standard). Our data suggest that the entire liver should be contoured on at least every 10th slice to achieve close agreement with the gold standard.}, }
@article {pmid33381260, year = {2020}, author = {Jia, L and Lu, W and Niemtzow, RC and Crawford, P and Greenlee, H and Ma, Q and Mao, JJ and Lin, Y and Olaku, O}, title = {A Virtual Roundtable Discussion Highlighting the Latest Acupuncture Research and Practice.}, journal = {Medical acupuncture}, volume = {32}, number = {6}, pages = {336-344}, pmid = {33381260}, issn = {1933-6586}, }
@article {pmid33378609, year = {2020}, author = {Baden, LR and El Sahly, HM and Essink, B and Kotloff, K and Frey, S and Novak, R and Diemert, D and Spector, SA and Rouphael, N and Creech, CB and McGettigan, J and Kehtan, S and Segall, N and Solis, J and Brosz, A and Fierro, C and Schwartz, H and Neuzil, K and Corey, L and Gilbert, P and Janes, H and Follmann, D and Marovich, M and Mascola, J and Polakowski, L and Ledgerwood, J and Graham, BS and Bennett, H and Pajon, R and Knightly, C and Leav, B and Deng, W and Zhou, H and Han, S and Ivarsson, M and Miller, J and Zaks, T and , }, title = {Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2035389}, pmid = {33378609}, issn = {1533-4406}, abstract = {BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.<br><br>METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.<br><br>RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.<br><br>CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).}, }
@article {pmid33377866, year = {2020}, author = {Herman, JA and Miller, MP and Biggins, S}, title = {chTOG is a conserved mitotic error correction factor.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, doi = {10.7554/eLife.61773}, pmid = {33377866}, issn = {2050-084X}, support = {R01GM064386/NH/NIH HHS/United States ; P41GM103533/NH/NIH HHS/United States ; }, abstract = {Accurate chromosome segregation requires kinetochores on duplicated chromatids to biorient by attaching to dynamic microtubules from opposite spindle poles, which exerts forces to bring kinetochores under tension. However, kinetochores initially bind to microtubules indiscriminately, resulting in errors that must be corrected. While the Aurora B protein kinase destabilizes low-tension attachments by phosphorylating kinetochores, low-tension attachments are intrinsically less stable than those under higher tension in vitro independent of Aurora activity. Intrinsic tension-sensitive behavior requires the microtubule regulator Stu2 (budding yeast Dis1/XMAP215 ortholog), which we demonstrate here is likely a conserved function for the TOG protein family. The human TOG protein, chTOG, localizes to kinetochores independent of microtubules by interacting with Hec1. We identify a chTOG mutant that regulates microtubule dynamics but accumulates erroneous kinetochore-microtubule attachments that are not destabilized by Aurora B. Thus, TOG proteins confer a unique, intrinsic error correction activity to kinetochores that ensures accurate chromosome segregation.}, }
@article {pmid33377129, year = {2020}, author = {Pierson, SK and Khor, JS and Ziglar, J and Liu, A and Floess, K and NaPier, E and Gorzewski, AM and Tamakloe, MA and Powers, V and Akhter, F and Haljasmaa, E and Jayanthan, R and Rubenstein, A and Repasky, M and Elenitoba-Johnson, K and Ruth, J and Jacobs, B and Streetly, M and Angenendt, L and Patier, JL and Ferrero, S and Zinzani, PL and Terriou, L and Casper, C and Jaffe, E and Hoffmann, C and Oksenhendler, E and Fosså, A and Srkalovic, G and Chadburn, A and Uldrick, TS and Lim, M and van Rhee, F and Fajgenbaum, DC}, title = {ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder.}, journal = {Cell reports. Medicine}, volume = {1}, number = {9}, pages = {100158}, pmid = {33377129}, issn = {2666-3791}, abstract = {Geographically dispersed patients, inconsistent treatment tracking, and limited infrastructure slow research for many orphan diseases. We assess the feasibility of a patient-powered study design to overcome these challenges for Castleman disease, a rare hematologic disorder. Here, we report initial results from the ACCELERATE natural history registry. ACCELERATE includes a traditional physician-reported arm and a patient-powered arm, which enables patients to directly contribute medical data and biospecimens. This study design enables successful enrollment, with the 5-year minimum enrollment goal being met in 2 years. A median of 683 clinical, laboratory, and imaging data elements are captured per patient in the patient-powered arm compared with 37 in the physician-reported arm. These data reveal subgrouping characteristics, identify off-label treatments, support treatment guidelines, and are used in 17 clinical and translational studies. This feasibility study demonstrates that the direct-to-patient design is effective for collecting natural history data and biospecimens, tracking therapies, and providing critical research infrastructure.}, }
@article {pmid33375991, year = {2020}, author = {Ghezelayagh, TS and Pennington, KP and Norquist, BM and Khasnavis, N and Radke, MR and Kilgore, MR and Garcia, RL and Lee, M and Katz, R and Leslie, KK and Risques, RA and Swisher, EM}, title = {Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations.}, journal = {Gynecologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ygyno.2020.12.007}, pmid = {33375991}, issn = {1095-6859}, abstract = {OBJECTIVES: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes.<br><br>METHODS: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance.<br><br>RESULTS: TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome.<br><br>CONCLUSIONS: BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.}, }
@article {pmid33375773, year = {2020}, author = {Milan, T and Celton, M and Lagacé, K and Roques, É and Safa-Tahar-Henni, S and Bresson, E and Bergeron, A and Hebert, J and Meshinchi, S and Cellot, S and Barabé, F and Wilhelm, BT}, title = {Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis.}, journal = {Haematologica}, volume = {Online ahead of print}, number = {}, pages = {}, doi = {10.3324/haematol.2020.271619}, pmid = {33375773}, issn = {1592-8721}, abstract = {Chromosomal translocations involving KMT2A gene are one of the most common genetic alterations found in pediatric acute myeloid leukemias (AML) although the molecular mechanisms that initiate the disease remain incompletely defined. To elucidate these initiating events we have used a human model system of AML driven by the KMT2A-MLLT3 (KM3) fusion. More specifically, we investigated changes in DNA methylation, histone modifications, and chromatin accessibility at each stage of our model system and correlated these with expression changes. We observe the development of a profound hypomethylation phenotype in the early stages of leukemic transformation after KM3 addition along with loss of expression of stem cell associated genes along with skewed expression in other genes such as S100A8/9 implicated in leukemogenesis. In addition, early increases in the expression of the lysine demethylase KDM4B was functionally linked to these expression changes as well as other key transcription factors. Remarkably, our ATAC-seq data showed that there were relatively few leukemiaspecific changes and the vast majority corresponded to open chromatin regions and transcription factor clusters previously observed in other cell types. Integration of the gene expression and epigenetic changes revealed the adenylate cyclase gene ADCY9 as an essential gene in KM3-AML, and suggest the potential for autocrine signalling through the chemokine receptor CCR1 and CCL23 ligand. Together, our results suggest that KM3 induces subtle changes in the epigenome while co-opting the normal transcriptional machinery to drive leukemogenesis.}, }
@article {pmid33373709, year = {2020}, author = {Nyame, YA and Holt, SK and Diamontopolous, L and Winters, BR and Psutka, SP and Dash, A and Schade, GR and Lin, DW and Yu, EY and Grivas, P and Gore, JL and Wright, JL}, title = {Social and Clinical Correlates of Neoadjuvant Chemotherapy in Medicare Beneficiaries with Muscle Invasive Bladder Cancer from 2004-2015.}, journal = {Urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urology.2020.12.020}, pmid = {33373709}, issn = {1527-9995}, abstract = {OBJECTIVE: To asses social and clinical correlates of neoadjuvant chemotherapy (NAC) utilization among Medicare beneficiaries.<br><br>MATERIALS AND METHODS: A cohort of SEER-Medicare (2004-2015) patients with muscle-invasive bladder cancer treated by radical cystectomy were stratified into three-groups: standard of care NAC (cisplatin-based combination), non-standard of care NAC, and upfront cystectomy. Multivariable logistic regression analysis was used to assess social, demographic and clinical correlates of each treatment category. Survival analyses were performed to compare propensity matched treatment groups.<br><br>RESULTS: In total, 6,214 patients were identified with a median follow-up of 21 [IQR 7-54] months. NAC utilization increased from 10.7% to 39.1%, between 2004 and 2015, largely due to increased use of standard of care regimens. The most commonly used non-standard regimen was gemcitabine/carboplatin (50.2%). Older age, Hispanic and Black race, lower socioeconomic status, and contraindications to cisplatin were associated with increased odds of receiving non-standard of care NAC compared to standard of care. Standard of care NAC was associated with improved overall survival HR 0.85 (95% CI 0.76, 0.94) and HR 0.75 (95% CI 0.63, 0.89) compared to both upfront cystectomy and non-standard of care NAC, respectively.<br><br>CONCLUSION: NAC utilization has increased to nearly 40%; however, the use of non-standard of care NAC regimen have persisted (∼8%). Cisplatin-ineligibility, older age, race/ethnicity, and lower socioeconomic status were correlated with non-standard of care NAC, which provided no clinical benefit at the risk of potential harm. In accordance with current clinical guidelines, cisplatin-ineligible patients should be considered for timely upfront cystectomy or novel clinical trials.}, }
@article {pmid33373584, year = {2020}, author = {Kato, K and Ahmad, S and Zhu, Z and Young, JM and Mu, X and Park, S and Malik, HS and Hur, S}, title = {Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases.}, journal = {Molecular cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molcel.2020.11.047}, pmid = {33373584}, issn = {1097-4164}, abstract = {RNA helicases and E3 ubiquitin ligases mediate many critical functions in cells, but their actions have largely been studied in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryoelectron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement may apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses suggest not only conserved substrates for TRIM proteins but also, unexpectedly, deep evolutionary connections between TRIM proteins and RNA helicases, linking ubiquitin and RNA biology throughout animal evolution.}, }
@article {pmid33372817, year = {2020}, author = {Reyes, C and Thompson, B and Briant, KJ and Mendoza, J}, title = {Understanding a Diverse Cancer Center Catchment Area: A Qualitative Needs Assessment Built on a Theoretical Framework.}, journal = {Cancer control : journal of the Moffitt Cancer Center}, volume = {27}, number = {1}, pages = {1073274820983026}, doi = {10.1177/1073274820983026}, pmid = {33372817}, issn = {1526-2359}, abstract = {INTRODUCTION: Quantitative approaches to the cancer incidence and mortality of a geographic region may lack understanding of the human context in the region thereby affecting how relevant cancer prevention and control activities can best be targeted to a cancer center's catchment area.<br><br>OBJECTIVES: The objective of this study was to obtain and analyze qualitative data that described the barriers and facilitators in a cancer center's catchment area. A further objective was to use the assessment to plan a comprehensive approach to cancer prevention and control activities in the region.<br><br>METHODS: Extensive qualitative data were gathered from 32 key informants in the 13 county catchment area. We used the Warnecke Model for Analysis of Population Health and Health Disparities to analyze the qualitative data. We coded factors affecting cancer prevention and control using a directed content analysis approach guided by the Warnecke Model.<br><br>RESULTS: Four outcome types included fundamental barriers such as political environment and discrimination, gaps in resources, and lack of coordinated activities. Social and physical barriers included distrust, diverse language and cultures, and geographic distance. Individual barriers included lack of system negotiation, health literacy, and poverty. Biological barriers were disparate disease rates in specific groups.<br><br>CONCLUSION: The analysis and assessment led to the creation of a catchment area wide coalition that used the results to formulate a comprehensive strategic plan to address the barriers in the region.}, }
@article {pmid33370501, year = {2020}, author = {Kates, OS and Stohs, EJ and Pergam, SA and Rakita, RM and Michaels, MG and Wolfe, CR and Danziger-Isakov, L and Ison, MG and Blumberg, EA and Razonable, RR and Gordon, EJ and Diekema, DS}, title = {The limits of refusal: An ethical review of solid organ transplantation and vaccine hesitancy.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1111/ajt.16472}, pmid = {33370501}, issn = {1600-6143}, abstract = {Patients pursuing solid organ transplantation are encouraged to receive many vaccines on an accelerated timeline. Vaccination prior to transplantation offers the best chance of developing immunity and may expand the pool of donor organs that candidates can accept without needing post-transplant therapy. Furthermore, transplant recipients are at greater risk for acquiring vaccine-preventable illnesses or succumbing to severe sequelae of such illnesses. However, a rising rate of vaccine refusal has challenged transplant centers to address the phenomenon of vaccine hesitancy. Transplant centers may need to consider adopting a policy of denial of solid organ transplantation on the basis of vaccine refusal for non-medical reasons (i.e., philosophical or religious objections or personal beliefs that vaccines are unnecessary or unsafe). Arguments supporting such a policy are motivated by utility, stewardship, and beneficence. Arguments opposing such a policy emphasize justice and respect for persons, and seek to avoid worsening inequities or medical coercion. This paper examines these arguments and situates them within the special cases of pediatric transplantation, emergent transplantation, and living donation. Ultimately, a uniform national policy addressing vaccine refusal among transplant candidates is needed to resolve this ethical dilemma and establish a consistent, fair, and standard approach to vaccine refusal in transplantation.}, }
@article {pmid33370399, year = {2020}, author = {Jackson, LK and Potter, B and Schneider, S and Fitzgibbon, M and Blair, K and Farah, H and Krishna, U and Bedford, T and Peek, RM and Salama, NR}, title = {Helicobacter pylori diversification during chronic infection within a single host generates sub-populations with distinct phenotypes.}, journal = {PLoS pathogens}, volume = {16}, number = {12}, pages = {e1008686}, doi = {10.1371/journal.ppat.1008686}, pmid = {33370399}, issn = {1553-7374}, abstract = {Helicobacter pylori chronically infects the stomach of approximately half of the world's population. Manifestation of clinical diseases associated with H. pylori infection, including cancer, is driven by strain properties and host responses; and as chronic infection persists, both are subject to change. Previous studies have documented frequent and extensive within-host bacterial genetic variation. To define how within-host diversity contributes to phenotypes related to H. pylori pathogenesis, this project leverages a collection of 39 clinical isolates acquired prospectively from a single subject at two time points and from multiple gastric sites. During the six years separating collection of these isolates, this individual, initially harboring a duodenal ulcer, progressed to gastric atrophy and concomitant loss of acid secretion. Whole genome sequence analysis identified 1,767 unique single nucleotide polymorphisms (SNPs) across isolates and a nucleotide substitution rate of 1.3x10-4 substitutions/site/year. Gene ontology analysis identified cell envelope genes among the genes with excess accumulation of nonsynonymous SNPs (nSNPs). A maximum likelihood tree based on genetic similarity clusters isolates from each time point separately. Within time points, there is segregation of subgroups with phenotypic differences in bacterial morphology, ability to induce inflammatory cytokines, and mouse colonization. Higher inflammatory cytokine induction in recent isolates maps to shared polymorphisms in the Cag PAI protein, CagY, while rod morphology in a subgroup of recent isolates mapped to eight mutations in three distinct helical cell shape determining (csd) genes. The presence of subgroups with unique genetic and phenotypic properties suggest complex selective forces and multiple niches within the stomach during chronic infection.}, }
@article {pmid33369671, year = {2020}, author = {Huang, Y and Moodie, Z and Juraska, M and Fong, Y and Carpp, LN and Chambonneau, L and Coronel, DL and Dayan, GH and DiazGranados, CA and Gilbert, PB}, title = {Immunobridging efficacy of a tetravalent dengue vaccine against dengue and against hospitalized dengue from children/adolescents to adults in highly endemic countries.}, journal = {Transactions of the Royal Society of Tropical Medicine and Hygiene}, volume = {}, number = {}, pages = {}, doi = {10.1093/trstmh/traa154}, pmid = {33369671}, issn = {1878-3503}, abstract = {BACKGROUND: CYD-TDV demonstrated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype from month 13 to month 25 (VCD-DENV-AnyM13→M25) in the CYD14 (2-14-y-olds) and CYD15 (9-16-y-olds) phase 3 trials. Fifty percent plaque reduction neutralization test (PRNT50) titers are a potential surrogate for immunobridging VE to adults.<br><br>METHODS: Using PRNT50 calibration datasets, we applied immunobridging approaches using baseline and/or M13 PRNT50 titers to estimate VE against VCD-DENV-AnyM0→M25 and against hospitalized VCD (HVCD)-DENV-AnyM0→M72 in hypothetical 18-45-y-old and 46-50-y-old CYD14 and CYD15 cohorts.<br><br>RESULTS: Baseline and M13 geometric mean PRNT50 titers were greater in 18-45-y-olds and in 46-50-y-olds vs 9-16-y-olds for most comparisons. Estimated VE (95% CIs against VCD-DENV-AnyM0→M25 ranged from 75.3% to 90.9% (52.5% to 100%) for 18-45-y-olds and 74.8% to 92.0% (53.4% to 100%) for 46-50-y-olds. Estimated VE (95% CIs) against HVCD-DENV-AnyM0→M72 ranged from 58.8% to 78.1% (40.9 to 98.9%) for 18-45-y-olds and 57.2% to 78.4% (40.5 to 97.6%) for 46-50-y-olds. Corresponding predictions among baseline-seropositive individuals yielded comparable or higher VE estimates.<br><br>CONCLUSIONS: VE M0→M25 against DENV-Any and VE against HVCD-DENV-AnyM0→M72 are both expected to be higher in 18-45 and 46-50-y-olds vs CYD14 and CYD15 9-16-y-olds.}, }
@article {pmid33369665, year = {2020}, author = {Reis-Filho, JS and Davidson, NE}, title = {Ki67 Assessment in Breast Cancer: Are We There yet?.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaa202}, pmid = {33369665}, issn = {1460-2105}, }
@article {pmid33369658, year = {2020}, author = {Sedrak, MS and Sun, CL and Hershman, DL and Unger, JM and Liu, J and Dale, W and Dizon, DS}, title = {Investigator Use of Social Media for Recruitment of Patients for Cancer Clinical Trials.}, journal = {JAMA network open}, volume = {3}, number = {12}, pages = {e2031202}, doi = {10.1001/jamanetworkopen.2020.31202}, pmid = {33369658}, issn = {2574-3805}, }
@article {pmid33367885, year = {2020}, author = {Chuntova, P and Chow, F and Watchmaker, P and Galvez, M and Heimberger, AB and Newell, EW and Diaz, A and DePinho, RA and Li, MO and Wherry, EJ and Mitchell, D and Terabe, M and Wainwright, DA and Berzofsky, JA and Herold-Mende, C and Heath, JR and Lim, M and Margolin, KA and Chiocca, EA and Kasahara, N and Ellingson, BM and Brown, C and Chen, Y and Fecci, P and Reardon, DA and Dunn, GP and Liau, LM and Costello, JF and Wick, W and Cloughesy, T and Timmer, WC and Wen, PY and Prins, RM and Platten, M and Okada, H}, title = {Unique challenges for glioblastoma immunotherapy - Discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaa277}, pmid = {33367885}, issn = {1523-5866}, abstract = {Cancer immunotherapy has made remarkable advances with over fifty separate Food and Drug Administration (FDA) approvals as first or second line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T-cells and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights in the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells and T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.}, }
@article {pmid33367735, year = {2020}, author = {Hudson, PL and Ling, W and Wu, MC and Hayward, MR and Mitchell, AJ and Larson, J and Guthrie, KA and Reed, SD and Kwon, DS and Mitchell, CM}, title = {Comparison of the vaginal microbiota in postmenopausal Black and White women.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaa780}, pmid = {33367735}, issn = {1537-6613}, abstract = {OBJECTIVE: We compared vaginal microbial communities in postmenopausal Black and White women.<br><br>METHODS: Shotgun sequencing of vaginal swabs from postmenopausal women self-identified as Black or White was compared using MiRKAT.<br><br>RESULTS: Vaginal community dominance by Lactobacillus crispatus or L. gasseri was more common in 44 postmenopausal Black women (n = 12, 27%) than among 44 matched White women (N = 2, 5%; p = 0.01). No individual taxa were significantly more abundant in either group.<br><br>CONCLUSIONS: We identified small overall differences in vaginal microbial communities of Black and White postmenopausal women. L. crispatus dominance was more common in Black women.}, }
@article {pmid33367152, year = {2020}, author = {Santiago-Torres, M and Shi, Z and Tinker, LF and Lampe, JW and Allison, MA and Barrington, W and Crane, TE and Garcia, DO and Hayden, KM and Isasi, CR and Valdiviezo-Schlomp, CI and Martin, LW and Neuhouser, ML}, title = {Diet quality indices and risk of metabolic syndrome among postmenopausal women of Mexican ethnic descent in the Women's Health Initiative Observational Study.}, journal = {Nutrition and healthy aging}, volume = {5}, number = {4}, pages = {261-272}, pmid = {33367152}, issn = {2451-9480}, abstract = {BACKGROUND: The prevalence of metabolic syndrome is higher among minority populations, including individuals of Mexican ethnic descent. Whether alignment to healthy dietary patterns is associated with lower risk of metabolic syndrome in this population is largely unknown.<br><br>OBJECTIVE: To prospectively evaluate the associations between a priori diet quality scores and risk of metabolic syndrome and its components among postmenopausal women of Mexican ethnic descent.<br><br>METHODS: A total of 334 women of Mexican ethnic descent who participated in the Women's Health Initiative (WHI) observational study without metabolic syndrome or diabetes at baseline (1993-1998) were included. Baseline diets were scored with the Alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), the Healthy Eating Index (HEI-2010), the Mediterranean Diet Score (MDS), and the traditional Mexican Diet (MexD) score. Multivariable linear and logistic regression models were used to test the associations between baseline diet quality and risk of metabolic syndrome and its individual components at follow-up (2012-2013).<br><br>RESULTS: Approximately 16% of women met the criteria for metabolic syndrome at follow-up. None of the diet quality indices were associated with risk of metabolic syndrome. However, higher vs lower DASH scores were associated with lower waist circumference (85.2 vs 88.0 cm) and glucose concentrations (90.0 vs 95.1 mg/dL), and higher HDL cholesterol (62.6 vs 59.0 mg/dL), while higher vs lower HEI-2010 scores were associated with lower waist circumference (83.9 vs 88.1 cm), triglycerides (103 vs 117 mg/dL) and glucose concentrations (89.5 vs 94.4 mg/dL), and higher HDL cholesterol levels (63.9 vs 58.5 mg/dL).<br><br>CONCLUSIONS: Diet quality was not associated with risk of metabolic syndrome in this population. However, the results suggest that alignment to DASH and HEI-2010 recommendations may be beneficial for reducing some individual components of metabolic syndrome among postmenopausal women of Mexican descent.}, }
@article {pmid33362208, year = {2020}, author = {Molaro, A and Wood, AJ and Janssens, D and Kindelay, SM and Eickbush, MT and Wu, S and Singh, P and Muller, CH and Henikoff, S and Malik, HS}, title = {Biparental contributions of the H2A.B histone variant control embryonic development in mice.}, journal = {PLoS biology}, volume = {18}, number = {12}, pages = {e3001001}, doi = {10.1371/journal.pbio.3001001}, pmid = {33362208}, issn = {1545-7885}, abstract = {Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.}, }
@article {pmid33358575, year = {2020}, author = {Graf, SA and Cassaday, RD and Morris, K and Voutsinas, JM and Wu, QV and Behnia, S and Lynch, RC and Krakow, E and Rasmussen, H and Chauncey, TR and Kanan, S and Soma, L and Smith, SD and Gopal, AK}, title = {Ibrutinib Monotherapy in Relapsed or Refractory, Transformed Diffuse Large B-cell Lymphoma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2020.11.023}, pmid = {33358575}, issn = {2152-2669}, abstract = {BACKGROUND: Histologic transformation to diffuse large B-cell lymphoma (tDLBCL) occurs in a significant proportion of indolent lymphomas. However, few studies of novel agents inform its management, particularly when relapsed after or refractory (R/R) to prior treatment.<br><br>PATIENTS AND METHODS: We prospectively evaluated ibrutinib monotherapy in pathologically documented patients with R/R tDLBCL in a single-arm study. The primary endpoint was overall response rate.<br><br>RESULTS: Twenty patients who had received a median of 4 (range, 2-9) prior lines of therapy overall (median, 2.5; range, 1-9 for tDLBCL) were treated. The overall response rate was 35%, including complete responses in 15%. The median progression-free survival and overall survival were 4.1 months (95% confidence interval, 2.4-6.2 months) and 22.4 months (95% confidence interval, 7.5 months to not reached), respectively. Disease control > 2 months was seen in 75% and > 1 year in 15%. Response was associated with either low tumor bulk or low metabolic tumor volume (P = .05) but not with antecedent lymphoma histology (P = 1.0). Treatment-related adverse events were consistent with prior studies of ibrutinib.<br><br>CONCLUSIONS: Ibrutinib showed low toxicity and meaningful efficacy in R/R tDLBCL, including short-term disease control in most cases. Results demonstrate the potential utility of ibrutinib in this challenging clinical setting, including as a potential bridge to more definitive treatments.}, }
@article {pmid33358401, year = {2020}, author = {Borghaei, H and Redman, MW and Kelly, K and Waqar, SN and Robert, F and Kiefer, GJ and Stella, PJ and Minichiello, K and Gandara, DR and Herbst, RS and Papadimitrakopoulou, VA}, title = {SWOG S1400A (NCT02154490): A Phase II Study of Durvalumab for Patients With Previously Treated Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-study).}, journal = {Clinical lung cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cllc.2020.10.015}, pmid = {33358401}, issn = {1938-0690}, abstract = {INTRODUCTION: The objective of the Lung-MAP sub-study S1400A was to evaluate the response rate to durvalumab, an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with squamous non-small-cell lung cancer (SqNSCLC).<br><br>PATIENTS AND METHODS: Patients who progressed on at least 1 prior platinum-based chemotherapy were eligible. The study was designed as a phase II/III trial comparing durvalumab with docetaxel but was modified to a single-arm, phase II trial with the primary endpoint of objective response when immunotherapy became an approved treatment.<br><br>RESULTS: A total of 116 patients were registered to this sub-study; 78 to durvalumab and 38 to docetaxel. Of the 78 patients, 9 were ineligible, and 1 was not evaluable for endpoints. Responses were achieved in 11 patients among the 68 eligible and evaluable patients on durvalumab (overall response rate, 16%; 95% confidence interval [CI], 7%-25%). The disease control rate was 54% (95% CI, 43%-66%), the median overall survival was 11.6 months (95% CI, 10.2-14.3 months), and the median progression-free survival was 2.9 months (95% CI, 2.0-4.0 months). PD-L1 data was available for 43 patients on durvalumab, with 14 (33%) patients who were PD-L1-positive (≥ 25%) and 2 responses (overall response rate, 14%; 95% CI, 0%-33%), the disease control rate was 57% (95% CI, 31%-83%), the median overall survival and progression-free survival were 10.7 months (95% CI, 9.2-14.3 months) and 2.3 months (95% CI, 1.4-4.2 months), respectively. Grade ≥ 3 treatment-related adverse events occurred in 22 (32%) patients on durvalumab, with 6 discontinuing owing to drug-related adverse events (9%; 95% CI, 2%-16%).<br><br>CONCLUSIONS: Durvalumab shows single-agent activity and toxicities in this sub-group of patients that is comparable with other anti-programmed cell death protein 1/PD-L1 antibodies.}, }
@article {pmid33357452, year = {2020}, author = {Srivastava, S and Furlan, SN and Jaeger-Ruckstuhl, CA and Sarvothama, M and Berger, C and Smythe, KS and Garrison, SM and Specht, JM and Lee, SM and Amezquita, RA and Voillet, V and Muhunthan, V and Yechan-Gunja, S and Pillai, SPS and Rader, C and Houghton, AM and Pierce, RH and Gottardo, R and Maloney, DG and Riddell, SR}, title = {Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2020.11.005}, pmid = {33357452}, issn = {1878-3686}, abstract = {Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.}, }
@article {pmid33356566, year = {2020}, author = {Gbadamosi, MO and Shastri, VM and Hylkema, T and Papageorgiou, I and Pardo, L and Cogle, CR and Doty, A and Loken, MR and Meshinchi, S and Lamba, JK}, title = {Novel CD33 antibodies unravel localization, biology and therapeutic implications of CD33 isoforms.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.2217/fon-2020-0746}, pmid = {33356566}, issn = {1744-8301}, support = {//University of Florida Foundation/ ; //St Baldrick's Foundation/ ; 6610-20//Leukemia &amp; Lymphoma Society/ ; }, abstract = {The aim of this study was to establish the therapeutic relevance of the CD33D2 isoform by developing novel antibodies targeting the IgC domain of CD33. Two novel IgC-targeting antibodies, HL2541 and 5C11-2, were developed, and CD33 isoforms were assessed using multiple assays in cells overexpressing either CD33FL or CD33D2 isoforms, unmodified acute myeloid leukemia (AML) cell lines and primary AML specimens representing different genotypes for the CD33 splicing single nucleotide polymorphism. CD33D2 was recognized on cells overexpressing CD33D2 and unmodified AML cell lines; however, minimal/no cell surface detection of CD33D2 was observed in primary AML specimens. Both isoforms were detected intracellularly using novel antibodies. Minimal cell surface expression of CD33D2 on primary AML/progenitor cells warrants further studies on anti-CD33D2 immunotherapeutics.}, }
@article {pmid33355599, year = {2020}, author = {Galukande, M and Schüz, J and Anderson, BO and Zietsman, A and Adisa, C and Anele, A and Parham, G and Pinder, LF and Mutumba, S and Lombe, D and Cabanes, A and Foerster, M and Dos-Santos-Silva, I and McCormack, V}, title = {Maternally Orphaned Children and Intergenerational Concerns Associated With Breast Cancer Deaths Among Women in Sub-Saharan Africa.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2020.6583}, pmid = {33355599}, issn = {2374-2445}, abstract = {Importance: Low breast cancer survival in sub-Saharan Africa's young population increases the likelihood that breast cancer deaths result in maternal orphans, ie, children (<18 years) losing their mother.<br><br>Objective: To estimate the number of maternal orphans and their ages for every 100 breast cancer deaths in sub-Saharan African settings during 2014-2019 and to describe family concerns about the orphaned children.<br><br>Deaths occurring between September 1, 2014, and July 1, 2019, in the African Breast Cancer-Disparities in Outcomes (ABC-DO) were examined in a cohort of women diagnosed with breast cancer during 2014-2017 at major cancer treatment hospitals in Namibia, Nigeria, Uganda, and Zambia. The cohort was actively followed up for vital status via a trimonthly mobile phone call to each woman or her next of kin (typically a partner, husband, or child).<br><br>Main Outcomes and Measures: The number (Poisson counts) and ages of new orphans at the time of maternal death.<br><br>Results: This cohort study found that a total of 795 deaths resulted in 964 new maternal orphans, with deaths occurring in women younger than 50 years accounting for 85% of the orphans. For every 100 deaths in women younger than 50 years, there were 210 new orphans (95% CI, 196-225) overall, with country-specific estimates of 189 in Nigerian, 180 in Namibian, 222 in Ugandan, and 247 in Zambian Black women. For every 100 deaths of the women at any age, there were 121 maternal orphans, 17% of whom were younger than 5 years, 32% aged 5 to 9 years, and 51% aged 10 to 17 years at the time of maternal death. In follow-up interviews, families' concerns for children's education and childcare were reported to be exacerbated by the financial expenses associated with cancer treatment.<br><br>Conclusions and Relevance: This study provides evidence that the number of maternal orphans due to breast cancer exceeds the number of breast cancer deaths among women in sub-Saharan Africa. The intergenerational consequences associated with cancer deaths in sub-Saharan Africa appear to be large and support the need for continued action to improve survival.}, }
@article {pmid33355237, year = {2020}, author = {McLouth, LE and Nightingale, CL and Dressler, EV and Snavely, AC and Hudson, MF and Unger, JM and Kazak, AE and Lee, SJC and Edward, J and Carlos, R and Kamen, CS and Neuman, HB and Weaver, KE}, title = {Current Practices for Screening and Addressing Financial Hardship within the National Cancer Institute's Community Oncology Research Program.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-1157}, pmid = {33355237}, issn = {1538-7755}, abstract = {BACKGROUND: Cancer-related financial hardship is associated with poor care outcomes and reduced quality-of-life for patients and families. Scalable intervention development to address financial hardship requires knowledge of current screening practices and services within community cancer care.<br><br>METHODS: The National Cancer Institute's Community Oncology Research Program (NCORP) 2017 Landscape Assessment survey assessed financial screening and financial navigation practices within U.S. community oncology practices. Logistic models evaluated associations between financial hardship screening and availability of a cancer-specific financial navigator and practice group characteristics (e.g., safety-net designation, critical access hospital, proportion of racial and ethnic minority patients served).<br><br>RESULTS: Of 221 participating NCORP practice groups, 72% reported a financial screening process and 50% had a cancer-specific financial navigator. Practice groups with more than 10% of new cancer patients enrolled in Medicaid (adjOR = 2.81, p = .02) and with less than 30% racial/ethnic minority cancer patient composition (adjOR = 3.91, p <.01) were more likely to screen for financial concerns. Practice groups with less than 30% racial/ethnic minority cancer patient composition (adjOR = 2.37, p <.01) were more likely to have a dedicated financial navigator or counselor for cancer patients.<br><br>CONCLUSIONS: Most NCORP practice groups screen for financial concerns and half have a cancer-specific financial navigator. Practices serving more racial or ethnic minority patients are less likely to screen and have a designated financial navigator.<br><br>IMPACT: The effectiveness of financial screening and navigation for mitigating financial hardship could be tested within NCORP, along with specific interventions to address cancer care inequities.}, }
@article {pmid33354722, year = {2020}, author = {Do, WL and Whitsel, EA and Costeira, R and Masachs, OM and Le Roy, CI and Bell, JT and RStaimez, L and Stein, AD and Smith, AK and Horvath, S and Assimes, TL and Liu, S and Manson, JE and Shadyab, AH and Li, Y and Hou, L and Bhatti, P and Jordahl, K and Narayan, KMV and Conneely, KN}, title = {Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.}, journal = {International journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ije/dyaa215}, pmid = {33354722}, issn = {1464-3685}, abstract = {BACKGROUND: Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445 548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.<br><br>DESIGN: The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P < 0.05 and a consistent direction.<br><br>RESULTS: Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P = 2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).<br><br>CONCLUSIONS: Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.}, }
@article {pmid33354707, year = {2020}, author = {Whitney, BM and Srinivasan, S and Tapia, K and Muriuki, EM and Chohan, BH and Wallis, JM and Liu, C and Guthrie, BL and McClelland, RS and Hoffman, NG and Fredricks, DN and Roxby, AC}, title = {Influence of intramuscular depot-medroxyprogesterone acetate initiation on vaginal microbiota in the postpartum period.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1876}, pmid = {33354707}, issn = {1537-6591}, abstract = {BACKGROUND: The vaginal microbiome plays a key role in women's reproductive health. Use of exogenous hormones, such as intramuscular depot-medroxyprogesterone acetate (DMPA-IM), may alter the composition of vaginal bacterial community.<br><br>METHODS: Vaginal swabs were collected from postpartum Kenyan women initiating DMPA-IM or non-hormonal contraception (non-HC). Bacterial vaginosis was assessed by Nugent score (Nugent-BV) and bacterial community composition was evaluated using broad-range 16S rRNA gene PCR with high-throughput sequencing. Changes in Nugent score, alpha diversity (Shannon diversity index), and total bacterial load between contraceptive groups from enrollment to three-months post-initiation were estimated using multivariable linear mixed effects regression.<br><br>RESULTS: Among 54 HIV-negative women, 33 choosing DMPA-IM and 21 choosing non-HC, Nugent-BV was more common among DMPA-IM users at enrollment. At follow-up, Nugent score had decreased significantly among DMPA-IM users (Δ=-1.89 (95%CI:-3.53, -0.25; p=0.02) while alpha diversity remained stable (Δ=0.03, 95%CI:-0.24, 0.30; p=0.83). Conversely, Nugent score remained relatively stable among non-HC users (Δ=-0.73, 95%CI:-2.18, 0.73; p=0.33) while alpha diversity decreased (Δ=-0.34, 95%CI:-0.67, -0.001; p=0.05). Total bacterial load decreased slightly in DMPA-IM users and increased slightly among non-HC users, resulting in a significant difference in change between the contraceptive groups (difference=-0.64 log10 gene copies/swab, 95%CI:-1.19, -0.08; p=0.02). While significant changes in Nugent score and alpha diversity were observed within contraceptive groups, changes between groups were not significantly different.<br><br>CONCLUSIONS: Postpartum vaginal bacterial diversity did not change in DMPA-IM users despite a reduction in Nugent-BV, but decreased significantly among women using non-HC. Choice of contraception may influence Lactobacillus recovery in postpartum women.}, }
@article {pmid33354340, year = {2020}, author = {Buszkiewicz, J and Rose, C and Gupta, S and Ko, LK and Mou, J and Moudon, AV and Hurvitz, PM and Cook, A and Aggarwal, A and Drewnowski, A}, title = {A cross-sectional analysis of physical activity and weight misreporting in diverse populations: The Seattle Obesity Study III.}, journal = {Obesity science &amp; practice}, volume = {6}, number = {6}, pages = {615-627}, pmid = {33354340}, issn = {2055-2238}, support = {R01 DK076608/DK/NIDDK NIH HHS/United States ; }, abstract = {Background: In-person assessments of physical activity (PA) and body weight can be burdensome for participants and cost prohibitive for researchers. This study examined self-reported PA and weight accuracy and identified patterns of misreporting in a diverse sample.<br><br>Methods: King, Pierce and Yakima county residents, aged 21-59 years (n = 728), self-reported their moderate-to-vigorous PA (MVPA) and weight, in kilograms. Self-reports were compared with minutes of bout-level MVPA, from 3 days of accelerometer data, and measured weights. Regression models examined characteristics associated with underreporting and overreporting of MVPA and weight, the potential bias introduced using each measure and the relation between perceived and measured PA and weight.<br><br>Results: MVPA underreporting was higher among males and college educated participants; however, there was no differential MVPA overreporting. Weight underreporting was higher among males, those age 40-49 years and persons with obesity. Weight overreporting was higher among Hispanic participants and those reporting stress, unhappiness and fair or poor health. The estimated PA-obesity relation was similar using measured and self-reported PA but not self-reported weight. Perceived PA and weight predicted measured values.<br><br>Conclusion: Self-reported PA and weight may be useful should objective measurement be infeasible; however, though population-specific adjustment for differential reporting should be considered.}, }
@article {pmid33352384, year = {2020}, author = {Jiang, M and Fares, AF and Shepshelovich, D and Yang, P and Christiani, D and Zhang, J and Shiraishi, K and Ryan, BM and Chen, C and Schwartz, AG and Tardon, A and Shete, S and Schabath, MB and Teare, MD and Le Marchand, L and Zhang, ZF and Field, JK and Brenner, H and Diao, N and Xie, J and Kohno, T and Harris, CC and Wenzlaff, AS and Fernandez-Tardon, G and Ye, Y and Taylor, F and Wilkens, LR and Davies, M and Liu, Y and Barnett, MJ and Goodman, GE and Morgenstern, H and Holleczek, B and Thomas, S and Brown, MC and Hung, RJ and Xu, W and Liu, G}, title = {The relationship between body-mass index and overall survival in non-small cell lung cancer by sex, smoking status, and race: A pooled analysis of 20,937 International lung Cancer consortium (ILCCO) patients.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {152}, number = {}, pages = {58-65}, doi = {10.1016/j.lungcan.2020.11.029}, pmid = {33352384}, issn = {1872-8332}, abstract = {INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC).<br><br>METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses.<br><br>RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers.<br><br>CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.}, }
@article {pmid33350501, year = {2020}, author = {Miles, S and Bradley, GT and Breeden, LL}, title = {The budding yeast transition to quiescence.}, journal = {Yeast (Chichester, England)}, volume = {}, number = {}, pages = {}, doi = {10.1002/yea.3546}, pmid = {33350501}, issn = {1097-0061}, abstract = {A subset of Saccharomyces cerevisiae cells in a stationary phase culture achieve a unique quiescent state characterized by increased cell density, stress tolerance and longevity. Trehalose accumulation is necessary but not sufficient for conferring this state and it is not recapitulated by abrupt starvation. The fraction of cells that achieve this state varies widely in haploids and diploids and can approach 100%, indicating that both mother and daughter cells can enter quiescence. The transition begins when about half the glucose has been taken up from the medium. The high affinity glucose transporters are turned on, glycogen storage begins, the Rim15 kinase enters the nucleus and the accumulation of cells in G1 is initiated. After the diauxic shift (DS), when glucose is exhausted from the medium, growth promoting genes are repressed by the recruitment of the histone deacetylase Rpd3 by quiescence-specific repressors. The final division that takes place post-DS is highly asymmetrical and G1 arrest is complete after 48 hours. The timing of these events can vary considerably, but they are tightly correlated with total biomass of the culture, suggesting that the transition to quiescence is tightly linked to changes in external glucose levels. After seven days in culture, there are massive morphological changes at the protein and organelle level. There are global changes in histone modification. An extensive array of condensin-dependent, long-range chromatin interactions lead to genome-wide chromatin compaction that is conserved in yeast and human cells. These interactions are required for the global transcriptional repression that occurs in quiescent yeast.}, }
@article {pmid33350436, year = {2020}, author = {Al-Shaar, L and Yuan, C and Rosner, B and Dean, SB and Ivey, KL and Clowry, CM and Sampson, LA and Barnett, JB and Rood, J and Harnack, LJ and Block, J and Manson, JE and Stampfer, MJ and Willett, WC and Rimm, EB}, title = {Reproducibility and Validity of a Semi-quantitative Food Frequency Questionnaire in Men Assessed by Multiple Methods.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaa280}, pmid = {33350436}, issn = {1476-6256}, abstract = {Among 626 participants of the Men's Lifestyle Validation Study (2011-2013), we evaluated the validity and reproducibility of a self-administered 152-item semiquantitative food frequency questionnaire (SFFQ) using two 7-day dietary records (7DDRs), four automated self-administered 24-hour dietary recalls (ASA24s), four 24-hour urine samples, one doubly-labeled water measurement (repeated in 104 participants), and two fasting blood samples, collected over 15 months. Compared to 7DDRs, SFFQs underestimated energy intake, macronutrients, and sodium intake, but overestimated some micronutrients. The mean of Spearman correlation coefficients was 0.66 (range 0.38 to 0.88) between 46 energy-adjusted nutrients estimated from 7DDRs and the final SFFQ, de-attenuated for within-person variation in the 7DDRs. These deattenuated correlations were similar using ASA24s as the comparison. Relative to biomarkers, SFFQs underestimated energy, sodium, and protein intakes, and the sodium:potassium ratio. The energy-adjusted correlations between the final SFFQ and the biomarkers were slightly lower than the correlations between the SFFQ and 7DDRs. Using method of triads to calculate validity coefficients (VC), the median VC between SFFQ and true intake was 0.65 and 0.69 using 7DDRs or ASA24s as the third method. These data indicate that this SFFQ provided reasonably valid estimates for a wide range of nutrients when evaluated by multiple comparison methods.}, }
@article {pmid33349793, year = {2020}, author = {Bryan, A and Fink, SL and Gattuso, MA and Pepper, G and Chaudhary, A and Wener, MH and Morishima, C and Jerome, KR and Mathias, PC and Greninger, AL}, title = {SARS-CoV-2 Viral Load on Admission Is Associated With 30-Day Mortality.}, journal = {Open forum infectious diseases}, volume = {7}, number = {12}, pages = {ofaa535}, doi = {10.1093/ofid/ofaa535}, pmid = {33349793}, issn = {2328-8957}, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load on admission was associated with a significantly increased 30-day mortality (odds ratio [OR], 4.20; 95% CI, 1.62-10.86), and anti-SARS-CoV-2 nucleocapisid IgG seropositivity on admission trended toward a reduced 30-day mortality (OR, 0.43; 95% CI, 0.15-1.26). Reporting of quantitative SARS-CoV-2 viral load and serologic assays may offer prognostic clinical information.}, }
@article {pmid33346587, year = {2020}, author = {Carter, KA and Srinivasan, S and Fiedler, TL and Anzala, O and Kimani, J and Mochache, V and Wallis, JM and Fredricks, DN and McClelland, RS and Balkus, JE}, title = {Vaginal bacteria and risk of incident and persistent infection with high risk sub-types of human papillomavirus: a cohort study among Kenyan women.}, journal = {Sexually transmitted diseases}, volume = {Publish Ahead of Print}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000001343}, pmid = {33346587}, issn = {1537-4521}, abstract = {BACKGROUND: Bacterial vaginosis (BV) is associated with increased risk of high-risk HPV (hrHPV), whereas Lactobacillus-dominated vaginal microbiotas are associated with reduced burden of hrHPV. Few epidemiologic studies have prospectively investigated the relationships between vaginal bacteria and hrHPV, particularly among women from countries in Africa.<br><br>METHODS: We conducted a prospective cohort study nested within the Preventing Vaginal Infections trial to evaluate associations between vaginal bacteria and hrHPV incidence and persistence. Sexually active, HIV-seronegative women age 18-45 who had a vaginal infection at screening were eligible to enroll. Analyses were restricted to participants enrolled in Kenya and randomized to placebo. At enrollment and months 2, 4, 6, 8, 10, and 12, hrHPV testing, quantitative PCR (measuring taxon quantity per swab), and 16S rRNA gene amplicon sequencing of the vaginal microbiota were performed. Generalized estimating equations multinomial logistic regression models were fit to evaluate associations between vaginal bacteria and incident and persistent hrHPV.<br><br>RESULTS: Eighty-four participants were included in this analysis. Higher concentrations of Lactobacillus crispatus were inversely associated with persistent hrHPV detection. Specifically, one tertile higher L. crispatus concentration was associated with 50% reduced odds of persistent hrHPV detection (OR = 0.50, 95% CI 0.29-0.85).<br><br>CONCLUSIONS: This study is consistent with reports that vaginal L. crispatus is associated with reduced susceptibility to hrHPV persistence. Evidence from in vitro studies provides insight into potential mechanisms by which L. crispatus may mediate hrHPV risk. Future studies should further explore in vivo mechanisms that may drive this relationship and opportunities for intervention.}, }
@article {pmid33346201, year = {2020}, author = {O'Brien, VP and Joens, MS and Lewis, AL and Gilbert, NM}, title = {Recurrent Escherichia coli Urinary Tract Infection Triggered by Gardnerella vaginalis Bladder Exposure in Mice.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {166}, pages = {}, doi = {10.3791/61967}, pmid = {33346201}, issn = {1940-087X}, abstract = {Recurrent urinary tract infections (rUTI) caused by uropathogenic Escherichia coli (UPEC) are common and costly. Previous articles describing models of UTI in male and female mice have illustrated the procedures for bacterial inoculation and enumeration in urine and tissues. During an initial bladder infection in C57BL/6 mice, UPEC establish latent reservoirs inside bladder epithelial cells that persist following clearance of UPEC bacteriuria. This model builds on these studies to examine rUTI caused by the emergence of UPEC from within latent bladder reservoirs. The urogenital bacterium Gardnerella vaginalis is used as the trigger of rUTI in this model because it is frequently present in the urogenital tracts of women, especially in the context of vaginal dysbiosis that has been associated with UTI. In addition, a method for in situ bladder fixation followed by scanning electron microscopy (SEM) analysis of bladder tissue is also described, with potential application to other studies involving the bladder.}, }
@article {pmid33345655, year = {2020}, author = {Chen, X and Othus, M and Wood, BL and Walter, RB and Becker, PS and Percival, ME and Abkowitz, JL and Appelbaum, FR and Estey, EH}, title = {Comparison of myeloid blast counts and variant allele frequencies of gene mutations in myelodysplastic syndrome with excess blasts and secondary acute myeloid leukemia.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/10428194.2020.1861267}, pmid = {33345655}, issn = {1029-2403}, abstract = {Secondary acute myeloid leukemia (sAML) is biologically and clinically distinct from de novo AML and shares specific genetic mutations with myelodysplastic syndromes (MDS). We retrospectively analyzed data from 295 adults with MDS or AML with mutational analysis by next-generation sequencing (NGS), and examined differences in functional grouping of mutations and relation between morphologic blast count and variant allele frequency (VAF) of mutations. Our analysis showed the distribution of mutations differed in MDS and AML. However, these differences largely disappeared when we compared MDS with excess blasts (MDS-EB) and sAML. VAF of mutations generally did not correlate with morphologic blast count and the distribution of VAF was similar above and below the 20% cutpoint. Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity therapy and survival was also similar. These results support that MDS-EB and sAML have overlapping features and may represent a spectrum of the same disease. Key points The distribution of genetic mutations is similar in myelodysplastic syndrome with excess blasts (MDS-EB) and secondary acute myeloid leukemia (sAML) regardless of morphologic blast count. Variant allele frequencies (VAFs) of gene mutations do not correlate well with morphologic blast counts, particularly in MDS-EB and sAML. Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity or low intensity therapy.}, }
@article {pmid33342724, year = {2020}, author = {Grant, SJ and Mian, HS and Giri, S and Boutin, M and Dottorini, L and Neuendorff, NR and Krok-Schoen, JL and Nikita, N and Rosko, AE and Wildes, TM and Zweegman, S}, title = {Transplant-ineligible newly diagnosed multiple myeloma: Current and future approaches to clinical care: A Young International Society of Geriatric Oncology Review Paper.}, journal = {Journal of geriatric oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jgo.2020.12.001}, pmid = {33342724}, issn = {1879-4076}, abstract = {Multiple myeloma is the second most common hematological malignancy in the USA and Europe. Despite improvements in the 5-year and overall survival rates over the past decade, older adults (aged ≥65 years) with multiple myeloma continue to experience disproportionately worse outcomes than their younger counterparts. These differences in outcomes arise from the increased prevalence of vulnerabilities such as medical comorbidities and frailty seen with advancing age that can influence treatment-delivery and tolerance and impact survival. In general, geriatric assessments can help identify those patients more likely to benefit from enhanced toxicity risk-prediction and aid treatment decision-making. Despite the observed benefits of geriatric assessments and other screening frailty tools, provider and systems-level barriers continue to influence the overall perception of the feasibility of geriatric assessments in clinical practice settings. Clinical trials are underway evaluating the efficacy and safety of various multiple myeloma therapies in less fit/frail older adults, with a minority examining fitness-based/risk-adapted approaches. Thus, significant gaps exist in knowing which myeloma therapies are most appropriate for older and more vulnerable adults with multiple myeloma. The purpose of this Review is to discuss how geriatric assessments can be used to guide the management of transplant-ineligible patients; and to highlight frontline therapies for standard-risk and high-risk cytogenetic abnormalities [i.e., t(4;14), t(14;16), and del(17p)] associated with multiple myeloma. We also discuss the current shortcomings of the existing clinical approaches to care and highlight ongoing clinical trials evaluating newer fitness-based approaches to managing transplant-ineligible patients.}, }
@article {pmid33342584, year = {2020}, author = {Alabdaljabar, MS and Muhsen, IN and Knight, JM and Syrjala, KL and Hashmi, SK}, title = {Free of malignancy but not of fears: A closer look at Damocles syndrome in survivors of hematologic malignancies.}, journal = {Blood reviews}, volume = {}, number = {}, pages = {100783}, doi = {10.1016/j.blre.2020.100783}, pmid = {33342584}, issn = {1532-1681}, support = {R01 CA215134/CA/NCI NIH HHS/United States ; U01 CA246659/CA/NCI NIH HHS/United States ; }, abstract = {Fear of cancer recurrence (FoR) is an important yet underestimated long term sequela that many cancer survivors suffer from. The continuous state of uncertainty the survivors might go through can lead to a serious impact on their quality of life (QoL), which is collectively referred to as Damocles syndrome. Given the increasing numbers of cancer survivors, it is crucial to understand the different psychological issues that face them, including Damocles syndrome. Herein, we review the current literature of Damocles syndrome specifically in hematologic cancer survivors. Although with inconsistent terms, current literature demonstrates the impact and the prevalence of Damocles syndrome on QoL of survivors of leukemia, lymphoma, and hematopoietic cell transplant. Interventional studies are very limited in this area. Moreover, hematologic malignancy survivors can also meet the diagnostic criteria of other psychiatric diseases, including depression, anxiety, and post-traumatic stress disorder, wherein they should be managed accordingly. It is important to increase the awareness about Damocles syndrome and screen patients for it and other related psychological disorders. Additionally, this review has shown the need for standardization of Damocles syndrome definitions. Finally, the lack of interventional studies that target survivors' psychosocial challenges calls for prospective research to better address this rising problem.}, }
@article {pmid33342000, year = {2020}, author = {Lindsay, J and Othman, J and Kerridge, I and Fay, K and Stevenson, W and Arthur, C and Chen, SC and Kong, DC and Pergam, SA and Liu, C and Slavin, MA and Greenwood, M}, title = {Cytomegalovirus (CMV) management in allogeneic hematopoietic cell transplantation: Pre-transplant predictors of survival, reactivation and spontaneous clearance.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e13548}, doi = {10.1111/tid.13548}, pmid = {33342000}, issn = {1399-3062}, abstract = {Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplant (alloHCT). We analyzed 159 alloHCT recipients with 4409 quantitative CMV viral loads to determine pre-transplant predictors of CMV reactivation, clinically significant CMV infection (cs-CMVi, defined as CMV viral load >1000 IU/mL), CMV disease, kinetics of spontaneous clearance of CMV and survival using a standardised pre-emptive therapy approach to identify at-risk groups to target prevention strategies. Cs-CMVi was most common in D-/R+ unrelated donor transplants (URD). Spontaneous CMV clearance occurred in 26% of patients who reached a viral load of 56-137 IU/mL, 6% at 138-250 IU/mL and in 1 patient >250 IU/mL. Median time between the first CMV reactivation (>56 IU/mL) and a viral load >250 IU/mL was 13 days, whereas the time from the first viral load >250 IU/mL to reach a vial load >1000 IU/mL was 4 days. Cs-CMVi was associated with a significant increase in non-relapse mortality (NRM) on multivariate analysis. Overall, this study indicates that D-/R+URD recipients are at high-risk for cs-CMVi and CMV related mortality, and are potential candidates for targeted CMV prophylaxis. Spontaneous clearance of CMV beyond a viral load of 250 IU/mL is uncommon, suggesting that this could be used as an appropriate threshold to initiate pre-emptive therapy.}, }
@article {pmid33340397, year = {2020}, author = {Lin, DY and Zeng, D and Mehrotra, DV and Corey, L and Gilbert, PB}, title = {Evaluating the Efficacy of COVID-19 Vaccines.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1863}, pmid = {33340397}, issn = {1537-6591}, abstract = {A large number of studies are being conducted to evaluate the efficacy and safety of candidate vaccines against novel coronavirus disease-2019 (COVID-19). Most Phase 3 tri- als have adopted virologically confirmed symptomatic COVID-19 disease as the primary efficacy endpoint, although laboratory-confirmed SARS-CoV-2 is also of interest. In addi- tion, it is important to evaluate the effect of vaccination on disease severity. To provide a full picture of vaccine efficacy and make efficient use of available data, we propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as dual or triple pri- mary endpoints. We demonstrate the advantages of this strategy through realistic simulation studies. Finally, we show how this approach can provide rigorous interim monitoring of the trials and efficient assessment of the durability of vaccine efficacy.}, }
@article {pmid33339817, year = {2020}, author = {Nielsen, JB and Rom, O and Surakka, I and Graham, SE and Zhou, W and Roychowdhury, T and Fritsche, LG and Gagliano Taliun, SA and Sidore, C and Liu, Y and Gabrielsen, ME and Skogholt, AH and Wolford, B and Overton, W and Zhao, Y and Chen, J and Zhang, H and Hornsby, WE and Acheampong, A and Grooms, A and Schaefer, A and Zajac, GJM and Villacorta, L and Zhang, J and Brumpton, B and Løset, M and Rai, V and Lundegaard, PR and Olesen, MS and Taylor, KD and Palmer, ND and Chen, YD and Choi, SH and Lubitz, SA and Ellinor, PT and Barnes, KC and Daya, M and Rafaels, N and Weiss, ST and Lasky-Su, J and Tracy, RP and Vasan, RS and Cupples, LA and Mathias, RA and Yanek, LR and Becker, LC and Peyser, PA and Bielak, LF and Smith, JA and Aslibekyan, S and Hidalgo, BA and Arnett, DK and Irvin, MR and Wilson, JG and Musani, SK and Correa, A and Rich, SS and Guo, X and Rotter, JI and Konkle, BA and Johnsen, JM and Ashley-Koch, AE and Telen, MJ and Sheehan, VA and Blangero, J and Curran, JE and Peralta, JM and Montgomery, C and Sheu, WH and Chung, RH and Schwander, K and Nouraie, SM and Gordeuk, VR and Zhang, Y and Kooperberg, C and Reiner, AP and Jackson, RD and Bleecker, ER and Meyers, DA and Li, X and Das, S and Yu, K and LeFaive, J and Smith, A and Blackwell, T and Taliun, D and Zollner, S and Forer, L and Schoenherr, S and Fuchsberger, C and Pandit, A and Zawistowski, M and Kheterpal, S and Brummett, CM and Natarajan, P and Schlessinger, D and Lee, S and Kang, HM and Cucca, F and Holmen, OL and Åsvold, BO and Boehnke, M and Kathiresan, S and Abecasis, GR and Chen, YE and Willer, CJ and Hveem, K}, title = {Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {6417}, pmid = {33339817}, issn = {2041-1723}, support = {R01 HL123333/HL/NHLBI NIH HHS/United States ; R35-HL135824//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, abstract = {Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.}, }
@article {pmid33339211, year = {2020}, author = {DeJong, CS and Maurice, NJ and McCartney, SA and Prlic, M}, title = {Human Tissue-Resident Memory T Cells in the Maternal-Fetal Interface. Lost Soldiers or Special Forces?.}, journal = {Cells}, volume = {9}, number = {12}, pages = {}, pmid = {33339211}, issn = {2073-4409}, support = {TL1 TR002318/NH/NIH HHS/United States ; F31 HD098769/NH/NIH HHS/United States ; R21 AI144677/NH/NIH HHS/United States ; }, abstract = {The immune system plays a critical role during pregnancy, but the specific mechanisms and immune cell function needed to support pregnancy remain incompletely understood. Despite decades of research efforts, it is still unclear how the immune system maintains tolerance of fetal-derived tissues, which include most cells of the placenta and of course the fetus itself, without forfeiting the ability to protect against harmful infections. T cells recognize antigen in the context of major histocompatibility complex (MHC) encoded proteins, but classical MHC class I and II expression are diminished in fetal-derived cells. Can T cells present at the maternal-fetal interface (MFI) protect these cells from infection? Here we review what is known in regard to tissue-resident memory T (Trm) cells at the MFI. We mainly focus on how Trm cells can contribute to protection in the context of the unique features of the MFI, such as limited MHC expression as well as the temporary nature of the MFI, that are not found in other tissues.}, }
@article {pmid33338273, year = {2020}, author = {Im, C and Li, N and Moon, W and Liu, Q and Morton, LM and Leisenring, WM and Howell, RM and Chow, EJ and Sklar, CA and Wilson, CL and Wang, Z and Sapkota, Y and Chemaitilly, W and Ness, KK and Hudson, MM and Robison, LL and Bhatia, S and Armstrong, GT and Yasui, Y}, title = {Genome-wide Association Studies Reveal Novel Locus With Sex-/Therapy-Specific Fracture Risk Effects in Childhood Cancer Survivors.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {}, number = {}, pages = {}, doi = {10.1002/jbmr.4234}, pmid = {33338273}, issn = {1523-4681}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; //Childhood Cancer Survivor Study Career Development Award/ ; CA21765/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; U24 CA55727/CA/NCI NIH HHS/United States ; }, abstract = {Childhood cancer survivors treated with radiation therapy (RT) and osteotoxic chemotherapies are at increased risk for fractures. However, understanding of how genetic and clinical susceptibility factors jointly contribute to fracture risk among survivors is limited. To address this gap, we conducted genome-wide association studies of fracture risk after cancer diagnosis in 2453 participants of European ancestry from the Childhood Cancer Survivor Study (CCSS) with 930 incident fractures using Cox regression models (ie, time-to-event analysis) and prioritized sex- and treatment-stratified genetic associations. We performed replication analyses in 1417 survivors of European ancestry with 652 incident fractures from the St. Jude Lifetime Cohort Study (SJLIFE). In discovery, we identified a genome-wide significant (p < 5 × 10-8) fracture risk locus, 16p13.3 (HAGHL), among female CCSS survivors (n = 1289) with strong evidence of sex-specific effects (psex-heterogeneity < 7 × 10-6). Combining discovery and replication data, rs1406815 showed the strongest association (hazard ratio [HR] = 1.43, p = 8.2 × 10-9 ; n = 1935 women) at this locus. In treatment-stratified analyses in the discovery cohort, the association between rs1406815 and fracture risk among female survivors with no RT exposures was weak (HR = 1.22, 95% confidence interval [CI] 0.95-1.57, p = 0.11) but increased substantially among those with greater head/neck RT doses (any RT: HR = 1.88, 95% CI 1.54-2.28, p = 2.4 × 10-10 ; >36 Gray only: HR = 3.79, 95% CI 1.95-7.34, p = 8.2 × 10-5). These head/neck RT-specific HAGHL single-nucleotide polymorphism (SNP) effects were replicated in female SJLIFE survivors. In silico bioinformatics analyses suggest these fracture risk alleles regulate HAGHL gene expression and related bone resorption pathways. Genetic risk profiles integrating this locus may help identify female survivors who would benefit from targeted interventions to reduce fracture risk. © 2020 American Society for Bone and Mineral Research (ASBMR).}, }
@article {pmid33336414, year = {2020}, author = {Poston, JN and Jash, A and Hannan, LM and Hay, AM and Usaneerungrueng, C and Howie, HL and Kapp, LM and Zimring, JC}, title = {In utero exposure to alloantigens primes alloimmunization to platelet transfusion in mice.}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.16224}, pmid = {33336414}, issn = {1537-2995}, support = {//Novo Nordisk Inc/ ; }, abstract = {BACKGROUND: Platelet transfusions remain a mainstay of treatment for many patients with thrombocytopenia, but can lead to alloantibodies to Human Leukocyte Antigens (anti-HLA) resulting in inadequate responses to subsequent platelet transfusions (refractoriness), as well as complicate transplantation. Despite substantial decreases in alloimmunization with the implementation of leukoreduction, a significant percentage of patients still become alloimmunized following platelet transfusions. It remains unclear why some patients make anti-HLA antibodies, but others do not make anti-HLA antibodies even with chronic transfusion. Antecedent pregnancy correlates with risk of alloimmunization due to platelet transfusion in humans - however, isolation of pregnancy as a single variable is not possible in human populations.<br><br>STUDY DESIGN AND METHODS: A tractable murine model of pregnancy and transfusion was engineered by breeding C57BL/6 (H-2b) dames with BALB/c (H-2d) sires. After pregnancy, female mice were transfused with leukoreduced platelets from F1 (H-2b/d) donors that expressed the same paternal major histocompatibility complex (MHC) H-2d alloantigens as the sires. Control groups allowed isolation of pregnancy or transfusion alone as independent variables. Alloimmunization was determined by testing serum for antibodies to H-2d MHC alloantigens.<br><br>RESULTS: No alloantibodies were detected after pregnancy alone, or in response to transfusion of platelets alone; however, significant levels of alloantibodies were detected when pregnancy was followed by transfusion.<br><br>CONCLUSIONS: These findings isolate antecedent pregnancy as a causal contribution to increased frequencies of alloimmunization by subsequent platelet transfusion in mice and provide a platform for ongoing mechanistic investigation.}, }
@article {pmid33335945, year = {2021}, author = {Humes, D and Rainwater, S and Overbaugh, J}, title = {The TOP vector: a new high-titer lentiviral construct for delivery of sgRNAs and transgenes to primary T cells.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {20}, number = {}, pages = {30-38}, pmid = {33335945}, issn = {2329-0501}, abstract = {Efficient delivery of nucleic acids for the engineering of primary T cells is central to the study of the basic biology of these key immune effector cells and has clinical implications. To date, lentiviral vectors delivering guide RNAs for CRISPR-Cas9 editing are not optimal for use in primary cells. Herein, we describe the T cell optimized for packaging (TOP) vector for delivering guide RNAs and transgenes into primary T cells. The TOP vector produces high-titer virus compared to a routinely used guide RNA vector, resulting in a ~10-fold increase in transduction in T cells. Moreover, a TOP vector expressing a chimeric antigen receptor and a guide RNA targeting the T cell receptor showed an ~5- to 9-fold increased transduction efficiency with ~2- to 3-fold higher expression compared to the commonly used epHIV7 vector and was simultaneously able to mediate efficient knockout of the endogenous T cell receptor in >71% of transduced cells upon Cas9 electroporation. The increased packaging of the TOP vector genome into viral particles appears to contribute to its higher transduction efficiency. The TOP vector represents an optimal tool for tandem delivery of transgenes and guide RNAs to primary T cells for use in functional screens and immunotherapy applications.}, }
@article {pmid33335088, year = {2020}, author = {Wisdom, AJ and Mowery, YM and Hong, CS and Himes, JE and Nabet, BY and Qin, X and Zhang, D and Chen, L and Fradin, H and Patel, R and Bassil, AM and Muise, ES and King, DA and Xu, ES and Carpenter, DJ and Kent, CL and Smythe, KS and Williams, NT and Luo, L and Ma, Y and Alizadeh, AA and Owzar, K and Diehn, M and Bradley, T and Kirsch, DG}, title = {Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {6410}, pmid = {33335088}, issn = {2041-1723}, support = {F30 CA221268/CA/NCI NIH HHS/United States ; U24 CA220245/CA/NCI NIH HHS/United States ; R35 CA197616/CA/NCI NIH HHS/United States ; P01 CA142538/CA/NCI NIH HHS/United States ; T32 GM007171/GM/NIGMS NIH HHS/United States ; P30 CA016086/CA/NCI NIH HHS/United States ; R38 CA245204/CA/NCI NIH HHS/United States ; U54 CA168512/CA/NCI NIH HHS/United States ; }, abstract = {Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.}, }
@article {pmid33335028, year = {2020}, author = {Maus, MV and Alexander, S and Bishop, MR and Brudno, JN and Callahan, C and Davila, ML and Diamonte, C and Dietrich, J and Fitzgerald, JC and Frigault, MJ and Fry, TJ and Holter-Chakrabarty, JL and Komanduri, KV and Lee, DW and Locke, FL and Maude, SL and McCarthy, PL and Mead, E and Neelapu, SS and Neilan, TG and Santomasso, BD and Shpall, EJ and Teachey, DT and Turtle, CJ and Whitehead, T and Grupp, SA}, title = {Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33335028}, issn = {2051-1426}, abstract = {Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.}, }
@article {pmid33335027, year = {2020}, author = {Potluri, HK and Ng, TL and Newton, MA and Zhang, J and Maher, CA and Nelson, PS and McNeel, DG}, title = {Antibody profiling of patients with prostate cancer reveals differences in antibody signatures among disease stages.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33335027}, issn = {2051-1426}, support = {T32 GM008692/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Previous studies of prostate cancer autoantibodies have largely focused on diagnostic applications. So far, there have been no reports attempting to more comprehensively profile the landscape of prostate cancer-associated antibodies. Specifically, it is unknown whether the quantity of antibodies or the types of proteins recognized change with disease progression.<br><br>METHODS: A peptide microarray spanning the amino acid sequences of the gene products of 1611 prostate cancer-associated genes was synthesized. Serum samples from healthy male volunteers (n=15) and patients with prostate cancer (n=85) were used to probe the array. These samples included patients with various clinical stages of disease: newly diagnosed localized prostate cancer (n=15), castration-sensitive non-metastatic prostate cancer (nmCSPC, n=40), castration-resistant non-metastatic prostate cancer (n=15) and castration-resistant metastatic disease (n=15). The patients with nmCSPC received treatment with either standard androgen deprivation therapy (ADT) or an antitumor DNA vaccine encoding prostatic acid phosphatase. Serial sera samples from these individuals were also used to probe the array, to secondarily determine whether this approach could be used to detect treatment-related changes.<br><br>RESULTS: We demonstrated that this peptide array yielded highly reproducible measurements of serum IgG levels. We found that the overall number of antibody responses did not increase with disease burden. However, the composition of recognized proteins shifted with clinical stage of disease. Our analysis revealed that the largest difference was between patients with castration-sensitive and castration-resistant disease. Patients with castration-resistant disease recognized more proteins associated with nucleic acid binding and gene regulation compared with men in other groups. Our longitudinal data showed that treatments can elicit antibodies detectable by this array, and notably vaccine-treated patients developed increased responses to more proteins over the course of treatment than did ADT-treated patients.<br><br>CONCLUSIONS: This study represents the largest survey of prostate cancer-associated antibodies to date. We have been able to characterize the classes of proteins recognized by patients and determine how they change with disease burden. Our findings further demonstrate the potential of this platform for measuring antigen spread and studying responses to immunomodulatory therapies.}, }
@article {pmid33335021, year = {2020}, author = {Luo, J and Rohan, TE and Neuhouser, ML and Liu, N and Saquib, N and Li, Y and Shadyab, AH and Qi, L and Wallace, RB and Hendryx, M}, title = {Hysterectomy, oophorectomy and risk of renal cell carcinoma.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-1373}, pmid = {33335021}, issn = {1538-7755}, abstract = {BACKGROUND: Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy and risk of RCC, and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy.<br><br>METHODS: Postmenopausal women (n= 144,599) aged 50-79 years at enrollment (1993-1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for potential confounders.<br><br>RESULTS: A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR=1.28, 95% CI: 1.03 - 1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR=1.34, 95% CI: 1.01 - 1.80) or older than 55 years (HR=1.52, 95% CI: 1.01-2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC.<br><br>CONCLUSION: In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use.<br><br>IMPACT: If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.}, }
@article {pmid33334176, year = {2020}, author = {Roth, JA and Yuan, Y and Othus, M and Danese, M and Wagner, S and Penrod, JR and Ramsey, SD}, title = {A comparison of mixture cure fraction models to traditional parametric survival models in estimation of the cost-effectiveness of nivolumab for relapsed small cell lung cancer.}, journal = {Journal of medical economics}, volume = {}, number = {}, pages = {1}, doi = {10.1080/13696998.2020.1857960}, pmid = {33334176}, issn = {1941-837X}, abstract = {BACKGROUND: In August 2018, the US FDA granted accelerated approval for nivolumab in small cell lung cancer (SCLC) that has progressed after platinum-based chemotherapy and at least one other line of therapy. The objective of this study was to evaluate the cost-effectiveness of nivolumab vs. usual care as third-line (3L) therapy for patients with recurrent SCLC (rSCLC) from the health payer perspective. Given the potential for a meaningful fraction of treated patients to achieve long-term response to nivolumab, we also assessed the impact of using mixture cure modeling (MCM) vs. parametric survival modeling on survival estimates and cost-effectiveness from the US Medicare payer perspective.<br><br>METHODS: We created a partitioned survival decision model to assess the cost-effectiveness of 3L nivolumab vs. usual care in rSCLC, based on observed US treatment patterns. Using this approach, we assessed the impact of extrapolating long-term survival from the CheckMate 032 trial, using both MCM and standard parametric curve fits. Nivolumab survival, resource use, and Grade 3/4 adverse event rates were derived from CheckMate 032. Usual care survival, resource use, and costs were derived from an analysis of patients receiving 3L treatment for rSCLC in the SEER-Medicare registry. We applied 2020 Wholesale Acquisition Cost for drugs and 2020 CMS reimbursement for procedures. Utilities were derived from the literature. We estimated life years (LY), quality-adjusted life years (QALYs), and costs over a lifetime horizon.<br><br>RESULTS: MCM and parametric survival model extrapolations resulted in 0.43 versus 0.38 more LYs, 0.34 versus 0.30 more QALYs, and $69,308 versus $61,336 more expenditure for nivolumab vs. usual care, respectively. The costs per QALY gained using mixture cure versus parametric survival modeling were $204,386 and $207,431, respectively.<br><br>CONCLUSIONS: Mixture cure modeling was equivalent compared to parametric modeling in estimating the cost-effectiveness of nivolumab-based therapy due to the small fraction of patients achieving a long-term response with nivolumab (12.9%).}, }
@article {pmid33331905, year = {2020}, author = {Van Poznak, CH and Unger, JM and Darke, AK and Moinpour, C and Bagramian, RA and Schubert, MM and Hansen, LK and Floyd, JD and Dakhil, SR and Lew, DL and Wade, JL and Fisch, MJ and Henry, NL and Hershman, DL and Gralow, J}, title = {Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {33331905}, issn = {2374-2445}, abstract = {Importance: Osteonecrosis of the jaw (ONJ) affects patients with cancer and metastatic bone disease (MBD) treated with bone-modifying agents (BMAs), yet the true incidence is unknown.<br><br>Objective: To define the cumulative incidence of ONJ at 3 years in patients receiving zoledronic acid for MBD from any malignant neoplasm.<br><br>This multicenter, prospective observational cohort study (SWOG Cancer Research Network S0702) included patients with MBD with either limited or no prior exposure to BMAs and a clinical care plan that included use of zoledronic acid within 30 days of registration. Medical, dental, and patient-reported outcome forms were submitted at baseline and every 6 months. Follow-up was 3 years. Osteonecrosis of the jaw was defined using established criteria. Data were collected from January 30, 2009, to December 13, 2013, and analyzed from August 24, 2018, to August 6, 2020.<br><br>Interventions/Exposures: Cancer treatments, BMAs, and dental care were administered as clinically indicated.<br><br>Main Outcomes and Measures: Cumulative incidence of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region present for more than 8 weeks with no concurrent radiotherapy to the craniofacial region. Risk factors for ONJ were also examined.<br><br>Results: The SWOG S0702 trial enrolled 3491 evaluable patients (1806 women [51.7%]; median age, 63.1 [range, 2.24-93.9] years), of whom 1120 had breast cancer; 580, myeloma; 702, prostate cancer; 666, lung cancer; and 423, other neoplasm. A baseline dental examination was performed in 2263 patients (64.8%). Overall, 90 patients developed confirmed ONJ, with cumulative incidence of 0.8% (95% CI, 0.5%-1.1%) at year 1, 2.0% (95% CI, 1.5%-2.5%) at year 2, and 2.8% (95% CI, 2.3%-3.5%) at year 3; 3-year cumulative incidence was highest in patients with myeloma (4.3%; 95% CI, 2.8%-6.4%). Patients with planned zoledronic acid dosing intervals of less than 5 weeks were more likely to experience ONJ than patients with planned dosing intervals of 5 weeks or more (hazard ratio [HR], 4.65; 95% CI, 1.46-14.81; P = .009). A higher rate of ONJ was associated with fewer total number of teeth (HR, 0.51; 95% CI, 0.31-0.83; P = .006), the presence of dentures (HR, 1.83; 95% CI, 1.10-3.03; P = .02), and current smoking (HR, 2.12; 95% CI, 1.12-4.02; P = .02).<br><br>Conclusions and Relevance: As the findings show, the cumulative incidence of ONJ after 3 years was 2.8% in patients receiving zoledronic acid for MBD. Cancer type, oral health, and frequency of dosing were associated with the risk of ONJ. These data provide information to guide stratification of risk for developing ONJ in patients with MBD receiving zoledronic acid.}, }
@article {pmid33330926, year = {2020}, author = {Chen, GC and Chen, LH and Mossavar-Rahmani, Y and Kamensky, V and Shadyab, AH and Haring, B and Wild, RA and Silver, B and Kuller, LH and Sun, Y and Saquib, N and Howard, B and Snetselaar, LG and Neuhouser, ML and Allison, MA and Van Horn, L and Manson, JE and Wassertheil-Smoller, S and Qi, Q}, title = {Dietary cholesterol and egg intake in relation to incident cardiovascular disease and all-cause and cause-specific mortality in postmenopausal women.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqaa353}, pmid = {33330926}, issn = {1938-3207}, abstract = {BACKGROUND: The potential cardiovascular impact of dietary cholesterol intake has been actively debated for decades.<br><br>OBJECTIVES: We aimed to evaluate associations of dietary cholesterol and egg intakes with incident cardiovascular disease (CVD) and all-cause and cause-specific mortality.<br><br>METHODS: We included 96,831 US postmenopausal women aged 50-79 y without known CVD or cancer during baseline enrollment (1993-1998) of the Women's Health Initiative. Dietary information was collected using a validated FFQ. Incident CVD [i.e., ischemic heart disease (IHD) and stroke] and all-cause and cause-specific mortality were ascertained and adjudicated through February 2018.<br><br>RESULTS: A total of 9808 incident CVD cases and 19,508 all-cause deaths occurred during a median follow-up of 17.8 y and 18.9 y, respectively. After multivariable adjustment for traditional risk factors and key dietary nutrients including dietary saturated fat, there were modest associations of dietary cholesterol intake with incident CVD (HRQ5versusQ1: 1.12; 95% CI: 1.03, 1.21; P-trend < 0.001) and all-cause mortality (HRQ5versusQ1: 1.09; 95% CI: 1.02, 1.15; P-trend < 0.001). Significant positive associations were also observed between dietary cholesterol and incident IHD (P-trend = 0.007), incident ischemic stroke (P-trend = 0.002), and CVD mortality (P-trend = 0.002), whereas there was an inverse association for incident hemorrhagic stroke (P-trend = 0.037) and no association for mortality from cancer, Alzheimer disease/dementia, respiratory diseases, or other causes (P-trend > 0.05). Higher egg consumption was also associated with modestly higher risk of incident CVD (P-trend = 0.004) and all-cause mortality (P-trend < 0.001), with HRs of 1.14 (95% CI: 1.04, 1.25) and 1.14 (95% CI: 1.07, 1.22), respectively, when comparing ≥1 egg/d with <1 egg/wk.<br><br>CONCLUSIONS: Both higher dietary cholesterol intake and higher egg consumption appeared to be associated with modestly elevated risk of incident CVD and all-cause mortality in US postmenopausal women.}, }
@article {pmid33328650, year = {2020}, author = {Haffner, MC and Zwart, W and Roudier, MP and True, LD and Nelson, WG and Epstein, JI and De Marzo, AM and Nelson, PS and Yegnasubramanian, S}, title = {Genomic and phenotypic heterogeneity in prostate cancer.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {33328650}, issn = {1759-4820}, abstract = {From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.}, }
@article {pmid33328623, year = {2020}, author = {Bosetti, C and Traini, E and Alam, T and Allen, CA and Carreras, G and Compton, K and Fitzmaurice, C and Force, LM and Gallus, S and Gorini, G and Harvey, JD and Kocarnik, JM and La Vecchia, C and Lugo, A and Naghavi, M and Pennini, A and Piccinelli, C and Ronfani, L and Xu, R and Monasta, L}, title = {National burden of cancer in Italy, 1990-2017: a systematic analysis for the global burden of disease study 2017.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {22099}, pmid = {33328623}, issn = {2045-2322}, abstract = {We monitored the burden of cancer in Italy and its trends over the last three decades, providing estimates of cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs), for cancer overall and 30 cancer sites using data from the Global Burden of Disease study 2017. An overview of mortality trends between 1990 and 2017 was also provided. In 2017, there were 254,336 new cancer cases in men and 214,994 in women, corresponding to an age-standardized incidence rate (ASIR) of 438 and 330/100,000, respectively. Between 1990 and 2017, incident cancer cases, and, to a lesser extent, ASIRs significantly increased overall and for almost all cancer sites, but ASIRs significantly declined for lung and other tobacco-related neoplasms. In 2017, there were 101,659 cancer deaths in men (age-standardized death rate, ASDR, 158.5/100,000) and 78,918 in women (ASDR 93.9/100,000). Cancer deaths significantly increased between 1990 and 2017 (+ 18%), but ASDR significantly decreased (- 28%). Deaths significantly increased for many cancer sites, but decreased for stomach, esophageal, laryngeal, Hodgkin lymphoma, and testicular cancer. ASDRs significantly decreased for most neoplasms, with the main exceptions of cancer of the pancreas and uterus, and multiple myeloma. In 2017, cancer caused 3,204,000 DALYs. Between 1990 and 2017, DALYs and age-standardized DALY rates significantly declined (-3.4% and -33%, respectively). Age-standardized mortality rates in Italy showed favorable patterns over the last few decades. However, the absolute number of cancer cases and, to a lower extent, of cancer deaths increased likely due to the progressive ageing of the population, this calling for a continuous effort in cancer prevention, early diagnosis, and treatment.}, }
@article {pmid33328603, year = {2020}, author = {Walter, RB and Appelbaum, FR and Estey, EH}, title = {Optimal dosing of cytarabine in induction and post-remission therapy of acute myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {33328603}, issn = {1476-5551}, }
@article {pmid33327948, year = {2020}, author = {Bull, CJ and Bell, JA and Murphy, N and Sanderson, E and Davey Smith, G and Timpson, NJ and Banbury, BL and Albanes, D and Berndt, SI and Bézieau, S and Bishop, DT and Brenner, H and Buchanan, DD and Burnett-Hartman, A and Casey, G and Castellví-Bel, S and Chan, AT and Chang-Claude, J and Cross, AJ and de la Chapelle, A and Figueiredo, JC and Gallinger, SJ and Gapstur, SM and Giles, GG and Gruber, SB and Gsur, A and Hampe, J and Hampel, H and Harrison, TA and Hoffmeister, M and Hsu, L and Huang, WY and Huyghe, JR and Jenkins, MA and Joshu, CE and Keku, TO and Kühn, T and Kweon, SS and Le Marchand, L and Li, CI and Li, L and Lindblom, A and Martín, V and May, AM and Milne, RL and Moreno, V and Newcomb, PA and Offit, K and Ogino, S and Phipps, AI and Platz, EA and Potter, JD and Qu, C and Quirós, JR and Rennert, G and Riboli, E and Sakoda, LC and Schafmayer, C and Schoen, RE and Slattery, ML and Tangen, CM and Tsilidis, KK and Ulrich, CM and van Duijnhoven, FJB and van Guelpen, B and Visvanathan, K and Vodicka, P and Vodickova, L and Wang, H and White, E and Wolk, A and Woods, MO and Wu, AH and Campbell, PT and Zheng, W and Peters, U and Vincent, EE and Gunter, MJ}, title = {Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.}, journal = {BMC medicine}, volume = {18}, number = {1}, pages = {396}, pmid = {33327948}, issn = {1741-7015}, support = {17/0005587/DUK_/Diabetes UK/United Kingdom ; 202802/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 204813/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; IIG_2019_2009//World Cancer Research Fund International/ ; C18281/A19169/CRUK_/Cancer Research UK/United Kingdom ; 217065/Z/19/Z//Medical Research Council and Wellcome Trust/ ; BRC-1215-20011//National Institute for Health Research/ ; MC_UU_12013/3/MRC_/Medical Research Council/United Kingdom ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.<br><br>METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.<br><br>RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.<br><br>CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.}, }
@article {pmid33326609, year = {2020}, author = {Zhu, J and Smith-Warner, SA and Yu, D and Zhang, X and Blot, WJ and Xiang, YB and Sinha, R and Park, Y and Tsugane, S and White, E and Koh, WP and Park, SK and Sawada, N and Kanemura, S and Sugawara, Y and Tsuji, I and Robien, K and Tomata, Y and Yoo, KY and Kim, J and Yuan, JM and Gao, YT and Rothman, N and Lazovich, D and Abe, SK and Rahman, MS and Loftfield, E and Takata, Y and Li, X and Lee, JE and Saito, E and Freedman, ND and Inoue, M and Lan, Q and Willett, WC and Zheng, W and Shu, XO}, title = {Associations of coffee and tea consumption with lung cancer risk.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33445}, pmid = {33326609}, issn = {1097-0215}, support = {//Ingram Cancer Professorship Fund/ ; R03 CA183021/NH/NIH HHS/United States ; }, abstract = {Associations of coffee and tea consumption with lung cancer risk have been inconsistent, and most lung cancer cases investigated were smokers. Included in this study were over 1.1 million participants from 17 prospective cohorts. Cox regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential effect modifications by sex, smoking, race, cancer subtype and coffee type were assessed. After a median 8.6 years of follow-up, 20 280 incident lung cancer cases were identified. Compared with noncoffee and nontea consumption, HRs (95% CIs) associated with exclusive coffee drinkers (≥2 cups/d) among current, former and never smokers were 1.30 (1.15-1.47), 1.49 (1.27-1.74) and 1.35 (1.15-1.58), respectively. Corresponding HRs for exclusive tea drinkers (≥2 cups/d) were 1.16 (1.02-1.32), 1.10 (0.92-1.32) and 1.37 (1.17-1.61). In general, the coffee and tea associations did not differ significantly by sex, race or histologic subtype. Our findings suggest that higher consumption of coffee or tea is associated with increased lung cancer risk. However, these findings should not be assumed to be causal because of the likelihood of residual confounding by smoking, including passive smoking, and change of coffee and tea consumption after study enrolment.}, }
@article {pmid33325511, year = {2020}, author = {George, SM and Reedy, J and Cespedes Feliciano, EM and Aragaki, A and Caan, BJ and Kahle, L and Manson, JE and Rohan, TE and Snetselaar, LG and Tinker, LF and Van Horn, L and Neuhouser, ML}, title = {Alignment of dietary patterns with the Dietary Guidelines for Americans 2015-2020 and risk of all-cause and cause-specific mortality in the Women's Health Initiative Observational Study.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaa268}, pmid = {33325511}, issn = {1476-6256}, abstract = {Poor diet quality is a leading risk factor for death in the United States (U.S.). We examined the association between Healthy Eating Index-2015 (HEI-2015) scores and death from all-causes, cardiovascular disease (CVD), cancer, Alzheimer's Disease and Dementia not otherwise specified (NOS) among postmenopausal women in the Women's Health Initiative Observational Study (1993-2017). This analysis included 59,388 participants who completed a food frequency questionnaire and were free of cancer, CVD and diabetes at enrollment. Stratified Cox proportional hazards models were fit using person-years from enrollment as the underlying time metric. We estimated multivariable adjusted hazard ratios and 95% confidence intervals for risk of death associated with HEI-2015 quintiles, with higher scores reflecting more optimal diet quality. Over a median of 18.2 years, 9,679 total deaths 3,303 cancer deaths, 2,362 CVD deaths, and 488 deaths from Alzheimer's Disease and Dementia NOS occurred. Compared to those with lower scores, women with higher HEI-2015 scores had an 18% lower risk of all-cause mortality and 21% lower risk of cancer mortality. HEI-2015 scores were not associated with mortality from CVD, Alzheimer's Disease and dementia NOS. Consuming a diet aligned with 2015-2020 U.S. Dietary Guidelines may have beneficial impacts for preventing death from cancer and overall.}, }
@article {pmid33323535, year = {2020}, author = {Pathi, A and Wright, M and Smed, MK and Nelson, JL and Olsen, J and Hetland, ML and Zoffmann, V and Jawaheer, D}, title = {The rheumatoid arthritis gene expression signature among women who improve or worsen during pregnancy - a pilot study.}, journal = {The Journal of rheumatology}, volume = {}, number = {}, pages = {}, doi = {10.3899/jrheum.201128}, pmid = {33323535}, issn = {0315-162X}, abstract = {OBJECTIVE: To assess whether gene expression signatures associated with rheumatoid arthritis (RA) before pregnancy differ between women who improve or worsen during pregnancy, and determine whether these expression signatures are altered during pregnancy when RA improves or worsens.<br><br>METHODS: Clinical data and blood samples were collected before pregnancy (T0) and at the third trimester (T3) from 11 RA and 5 healthy women. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI). At each time-point, RA-associated gene expression signatures were identified using differential expression analysis of RNA sequencing profiles between RA and healthy women.<br><br>RESULTS: Of the women with RA, 6 improved by T3 (RAimproved), 3 worsened (RAworsened) and 2 were excluded. At T0, mean CDAI scores were similar in both groups (RAimproved: 11.2±9.8; RAworsened: 13.8±6.7; Wilcoxon-rank test: p=0.6). In the RAimproved group, 89 genes were differentially expressed at T0 (q<0.05 and fold-change (FC)≥2) compared to healthy women. When RA improved at T3, 65 of 89 (73%) of these no longer displayed RA-associated expression. In the RAworsened group, a largely different RA gene expression signature (429 genes) was identified at T0. When RA disease activity worsened at T3, 207 of 429 (48%) lost their differential expression, while an additional 157 genes became newly differentially expressed.<br><br>CONCLUSION: In our pilot dataset, pre-pregnancy RA expression signatures differed between women who subsequently improved or worsened during pregnancy, suggesting that inherent genomic differences perhaps influence how pregnancy impacts disease activity. Further, these RA signatures were altered during pregnancy, as disease activity changed.}, }
@article {pmid33320842, year = {2020}, author = {Boonyaratanakornkit, J and Morishima, C and Selke, S and Zamora, D and McGuffin, SA and Shapiro, AE and Campbell, VL and McClurkan, CL and Jing, L and Gross, R and Liang, J and Postnikova, E and Mazur, S and Lukin, VV and Chaudhary, A and Das, MK and Fink, SL and Bryan, A and Greninger, AL and Jerome, KR and Holbrook, MR and Gernsheimer, TB and Wener, MH and Wald, A and Koelle, DM}, title = {Clinical, laboratory, and temporal predictors of neutralizing antibodies to SARS-CoV-2 among COVID-19 convalescent plasma donor candidates.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI144930}, pmid = {33320842}, issn = {1558-8238}, abstract = {BACKGROUND: SARS-CoV-2-specific antibodies may protect from reinfection and disease, providing rationale for administration of plasma containing SARS-CoV-2 neutralizing antibodies (nAb) as a treatment for COVID-19. Clinical factors and laboratory assays to streamline plasma donor selection, and the durability of nAb responses, are incompletely understood.<br><br>METHODS: Potential convalescent plasma donors with virologically-documented SARS-CoV-2 infection were tested for serum IgG to SARS-CoV-2 spike protein S1 domain, nucleoprotein (NP), and for nAb.<br><br>RESULTS: Amongst 250 consecutive persons, including 27 (11%) requiring hospitalization, studied a median of 67 days since symptom onset, 97% were seropositive on one or more assays. Sixty percent of donors had nAb titers ≥1:80. Correlates of higher nAb titer included older age (adjusted odds ratio [AOR] 1.03/year of age, 95% CI 1.00-1.06), male sex (AOR 2.08, 95% CI 1.13-3.82), fever during acute illness (AOR 2.73, 95% CI 1.25-5.97), and disease severity represented by hospitalization (AOR 6.59, 95% CI 1.32-32.96). Receiver operating characteristic (ROC) analyses of anti-S1 and anti-NP antibody results yielded cutoffs that corresponded well with nAb titers, with the anti-S1 assay being slightly more predictive. NAb titers declined in 37 of 41 paired specimens collected a median of 98 days (range, 77-120) apart (P<0.001). Seven individuals (2.8%) were persistently seronegative and lacked T cell responses.<br><br>CONCLUSIONS: Nab titers correlated with COVID-19 severity, age, and sex. Standard commercially available SARS-CoV-2 IgG results can serve as useful surrogates for nAb testing. Functional nAb levels were found to decline and a small proportion of persons recovered from COVID-19 lack adaptive immune responses.}, }
@article {pmid33320706, year = {2020}, author = {Biggins, S and Hartwell, L and Toczyski, D}, title = {Fifty years of cycling.}, journal = {Molecular biology of the cell}, volume = {31}, number = {26}, pages = {2868-2870}, doi = {10.1091/mbc.E20-07-0495}, pmid = {33320706}, issn = {1939-4586}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, abstract = {Fifty years ago, the first isolation of conditional budding yeast mutants that were defective in cell division was reported. Looking back, we now know that the analysis of these mutants revealed the molecular mechanisms and logic of the cell cycle, identified key regulatory enzymes that drive the cell cycle, elucidated structural components that underly essential cell cycle processes, and influenced our thinking about cancer and other diseases. Here, we briefly summarize what was concluded about the coordination of the cell cycle 50 years ago and how that relates to our current understanding of the molecular events that have since been elucidated.}, }
@article {pmid33318029, year = {2020}, author = {Nounu, A and Greenhough, A and Heesom, KJ and Richmond, RC and Zheng, J and Weinstein, SJ and Albanes, D and Baron, JA and Hopper, JL and Figueiredo, JC and Newcomb, PA and Lindor, NM and Casey, G and Platz, EA and Le Marchand, L and Ulrich, CM and Li, CI and van Duijnhoven, FJB and Gsur, A and Campbell, P and Moreno, V and Vodicka, P and Vodickova, L and Brenner, H and Chang-Claude, J and Hoffmeister, M and Sakoda, LC and Slattery, ML and Schoen, RE and Gunter, MJ and Castellví-Bel, S and Kim, HR and Kweon, SS and Chan, AT and Li, L and Zheng, W and Bishop, DT and Buchanan, DD and Giles, GG and Gruber, SB and Rennert, G and Stadler, ZK and Harrison, TA and Lin, Y and Keku, TO and Woods, MO and Schafmayer, C and Van Guelpen, B and Gallinger, S and Hampel, H and Berndt, SI and Pharoah, PDP and Lindblom, A and Wolk, A and Wu, AH and White, E and Peters, U and Drew, DA and Scherer, D and Bermejo, JL and Williams, AC and Relton, CL}, title = {A combined proteomics and Mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-1176}, pmid = {33318029}, issn = {1538-7755}, abstract = {BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.<br><br>METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labelling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N=3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N=31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).<br><br>RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2 and ARFIP2 expression and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR:1.08, 95% CI:1.03-1.13, OR:3.33, 95% CI:2.46-4.50 and OR:1.15, 95% CI:1.02-1.29, respectively).<br><br>CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation indicating a possible role in aspirin's reduction of metastasis.<br><br>IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.}, }
@article {pmid33317623, year = {2020}, author = {Charmpi, K and Guo, T and Zhong, Q and Wagner, U and Sun, R and Toussaint, NC and Fritz, CE and Yuan, C and Chen, H and Rupp, NJ and Christiansen, A and Rutishauser, D and Rüschoff, JH and Fankhauser, C and Saba, K and Poyet, C and Hermanns, T and Oehl, K and Moore, AL and Beisel, C and Calzone, L and Martignetti, L and Zhang, Q and Zhu, Y and Martínez, MR and Manica, M and Haffner, MC and Aebersold, R and Wild, PJ and Beyer, A}, title = {Convergent network effects along the axis of gene expression during prostate cancer progression.}, journal = {Genome biology}, volume = {21}, number = {1}, pages = {302}, pmid = {33317623}, issn = {1474-760X}, support = {3100A0-688 107679//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (CH)/ ; ERC-2008-AdG 233226/ERC_/European Research Council/International ; ERC-2014-AdG670821/ERC_/European Research Council/International ; LR19C050001//Natural Science Foundation of Zhejiang Province/ ; 20190101A04//Ministère de l'Agriculture, de l'Agroalimentaire et de la Forêt (FR)/ ; Sybacol//Bundesministerium für Bildung und Forschung (DE)/ ; PhosphoNet PPM//Bundesministerium für Bildung und Forschung (DE)/ ; }, abstract = {BACKGROUND: Tumor-specific genomic aberrations are routinely determined by high-throughput genomic measurements. It remains unclear how complex genome alterations affect molecular networks through changing protein levels and consequently biochemical states of tumor tissues.<br><br>RESULTS: Here, we investigate the propagation of genomic effects along the axis of gene expression during prostate cancer progression. We quantify genomic, transcriptomic, and proteomic alterations based on 105 prostate samples, consisting of benign prostatic hyperplasia regions and malignant tumors, from 39 prostate cancer patients. Our analysis reveals the convergent effects of distinct copy number alterations impacting on common downstream proteins, which are important for establishing the tumor phenotype. We devise a network-based approach that integrates perturbations across different molecular layers, which identifies a sub-network consisting of nine genes whose joint activity positively correlates with increasingly aggressive tumor phenotypes and is predictive of recurrence-free survival. Further, our data reveal a wide spectrum of intra-patient network effects, ranging from similar to very distinct alterations on different molecular layers.<br><br>CONCLUSIONS: This study uncovers molecular networks with considerable convergent alterations across tumor sites and patients. It also exposes a diversity of network effects: we could not identify a single sub-network that is perturbed in all high-grade tumor regions.}, }
@article {pmid33316767, year = {2020}, author = {Zou, F and Abu-Sbeih, H and Ma, W and Peng, Y and Qiao, W and Wang, J and Shah, AY and Glitza Oliva, IC and Piha-Paul, SA and Thompson, JA and Zhang, HC and Thomas, AS and Wang, Y}, title = {Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {}, number = {}, pages = {1-9}, doi = {10.6004/jnccn.2020.7647}, pmid = {33316767}, issn = {1540-1413}, abstract = {BACKGROUND: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes.<br><br>METHODS: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis.<br><br>RESULTS: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018).<br><br>CONCLUSIONS: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.}, }
@article {pmid33316043, year = {2020}, author = {Dellicour, S and Durkin, K and Hong, SL and Vanmechelen, B and Martí-Carreras, J and Gill, MS and Meex, C and Bontems, S and André, E and Gilbert, M and Walker, C and De Maio, N and Faria, NR and Hadfield, J and Hayette, MP and Bours, V and Wawina-Bokalanga, T and Artesi, M and Baele, G and Maes, P}, title = {A Phylodynamic Workflow to Rapidly Gain Insights into the Dispersal History and Dynamics of SARS-CoV-2 Lineages.}, journal = {Molecular biology and evolution}, volume = {}, number = {}, pages = {}, doi = {10.1093/molbev/msaa284}, pmid = {33316043}, issn = {1537-1719}, abstract = {Since the start of the COVID-19 pandemic, an unprecedented number of genomic sequences of SARS-CoV-2 have been generated and shared with the scientific community. The unparalleled volume of available genetic data presents a unique opportunity to gain real-time insights into the virus transmission during the pandemic, but also a daunting computational hurdle if analyzed with gold-standard phylogeographic approaches. To tackle this practical limitation, we here describe and apply a rapid analytical pipeline to analyze the spatiotemporal dispersal history and dynamics of SARS-CoV-2 lineages. As a proof of concept, we focus on the Belgian epidemic, which has had one of the highest spatial densities of available SARS-CoV-2 genomes. Our pipeline has the potential to be quickly applied to other countries or regions, with key benefits in complementing epidemiological analyses in assessing the impact of intervention measures or their progressive easement.}, }
@article {pmid33315116, year = {2020}, author = {Madewell, ZJ and Yang, Y and Longini, IM and Halloran, ME and Dean, NE}, title = {Household Transmission of SARS-CoV-2: A Systematic Review and Meta-analysis.}, journal = {JAMA network open}, volume = {3}, number = {12}, pages = {e2031756}, pmid = {33315116}, issn = {2574-3805}, support = {R01 AI139761/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; COVID-19/*epidemiology/*transmission ; Child ; Family ; Family Characteristics ; Female ; Humans ; Male ; SARS-CoV-2 ; Young Adult ; }, abstract = {Importance: Crowded indoor environments, such as households, are high-risk settings for the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).<br><br>Objectives: To examine evidence for household transmission of SARS-CoV-2, disaggregated by several covariates, and to compare it with other coronaviruses.<br><br>Data Source: PubMed, searched through October 19, 2020. Search terms included SARS-CoV-2 or COVID-19 with secondary attack rate, household, close contacts, contact transmission, contact attack rate, or family transmission.<br><br>Study Selection: All articles with original data for estimating household secondary attack rate were included. Case reports focusing on individual households and studies of close contacts that did not report secondary attack rates for household members were excluded.<br><br>Data Extraction and Synthesis: Meta-analyses were done using a restricted maximum-likelihood estimator model to yield a point estimate and 95% CI for secondary attack rate for each subgroup analyzed, with a random effect for each study. To make comparisons across exposure types, study was treated as a random effect, and exposure type was a fixed moderator. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.<br><br>Main Outcomes and Measures: Secondary attack rate for SARS-CoV-2, disaggregated by covariates (ie, household or family contact, index case symptom status, adult or child contacts, contact sex, relationship to index case, adult or child index cases, index case sex, number of contacts in household) and for other coronaviruses.<br><br>Results: A total of 54 relevant studies with 77 758 participants reporting household secondary transmission were identified. Estimated household secondary attack rate was 16.6% (95% CI, 14.0%-19.3%), higher than secondary attack rates for SARS-CoV (7.5%; 95% CI, 4.8%-10.7%) and MERS-CoV (4.7%; 95% CI, 0.9%-10.7%). Household secondary attack rates were increased from symptomatic index cases (18.0%; 95% CI, 14.2%-22.1%) than from asymptomatic index cases (0.7%; 95% CI, 0%-4.9%), to adult contacts (28.3%; 95% CI, 20.2%-37.1%) than to child contacts (16.8%; 95% CI, 12.3%-21.7%), to spouses (37.8%; 95% CI, 25.8%-50.5%) than to other family contacts (17.8%; 95% CI, 11.7%-24.8%), and in households with 1 contact (41.5%; 95% CI, 31.7%-51.7%) than in households with 3 or more contacts (22.8%; 95% CI, 13.6%-33.5%).<br><br>Conclusions and Relevance: The findings of this study suggest that given that individuals with suspected or confirmed infections are being referred to isolate at home, households will continue to be a significant venue for transmission of SARS-CoV-2.}, }
@article {pmid33312760, year = {2020}, author = {Somaiah, N and Chawla, SP and Block, MS and Morris, JC and Do, K and Kim, JW and Druta, M and Sankhala, KK and Hwu, P and Jones, RL and Gnjatic, S and Kim-Schulze, S and Tuballes, K and Yishak, M and Lu, H and Yakovich, A and Ter Meulen, J and Chen, M and Kenney, RT and Bohac, C and Pollack, SM}, title = {A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1.}, journal = {Oncoimmunology}, volume = {9}, number = {1}, pages = {1847846}, pmid = {33312760}, issn = {2162-402X}, abstract = {Preclinical data suggest that a &quot;prime-boost&quot; vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.}, }
@article {pmid33312265, year = {2020}, author = {Zheng, C and Chen, YQ}, title = {On a Shape-Invariant Hazard Regression Model with application to an HIV Prevention Study of Mother-to-Child Transmission.}, journal = {Statistics in biosciences}, volume = {12}, number = {3}, pages = {340-352}, pmid = {33312265}, issn = {1867-1764}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; }, abstract = {In survival analysis, Cox model is widely used for most clinical trial data. Alternatives include the additive hazard model, the accelerated failure time (AFT) model and a more general transformation model. All these models assume that the effects for all covariates are on the same scale. However, it is possible that for different covariates, the effects are on different scales. In this paper, we propose a shape-invariant hazard regression model that allows us to estimate the multiplicative treatment effect with adjustment of covariates that have non-multiplicative effects. We propose moment-based inference procedures for the regression parameters. We also discuss the risk prediction and the goodness of fit test for our proposed model. Numerical studies show good finite sample performance of our proposed estimator. We applied our method to the HIVNET 012 study, a milestone trial of single-dose nevirapine in prevention of mother-to-child transmission of HIV. From the HIVNET 012 data analysis, single-dose nevirapine treatment is shown to improve 18-month infant survival significantly with appropriate adjustment of the maternal CD4 counts and the virus load.}, }
@article {pmid33312175, year = {2020}, author = {Roe, D and Vierra-Green, C and Pyo, CW and Geraghty, DE and Spellman, SR and Maiers, M and Kuang, R}, title = {A Detailed View of KIR Haplotype Structures and Gene Families as Provided by a New Motif-Based Multiple Sequence Alignment.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {585731}, pmid = {33312175}, issn = {1664-3224}, abstract = {Human chromosome 19q13.4 contains genes encoding killer-cell immunoglobulin-like receptors (KIR). Reported haplotype lengths range from 67 to 269 kb and contain 4 to 18 genes. The region has certain properties such as single nucleotide variation, structural variation, homology, and repetitive elements that make it hard to align accurately beyond single gene alleles. To the best of our knowledge, a multiple sequence alignment of KIR haplotypes has never been published or presented. Such an alignment would be useful to precisely define KIR haplotypes and loci, provide context for assigning alleles (especially fusion alleles) to genes, infer evolutionary history, impute alleles, interpret and predict co-expression, and generate markers. In order to extend the framework of KIR haplotype sequences in the human genome reference, 27 new sequences were generated including 24 haplotypes from 12 individuals of African American ancestry that were selected for genotypic diversity and novelty to the reference, to bring the total to 68 full length genomic KIR haplotype sequences. We leveraged these data and tools from our long-read KIR haplotype assembly algorithm to define and align KIR haplotypes at <5 kb resolution on average. We then used a standard alignment algorithm to refine that alignment down to single base resolution. This processing demonstrated that the high-level alignment recapitulates human-curated annotation of the human haplotypes as well as a chimpanzee haplotype. Further, assignments and alignments of gene alleles were consistent with their human curation in haplotype and allele databases. These results define KIR haplotypes as 14 loci containing 9 genes. The multiple sequence alignments have been applied in two software packages as probes to capture and annotate KIR haplotypes and as markers to genotype KIR from WGS.}, }
@article {pmid33311956, year = {2020}, author = {Zhang, C and Chen, J and Fu, H and He, X and Zhao, YQ and Liu, Y}, title = {Multicategory Outcome Weighted Margin-based Learning for Estimating Individualized Treatment Rules.}, journal = {Statistica Sinica}, volume = {30}, number = {}, pages = {1857-1879}, pmid = {33311956}, issn = {1017-0405}, support = {R01 DK108073/DK/NIDDK NIH HHS/United States ; }, abstract = {Due to heterogeneity for many chronic diseases, precise personalized medicine, also known as precision medicine, has drawn increasing attentions in the scientific community. One main goal of precision medicine is to develop the most effective tailored therapy for each individual patient. To that end, one needs to incorporate individual characteristics to detect a proper individual treatment rule (ITR), by which suitable decisions on treatment assignments can be made to optimize patients' clinical outcome. For binary treatment settings, outcome weighted learning (OWL) and several of its variations have been proposed recently to estimate the ITR by optimizing the conditional expected outcome given patients' information. However, for multiple treatment scenarios, it remains unclear how to use OWL effectively. It can be shown that some direct extensions of OWL for multiple treatments, such as one-versus-one and one-versus-rest methods, can yield suboptimal performance. In this paper, we propose a new learning method, named Multicategory Outcome weighted Margin-based Learning (MOML), for estimating ITR with multiple treatments. Our proposed method is very general and covers OWL as a special case. We show Fisher consistency for the estimated ITR, and establish convergence rate properties. Variable selection using the sparse l1 penalty is also considered. Analysis of simulated examples and a type 2 diabetes mellitus observational study are used to demonstrate competitive performance of the proposed method.}, }
@article {pmid33311501, year = {2020}, author = {Geoghegan, JL and Ren, X and Storey, M and Hadfield, J and Jelley, L and Jefferies, S and Sherwood, J and Paine, S and Huang, S and Douglas, J and Mendes, FK and Sporle, A and Baker, MG and Murdoch, DR and French, N and Simpson, CR and Welch, D and Drummond, AJ and Holmes, EC and Duchêne, S and de Ligt, J}, title = {Genomic epidemiology reveals transmission patterns and dynamics of SARS-CoV-2 in Aotearoa New Zealand.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {6351}, pmid = {33311501}, issn = {2041-1723}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; COVID-19/*epidemiology/virology ; Child ; Child, Preschool ; Female ; Genome, Viral/*genetics ; Genomics/*methods ; Geography ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; New Zealand/epidemiology ; Pandemics ; Phylogeny ; SARS-CoV-2/classification/*genetics/physiology ; Whole Genome Sequencing/methods ; Young Adult ; }, abstract = {New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate 649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, Re of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.}, }
@article {pmid33310764, year = {2020}, author = {Perchetti, GA and Huang, ML and Mills, MG and Jerome, KR and Greninger, AL}, title = {Analytical Sensitivity of the Abbott BinaxNOW COVID-19 Ag CARD.}, journal = {Journal of clinical microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1128/JCM.02880-20}, pmid = {33310764}, issn = {1098-660X}, abstract = {Multiple rapid antigen tests for SARS-CoV-2 have recently received Emergency Use Authorization (EUA) from the United States Food and Drug Administration (FDA). Although less sensitive than molecular detection methods, rapid antigen testing offers the potential for cheap, quick, decentralized testing. Robust analytical sensitivity data in comparison to qRT-PCR is currently lacking for many rapid antigen tests. Here, we evaluated the analytical sensitivity of Abbott BinaxNOW COVID-19 Ag CARD using SARS-CoV-2 positive clinical specimens quantified by RT-ddPCR and multiple FDA EUA qRT-PCR platforms using RNA standards. Initial and confirmatory limits of detection for the BinaxNOW COVID-19 Ag CARD were determined to be equivalent to 4.04 - 8.06x104 copies/swab. We further confirmed this limit of detection with 72 additional clinical samples positive for SARS-CoV-2 in either phosphate-buffered saline or viral transport media.100% of samples with viral loads >40,000 copies/swab were detected by rapid antigen testing. These data indicate that the BinaxNOW COVID-19 Ag CARD has the approximate analytical sensitivity equivalent to a generic qRT-PCR CT of 29-30.}, }
@article {pmid33310760, year = {2021}, author = {O'Brien, VP and Koehne, AL and Dubrulle, J and Rodriguez, AE and Leverich, CK and Kong, VP and Campbell, JS and Pierce, RH and Goldenring, JR and Choi, E and Salama, NR}, title = {Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model.}, journal = {Life science alliance}, volume = {4}, number = {2}, pages = {}, doi = {10.26508/lsa.202000967}, pmid = {33310760}, issn = {2575-1077}, abstract = {More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.}, }
@article {pmid33306991, year = {2020}, author = {Day, TA and Penn-Nicholson, A and Luabeya, AKK and Fiore-Gartland, A and Du Plessis, N and Loxton, AG and Vergara, J and Rolf, TA and Reid, TD and Toefy, A and Shenje, J and Geldenhuys, H and Tameris, M and Mabwe, S and Bilek, N and Bekker, LG and Diacon, A and Walzl, G and Ashman, J and Frevol, A and Sagawa, ZK and Lindestam Arlehamn, C and Sette, A and Reed, SG and Coler, RN and Scriba, TJ and Hatherill, M and , }, title = {Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial.}, journal = {The Lancet. Respiratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2213-2600(20)30319-2}, pmid = {33306991}, issn = {2213-2619}, abstract = {BACKGROUND: A therapeutic vaccine that prevents recurrent tuberculosis would be a major advance in the development of shorter treatment regimens. We aimed to assess the safety and immunogenicity of the ID93 + GLA-SE vaccine at various doses and injection schedules in patients with previously treated tuberculosis.<br><br>METHODS: This randomised, double-blind, placebo-controlled, phase 2a trial was conducted at three clinical sites near Cape Town, South Africa. Patients were recruited at local clinics after receiving 4 months of tuberculosis treatment, and screened for eligibility after providing written informed consent. Participants were aged 18-60 years, BCG-vaccinated, HIV-uninfected, and diagnosed with drug-sensitive pulmonary tuberculosis. Eligible patients had completed standard treatment for pulmonary tuberculosis in the past 28 days. Participants were enrolled after completing standard treatment and randomly assigned sequentially to receive vaccine or placebo in three cohorts: 2 μg intramuscular ID93 + 2 μg GLA-SE on days 0 and 56 (cohort 1); 10 μg ID93 + 2 μg GLA-SE on days 0 and 56 (cohort 2); 2 μg ID93 + 5 μg GLA-SE on days 0 and 56 and placebo on day 28 (cohort 3); 2 μg ID93 + 5 μg GLA-SE on days 0, 28, and 56 (cohort 3); or placebo on days 0 and 56 (cohorts 1 and 2), with the placebo group for cohort 3 receiving an additional injection on day 28. Randomisation was in a ratio of 3:1 for ID93 + GLA-SE and saline placebo in cohorts 1 and 2, and in a ratio of 3:3:1 for (2 ×) ID93 + GLA-SE, (3 ×) ID93 + GLA-SE, and placebo in cohort 3. The primary outcomes were safety and immunogenicity (vaccine-specific antibody response and T-cell response). For the safety outcome, participants were observed for 30 min after each injection, injection site reactions and systemic adverse events were monitored until day 84, and serious adverse events and adverse events of special interest were monitored for 6 months after the last injection. Vaccine-specific antibody responses were measured by serum ELISA, and T-cell responses after stimulation with vaccine antigens were measured in cryopreserved peripheral blood mononuclear cells specimens using intracellular cytokine staining followed by flow cytometry. This study is registered with ClinicalTrials.gov, number NCT02465216.<br><br>FINDINGS: Between June 17, 2015, and May 30, 2016, we assessed 177 patients for inclusion. 61 eligible patients were randomly assigned to receive: saline placebo (n=5) or (2 ×) 2 μg ID93 + 2 μg GLA-SE (n=15) on days 0 and 56 (cohort 1); saline placebo (n=2) or (2 ×) 10 μg ID93 + 2 μg GLA-SE (n=5) on days 0 and 56 (cohort 2); saline placebo (n=5) on days 0, 28 and 56, or 2 μg ID93 + 5 μg GLA-SE (n=15) on days 0 and 56 and placebo injection on day 28, or (3 ×) 2 μg ID93 + 5 μg GLA-SE (n=14) on days 0, 28, and 56 (cohort 3). ID93 + GLA-SE induced robust and durable antibody responses and specific, polyfunctional CD4 T-cell responses to vaccine antigens. Two injections of the 2 μg ID93 + 5 μg GLA-SE dose induced antigen-specific IgG and CD4 T-cell responses that were significantly higher than those with placebo and persisted for the 6-month study duration. Mild to moderate injection site pain was reported after vaccination across all dose combinations, and induration and erythema in patients given 2 μg ID93 + 5 μg GLA-SE in two or three doses. One participant had grade 3 erythema and induration at the injection site. No vaccine-related serious adverse events were observed.<br><br>INTERPRETATION: Vaccination with ID93 + GLA-SE was safe and immunogenic for all tested regimens. These data support further evaluation of ID93 + GLA-SE in therapeutic vaccination strategies to improve tuberculosis treatment outcomes.<br><br>FUNDING: Wellcome Trust (102028/Z/13/Z).}, }
@article {pmid33306674, year = {2020}, author = {Nakamura, M and Verboon, JM and Allen, TE and Abreu-Blanco, MT and Liu, R and Dominguez, ANM and Delrow, JJ and Parkhurst, SM}, title = {Autocrine insulin pathway signaling regulates actin dynamics in cell wound repair.}, journal = {PLoS genetics}, volume = {16}, number = {12}, pages = {e1009186}, doi = {10.1371/journal.pgen.1009186}, pmid = {33306674}, issn = {1553-7404}, abstract = {Cells are exposed to frequent mechanical and/or chemical stressors that can compromise the integrity of the plasma membrane and underlying cortical cytoskeleton. The molecular mechanisms driving the immediate repair response launched to restore the cell cortex and circumvent cell death are largely unknown. Using microarrays and drug-inhibition studies to assess gene expression, we find that initiation of cell wound repair in the Drosophila model is dependent on translation, whereas transcription is required for subsequent steps. We identified 253 genes whose expression is up-regulated (80) or down-regulated (173) in response to laser wounding. A subset of these genes were validated using RNAi knockdowns and exhibit aberrant actomyosin ring assembly and/or actin remodeling defects. Strikingly, we find that the canonical insulin signaling pathway controls actin dynamics through the actin regulators Girdin and Chickadee (profilin), and its disruption leads to abnormal wound repair. Our results provide new insight for understanding how cell wound repair proceeds in healthy individuals and those with diseases involving wound healing deficiencies.}, }
@article {pmid33306276, year = {2020}, author = {Rudzinski, ER and Kelsey, A and Vokuhl, C and Linardic, CM and Shipley, J and Hettmer, S and Koscielniak, E and Hawkins, DS and Bisogno, G}, title = {Pathology of childhood rhabdomyosarcoma: A consensus opinion document from the Children's Oncology Group, European Paediatric Soft Tissue Sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e28798}, doi = {10.1002/pbc.28798}, pmid = {33306276}, issn = {1545-5017}, abstract = {The diagnosis and classification of rhabdomyosarcoma (RMS) has undergone several shifts over the last 30 years. While the main diagnostic categories remained the same, changes in the histologic criteria necessary for diagnosis, as well as varied reliance on immunohistochemical and molecular data over time, have created confusion, particularly regarding how these shifts impacted risk stratification and enrollment onto clinical trials. The goal of this report is to review the evolution and current status of RMS diagnosis, focusing on diagnostic criteria in the Children's Oncology Group (COG), the European Paediatric Soft Tissue Sarcoma Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). In addition, we emphasize research tools used to classify RMS and address biological questions within current clinical trials run by each group. The INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT) initiative will maximize potential to optimize risk stratification by recognizing and accounting for differences in historical data and current practices.}, }
@article {pmid33305293, year = {2020}, author = {Pruessmann, W and Rytlewski, J and Wilmott, J and Mihm, MC and Attrill, GH and Dyring-Andersen, B and Fields, P and Zhan, Q and Colebatch, AJ and Ferguson, PM and Thompson, JF and Kallenbach, K and Yusko, E and Clark, RA and Robins, H and Scolyer, RA and Kupper, TS}, title = {Molecular analysis of primary melanoma T cells identifies patients at risk for metastatic recurrence.}, journal = {Nature cancer}, volume = {1}, number = {2}, pages = {197-209}, pmid = {33305293}, issn = {2662-1347}, support = {R01 AI127654/AI/NIAID NIH HHS/United States ; R01 CA203721/CA/NCI NIH HHS/United States ; }, abstract = {Primary melanomas >1 mm thickness are potentially curable by resection, but can recur metastatically. We assessed the prognostic value of T cell fraction (TCFr) and repertoire T cell clonality, measured by high-throughput-sequencing of the T cell receptor beta chain (TRB) in T2-T4 primary melanomas (n=199). TCFr accurately predicted progression-free survival (PFS) and was independent of thickness, ulceration, mitotic rate, or age. TCFr was second only to tumor thickness in its predictive value, using a gradient boosted model. For accurate PFS prediction, adding TCFr to tumor thickness was superior to adding any other histopathological variable. Furthermore, a TCFr >20% was protective regardless of tumor ulceration status, mitotic rate or presence of nodal disease. TCFr is a quantitative molecular assessment that predicts metastatic recurrence in primary melanoma patients whose disease has been resected surgically. This study suggests that a successful T cell-mediated antitumor response can be present in primary melanomas.}, }
@article {pmid33301010, year = {2020}, author = {Etzioni, R and Shen, Y and Shih, YT}, title = {Identifying Preferred Breast Cancer Risk Predictors: A Holistic Perspective.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaa181}, pmid = {33301010}, issn = {1460-2105}, }
@article {pmid33300963, year = {2020}, author = {Niyonzima, N and Wannume, H and Kadhumbula, S and Wasswa, H and Osinde, G and Mulumba, Y and Tusabe, T and Kalungi, S and Orem, J}, title = {Strengthening Laboratory Diagnostic Capacity to Support Cancer Care in Uganda.}, journal = {American journal of clinical pathology}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcp/aqaa218}, pmid = {33300963}, issn = {1943-7722}, abstract = {OBJECTIVES: An accurate cancer diagnosis is critical to providing quality care to patients with cancer. We describe the results of a laboratory improvement process that started in 2017 to improve access to cancer diagnostics at the Uganda Cancer Institute (UCI). The overall objective of the project was to build capacity for the provision of quality and timely laboratory diagnostics to support cancer care in Uganda.<br><br>METHODS: A phased multistep approach was used to improve laboratory capacity, including staff training, additional staff recruitment, equipment overhaul, and optimization of the supply chain.<br><br>RESULTS: The program led to the establishment of a pathology laboratory that handled 5,700 tissue diagnoses in 2019. Immunohistochemistry services are now offered routinely. Turnaround time for histopathology has also reduced from an average of 7 to 14 days to 5.4 days. The main clinical laboratory has also increased both the test volume and the test capacity, with the additional establishment of a molecular diagnostics laboratory.<br><br>CONCLUSIONS: Our project shows a pathway to the improvement of laboratory diagnostic capacity in cancer care centers in sub-Saharan Africa (SSA). Improved laboratory diagnostic capacity is critical to improving cancer care in SSA and more rational use of targeted therapies.}, }
@article {pmid33300568, year = {2020}, author = {Dighe, SG and Chen, J and Yan, L and He, Q and Gharahkhani, P and Onstad, L and Levine, DM and Palles, C and Ye, W and Gammon, MD and Iyer, PG and Anderson, LA and Liu, G and Wu, AH and Dai, JY and Chow, WH and Risch, HA and Lagergren, J and Shaheen, NJ and Bernstein, L and Corley, DA and Prenen, H and deCaestecker, J and MacDonald, D and Moayyedi, P and Barr, H and Love, SB and Chegwidden, L and Attwood, S and Watson, P and Harrison, R and Ott, K and Moebus, S and Venerito, M and Lang, H and Mayershofer, R and Knapp, M and Veits, L and Gerges, C and Weismüller, J and Gockel, I and Vashist, Y and Nöthen, MM and Izbicki, JR and Manner, H and Neuhaus, H and Rösch, T and Böhmer, AC and Hölscher, AH and Anders, M and Pech, O and Schumacher, B and Schmidt, C and Schmidt, T and Noder, T and Lorenz, D and Vieth, M and May, A and Hess, T and Kreuser, N and Becker, J and Ell, C and Ambrosone, CB and Moysich, KB and MacGregor, S and Tomlinson, I and Whiteman, DC and Jankowski, J and Schumacher, J and Vaughan, TL and Madeleine, MM and Hardie, LJ and Buas, MF}, title = {Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma.}, journal = {Carcinogenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/carcin/bgaa132}, pmid = {33300568}, issn = {1460-2180}, abstract = {Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling, and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal components analysis (PCA) was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 SNPs in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases, and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17,159 controls). Global variation in the IGF pathway was associated with risk of BE (P=0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; p=0.00046, FDR q=0.0056) and IGF1R (IGF1 receptor; p=0.0090, q=0.0542). These gene-level signals remained significant at q<0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.}, }
@article {pmid33300385, year = {2020}, author = {Wagner-Johnston, ND and Schuster, SJ and deVos, S and Salles, G and Jurczak, WJ and Flowers, CR and Viardot, A and Flinn, IW and Martin, P and Xing, G and Rajakumaraswamy, N and Gopal, AK}, title = {Outcomes of patients with up to 6 years of follow-up from a phase 2 study of idelalisib for relapsed indolent lymphomas.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/10428194.2020.1855344}, pmid = {33300385}, issn = {1029-2403}, abstract = {The phase 2 study of idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. Patients with iNHL refractory to both rituximab and an alkylating agent were enrolled and received 150 mg idelalisib twice daily (N = 125). Idelalisib resulted in an overall response rate of 57.6% with 34.4% continuing therapy for ≥12 months. The median progression-free survival and duration of response were 11.0 and 11.8 months for follicular lymphoma, 22.2 and 20.4 months for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM), and 6.6 and 18.4 months for marginal zone lymphoma (MZL). Median overall survival after extended follow-up was 48.6 (95% CI 33.9, 71.7) months. Long-term follow-up did not reveal new safety concerns. These data indicate beneficial outcomes with longer follow-up after idelalisib for treatment of iNHL including in patients with LPL/WM and MZL.}, }
@article {pmid33300155, year = {2020}, author = {Pan, TD and Kanaan, SB and Lee, NR and Avila, JL and Nelson, JL and Eisenberg, DTA}, title = {Predictors of maternal-origin microchimerism in young women in the Philippines.}, journal = {American journal of physical anthropology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajpa.24191}, pmid = {33300155}, issn = {1096-8644}, support = {P2C HD042828/NH/NIH HHS/United States ; R01 HL117737/NH/NIH HHS/United States ; T32 HD007543/NH/NIH HHS/United States ; BA-DDRIG 1751388//National Science Foundation/ ; BCS 1519110//National Science Foundation/ ; BCS-DDIG 0962282//National Science Foundation/ ; Dissertation Fieldwork Grant 8111//Wenner-Gren Foundation/ ; Dissertation Fieldwork Grant 9662//Wenner-Gren Foundation/ ; }, abstract = {OBJECTIVES: Microchimerism is the presence of a small quantity of cells or DNA from a genetically distinct individual. This phenomenon occurs with bidirectional maternal-fetal exchange during pregnancy. Microchimerism can persist for decades after delivery and have long-term health implications. However, little is known about why microchimerism is detectable at varying levels in different individuals. We examine the variability and the following potential determinants of maternal-origin microchimerism (MMc) in young women in the Philippines: gestational duration (in utero exposure to MMc), history of being breastfed (postpartum exposure to MMc), maternal telomere length (maternal cells' ability to replicate and persist), and participant's pregnancies in young adulthood (effect of adding fetal-origin microchimerism to preexisting MMc).<br><br>MATERIALS AND METHODS: Data are from the Cebu Longitudinal Health and Nutrition Survey, a population-based study of infant feeding practices and long-term health outcomes. We quantified MMc using quantitative PCR (qPCR) in 89 female participants, ages 20-22, and analyzed these data using negative binomial regression.<br><br>RESULTS: In a multivariate model including all predictors, being breastfed substantially predicted decreased MMc (detection rate ratio = 0.15, p = 0.007), and there was a trend of decreasing MMc in participants who had experienced more pregnancies (detection rate ratio = 0.55, p = 0.057).<br><br>DISCUSSION: These results might be explained by breastfeeding having lasting impact on immune regulatory networks, thus reducing MMc persistence. MMc may also decrease in response to the introduction of fetal-origin microchimerism with pregnancies experienced in adulthood.}, }
@article {pmid33300045, year = {2020}, author = {Ross, JL and Chen, Z and Herting, CJ and Grabovska, Y and Szulzewsky, F and Puigdelloses, M and Monterroza, L and Switchenko, J and Wadhwani, NR and Cimino, PJ and Mackay, A and Jones, C and Read, RD and MacDonald, TJ and Schniederjan, M and Becher, OJ and Hambardzumyan, D}, title = {Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaa382}, pmid = {33300045}, issn = {1460-2156}, support = {P30 CA138292/CA/NCI NIH HHS/United States ; }, abstract = {Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.}, }
@article {pmid33298619, year = {2020}, author = {Veatch, JR and Singhi, N and Jesernig, B and Paulson, KG and Zalevsky, J and Iaccucci, E and Tykodi, SS and Riddell, SR}, title = {Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33298619}, issn = {2051-1426}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; }, abstract = {T cells that recognize self-antigens and mutated neoantigens are thought to mediate antitumor activity of immune checkpoint blockade (ICB) in melanoma. Few studies have analyzed self and neoantigen-specific T cell responses in patients responding to ICB. Here, we report a patient with metastatic melanoma who had a durable clinical response after treatment with the programmed cell death protein 1 inhibitor, nivolumab, combined with the first-in-class CD122-preferential interleukin-2 pathway agonist, bempegaldesleukin (BEMPEG, NKTR-214). We used a combination of antigen-specific T cell expansion and measurement of interferon-γ secretion to identify multiple CD4+ and CD8+ T cell clones specific for neoantigens, lineage-specific antigens and cancer testis antigens in blood and tumor from this patient prior to and after therapy. Polyclonal CD4+ and CD8+ T cells specific to multiple neoantigens but not self-antigens were highly enriched in pretreatment tumor compared with peripheral blood. Neoantigen, but not self-antigen-specific T cell clones expanded in frequency in the blood during successful treatment. There was evidence of dramatic immune infiltration into the tumor on treatment, and a modest increase in the relative frequency of intratumoral neoantigen-specific T cells. These observations suggest that diverse CD8+ and CD4+ T cell clones specific for neoantigens present in tumor before treatment had a greater role in immune tumor rejection as compared with self-antigen-specific T cells in this patient. Trial registration number: NCT02983045.}, }
@article {pmid33297484, year = {2020}, author = {Coluzzi, F and Rocco, M and Green Gladden, R and Persiani, P and Thur, LA and Milano, F}, title = {Pain Management in Childhood Leukemia: Diagnosis and Available Analgesic Treatments.}, journal = {Cancers}, volume = {12}, number = {12}, pages = {}, pmid = {33297484}, issn = {2072-6694}, abstract = {Pain is one of the most common symptoms in children suffering from leukemia, who are often misdiagnosed with other childhood painful diseases such as juvenile idiopathic arthritis. Corticosteroid-induced osteonecrosis (ON) and vincristine-induced peripheral neuropathy (VIPN) are the most common painful manifestations. Additionally, ongoing pain may continue to impact quality of life in survivorship. This narrative review focuses on the pathophysiological mechanisms of pain in childhood leukemia and current available indications for analgesic treatments. Pain management in children is often inadequate because of difficulties in pain assessment, different indications across countries, and the lack of specific pediatric trials. Analgesic drugs are often prescribed off-label to children by extrapolating information from adult guidelines, with possible increased risk of adverse events. Optimal pain management should involve a multidisciplinary team to ensure assessment and interventions tailored to the individual patient.}, }
@article {pmid33297341, year = {2020}, author = {Edupuganti, S and C De Rosa, S and Elizaga, M and Lu, Y and Han, X and Huang, Y and Swann, E and Polakowski, L and A Kalams, S and Keefer, M and Maenza, J and C Wise, M and Yan, J and Morrow, MP and Khan, AS and Boyer, JD and Humeau, L and White, S and Sardesai, NY and Bagarazzi, ML and Gilbert, PB and Kublin, JG and Corey, L and Weiner, DB and On Behalf Of The Hvtn Study Team,  and The Niaid-Funded Hiv Vaccine Trials Network, }, title = {Intramuscular and Intradermal Electroporation of HIV-1 PENNVAX-GP® DNA Vaccine and IL-12 Is Safe, Tolerable, Acceptable in Healthy Adults.}, journal = {Vaccines}, volume = {8}, number = {4}, pages = {}, pmid = {33297341}, issn = {2076-393X}, support = {U01 AI069418-08/NH/NIH HHS/United States ; }, abstract = {Background: Several techniques are under investigation to improve the immunogenicity of HIV-1 DNA vaccine candidates. DNA vaccines are advantageous due to their ease of design, expression of multiple antigens, and safety.<br><br>METHODS: The HVTN 098 trial assessed the PENNVAX®-GP DNA vaccine (encoding HIV env, gag, pol) administered with or without plasmid IL-12 at 0-, 1-, 3-, and 6-month timepoints via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, adult participants. We report on safety, tolerability, and acceptability.<br><br>RESULTS: HVTN 098 enrolled 94 participants: 85 received PENNVAX®-GP and nine received placebo. Visual analog scale (VAS) pain scores immediately after each vaccination were lower in the ID/EP than in the IM/EP group (medians 4.1-4.6 vs. 6-6.5, p < 0.01). IM/EP participants reported greater pain and/or tenderness at the injection site. Most ID/EP participants had skin lesions such as scabs/eschars, scars, and pigmentation changes, which resolved within 6 months in 51% of participants (24/55). Eighty-two percent of IM/EP and 92% of ID/EP participant survey responses showed acceptable levels of discomfort.<br><br>CONCLUSIONS: ID/EP and IM/EP are distinct experiences; however, HIV-1 DNA vaccination by either route was safe, tolerable and acceptable by most study participants.}, }
@article {pmid33294838, year = {2020}, author = {Rothschild, CW and Richardson, BA and Guthrie, BL and Kithao, P and Omurwa, T and Mukabi, J and Lokken, EM and John-Stewart, G and Unger, JA and Kinuthia, J and Drake, AL}, title = {A risk scoring tool for predicting Kenyan women at high risk of contraceptive discontinuation.}, journal = {Contraception: X}, volume = {2}, number = {}, pages = {100045}, pmid = {33294838}, issn = {2590-1516}, abstract = {Objective: We developed and validated a pragmatic risk assessment tool for identifying contraceptive discontinuation among Kenyan women who do not desire pregnancy.<br><br>Study design: Within a prospective cohort of contraceptive users, participants were randomly allocated to derivation (n = 558) and validation (n = 186) cohorts. Risk scores were developed by selecting the Cox proportional hazards model with the minimum Akaike information criterion. Predictive performance was evaluated using time-dependent receiver operating characteristic curves and area under the curve (AUC).<br><br>Results: The overall contraceptive discontinuation rate was 36.9 per 100 woman-years (95% confidence interval [CI] 30.3-44.9). The predictors of discontinuation selected for the risk score included use of a short-term method or copper intrauterine device (vs. injectable or implant), method continuation or switch (vs. initiation), < 9 years of completed education, not having a child aged < 6 months, and having no spouse or a spouse supportive of family planning (vs. having a spouse who has unsupportive or uncertain attitudes towards family planning). AUC at 24 weeks was 0.76 (95% CI 0.64-0.87) with 70.0% sensitivity and 78.6% specificity at the optimal cut point in the derivation cohort. Discontinuation was 3.8-fold higher among high- vs. low-risk women (95% CI 2.33-6.30). AUC was 0.68 (95% CI 0.47-0.90) in the validation cohort. A simplified score comprising routinely collected variables demonstrated similar performance (derivation-AUC: 0.73 [95% CI 0.60-0.85]; validation-AUC: 0.73 [95% CI 0.51-0.94]). Positive predictive value in the derivation cohort was 31.4% for the full and 28.1% for the simplified score.<br><br>Conclusions: The risk scores demonstrated moderate predictive ability but identified large proportions of women as high risk. Future research is needed to improve sensitivity and specificity of a clinical tool to identify women at high risk for experiencing method-related challenges.<br><br>Implications: Contraceptive discontinuation is a major driver of unmet contraceptive need globally. Few tools exist for identifying women who may benefit most from additional support in order to meet their contraceptive needs and preferences. This study developed and assessed the validity of a provider-focused risk prediction tool for contraceptive discontinuation among Kenyan women using modern contraception. High rates of early discontinuation observed in this study emphasize the necessity of investing in efforts to develop new contraceptive technologies and stronger delivery systems to better align with women's needs and preferences for voluntary family planning.}, }
@article {pmid33294745, year = {2021}, author = {Bracis, C and Burns, E and Moore, M and Swan, D and Reeves, DB and Schiffer, JT and Dimitrov, D}, title = {Widespread testing, case isolation and contact tracing may allow safe school reopening with continued moderate physical distancing: A modeling analysis of King County, WA data.}, journal = {Infectious Disease Modelling}, volume = {6}, number = {}, pages = {24-35}, pmid = {33294745}, issn = {2468-0427}, abstract = {Background: In late March 2020, a &quot;Stay Home, Stay Healthy&quot; order was issued in Washington State in response to the COVID-19 pandemic. On May 1, a 4-phase reopening plan began. We investigated whether adjunctive prevention strategies would allow less restrictive physical distancing to avoid second epidemic waves and secure safe school reopening.<br><br>Methods: We developed a mathematical model, stratifying the population by age, infection status and treatment status to project SARS-CoV-2 transmission during and after the reopening period. The model was parameterized with demographic and contact data from King County, WA and calibrated to confirmed cases, deaths and epidemic peak timing. Adjunctive prevention interventions were simulated assuming different levels of pre-COVID physical interactions (pC_PI) restored.<br><br>Results: The best model fit estimated ~35% pC_PI under the lockdown which prevented ~17,000 deaths by May 15. Gradually restoring 75% pC_PI for all age groups between May 15-July 15 would have resulted in ~350 daily deaths by early September 2020. Maintaining <45% pC_PI was required with current testing practices to ensure low levels of daily infections and deaths. Increased testing, isolation of symptomatic infections, and contact tracing permitted 60% pC_PI without significant increases in daily deaths before November and allowed opening of schools with <15 daily deaths. Inpatient antiviral treatment was predicted to reduce deaths significantly without lowering cases or hospitalizations.<br><br>Conclusions: We predict that widespread testing, contact tracing and case isolation would allow relaxation of physical distancing, as well as opening of schools, without a surge in local cases and deaths.}, }
@article {pmid33294492, year = {2020}, author = {Rust, BJ and Becker, PS and Chandrasekaran, D and Kubek, SP and Peterson, CW and Adair, JE and Kiem, HP}, title = {Envelope-Specific Adaptive Immunity following Transplantation of Hematopoietic Stem Cells Modified with VSV-G Lentivirus.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {19}, number = {}, pages = {438-446}, pmid = {33294492}, issn = {2329-0501}, abstract = {Current approaches for hematopoietic stem cell gene therapy typically involve lentiviral gene transfer in tandem with a conditioning regimen to aid stem cell engraftment. Although many pseudotyped envelopes have the capacity to be immunogenic due to their viral origins, thus far immune responses against the most common envelope, vesicular stomatitis virus glycoprotein G (VSV-G), have not been reported in hematopoietic stem cell gene therapy trials. Herein, we report on two Fanconi anemia patients who underwent autologous transplantation of a lineage-depleted, gene-modified hematopoietic stem cell product without conditioning. We observed the induction of robust VSV-G-specific immunity, consistent with low/undetectable gene marking in both patients. Upon further interrogation, adaptive immune mechanisms directed against VSV-G were detected following transplantation in both patients, including increased VSV-G-specific T cell responses, anti-VSV-G immunoglobulin G (IgG), and cytotoxic responses that can specifically kill VSV-G-expressing target cell lines. A proportion of healthy controls also displayed preexisting VSV-G-specific CD4+ and CD8+ T cell responses, as well as VSV-G-specific IgG. Taken together, these data show that VSV-G-pseudotyped lentiviral vectors have the ability to elicit interfering adaptive immune responses in the context of certain hematopoietic stem cell transplantation settings.}, }
@article {pmid33293425, year = {2020}, author = {Curtius, K and Dewanji, A and Hazelton, WD and Rubenstein, JH and Luebeck, GE}, title = {Optimal timing for cancer screening and adaptive surveillance using mathematical modeling.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-20-0335}, pmid = {33293425}, issn = {1538-7445}, abstract = {Cancer screening and early detection efforts have been partially successful in reducing incidence and mortality, but many improvements are needed. Although current medical practice is informed by epidemiological studies and experts, the decisions for guidelines are ultimately ad hoc. We propose here that quantitative optimization of protocols can potentially increase screening success and reduce overdiagnosis. Mathematical modeling of the stochastic process of cancer evolution can be used to derive and optimize the timing of clinical screens so that the probability is maximal that a patient is screened within a certain &quot;window of opportunity&quot; for intervention when early cancer development may be observable. Alternative to a strictly empirical approach or microsimulations of a multitude of possible scenarios, biologically-based mechanistic modeling can be used for predicting when best to screen and begin adaptive surveillance. We introduce a methodology for optimizing screening, assessing potential risks, and quantifying associated costs to healthcare using multiscale models. As a case study in Barrett's esophagus (BE), these methods were applied for a model of esophageal adenocarcinoma (EAC) that was previously calibrated to US cancer registry data. Optimal screening ages for patients with symptomatic gastroesophageal reflux disease was older (58 for men, 64 for women) than what is currently recommended (age > 50 years). These ages are in a cost-effective range to start screening and were independently validated by data used in current guidelines. Collectively, our framework captures critical aspects of cancer evolution within BE patients for a more personalized screening design.}, }
@article {pmid33292036, year = {2020}, author = {Gourgou, E and Willis, AR and Giunti, S and De Rosa, MJ and Charlesworth, AG and Hernandez Lima, M and Glater, E and Soo, S and Pereira, B and Akbaş, K and Deb, A and Kamak, M and Moyle, MW and Traa, A and Singhvi, A and Sural, S and Ji, EJ}, title = {A journey to 'tame a small metazoan organism', ‡ seen through the artistic eyes of C. elegans researchers.}, journal = {Journal of neurogenetics}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/01677063.2020.1839449}, pmid = {33292036}, issn = {1563-5260}, abstract = {In the following pages, we share a collection of photos, drawings, and mixed-media creations, most of them especially made for this JoN issue, manifesting C. elegans researchers' affection for their model organism and the founders of the field. This is a celebration of our community's growth, flourish, spread, and bright future. Descriptions provided by the contributors, edited for space. 1.}, }
@article {pmid33290576, year = {2020}, author = {Williamson, BD and Gilbert, PB and Carone, M and Simon, N}, title = {Rejoinder to &quot;Nonparametric variable importance assessment using machine learning techniques&quot;.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13389}, pmid = {33290576}, issn = {1541-0420}, support = {UM1AI068635//National Institute of Allergy and Infectious Diseases/ ; F31AI140836//National Institute of Allergy and Infectious Diseases/ ; R01AI029168//National Institute of Allergy and Infectious Diseases/ ; CP5OD019820/NH/NIH HHS/United States ; }, }
@article {pmid33289953, year = {2020}, author = {Kollmannsberger, C and Choueiri, TK and Heng, DYC and George, S and Jie, F and Croitoru, R and Poondru, S and Thompson, JA}, title = {A Randomized Phase II Study of AGS-16C3F Versus Axitinib in Previously Treated Patients with Metastatic Renal Cell Carcinoma.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1002/onco.13628}, pmid = {33289953}, issn = {1549-490X}, abstract = {LESSONS LEARNED: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previosuly treated patients with metastatic renal cell carcinoma (mRCC) was not met. The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue and nausea in the AGS-16C3F arm and fatigue and diarrhea in the axitinib arm These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.<br><br>BACKGROUND: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ENPP3 and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC).<br><br>METHODS: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST v1.1).<br><br>RESULTS: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (N = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%).<br><br>CONCLUSION: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC.}, }
@article {pmid33288862, year = {2020}, author = {Maziarz, RT and Levis, M and Patnaik, MM and Scott, BL and Mohan, SR and Deol, A and Rowley, SD and Kim, DDH and Hernandez, D and Rajkhowa, T and Haines, K and Bonifacio, G and Rine, P and Purkayastha, D and Fernandez, HF}, title = {Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-020-01153-1}, pmid = {33288862}, issn = {1476-5365}, abstract = {We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).}, }
@article {pmid33287224, year = {2020}, author = {Acharya, UH and Walter, RB}, title = {Chimeric Antigen Receptor (CAR)-Modified Immune Effector Cell Therapy for Acute Myeloid Leukemia (AML).}, journal = {Cancers}, volume = {12}, number = {12}, pages = {}, pmid = {33287224}, issn = {2072-6694}, abstract = {Despite the availability of an increasing number of targeted therapeutics and wider use of allogeneic hematopoietic stem cell transplantation, many patients with acute myeloid leukemia (AML) ultimately succumb to this disease. Given their remarkable efficacy in B-acute lymphoblastic leukemia and other CD19-expressing B cell malignancies, there is hope adoptive cellular transfer, particularly chimeric antigen receptor (CAR)-modified immune effector cell (IEC) therapies, may afford a novel, potent immune-based approach for the treatment of AML that complements or replaces existing ones and improves cure rates. However, it is unclear how best to translate the success of these therapies from B cell malignancies, where use of highly potent immunotherapies is facilitated by identified target antigens with near ubiquitous expression on malignant cells and non-fatal consequences from &quot;on-target, off-tumor cell&quot; toxicities. Herein, we review the current status of CAR-modified IEC therapies for AML, with considerations regarding suitable, relatively leukemia-restricted target antigens, expected toxicities, and interactions of the engineered cells with a profoundly immunosuppressive tumor microenvironment that restricts their therapeutic efficacy. With these challenges in mind, we will discuss possible strategies to improve the cells' potency as well as their therapeutic window for optimal clinical use in AML.}, }
@article {pmid33286736, year = {2020}, author = {Otwinowski, J and LaMont, CH and Nourmohammad, A}, title = {Information-Geometric Optimization with Natural Selection.}, journal = {Entropy (Basel, Switzerland)}, volume = {22}, number = {9}, pages = {}, pmid = {33286736}, issn = {1099-4300}, support = {SFB1310//Deutsche Forschungsgemeinschaft/ ; MPRG funding//Max-Planck-Gesellschaft/ ; }, abstract = {Evolutionary algorithms, inspired by natural evolution, aim to optimize difficult objective functions without computing derivatives. Here we detail the relationship between classical population genetics of quantitative traits and evolutionary optimization, and formulate a new evolutionary algorithm. Optimization of a continuous objective function is analogous to searching for high fitness phenotypes on a fitness landscape. We describe how natural selection moves a population along the non-Euclidean gradient that is induced by the population on the fitness landscape (the natural gradient). We show how selection is related to Newton's method in optimization under quadratic fitness landscapes, and how selection increases fitness at the cost of reducing diversity. We describe the generation of new phenotypes and introduce an operator that recombines the whole population to generate variants. Finally, we introduce a proof-of-principle algorithm that combines natural selection, our recombination operator, and an adaptive method to increase selection and find the optimum. The algorithm is extremely simple in implementation; it has no matrix inversion or factorization, does not require storing a covariance matrix, and may form the basis of more general model-based optimization algorithms with natural gradient updates.}, }
@article {pmid33285419, year = {2020}, author = {Mitchell, KM and Dimitrov, D and Hughes, JP and Moore, M and Vittinghoff, E and Liu, A and Cohen, MS and Beyrer, C and Donnell, D and Boily, MC}, title = {Assessing the use of surveillance data to estimate the impact of prevention interventions on HIV incidence in cluster-randomized controlled trials.}, journal = {Epidemics}, volume = {33}, number = {}, pages = {100423}, doi = {10.1016/j.epidem.2020.100423}, pmid = {33285419}, issn = {1878-0067}, abstract = {BACKGROUND: In cluster-randomized controlled trials (C-RCTs) of HIV prevention strategies, HIV incidence is expensive to measure directly. Surveillance data on HIV diagnoses or viral suppression could provide cheaper incidence estimates. We used mathematical modelling to evaluate whether these measures can replace HIV incidence measurement in C-RCTs.<br><br>METHODS: We used a US HIV transmission model to simulate C-RCTs of expanded antiretroviral therapy(ART), pre-exposure prophylaxis(PrEP) and HIV testing, together or alone. We tested whether modelled reductions in total new HIV diagnoses, diagnoses with acute infection, diagnoses with early infection(CD4 > 500 cells/μl), diagnoses adjusted for testing volume, or the proportion virally non-suppressed, reflected HIV incidence reductions.<br><br>RESULTS: Over a two-year trial expanding PrEP alone, modelled reductions in total diagnoses underestimated incidence reductions by a median six percentage points(pp), with acceptable variability(95 % credible interval -14,-2pp). For trials expanding HIV testing alone or alongside ART + PrEP, greater, highly variable bias was seen[-20pp(-128,-1) and -30pp(-134,-16), respectively]. Acceptable levels of bias were only seen over longer trial durations when levels of awareness of HIV-positive status were already high. Expanding ART alone, only acute and early diagnoses reductions reflected incidence reduction well, with some bias[-3pp(-6,-1) and -8pp(-16,-3), respectively]. Early and adjusted diagnoses also reliably reflected incidence when scaling up PrEP alone[bias -5pp(-11,1) and 10pp(3,18), respectively]. For trials expanding testing (alone or with ART + PrEP), bias for all measures explored was too variable for them to replace direct incidence measures, unless using diagnoses when HIV status awareness was already high.<br><br>CONCLUSIONS: Surveillance measures based on HIV diagnoses may sometimes be adequate surrogates for HIV incidence reduction in C-RCTs expanding ART or PrEP only, if adjusted for bias. However, all surveillance measures explored failed to approximate HIV incidence reductions for C-RCTs expanding HIV testing, unless levels of awareness of HIV-positive status were already high.}, }
@article {pmid33284946, year = {2020}, author = {van Rhee, F and Oksenhendler, E and Srkalovic, G and Voorhees, P and Lim, M and Dispenzieri, A and Ide, M and Parente, S and Schey, S and Streetly, M and Wong, R and Wu, D and Maillard, I and Brandstadter, J and Munshi, N and Bowne, W and Elenitoba-Johnson, KS and Fössa, A and Lechowicz, MJ and Chandrakasan, S and Pierson, SK and Greenway, A and Nasta, S and Yoshizaki, K and Kurzrock, R and Uldrick, TS and Casper, C and Chadburn, A and Fajgenbaum, DC}, title = {International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.}, journal = {Blood advances}, volume = {4}, number = {23}, pages = {6039-6050}, pmid = {33284946}, issn = {2473-9537}, abstract = {Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.}, }
@article {pmid33284945, year = {2020}, author = {Chisholm, KM and Heerema-McKenney, AE and Choi, JK and Smith, J and Ries, RE and Hirsch, BA and Raimondi, SC and Alonzo, TA and Wang, YC and Aplenc, R and Sung, L and Gamis, AS and Meshinchi, S and Kahwash, SB}, title = {Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group.}, journal = {Blood advances}, volume = {4}, number = {23}, pages = {6000-6008}, pmid = {33284945}, issn = {2473-9537}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, abstract = {Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.}, }
@article {pmid33284732, year = {2020}, author = {Goulart, BHL and Unger, JM and Chennupati, S and Fedorenko, CR and Ramsey, SD}, title = {Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non-Small-Cell Lung Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2000692}, doi = {10.1200/OP.20.00692}, pmid = {33284732}, issn = {2688-1535}, abstract = {PURPOSE: We investigated the association of out-of-pocket (OOP) costs for tyrosine kinase inhibitors (TKIs) with overall survival (OS) in epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We secondarily investigated associations of TKI OOP costs with TKI adherence, duration of therapy (DOT), and TKI discontinuation.<br><br>METHODS: We used the Hutchinson Institute for Cancer Outcomes Research registry-claims database to identify patients with stage IV EGFR- or ALK-positive NSCLC; ≥ 1 claims for EGFR or ALK TKIs; and ≥ 3-month survival from TKI initiation. We estimated the average monthly TKI OOP costs per patient up to 3 months from TKI initiation, categorizing patients into quartiles of TKI OOP costs (Q1 < Q2 < Q3 < Q4). We conducted landmark analysis at 3 months from TKI initiation to compare Q1-3 v Q4 TKI OOP costs with respect to OS, TKI DOT, TKI adherence, and TKI discontinuation.<br><br>RESULTS: Seventy-eight and twenty-seven patients comprised the Q1-3 and Q4 groups, respectively. Median monthly TKI OOP costs were $1,431 (Q1-3) v $2,888 (Q4). Compared with Q1-3, Q4 patients had inferior OS (adjusted hazard ratio [HR], 1.85; [95% CI, 1.11 to 3.10], similar TKI DOT (adjusted HR, 1.06; 95% CI, 0.53 to 2.15), decreased TKI adherence (adjusted odds ratio [OR], 0.28; 95% CI, 0.10 to 0.76), and higher TKI discontinuation rate (adjusted OR, 8.75; 95% CI, 2.59 to 29.52).<br><br>CONCLUSION: Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI OOP costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival.}, }
@article {pmid33284679, year = {2020}, author = {Barnabas, RV and Brown, ER and Bershteyn, A and Stankiewicz Karita, HC and Johnston, C and Thorpe, LE and Kottkamp, A and Neuzil, KM and Laufer, MK and Deming, M and Paasche-Orlow, MK and Kissinger, PJ and Luk, A and Paolino, K and Landovitz, RJ and Hoffman, R and Schaafsma, TT and Krows, ML and Thomas, KK and Morrison, S and Haugen, HS and Kidoguchi, L and Wener, M and Greninger, AL and Huang, ML and Jerome, KR and Wald, A and Celum, C and Chu, HY and Baeten, JM}, title = {Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, pmid = {33284679}, issn = {1539-3704}, abstract = {BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently limited to nonpharmaceutical strategies. Laboratory and observational data suggested that hydroxychloroquine had biological activity against SARS-CoV-2, potentially permitting its use for prevention.<br><br>OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2 infection.<br><br>DESIGN: Household-randomized, double-blind, controlled trial of hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).<br><br>SETTING: National U.S. multicenter study.<br><br>PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with diagnosed SARS-CoV-2 infection.<br><br>INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for 11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a placebo-equivalent control.<br><br>MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to 14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome was PCR-confirmed incident SARS-CoV-2 infection among persons who were SARS-CoV-2 negative at enrollment.<br><br>RESULTS: Between March and August 2020, 671 households were randomly assigned: 337 (407 participants) to the hydroxychloroquine group and 334 (422 participants) to the control group. Retention at day 14 was 91%, and 10 724 of 11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who were SARS-CoV-2 negative at baseline, there was no difference between the hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53 versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20). The frequency of participants experiencing adverse events was higher in the hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%], respectively; P = 0.026).<br><br>LIMITATION: The delay between exposure, and then baseline testing and the first dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.<br><br>CONCLUSION: This rigorous randomized controlled trial among persons with recent exposure excluded a clinically meaningful effect of hydroxychloroquine as postexposure prophylaxis to prevent SARS-CoV-2 infection.<br><br>PRIMARY FUNDING SOURCE: Bill &amp; Melinda Gates Foundation.}, }
@article {pmid33283555, year = {2020}, author = {Chow, EJ and Doody, DR and Wilkes, JJ and Becker, LK and Chennupati, S and Morin, PE and Winestone, LE and Henk, HJ and Lyman, GH}, title = {Adverse events among chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors: a real-world analysis of health plan enrollees.}, journal = {Leukemia &amp; lymphoma}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/10428194.2020.1855340}, pmid = {33283555}, issn = {1029-2403}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p < 0.05). Increased risk of infections, cardiopulmonary and skin issues associated with later generation TKIs persisted in subsequent years. In this real-world population, TKI therapy was associated with a high burden of adverse events. Later generation TKIs may have greater toxicity than imatinib.}, }
@article {pmid33283195, year = {2020}, author = {Gulleen, EA and Ameko, MK and Ainsworth, JE and Barnes, LE and Moore, CC}, title = {Predictive Models of Fever, ICU Transfer, and Mortality in Hospitalized Patients With Neutropenia.}, journal = {Critical care explorations}, volume = {2}, number = {12}, pages = {e0289}, pmid = {33283195}, issn = {2639-8028}, abstract = {Neutropenia is a common side effect of myelosuppressive chemotherapy and is associated with adverse outcomes. Early Warning Scores are used to identify at-risk patients and facilitate rapid clinical interventions. Since few Early Warning Scores have been validated in patients with neutropenia, we aimed to create predictive models and nomograms of fever, ICU transfer, and mortality in hospitalized neutropenic patients.<br><br>Design: Development of statistical prediction models and nomograms using data from a retrospective cohort study of hospitalized patients with neutropenia.<br><br>Setting: University of Virginia Medical Center, a tertiary-care academic medical center in Charlottesville, VA.<br><br>Patients: The derivation and validation cohorts included hospitalized adult patients with neutropenia who were admitted to the inpatient wards between October 2010 and January 2015, and April 2017 and April 2020, respectively. We defined neutropenia as an absolute neutrophil count of less than 500 cells/mm3.<br><br>Interventions: None.<br><br>Measurements and Main Results: The derivation cohort included 1,531 hospital admissions in patients with neutropenia. Fever, ICU transfer, and in-hospital mortality occurred in 955 admissions (62%), 297 admissions (19%), and 147 admissions (10%), respectively. In the derivation cohort, the internally validated area under the curves with 95% CI for the fever, ICU transfer, and mortality models were HYPERLINK &quot;callto:0.74%20(0.67-0.84),%200.77&quot;0.74 (0.67-0.84), 0.77 (0.67-0.86), and HYPERLINK &quot;callto:0.95%20(0.0.87-1.0&quot;0.95 (0.0.87-1.0), respectively. The validation cohort included 1,250 admissions in patients with neutropenia. In the validation cohort, the area under the curve (95% CI) for the fever, ICU transfer, and mortality models were HYPERLINK &quot;callto:0.70%20(0.67-0.73),%200.78&quot;0.70 (0.67-0.73), 0.78 (0.72-0.84), and HYPERLINK &quot;callto:0.91%20(0.88-0.94&quot;0.91 (0.88-0.94), respectively. Using these models, we developed clinically applicable nomograms which detected adverse events a median of 4.0-11.4 hours prior to onset.<br><br>Conclusions: We created predictive models and nomograms for fever, ICU transfer, and mortality in patients with neutropenia. These models could be prospectively validated to detect high-risk patients and facilitate early clinical intervention to improve patient outcomes.}, }
@article {pmid33282876, year = {2020}, author = {Heck, AM and Ishida, T and Hadland, B}, title = {Location, Location, Location: How Vascular Specialization Influences Hematopoietic Fates During Development.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {602617}, pmid = {33282876}, issn = {2296-634X}, abstract = {During embryonic development, sequential waves of hematopoiesis give rise to blood-forming cells with diverse lineage potentials and self-renewal properties. This process must accomplish two important yet divergent goals: the rapid generation of differentiated blood cells to meet the needs of the developing embryo and the production of a reservoir of hematopoietic stem cells to provide for life-long hematopoiesis in the adult. Vascular beds in distinct anatomical sites of extraembryonic tissues and the embryo proper provide the necessary conditions to support these divergent objectives, suggesting a critical role for specialized vascular niche cells in regulating disparate blood cell fates during development. In this review, we will examine the current understanding of how organ- and stage-specific vascular niche specialization contributes to the development of the hematopoietic system.}, }
@article {pmid33282337, year = {2019}, author = {Potter, BI and Kondor, R and Hadfield, J and Huddleston, J and Barnes, J and Rowe, T and Guo, L and Xu, X and Neher, RA and Bedford, T and Wentworth, DE}, title = {Evolution and rapid spread of a reassortant A(H3N2) virus that predominated the 2017-2018 influenza season.}, journal = {Virus evolution}, volume = {5}, number = {2}, pages = {vez046}, pmid = {33282337}, issn = {2057-1577}, abstract = {The 2017-2018 North American influenza season caused more hospitalizations and deaths than any year since the 2009 H1N1 pandemic. The majority of recorded influenza infections were caused by A(H3N2) viruses, with most of the virus's North American diversity falling into the A2 clade. Within A2, we observe a subclade which we call A2/re that rose to comprise almost 70 per cent of A(H3N2) viruses circulating in North America by early 2018. Unlike most fast-growing clades, however, A2/re contains no amino acid substitutions in the hemagglutinin (HA) segment. Moreover, hemagglutination inhibition assays did not suggest substantial antigenic differences between A2/re viruses and viruses sampled during the 2016-2017 season. Rather, we observe that the A2/re clade was the result of a reassortment event that occurred in late 2016 or early 2017 and involved the combination of the HA and PB1 segments of an A2 virus with neuraminidase (NA) and other segments a virus from the clade A1b. The success of this clade shows the need for antigenic analysis that targets NA in addition to HA. Our results illustrate the potential for non-HA drivers of viral success and necessitate the need for more thorough tracking of full viral genomes to better understand the dynamics of influenza epidemics.}, }
@article {pmid33280855, year = {2020}, author = {Wenzel, NS and Atkins, KE and van Leeuwen, E and Halloran, ME and Baguelin, M}, title = {Cost-effectiveness of live-attenuated influenza vaccination among school-age children.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2020.10.007}, pmid = {33280855}, issn = {1873-2518}, abstract = {The current pediatric vaccination program in England and Wales administers Live-Attenuated Influenza Vaccine (LAIV) to children ages 2-16 years old. Annual administration of LAIV to this age group is costly and poses substantial logistical issues. This study aims to evaluate the cost-effectiveness of prioritizing vaccination to age groups within the 2-16 year old age range to mitigate the operational and resource challenges of the current strategy. We performed economic evaluations comparing the influenza vaccination program from 1995-2013 to seven alternative strategies targeted at low risk individuals along the school age divisions Preschool (2-4 years old), Primary school (5-11 years old), and Secondary school (12-16 years old). These extensions are evaluated incrementally on the status quo scenario (vaccinating subgroups at high risk of influenza-related complications and individuals 65+ years old). Impact of vaccination was assessed using a transmission model from a previously published study and updated with new data. At all levels of coverage, all strategies had a 100% probability of being cost-effective at the current National Health Service threshold, £20,000/QALY gained. The incremental analysis demonstrated vaccinating Primary School children was the most cost-efficient strategy compared incrementally against others with an Incremental Cost-Effectiveness Ratio of £639 spent per QALY gained (Net Benefit: 404 M£ [155, 795]). When coverage was varied between 30%, 55%, and 70% strategies which included Primary school children had a higher probability of being cost-effective at lower willingness-to-pay levels. Although children were the vaccine target the majority of QALY gains occurred in the 25-44 years old and 65+ age groups. Influenza strain A/H3N2 incurred the greatest costs and QALYs lost regardless of which strategy was used. Improvement could be made to the current LAIV pediatric vaccination strategy by eliminating vaccination of 2-4 year olds and focusing on school-based delivery to Primary and Secondary school children in tandem.}, }
@article {pmid33279516, year = {2020}, author = {Grady, WM and Yu, M and Markowitz, SD}, title = {Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2020.09.058}, pmid = {33279516}, issn = {1528-0012}, support = {R01 CA220004/CA/NCI NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; U54 CA163060/CA/NCI NIH HHS/United States ; }, }
@article {pmid33276706, year = {2020}, author = {Crist, SB and Ghajar, CM}, title = {When a House Is Not a Home: A Survey of Antimetastatic Niches and Potential Mechanisms of Disseminated Tumor Cell Suppression.}, journal = {Annual review of pathology}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-pathmechdis-012419-032647}, pmid = {33276706}, issn = {1553-4014}, abstract = {Over the last four decades, the cancer biology field has concentrated on cellular and microenvironmental drivers of metastasis. Despite this focus, mortality rates upon diagnosis of metastatic disease remain essentially unchanged. Would a small change in perspective help? Knowing what constitutes an inhospitable, rather than hospitable, microenvironment could provide the inspiration necessary to develop better therapies and preventative strategies. In this review, we canvas the literature for hints about what characteristics three common antimetastatic niches-skeletal muscle, thyroid, and spleen-have in common. We posit that thorough molecular and mechanistic characterization of antimetastatic tissues may inspire reimagined therapies that inhibit metastatic development and/or progression in an enduring manner. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is January 25, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.}, }
@article {pmid33276046, year = {2020}, author = {Samuelson, C and Radtke, S and Cui, M and Perez, A and Kiem, HP and Humbert, O}, title = {AMD3100 redosing fails to repeatedly mobilize hematopoietic stem cells in the nonhuman primate and humanized mouse.}, journal = {Experimental hematology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.exphem.2020.11.001}, pmid = {33276046}, issn = {1873-2399}, abstract = {AMD3100 (plerixafor) is a vital component of many clinical and preclinical transplant protocols, facilitating harvest of hematopoietic stem and progenitor cells through mobilization into the peripheral blood circulation. Repeat mobilization with AMD3100 is also necessary for many patients with suboptimal first stem cell collection or those requiring repeat transplantation. In this study we investigated the mobilization efficacy of repeated AMD3100 dosages in the nonhuman primate and humanized mouse models. In nonhuman primates, we observed effective mobilization after the first AMD3100 administration but a significantly poorer response in CD34+ and hematopoietic stem cell-enriched CD90+ cells with subsequent doses of the drug. A similar loss of efficacy with repeated administration was noted in immunodeficient mice engrafted with human CD34+ cells, in whom the total human white cell population, and particularly human hematopoietic stem and progenitor cells, mobilized significantly less effectively following a second AMD3100 administration when compared with the first dose. Together, our results are expected to inform future mobilization protocols for the purposes of peripheral blood hematopoietic stem cell extraction or for applications in which hematopoietic stem cells must be made accessible for in vivo-delivered gene targeting agents.}, }
@article {pmid33275766, year = {2020}, author = {Tremblay, D and Mesa, R and Scott, B and Buckley, S and Roman-Torres, K and Verstovsek, S and Mascarenhas, J}, title = {Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden.}, journal = {Blood advances}, volume = {4}, number = {23}, pages = {5929-5935}, pmid = {33275766}, issn = {2473-9537}, abstract = {Myelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F- disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F- disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F- disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.}, }
@article {pmid33275713, year = {2020}, author = {Oehler, VG}, title = {First-generation vs second-generation tyrosine kinase inhibitors: which is best at diagnosis of chronic phase chronic myeloid leukemia?.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2020}, number = {1}, pages = {228-236}, pmid = {33275713}, issn = {1520-4383}, abstract = {In 2020, for the great majority of patients with chronic phase chronic myeloid leukemia (CML), life expectancy is unaffected by a diagnosis of CML because of the unparalleled efficacy of ABL-targeted tyrosine kinase inhibitors (TKIs) in halting disease progression. A wealth of choices exist for first-line treatment selection, including the first-generation TKI imatinib and the second-generation TKIs bosutinib, dasatinib, and nilotinib. How I select first-line therapy between first-generation and second-generation TKIs is discussed in the context of patient-specific CML disease risk, therapy-related risks, and treatment goals. Although rare, identifying patients with CML at higher risk for disease progression or resistance is important and influences first-line TKI selection. I review the impact of first-generation vs second-generation TKI selection on treatment response and outcomes; the ability to achieve, as well as the timing of, treatment-free remission; and the impact of specific TKIs on longer-term health.}, }
@article {pmid33275695, year = {2020}, author = {Scott, BL}, title = {Existing agents, novel agents, or transplantation for high-risk MDS.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2020}, number = {1}, pages = {411-417}, pmid = {33275695}, issn = {1520-4383}, abstract = {The decision algorithm for treatment of advanced myelodysplastic syndrome (MDS) (intermediate- to very high-risk by the revised International Prognostic Scoring System [IPSS-R]) is complex. Often, the appropriate choice is unknown and not currently addressed by available clinical evidence. Although allogeneic hematopoietic cell transplantation (alloHCT) is curative for some patients with MDS, there is a concurrent high risk of mortality and morbidity. Alternatively, although hypomethylating agents (HMAs) have low toxicity, they are not thought to be curative, with a median increase in overall survival of only 9 months. Initial attempts to improve outcomes with HMAs through addition of novel agents failed, but there is hope that newer combination strategies will improve outcomes. Challenging clinical questions include who should be considered for alloHCT, appropriate timing and preparation for alloHCT, and appropriate therapeutic choices for patients who are not candidates for alloHCT. Given the interplay between alloHCT and non-alloHCT approaches, a unified coordinated approach is optimal for patients with advanced MDS. When possible, patients with advanced MDS should be encouraged to enroll into clinical trials that include alloHCT and non-alloHCT approaches.}, }
@article {pmid33275691, year = {2020}, author = {Halpern, AB and Walter, RB}, title = {Practice patterns and outcomes for adults with acute myeloid leukemia receiving care in community vs academic settings.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2020}, number = {1}, pages = {129-134}, pmid = {33275691}, issn = {1520-4383}, abstract = {Consistent with observations in other disease settings, retrospective studies have indicated that treatment outcomes for adults with acute myeloid leukemia (AML) are better in higher- vs lower-volume hospitals and academic vs nonacademic centers, with greatest benefits noted in acute promyelocytic leukemia. Younger age, more frequent receipt of chemotherapy and hematopoietic cell transplantation, and differences in comorbidities and socioeconomic factors may partially account for these differences. With new therapeutic options including oral small molecule inhibitors and parenteral drugs suitable for outpatient administration, there is increasing interest from patients and physicians in treating AML in the community setting and avoiding referral to academic centers. This may be particularly true for older adults, for whom treatment rates in the community have historically been low, and for those with comorbidities, because treatment benefits are estimated to be low, and thus travel to academic centers is perceived as especially burdensome. How the volume-outcome relationship is affected by the shift of the treatment landscape in AML over the last few years is unknown. Additionally, improvements in supportive care (transfusion support, broad-spectrum oral antimicrobials), resulting in gradually decreasing early death rates over time, and the growing focus on the impact of AML therapy on quality of life and treatment cost concerns further fuel the larger trend toward an increasing proportion of care delivered in the outpatient setting. Here, we examine whether the current shift of administering chemotherapy and supportive care to the outpatient setting can be translated to the community setting without compromising patient outcomes.}, }
@article {pmid33274413, year = {2020}, author = {Dorsey, M and Wright, NAM and Chaimowitz, NS and Dávila Saldaña, BJ and Miller, H and Keller, MD and Thakar, MS and Shah, AJ and Abu-Arja, R and Andolina, J and Aquino, V and Barnum, JL and Bednarski, JJ and Bhatia, M and Bonilla, FA and Butte, MJ and Bunin, NJ and Burroughs, LM and Chandra, S and Chaudhury, S and Chen, K and Chong, H and Cuvelier, G and Dalal, J and DeFelice, ML and DeSantes, KB and Forbes, LR and Gillio, A and Goldman, F and Joshi, AY and Kapoor, N and Knutsen, AP and Kobrynski, L and Lieberman, JA and Leiding, JW and Oshrine, B and Patel, KP and Prockop, S and Quigg, TC and Quinones, R and Schultz, KR and Seroogy, C and Shyr, D and Siegel, S and Smith, AR and Torgerson, TR and Vander Lugt, MT and Yu, LC and Cowan, MJ and Buckley, RH and Dvorak, CC and Griffith, LM and Haddad, E and Kohn, DB and Logan, B and Notarangelo, LD and Pai, SY and Puck, J and Pulsipher, MA and Heimall, J}, title = {Correction to: Infections in Infants with SCID: Isolation, Infection Screening and Prophylaxis in PIDTC Centers.}, journal = {Journal of clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10875-020-00917-0}, pmid = {33274413}, issn = {1573-2592}, abstract = {A Correction to this paper has been published: https://doi.org/10.1007/s10875-020-00917-0.}, }
@article {pmid33273043, year = {2020}, author = {Bellettiere, J and LaMonte, MJ and Healy, GN and Liles, S and Evenson, KR and Di, C and Kerr, J and Lee, IM and Rillamas-Sun, E and Buchner, D and Hovell, MF and LaCroix, AZ}, title = {Sedentary Behavior and Diabetes Risk Among Women Over the Age of 65 Years: The OPACH Study.}, journal = {Diabetes care}, volume = {}, number = {}, pages = {}, doi = {10.2337/dc20-0709}, pmid = {33273043}, issn = {1935-5548}, abstract = {OBJECTIVE: To evaluate whether sedentary time (ST) and/or sedentary behavior patterns are related to incident diabetes in the U.S.'s oldest age-groups.<br><br>RESEARCH DESIGN AND METHODS: Women without physician-diagnosed diabetes (n = 4,839, mean ± SD age = 79 ± 7 years) wore accelerometers for ≥4 days and were followed up to 6 years for self-reported newly diagnosed diabetes requiring treatment with medications. Hazard ratios (HRs) for incident diabetes were estimated across quartiles of accelerometer-measured ST and mean bout duration with use of Cox proportional hazards models. We conducted isotemporal substitution analyses using Cox regression and tested associations with risk for diabetes after statistically replacing ST with light physical activity (PA) or moderate-to-vigorous PA (MVPA) and after replacing light PA with MVPA.<br><br>RESULTS: During 20,949 person-years, 342 diabetes cases were identified. Women in ST quartile (Q)2, Q3, and Q4 (vs. Q1) had incident diabetes HR 1.20 (95% CI 0.87-1.65), 1.33 (0.97-1.82), and 1.21 (0.86-1.70); Ptrend = 0.04. Respective HRs following additional adjustment for BMI and MVPA were 1.04 (95% CI 0.74-1.47), 1.04 (0.72-1.50), and 0.85 (0.56-1.29); Ptrend = 0.90. Fully adjusted isotemporal substitution results indicated that each 30 min of ST replaced with MVPA (but not light PA) was associated with 15% lower risk for diabetes (HR 0.85 [95% CI 0.75-0.96]; P = 0.01); the HR for replacing 30 min of light PA with MVPA was 0.85 (95% CI 0.73-0.98); P = 0.03. Mean bout duration was not associated with incident diabetes.<br><br>CONCLUSIONS: Statistically replacing ST or light PA with MVPA was associated with lower diabetes risk in older women. While reducing ST is important for several health outcomes, results indicate that to reduce diabetes risk among older adults, the primary public health focus should be on increasing MVPA.}, }
@article {pmid33270222, year = {2020}, author = {Begnel, ER and Drake, AL and Kinuthia, J and Matemo, D and Huang, ML and Ásbjörnsdóttir, KH and Chohan, V and Beima-Sofie, K and John-Stewart, G and Lehman, D and Slyker, J}, title = {Cervical cytomegalovirus reactivation, cytokines and spontaneous preterm birth in Kenyan women.}, journal = {Clinical and experimental immunology}, volume = {}, number = {}, pages = {}, doi = {10.1111/cei.13558}, pmid = {33270222}, issn = {1365-2249}, support = {P30 AI027757//Center for AIDS Research, University of Washington/ ; P01 HSD 064915//National Institutes of Health/ ; 5 R24 TW007988//Fogarty International Center/ ; }, abstract = {Genital cytomegalovirus (CMV) reactivation is common during the third trimester of pregnancy. We hypothesized that cervical CMV shedding may increase risk of spontaneous preterm birth (sPTB) through the release of inflammatory cytokines in the cervix. We conducted a nested case-control analysis to determine the relationship between CMV shedding and sPTB using data and samples from a prospective cohort study in western Kenya. Women who delivered between 28 + 0 and 33 + 6 weeks gestation were matched by gestational age at sample collection to controls who delivered ≥ 37 + 0 weeks. Levels of CMV DNA and interleukin (IL)-1 beta (β), IL-6, IL-8 and tumor necrosis factor (TNF)-α were measured in cervical swabs. We used conditional logistic regression to assess relationships between CMV shedding, cervical cytokine levels and sPTB. Among 86 cases and 86 matched controls, cervical CMV levels were not significantly associated with sPTB [odds ratio (OR) = 1·23, 95% confidence interval (CI) = 0·59-2·56], but were significantly associated with higher levels of cervical IL-6 (β = 0·15, 95% CI = 0·02-0·29) and TNF-α (β = 0·14, 95% CI = 0·01-0·27). In univariate analysis, higher odds of sPTB was associated with higher cervical IL-6 levels (OR = 1·54, 95% CI = 1·00-2·38), but not with other cervical cytokines. In this cohort of Kenyan women, we did not find a significant association between cervical CMV shedding and sPTB before 34 weeks.}, }
@article {pmid33268447, year = {2020}, author = {Carrot-Zhang, J and Soca-Chafre, G and Patterson, N and Thorner, AR and Nag, A and Watson, J and Genovese, G and Rodriguez, J and Gelbard, MK and Corrales-Rodriguez, L and Mitsuishi, Y and Ha, G and Campbell, JD and Oxnard, GR and Arrieta, O and Cardona, AF and Gusev, A and Meyerson, M}, title = {Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-20-1165}, pmid = {33268447}, issn = {2159-8290}, abstract = {Inherited lung cancer risk, particularly in non-smokers, is poorly understood. Genomic and ancestry analysis of 1153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden (TMB), and specific driver mutations in EGFR, KRAS, and STK11. A local Native American ancestry risk score was more strongly correlated with EGFR mutation frequency compared to global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities.}, }
@article {pmid33264614, year = {2020}, author = {Rakshit, S and Hingankar, N and Alampalli, SV and Adiga, V and Sundararaj, BK and Sahoo, PN and Finak, G and Uday Kumar J, AJ and Dhar, C and D'Souza, G and Virkar, RG and Ghate, M and Thakar, MR and Paranjape, RS and De Rosa, SC and Ottenhoff, THM and Vyakarnam, A}, title = {HIV Skews a Balanced Mtb-Specific Th17 Response in Latent Tuberculosis Subjects to a Pro-inflammatory Profile Independent of Viral Load.}, journal = {Cell reports}, volume = {33}, number = {9}, pages = {108451}, doi = {10.1016/j.celrep.2020.108451}, pmid = {33264614}, issn = {2211-1247}, abstract = {HIV infection predisposes latent tuberculosis-infected (LTBI) subjects to active TB. This study is designed to determine whether HIV infection of LTBI subjects compromises the balanced Mycobacterium tuberculosis (Mtb)-specific T helper 17 (Th17) response of recognized importance in anti-TB immunity. Comparative analysis of Mtb- and cytomegalovirus (CMV)-specific CD4+ T cell responses demonstrates a marked dampening of the Mtb-specific CD4+ T cell effectors and polyfunctional cells while preserving CMV-specific response. Additionally, HIV skews the Mtb-specific Th17 response in chronic HIV-infected LTBI progressors, but not long-term non-progressors (LTNPs), with preservation of pro-inflammatory interferon (IFN)-γ+/interleukin-17+ (IL-17+) and significant loss of anti-inflammatory IL-10+/IL-17+ effectors that is restored by anti-retroviral therapy (ART). HIV-driven impairment of Mtb-specific response cannot be attributed to preferential infection as cell-associated HIV DNA and HIV RNA reveal equivalent viral burden in CD4+ T cells from different antigen specificities. We therefore propose that beyond HIV-induced loss of Mtb-specific CD4+ T cells, the associated dysregulation of Mtb-specific T cell homeostasis can potentially enhance the onset of TB in LTBI subjects.}, }
@article {pmid33264543, year = {2020}, author = {,  and Krause, PR and Fleming, TR and Longini, IM and Peto, R and Beral, V and Bhargava, B and Cravioto, A and Cramer, J and Ellenberg, SS and Figueroa, JP and Halloran, E and Henao-Restrepo, AM and Ryan, MJ and Levine, MM and Nason, M and Nohynek, HM and Plotkin, S and Rees, H and Singh, JA and Swaminathan, S}, title = {Placebo-Controlled Trials of Covid-19 Vaccines - Why We Still Need Them.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMp2033538}, pmid = {33264543}, issn = {1533-4406}, }
@article {pmid33259788, year = {2020}, author = {Greaney, AJ and Starr, TN and Gilchuk, P and Zost, SJ and Binshtein, E and Loes, AN and Hilton, SK and Huddleston, J and Eguia, R and Crawford, KHD and Dingens, AS and Nargi, RS and Sutton, RE and Suryadevara, N and Rothlauf, PW and Liu, Z and Whelan, SPJ and Carnahan, RH and Crowe, JE and Bloom, JD}, title = {Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition.}, journal = {Cell host &amp; microbe}, volume = {}, number = {}, pages = {}, pmid = {33259788}, issn = {1934-6069}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and are a major contributor to neutralizing antibody responses elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies. They further enable the design of escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same RBD surface but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.}, }
@article {pmid33258502, year = {2020}, author = {Kapos, FP and White, LA and Schmidt, KA and Hawes, SE and Starr, JR}, title = {Risk of non-syndromic orofacial clefts by maternal rural-urban residence and race/ethnicity: A population-based case-control study in Washington State 1989-2014.}, journal = {Paediatric and perinatal epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ppe.12727}, pmid = {33258502}, issn = {1365-3016}, support = {T32CA094880/CA/NCI NIH HHS/United States ; R90DE23059/DE/NIDCR NIH HHS/United States ; //Institutes of Health under aw ard numbers R90DE023059 (FPK) and T32CA094880 (KAS)/ ; //Patrick-Beresford Fellowship in Social Epidemiology (FPK)/ ; //The content is solely the responsibility of the authors and does not necessarily represent the view s of the National Institutes of Health./ ; }, abstract = {BACKGROUND: Orofacial clefts (OFC) have multifactorial aetiology. Established risk factors explain a small proportion of cases.<br><br>OBJECTIVES: To evaluate OFC risk by maternal rural residence and race/ethnicity, and test whether these associations changed after US-mandated folic acid fortification.<br><br>METHODS: This population-based case-control study included all non-syndromic OFC cases among Washington State singleton livebirths between 1989-2014 and birth year-matched controls. Data sources included birth certificates and hospital records. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for OFC by maternal rural-urban residence (adjusted for maternal race/ethnicity) and by maternal race/ethnicity. We evaluated additive and multiplicative effect measure modification by time of folic acid fortification (before vs. after). Probabilistic quantitative bias analysis accounted for potential differential case ascertainment for infants born to Black mothers.<br><br>RESULTS: The overall non-syndromic OFC birth prevalence was 1.0 per 1000 livebirths (n = 2136 cases). Among controls (n = 25 826), 76% of mothers were urban residents and 72% were of White race/ethnicity. OFC risk was slightly higher for infants born to rural than to urban mothers, adjusting for race/ethnicity (OR 1.12, 95% CI 1.01, 1.25). The association was similar before and after US-mandated folic acid fortification. Compared with infants born to White mothers, OFC risk was higher for American Indian mothers (OR 1.73, 95% CI 1.35, 2.23) and lower for Black (OR 0.62, 95% CI 0.48, 0.81), Hispanic (OR 0.75, 95% CI 0.64, 0.87), and Asian/Pacific Islander (API) mothers (OR 0.87, 95% CI 0.74, 1.02). Bias analysis suggests the observed difference for Black mothers may be explained by selection bias. Post-fortification, the association of OFC with maternal API race/ethnicity decreased and with maternal Black race/ethnicity increased relative to maternal White race/ethnicity.<br><br>CONCLUSIONS: Infants born to rural mothers and to American Indian mothers in Washington State during 1989-2014 were at higher OFC risk before and after US-mandated folic acid fortification.}, }
@article {pmid33257847, year = {2020}, author = {Dominguez-Valentin, M and Crosbie, EJ and Engel, C and Aretz, S and Macrae, F and Winship, I and Capella, G and Thomas, H and Nakken, S and Hovig, E and Nielsen, M and Sijmons, RH and Bertario, L and Bonanni, B and Tibiletti, MG and Cavestro, GM and Mints, M and Gluck, N and Katz, L and Heinimann, K and Vaccaro, CA and Green, K and Lalloo, F and Hill, J and Schmiegel, W and Vangala, D and Perne, C and Strauß, HG and Tecklenburg, J and Holinski-Feder, E and Steinke-Lange, V and Mecklin, JP and Plazzer, JP and Pineda, M and Navarro, M and Vidal, JB and Kariv, R and Rosner, G and Piñero, TA and Gonzalez, ML and Kalfayan, P and Ryan, N and Ten Broeke, SW and Jenkins, MA and Sunde, L and Bernstein, I and Burn, J and Greenblatt, M and de Vos Tot Nederveen Cappel, WH and Della Valle, A and Lopez-Koestner, F and Alvarez, K and Büttner, R and Görgens, H and Morak, M and Holzapfel, S and Hüneburg, R and von Knebel Doeberitz, M and Loeffler, M and Rahner, N and Weitz, J and Pylvänäinen, K and Renkonen-Sinisalo, L and Lepistö, A and Auranen, A and Hopper, JL and Win, AK and Haile, RW and Lindor, NM and Gallinger, S and Le Marchand, L and Newcomb, PA and Figueiredo, JC and Thibodeau, SN and Therkildsen, C and Okkels, H and Ketabi, Z and Denton, OG and Rødland, EA and Vasen, H and Neffa, F and Esperon, P and Tjandra, D and Möslein, G and Sampson, JR and Evans, DG and Seppälä, TT and Møller, P}, title = {Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.}, journal = {Genetics in medicine : official journal of the American College of Medical Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41436-020-01029-1}, pmid = {33257847}, issn = {1530-0366}, support = {194751//Kreftforeningen/ ; }, abstract = {PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.<br><br>METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.<br><br>RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.<br><br>CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.}, }
@article {pmid33257776, year = {2020}, author = {Kanaan, SB and Delaney, C and Milano, F and Scaradavou, A and Besien, KV and Allen, J and Lambert, NC and Cousin, E and Thur, LA and Kahn, E and Forsyth, AM and Sensoy, O and Nelson, JL}, title = {Cord blood maternal microchimerism following unrelated cord blood transplantation.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-020-01149-x}, pmid = {33257776}, issn = {1476-5365}, support = {R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HL117737//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Cord blood transplantation (CBT) is associated with low risk of leukemia relapse. Mechanisms underlying antileukemia benefit of CBT are not well understood, however a previous study strongly but indirectly implicated cells from the mother of the cord blood (CB) donor. A fetus acquires a small number of maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes detectable in CB. From a series of 95 patients who underwent double or single CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68. We employed a technique of highly sensitive HLA-specific quantitative-PCR assays targeting polymorphisms unique to the CB mother to assay CB-MMc in patients post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple timepoints in 36 patients (529 specimens). CB-MMc was present in seven (19.4%) patients in bone marrow, peripheral blood, innate and adaptive immune cell subsets, and was detected up to 1-year post-CBT. Statistical trends to lower relapse, mortality, and treatment failure were observed for patients with vs. without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells of the CB graft can be tracked in recipients post-CBT, and underscore the importance of further investigating CB-MMc in sustained remission from leukemia following CBT.}, }
@article {pmid33257690, year = {2020}, author = {Fichtner, M and Bozkurt, E and Salvucci, M and McCann, C and McAllister, KA and Halang, L and Düssmann, H and Kinsella, S and Crawford, N and Sessler, T and Longley, DB and Prehn, JHM}, title = {Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant.}, journal = {Cell death &amp; disease}, volume = {11}, number = {11}, pages = {1020}, pmid = {33257690}, issn = {2041-4889}, support = {C11884/A24387/CRUK_/Cancer Research UK/United Kingdom ; }, abstract = {Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.}, }
@article {pmid33255329, year = {2020}, author = {Solan, JL and Lampe, PD}, title = {Src Regulation of Cx43 Phosphorylation and Gap Junction Turnover.}, journal = {Biomolecules}, volume = {10}, number = {12}, pages = {}, pmid = {33255329}, issn = {2218-273X}, support = {GM55632/GM/NIGMS NIH HHS/United States ; }, abstract = {The gap junction protein Connexin43 (Cx43) is highly regulated by phosphorylation at over a dozen sites by probably at least as many kinases. This Cx43 &quot;kinome&quot; plays an important role in gap junction assembly and turnover. We sought to gain a better understanding of the interrelationship of these phosphorylation events particularly related to src activation and Cx43 turnover. Using state-of-the-art live imaging methods, specific inhibitors and many phosphorylation-status specific antibodies, we found phospho-specific domains in gap junction plaques and show evidence that multiple pathways of disassembly exist and can be regulated at the cellular and subcellular level. We found Src activation promotes formation of connexisomes (internalized gap junctions) in a process involving ERK-mediated phosphorylation of S279/282. Proteasome inhibition dramatically and rapidly restored gap junctions in the presence of Src and led to dramatic changes in the Cx43 phospho-profile including to increased Y247, Y265, S279/282, S365, and S373 phosphorylation. Lysosomal inhibition, on the other hand, nearly eliminated phosphorylation on Y247 and Y265 and reduced S368 and S373 while increasing S279/282 phosphorylation levels. We present a model of gap junction disassembly where multiple modes of disassembly are regulated by phosphorylation and can have differential effects on cellular signaling.}, }
@article {pmid33253015, year = {2020}, author = {Perlman, JE and Gooley, TA and McNulty, B and Meyers, J and Hirsch, IB}, title = {HbA1c and Glucose Management Indicator Discordance: A Real-World Analysis.}, journal = {Diabetes technology &amp; therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1089/dia.2020.0501}, pmid = {33253015}, issn = {1557-8593}, abstract = {Background: There can be marked discordance between laboratory and estimated (using the glucose management indicator [GMI]) glycated hemoglobin (HbA1c) from continuous glucose monitoring (CGM). This may cause errors in diabetes management. This study evaluates discordance between laboratory and CGM-estimated HbA1c (eA1C). Methods: We performed a retrospective review of patients with diabetes who use CGM. The patients were seen at the University of Washington (UW) Diabetes Care Center from 2012 to 2019. We used UW's Institute of Translational Health Sciences to extract eligible encounters from the electronic medical record. We required that patients use CGM and that HbA1c and sensor data be obtained fewer than 4 weeks apart. There were no exclusion criteria. We calculated HbA1c-GMI discordance for each subject and assessed for any impact of comorbidities. We defined HbA1c-GMI discordance as absolute difference between laboratory and eA1C. Results: This study included 641 separate office encounters. Ninety-one percent of patients had type 1 diabetes. Most patients had diabetes for greater than 20 years. The mean duration of CGM wear was 24.5 ± 8 days. Only 11% of patients had HbA1c-GMI discordance <0.1%, but 50% and 22% had differences ≥0.5% and ≥1%. There was increased discordance with advanced chronic kidney disease (estimated glomerular filtration rate <60). Discussion: We found substantial discordance between laboratory and eA1C in a real-world setting. Clinicians need be aware that HbA1c may not as accurately reflect mean glucose as previously appreciated.}, }
@article {pmid33252629, year = {2020}, author = {Peres, LC and Bethea, TN and Camacho, TF and Bandera, EV and Beeghly-Fadiel, A and Chyn, DL and Harris, HR and Joslin, CE and Moorman, PG and Myers, E and Ochs-Balcom, HM and Rosenow, W and Setiawan, VW and Wu, AH and Rosenberg, L and Schildkraut, JM}, title = {Racial differences in population attributable risk for epithelial ovarian cancer in the OCWAA Consortium.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaa188}, pmid = {33252629}, issn = {1460-2105}, abstract = {BACKGROUND: The causes of racial disparities in epithelial ovarian cancer (EOC) incidence remain unclear. Differences in the prevalence of ovarian cancer risk factors may explain disparities in EOC incidence among African American (AA) and White women.<br><br>METHODS: We used data from four case-control studies and three case-control studies nested within prospective cohorts in the Ovarian Cancer in Women of African Ancestry Consortium to estimate race-specific associations of ten known or suspected EOC risk factors using logistic regression. Using the Bruzzi method, race-specific population attributable risks (PAR) were estimated for each risk factor individually and collectively, including groupings of exposures (reproductive factors and modifiable factors). All statistical tests were two-sided.<br><br>RESULTS: Among 3,244 White EOC cases and 9,638 controls and 1,052 AA EOC cases and 2,410 controls, AA women had a statistically significantly higher PAR (false discovery rate (FDR) P < .001) for first-degree family history of breast cancer (PAR = 10.1%, 95% CI = 6.5% to 13.7%) compared to White women (PAR = 2.6%, 95% CI = 0.8% to 4.4%). After multiple test correction, AA women had a higher PAR than White women when evaluating all risk factors collectively (PAR = 61.6%, 95% CI = 48.6% to 71.3% vs. PAR = 43.0%, 95% CI = 32.8% to 51.4%, respectively; FDR P = .06) and for modifiable exposures, including BMI, oral contraceptives, aspirin, and body powder (PAR = 36.0%, 95% CI = 21.0% to 48.8% vs. PAR = 13.8%, 95% CI = 4.5% to 21.8%, respectively; FDR P = .04).<br><br>CONCLUSIONS: Collectively, the selected risk factors accounted for slightly more of the risk among AA than White women, and interventions to reduce EOC incidence that are focused on multiple modifiable risk factors may be slightly more beneficial to AA women than White women at risk for EOC.}, }
@article {pmid33252489, year = {2020}, author = {Zeziulin, O and Mollan, KR and Shook-Sa, BE and Hanscom, B and Lancaster, KE and Dumchev, K and Go, VF and Chu, VA and Kiriazova, T and Syarif, Z and Dvoryaka, S and Reifeis, SA and Hamilton, E and Sarasvita, R and Rose, S and Richardson, P and Clarke, W and Latkin, CA and Metzger, DS and Hoffman, IF and Miller, WC}, title = {Depressive symptoms and use of HIV care and medication-assisted treatment among people living with HIV who inject drugs.}, journal = {AIDS (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1097/QAD.0000000000002774}, pmid = {33252489}, issn = {1473-5571}, abstract = {OBJECTIVE: Vietnam, Indonesia, and Ukraine have major burdens of injection drug use (IDU) and HIV. We estimated prevalence of depressive symptoms at baseline among people living with HIV (PLWH) who inject drugs, evaluated associations between depression at baseline and 12-month HIV care outcomes and medication-assisted treatment (MAT), and evaluated the study intervention effect by baseline depression subgroups.<br><br>DESIGN: HPTN 074 was a randomized study. The study intervention included psychosocial counseling, systems navigation, and antiretroviral treatment (ART) at any CD4 count.<br><br>METHODS: Moderate-to-severe depression was defined as a Patient Health Questionnaire (PHQ-9) score of 10 or above. ART and MAT were self-reported. Eligibility criteria were: 18-60 years of age, active IDU, and viral load ≥1000 cp/mL. Adjusted probability differences (aPD) were estimated using inverse-probability weighting.<br><br>RESULTS: 502 participants enrolled from April 2015-June 2016. Median age was 35 years; 85% identified as men. Prevalence of baseline moderate-to-severe depression was 14% in Vietnam, 14% in Indonesia, and 56% in Ukraine. No evident associations were detected between baseline depression and ART, viral suppression, or MAT at 12-month follow-up. The study intervention improved the proportions of PWID achieving 12-month viral suppression in both the depressed (intervention 44%; standard of care (SOC) 24%; estimated aPD = 25% [95%CI: 4.0%, 45%]) and non-depressed subgroups (intervention 38%; SOC 24%; aPD = 13% [95%CI: 2.0%, 25%]).<br><br>CONCLUSIONS: High levels of depressive symptoms were common among PLWH who inject drugs in Ukraine but were less common in Vietnam and Indonesia. The study intervention was effective among participants with or without baseline depression symptoms.}, }
@article {pmid33252141, year = {2020}, author = {Rosenberg, DE and Rillamas-Sun, E and Bellettiere, J and LaMonte, M and Buchner, DM and Di, C and Hunt, J and Marshall, S and Stefanick, M and Zhang, Y and LaCroix, AZ}, title = {Accelerometer-Measured Sedentary Patterns are Associated with Incident Falls in Older Women.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.16923}, pmid = {33252141}, issn = {1532-5415}, support = {K23HL119352/HL/NHLBI NIH HHS/United States ; R01HL105065/HL/NHLBI NIH HHS/United States ; T32HL079891-11/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN26820160//U.S. Department of Health and Human Services/ ; }, abstract = {BACKGROUND/OBJECTIVE: Falls cause significant problems for older adults. Sedentary time is associated with lower physical function and could increase the risk for falls.<br><br>DESIGN: Prospective study.<br><br>SETTING: Sites across the United States.<br><br>PARTICIPANTS: Older women (N = 5,545, mean age 79 years) from the Women' Health Initiative Objective Physical Activity and Cardiovascular Health study.<br><br>MEASUREMENTS: Accelerometers worn at the hip for up to 1 week collected measures of daily sedentary time and the mean sedentary bout duration, a commonly used metric for sedentary accumulation patterns. For up to 13 months after accelerometer wear, women reported daily whether they had fallen on monthly calendars.<br><br>RESULTS: In fully adjusted models, the incident rate ratios (95% confidence interval) for quartiles 1 (lowest), 2, 3, and 4 of sedentary time respectively were 1.0 (ref.), 1.07 (0.93-1.24), 1.07 (0.91-1.25), and 1.14 (0.96-1.35; P-trend = .65) and for mean sedentary bout duration was 1.0 (ref.), 1.05 (0.92-1.21), 1.02 (0.88-1.17), and 1.17 (1.01-1.37; P-trend = .01), respectively. Women with a history of two or more falls had stronger associations between sedentary time and falls incidence compared with women with a history of no or one fall (P for interaction = .046).<br><br>CONCLUSIONS: Older women in the highest quartile of mean sedentary bout duration had a significantly increased risk of falling. Women with a history of frequent falling may be at higher risk for falling if they have high sedentary time. Interventions testing whether shortening total sedentary time and/or sedentary bouts lowers fall risk are needed to confirm these observational findings.}, }
@article {pmid33251990, year = {2020}, author = {Roth, JA and Carlson, JJ and Xia, F and Williamson, T and Sullivan, SD}, title = {THE AUTHORS RESPOND.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {26}, number = {12}, pages = {1617-1618}, doi = {10.18553/jmcp.2020.26.12.1617}, pmid = {33251990}, issn = {2376-1032}, abstract = {DISCLOSURES: Funding for the study referred to in this letter was contributed by Bayer Healthcare. Xia and Williamson are employees of Bayer Healthcare. Roth, Carlson, and Sullivan are consultants to Bayer Healthcare. Carlson also reports fees from Adaptive Biotechnologies, unrelated to the study. Roth reports consulting fees from BMS, unrelated to the study.}, }
@article {pmid33248521, year = {2020}, author = {Nghiem, VT and Vaidya, R and Lyman, GH and Hershman, DL and Ramsey, SD and Unger, JM}, title = {Economic Evaluations in National Cancer Institute-Sponsored Network Cancer Clinical Trials.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {23}, number = {12}, pages = {1653-1661}, doi = {10.1016/j.jval.2020.08.2095}, pmid = {33248521}, issn = {1524-4733}, abstract = {OBJECTIVES: Amid a rapid increase in cancer care costs, we examined the extent to which economic evaluations (EEs) were conducted for new treatments evaluated in clinical trials at SWOG, a large National Cancer Institute-sponsored cancer research network.<br><br>METHODS: We investigated phase III cancer treatment clinical trials activated from 1980 onward with primary articles reporting the protocol-designated endpoints published in scientific journals by 2017. Using PubMed, Web of Science, and EconLit, we searched for EEs using trial name, cancer type, information on the comparison arms, and refined keywords for EE designs. We reported the overall proportion of trials with associated EEs and trends of this proportion over time. We synthesized and analyzed information on funding sources, health outcomes, and sources of quality-of-life and cost data from the EEs.<br><br>RESULTS: Among 182 examined trials, 15 EEs were associated with 13 (7.1%) trials. Among the EEs, almost half (7 of 15) were either unfunded or did not report funding information, whereas nearly half (7 of 15) were funded by pharmaceutical companies and 2 (2 of 15, 13.3%) were supported by federal funding. All EEs reported a healthcare payer perspective. The proportion of trials with an associated EE increased from 1980 to 1989 and 2000 to 2009, but never exceeded 11%. Sources for cost and quality-of-life data for the EEs primarily came from outside the clinical trials.<br><br>CONCLUSIONS: Few economic studies of treatments evaluated in National Cancer Institute-sponsored clinical trials have been conducted. Policymakers, payers, and patients lack economic evidence to consider newly evaluated cancer treatments, despite an urgent need to control healthcare costs.}, }
@article {pmid33247132, year = {2020}, author = {Fang, H and Bonora, G and Lewandowski, JP and Thakur, J and Filippova, GN and Henikoff, S and Shendure, J and Duan, Z and Rinn, JL and Deng, X and Noble, WS and Disteche, CM}, title = {Trans- and cis-acting effects of Firre on epigenetic features of the inactive X chromosome.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {6053}, pmid = {33247132}, issn = {2041-1723}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Alleles ; Animals ; Base Sequence ; Cell Line ; Cell Nucleus/genetics ; Chromatin/metabolism ; DNA, Complementary/genetics ; *Epigenesis, Genetic ; Female ; Gene Deletion ; Gene Ontology ; Genetic Loci ; Genome ; Histones/metabolism ; Lysine/metabolism ; Male ; Methylation ; Mice, Inbred C57BL ; Polycomb Repressive Complex 2/metabolism ; RNA, Long Noncoding/*genetics/metabolism ; Transgenes ; Up-Regulation/genetics ; X Chromosome/genetics ; X Chromosome Inactivation/*genetics ; }, abstract = {Firre encodes a lncRNA involved in nuclear organization. Here, we show that Firre RNA expressed from the active X chromosome maintains histone H3K27me3 enrichment on the inactive X chromosome (Xi) in somatic cells. This trans-acting effect involves SUZ12, reflecting interactions between Firre RNA and components of the Polycomb repressive complexes. Without Firre RNA, H3K27me3 decreases on the Xi and the Xi-perinucleolar location is disrupted, possibly due to decreased CTCF binding on the Xi. We also observe widespread gene dysregulation, but not on the Xi. These effects are measurably rescued by ectopic expression of mouse or human Firre/FIRRE transgenes, supporting conserved trans-acting roles. We also find that the compact 3D structure of the Xi partly depends on the Firre locus and its RNA. In common lymphoid progenitors and T-cells Firre exerts a cis-acting effect on maintenance of H3K27me3 in a 26 Mb region around the locus, demonstrating cell type-specific trans- and cis-acting roles of this lncRNA.}, }
@article {pmid33247092, year = {2020}, author = {Parayath, NN and Stephan, SB and Koehne, AL and Nelson, PS and Stephan, MT}, title = {In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {6080}, pmid = {33247092}, issn = {2041-1723}, mesh = {Animals ; CD8-Positive T-Lymphocytes/immunology ; Female ; Hemolysis ; Hep G2 Cells ; Hepatitis B virus/immunology ; Humans ; Immunocompetence ; Immunotherapy, Adoptive ; Leukemia/pathology ; Ligands ; Mice ; Nanoparticles/*chemistry ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Receptors, Antigen, T-Cell/*metabolism ; Receptors, Chimeric Antigen/metabolism ; T-Lymphocytes/*immunology ; *Transcription, Genetic ; Transgenes ; }, abstract = {Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.}, }
@article {pmid33245934, year = {2020}, author = {Su, F and Weiss, NS and Beste, LA and Moon, AM and Jin, GY and Green, P and Berry, K and Ioannou, GN}, title = {Screening is associated with a lower risk of hepatocellular carcinoma-related mortality in patients with chronic hepatitis B.}, journal = {Journal of hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jhep.2020.11.023}, pmid = {33245934}, issn = {1600-0641}, abstract = {BACKGROUND AND AIMS: Patients with chronic hepatitis B (CHB) infection routinely undergo screening for hepatocellular carcinoma (HCC), but the efficacy of screening remains unclear. We aimed to evaluate the impact of screening with ultrasound (USS) and/or serum alpha-fetoprotein (AFP) on HCC-related mortality in patients with CHB.<br><br>METHODS: We performed a matched case-control study of patients with CHB receiving care through the Veterans Affairs (VA) health administration. Cases were patients who died of HCC between 01/01/2004 and 12/31/2017, while controls were patients with CHB who did not die of HCC. Cases were matched to controls by CHB diagnosis date, age, sex, race/ethnicity, cirrhosis, antiviral therapy exposure, hepatitis B e antigen status, and viral load. We identified screening USS and AFPs obtained in the 4 years preceding HCC diagnosis in cases and the equivalent index date in controls. Using conditional logistic regression, we compared cases and controls with respect to receipt of screening. A lower likelihood of screening in cases corresponds to an association between screening and reduced risk of HCC-related mortality.<br><br>RESULTS: We identified 169 cases, matched to 169 controls. Fewer cases than controls underwent screening with either screening modality (33.7% versus 58.6%) or both modalities (19.5% versus 34.4%). In multivariable conditional logistic regression, screening with either modality was associated with a lower risk of HCC-related mortality (adjusted odds ratio [aOR] 0.21, 95% confidence interval [CI] 0.09-0.50), as was screening with both modalities (aOR of 0.13, 95% CI 0.04-0.43).<br><br>CONCLUSIONS: HCC screening was associated with a substantial reduction in HCC-related mortality in VA patients with CHB.}, }
@article {pmid33245207, year = {2020}, author = {Gallego, S and Chi, YY and De Salvo, GL and Li, M and Merks, JHM and Rodeberg, DA and van Scheltinga, ST and Mascarenhas, L and Orbach, D and Jenney, M and Million, L and Minard-Colin, V and Wolden, S and Zanetti, I and Parham, DM and Mandeville, H and Venkatramani, R and Bisogno, G and Hawkins, DS and , }, title = {Alveolar rhabdomyosarcoma with regional nodal involvement: Results of a combined analysis from two cooperative groups.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e28832}, doi = {10.1002/pbc.28832}, pmid = {33245207}, issn = {1545-5017}, support = {U10CA180886//Children's Oncology Group/ ; U10CA180899//Children's Oncology Group/ ; U10CA098543//Children's Oncology Group/ ; U10CA098413//Children's Oncology Group/ ; //St. Baldrick's Foundation/ ; //EpSSG/ ; //Fondazione Città della Speranza/ ; }, abstract = {BACKGROUND: Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG).<br><br>METHODS: We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols.<br><br>RESULTS: The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative.<br><br>CONCLUSIONS: The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients.}, }
@article {pmid33244440, year = {2020}, author = {Benkeser, D and Juraska, M and Gilbert, PB}, title = {Assessing trends in vaccine efficacy by pathogen genetic distance.}, journal = {Journal de la Societe francaise de statistique (2009)}, volume = {161}, number = {1}, pages = {164-175}, pmid = {33244440}, issn = {2102-6238}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; }, abstract = {Preventive vaccines are an effective public health intervention for reducing the burden of infectious diseases, but have yet to be developed for several major infectious diseases. Vaccine sieve analysis studies whether and how the efficacy of a vaccine varies with the genetics of the infectious pathogen, which may help guide future vaccine development and deployment. A standard statistical approach to sieve analysis compares the effect of the vaccine to prevent infection and disease caused by pathogen types defined dichotomously as genetically near or far from a reference pathogen strain inside the vaccine construct. For example, near may be defined by amino acid identity at all amino acid positions considered in a multiple alignment and far defined by at least one amino acid difference. An alternative approach is to study the efficacy of the vaccine as a function of genetic distance from a pathogen to a reference vaccine strain where the distance cumulates over the set of amino acid positions. We propose a nonparametric method for estimating and testing the trend in the effect of a vaccine across genetic distance. We illustrate the operating characteristics of the estimator via simulation and apply the method to a recent preventive malaria vaccine efficacy trial.}, }
@article {pmid33243876, year = {2020}, author = {Raghavan, S and Vasioukhin, V}, title = {Staying connected under tension.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6520}, pages = {1036-1037}, doi = {10.1126/science.abf2782}, pmid = {33243876}, issn = {1095-9203}, support = {R01 CA234050/CA/NCI NIH HHS/United States ; }, mesh = {*Mechanotransduction, Cellular ; *Microfilament Proteins ; }, }
@article {pmid33242424, year = {2020}, author = {Petralia, F and Tignor, N and Reva, B and Koptyra, M and Chowdhury, S and Rykunov, D and Krek, A and Ma, W and Zhu, Y and Ji, J and Calinawan, A and Whiteaker, JR and Colaprico, A and Stathias, V and Omelchenko, T and Song, X and Raman, P and Guo, Y and Brown, MA and Ivey, RG and Szpyt, J and Guha Thakurta, S and Gritsenko, MA and Weitz, KK and Lopez, G and Kalayci, S and Gümüş, ZH and Yoo, S and da Veiga Leprevost, F and Chang, HY and Krug, K and Katsnelson, L and Wang, Y and Kennedy, JJ and Voytovich, UJ and Zhao, L and Gaonkar, KS and Ennis, BM and Zhang, B and Baubet, V and Tauhid, L and Lilly, JV and Mason, JL and Farrow, B and Young, N and Leary, S and Moon, J and Petyuk, VA and Nazarian, J and Adappa, ND and Palmer, JN and Lober, RM and Rivero-Hinojosa, S and Wang, LB and Wang, JM and Broberg, M and Chu, RK and Moore, RJ and Monroe, ME and Zhao, R and Smith, RD and Zhu, J and Robles, AI and Mesri, M and Boja, E and Hiltke, T and Rodriguez, H and Zhang, B and Schadt, EE and Mani, DR and Ding, L and Iavarone, A and Wiznerowicz, M and Schürer, S and Chen, XS and Heath, AP and Rokita, JL and Nesvizhskii, AI and Fenyö, D and Rodland, KD and Liu, T and Gygi, SP and Paulovich, AG and Resnick, AC and Storm, PB and Rood, BR and Wang, P and ,  and , }, title = {Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer.}, journal = {Cell}, volume = {183}, number = {7}, pages = {1962-1985.e31}, doi = {10.1016/j.cell.2020.10.044}, pmid = {33242424}, issn = {1097-4172}, abstract = {We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.}, }
@article {pmid33238295, year = {2020}, author = {Rybak, MJ and Le, J and Lodise, TP and Levine, DP and Bradley, JS and Liu, C and Mueller, BA and Pai, MP and Beringer, AW and Rodvold, KA and Maples, HD}, title = {Questions on Vancomycin dosing.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1775}, pmid = {33238295}, issn = {1537-6591}, }
@article {pmid33237305, year = {2020}, author = {Lin, DW and Nelson, PS}, title = {Prognostic Genomic Biomarkers in Patients With Localized Prostate Cancer: Is Rising Utilization Justified by Evidence?.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2020.6045}, pmid = {33237305}, issn = {2374-2445}, }
@article {pmid33236329, year = {2020}, author = {Mamolo, C and Welch, V and Walter, RB and Cappelleri, JC and Brockbank, J and Cawson, M and Knight, C and Wilson, M}, title = {Budget Impact Analysis of Gemtuzumab Ozogamicin for the Treatment of CD33-Positive Acute Myeloid Leukemia.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40273-020-00976-6}, pmid = {33236329}, issn = {1179-2027}, abstract = {BACKGROUND: Gemtuzumab ozogamicin (GO) was approved in 2017 in the US for the treatment of adults with newly diagnosed CD33-positive (CD33+) acute myeloid leukemia (AML), and adults and pediatric patients with CD33+ relapsed/refractory (R/R) AML.<br><br>OBJECTIVE: The aim of this study was to estimate the budgetary impact of introducing GO to a 1-million-member US health plan over a 5-year period.<br><br>METHODS: We developed models to estimate the impact of introducing GO in combination with conventional induction chemotherapy or as monotherapy for newly diagnosed AML, and as monotherapy for R/R AML. Models were built using data on drug costs and treatment-related outcomes obtained from published clinical trials and other publicly available sources. Results were reported on a per member/per year and per member/per month (PMPM) basis.<br><br>RESULTS: Base-case results of the newly diagnosed model indicated that the addition of GO in the combination setting reduced the overall budget of a 1-million-member health plan. The estimated net cost (US$) savings ranged from $72,969 ($0.006 PMPM) in year 1 to $745,426 ($0.062 PMPM) in year 5. In the monotherapy setting, GO was associated with increased net costs ranging from $4118 (0.0003 PMPM) in year 1 to $31,885 ($0.003 PMPM) in year 5. Base-case results of the R/R AML model demonstrated increased net costs that ranged from $17,326 ($0.001 PMPM) in year 1 to $46,163 ($0.004 PMPM) in year 5. Scenario analyses in all settings indicated the budget impact was not overly sensitive to the selected input assumptions, with the exception of the scenario considering only the pharmacy budget impact in the combination setting.<br><br>CONCLUSIONS: The introduction of GO for newly diagnosed and R/R AML would have a minimal impact on the budget of a US health plan and could result in cost savings in the combination therapy setting for newly diagnosed AML.}, }
@article {pmid33235157, year = {2020}, author = {Field, MT and Chapple, A and Hoeppner, C and Boiko, JR and Tellinghuisen, A and Joshi, S and Vitanza, NA}, title = {Care Coordination in a SARS-CoV-2-infected Child With Newly Diagnosed Medulloblastoma and Fanconi Anemia.}, journal = {Journal of pediatric hematology/oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPH.0000000000002021}, pmid = {33235157}, issn = {1536-3678}, abstract = {COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for a global pandemic that can cause severe infections in children, especially those with comorbid conditions. Here, we report a case of a child with a newly diagnosed medulloblastoma, Fanconi Anemia, and SARS-CoV-2 infection. Through multidisciplinary care coordination and meticulous planning, we were able to safely initiate this patient's oncology care and implement a long-term model to address the patient's care. This approach could be replicated with any newly diagnosed pediatric patient that requires monitoring for signs of COVID-19 with concurrent oncology care.}, }
@article {pmid33232476, year = {2020}, author = {Gerds, AT and Savona, MR and Scott, BL and Talpaz, M and Egyed, M and Harrison, CN and Yacoub, A and Vannucchi, A and Mead, AJ and Kiladjian, JJ and O'Sullivan, J and García-Gutiérrez, V and Bose, P and Rampal, RK and Miller, CB and Palmer, J and Oh, ST and Buckley, SA and Mould, DR and Ito, K and Tyavanagimatt, S and Smith, JA and Roman-Torres, K and Devineni, S and Craig, AR and Mascarenhas, JO}, title = {Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis.}, journal = {Blood advances}, volume = {4}, number = {22}, pages = {5825-5835}, pmid = {33232476}, issn = {2473-9537}, abstract = {PAC203 is a randomized dose-finding study of pacritinib, an oral JAK2/IRAK1 inhibitor, in patients with advanced myelofibrosis who are intolerant of or resistant to ruxolitinib. Patients were randomized 1:1:1 to pacritinib 100 mg once per day, 100 mg twice per day, or 200 mg twice per day. Enhanced eligibility criteria, monitoring, and dose modifications were implemented to mitigate risk of cardiac and hemorrhagic events. Efficacy was based on ≥35% spleen volume response (SVR) and ≥50% reduction in the 7-component total symptom score (TSS) through week 24. Of 161 patients, 73% were intolerant of and 76% had become resistant to ruxolitinib; 50% met criteria for both. Severe thrombocytopenia (platelet count <50 × 103/μL) was present in 44%. SVR rates were highest with 200 mg twice per day (100 mg once per day, 0%; 100 mg twice per day, 1.8%; 200 mg twice per day, 9.3%), particularly among patients with baseline platelet counts <50 × 103/μL (17%; 4 of 24). Although TSS response rate was similar across doses (100 mg once per day, 7.7%; 100 mg twice per day, 7.3%; 200 mg twice per day, 7.4%), median percent reduction in TSS suggested a dose-response relationship (-3%, -16%, and -27%, respectively). Pharmacokinetic and pharmacodynamic modeling based on all available data showed greatest SVR and TSS reduction at 200 mg twice per day compared with lower doses. Common adverse events were gastrointestinal events, thrombocytopenia, and anemia. There was no excess of grade ≥3 hemorrhagic or cardiac events at 200 mg twice per day. Pacritinib 200 mg twice per day demonstrated clinical activity and an acceptable safety profile and was selected as the recommended dose for a pivotal phase 3 study in patients with myelofibrosis and severe thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT03165734.}, }
@article {pmid33232376, year = {2020}, author = {Taher, H and Mahyari, E and Kreklywich, C and Uebelhoer, LS and McArdle, MR and Moström, MJ and Bhusari, A and Nekorchuk, M and E, X and Whitmer, T and Scheef, EA and Sprehe, LM and Roberts, DL and Hughes, CM and Jackson, KA and Selseth, AN and Ventura, AB and Cleveland-Rubeor, HC and Yue, Y and Schmidt, KA and Shao, J and Edlefsen, PT and Smedley, J and Kowalik, TF and Stanton, RJ and Axthelm, MK and Estes, JD and Hansen, SG and Kaur, A and Barry, PA and Bimber, BN and Picker, LJ and Streblow, DN and Früh, K and Malouli, D}, title = {In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome.}, journal = {PLoS pathogens}, volume = {16}, number = {11}, pages = {e1008666}, pmid = {33232376}, issn = {1553-7374}, support = {R01 AI059457/AI/NIAID NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; R01 AI095113/AI/NIAID NIH HHS/United States ; U42 OD023038/OD/NIH HHS/United States ; U19 AI128741/AI/NIAID NIH HHS/United States ; DP2 HD075699/HD/NICHD NIH HHS/United States ; P01 AI129859/AI/NIAID NIH HHS/United States ; R37 AI054292/AI/NIAID NIH HHS/United States ; P01 AI094417/AI/NIAID NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; U42 OD010426/OD/NIH HHS/United States ; }, abstract = {Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the only available RhCMV clone that permits genetic modifications is based on the 68-1 strain which has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptations. As a result, 68-1 displays reduced viremia in RhCMV-naïve animals and limited shedding compared to non-clonal, low passage isolates. To overcome this limitation, we used sequence information from primary RhCMV isolates to construct a full-length (FL) RhCMV by repairing all mutations affecting open reading frames (ORFs) in the 68-1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naïve RM with the reconstituted virus resulted in significant viremia in the blood similar to primary isolates of RhCMV and furthermore led to high viral genome copy numbers in many tissues at day 14 post infection. In contrast, viral dissemination was greatly reduced upon deletion of genes also lacking in 68-1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68-1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques.}, }
@article {pmid33231879, year = {2020}, author = {Stock, W and Martinelli, G and Stelljes, M and DeAngelo, DJ and Gökbuget, N and Advani, AS and O'Brien, S and Liedtke, M and Merchant, AA and Cassaday, RD and Wang, T and Zhang, H and Vandendries, E and Jabbour, E and Marks, DI and Kantarjian, HM}, title = {Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33321}, pmid = {33231879}, issn = {1097-0142}, support = {//Pfizer Inc/ ; }, abstract = {BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options.<br><br>METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO.<br><br>RESULTS: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%).<br><br>CONCLUSION: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.}, }
@article {pmid33230300, year = {2020}, author = {Surendran, P and Feofanova, EV and Lahrouchi, N and Ntalla, I and Karthikeyan, S and Cook, J and Chen, L and Mifsud, B and Yao, C and Kraja, AT and Cartwright, JH and Hellwege, JN and Giri, A and Tragante, V and Thorleifsson, G and Liu, DJ and Prins, BP and Stewart, ID and Cabrera, CP and Eales, JM and Akbarov, A and Auer, PL and Bielak, LF and Bis, JC and Braithwaite, VS and Brody, JA and Daw, EW and Warren, HR and Drenos, F and Nielsen, SF and Faul, JD and Fauman, EB and Fava, C and Ferreira, T and Foley, CN and Franceschini, N and Gao, H and Giannakopoulou, O and Giulianini, F and Gudbjartsson, DF and Guo, X and Harris, SE and Havulinna, AS and Helgadottir, A and Huffman, JE and Hwang, SJ and Kanoni, S and Kontto, J and Larson, MG and Li-Gao, R and Lindström, J and Lotta, LA and Lu, Y and Luan, J and Mahajan, A and Malerba, G and Masca, NGD and Mei, H and Menni, C and Mook-Kanamori, DO and Mosen-Ansorena, D and Müller-Nurasyid, M and Paré, G and Paul, DS and Perola, M and Poveda, A and Rauramaa, R and Richard, M and Richardson, TG and Sepúlveda, N and Sim, X and Smith, AV and Smith, JA and Staley, JR and Stanáková, A and Sulem, P and Thériault, S and Thorsteinsdottir, U and Trompet, S and Varga, TV and Velez Edwards, DR and Veronesi, G and Weiss, S and Willems, SM and Yao, J and Young, R and Yu, B and Zhang, W and Zhao, JH and Zhao, W and Zhao, W and Evangelou, E and Aeschbacher, S and Asllanaj, E and Blankenberg, S and Bonnycastle, LL and Bork-Jensen, J and Brandslund, I and Braund, PS and Burgess, S and Cho, K and Christensen, C and Connell, J and Mutsert, R and Dominiczak, AF and Dörr, M and Eiriksdottir, G and Farmaki, AE and Gaziano, JM and Grarup, N and Grove, ML and Hallmans, G and Hansen, T and Have, CT and Heiss, G and Jørgensen, ME and Jousilahti, P and Kajantie, E and Kamat, M and Käräjämäki, A and Karpe, F and Koistinen, HA and Kovesdy, CP and Kuulasmaa, K and Laatikainen, T and Lannfelt, L and Lee, IT and Lee, WJ and ,  and Linneberg, A and Martin, LW and Moitry, M and Nadkarni, G and Neville, MJ and Palmer, CNA and Papanicolaou, GJ and Pedersen, O and Peters, J and Poulter, N and Rasheed, A and Rasmussen, KL and Rayner, NW and Mägi, R and Renström, F and Rettig, R and Rossouw, J and Schreiner, PJ and Sever, PS and Sigurdsson, EL and Skaaby, T and Sun, YV and Sundstrom, J and Thorgeirsson, G and Esko, T and Trabetti, E and Tsao, PS and Tuomi, T and Turner, ST and Tzoulaki, I and Vaartjes, I and Vergnaud, AC and Willer, CJ and Wilson, PWF and Witte, DR and Yonova-Doing, E and Zhang, H and Aliya, N and Almgren, P and Amouyel, P and Asselbergs, FW and Barnes, MR and Blakemore, AI and Boehnke, M and Bots, ML and Bottinger, EP and Buring, JE and Chambers, JC and Chen, YI and Chowdhury, R and Conen, D and Correa, A and Davey Smith, G and Boer, RA and Deary, IJ and Dedoussis, G and Deloukas, P and Di Angelantonio, E and Elliott, P and ,  and ,  and Felix, SB and Ferrières, J and Ford, I and Fornage, M and Franks, PW and Franks, S and Frossard, P and Gambaro, G and Gaunt, TR and Groop, L and Gudnason, V and Harris, TB and Hayward, C and Hennig, BJ and Herzig, KH and Ingelsson, E and Tuomilehto, J and Järvelin, MR and Jukema, JW and Kardia, SLR and Kee, F and Kooner, JS and Kooperberg, C and Launer, LJ and Lind, L and Loos, RJF and Majumder, AAS and Laakso, M and McCarthy, MI and Melander, O and Mohlke, KL and Murray, AD and Nordestgaard, BG and Orho-Melander, M and Packard, CJ and Padmanabhan, S and Palmas, W and Polasek, O and Porteous, DJ and Prentice, AM and Province, MA and Relton, CL and Rice, K and Ridker, PM and Rolandsson, O and Rosendaal, FR and Rotter, JI and Rudan, I and Salomaa, V and Samani, NJ and Sattar, N and Sheu, WH and Smith, BH and Soranzo, N and Spector, TD and Starr, JM and Sebert, S and Taylor, KD and Lakka, TA and Timpson, NJ and Tobin, MD and ,  and van der Harst, P and van der Meer, P and Ramachandran, VS and Verweij, N and Virtamo, J and Völker, U and Weir, DR and Zeggini, E and Charchar, FJ and ,  and Wareham, NJ and Langenberg, C and Tomaszewski, M and Butterworth, AS and Caulfield, MJ and Danesh, J and Edwards, TL and Holm, H and Hung, AM and Lindgren, CM and Liu, C and Manning, AK and Morris, AP and Morrison, AC and O'Donnell, CJ and Psaty, BM and Saleheen, D and Stefansson, K and Boerwinkle, E and Chasman, DI and Levy, D and Newton-Cheh, C and Munroe, PB and Howson, JMM}, title = {Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.}, journal = {Nature genetics}, volume = {52}, number = {12}, pages = {1314-1332}, pmid = {33230300}, issn = {1546-1718}, support = {RG/13/13/30194//British Heart Foundation (BHF)/ ; SP/09/002//British Heart Foundation (BHF)/ ; G0800270//RCUK | Medical Research Council (MRC)/ ; MR/L003120/1//RCUK | Medical Research Council (MRC)/ ; }, abstract = {Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.}, }
@article {pmid33230186, year = {2020}, author = {Sheth, VS and Gauthier, J}, title = {Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41409-020-01134-4}, pmid = {33230186}, issn = {1476-5365}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Treatment with CD19 or CD22-targeted chimeric antigen receptor-engineered T (CD19/CD22 CAR-T) cells achieve complete responses in 60-90% of adults and children with refractory or relapsed (R/R) acute lymphoblastic leukemia (ALL). This led to the approval of tisagenlecleucel (Kymriah) by the FDA and several European regulatory agencies in ALL patients up to 25 years of age. Although CAR T-cell therapy is likely to transform the ALL therapeutic landscape, its development and wide dissemination have been impacted by the occurrence of significant toxicities; namely, cytokine release syndrome (CRS) and Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) have been reported at higher rates in ALL patients compared to other B cell malignancies, particularly in the adult population. Here, we review recent data suggesting a significant proportion of ALL patients are at risk of developing severe, sometimes life-threatening, CRS, and ICANS after CD19 and CD22 CAR T-cell therapy. After describing the key clinical and laboratory features of severe CRS and ICANS, we explore the disease and treatment-related factors that may predict the severity of these toxicities. Last, we review strategies under investigation in the prophylactic and therapeutic settings to improve the safety of CAR T-cells for ALL.}, }
@article {pmid33229517, year = {2020}, author = {Wight, DJ and Aimola, G and Aswad, A and Jill Lai, CY and Bahamon, C and Hong, K and Hill, JA and Kaufer, BB}, title = {Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {49}, pages = {31410-31416}, pmid = {33229517}, issn = {1091-6490}, abstract = {Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus-subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.}, }
@article {pmid33229044, year = {2020}, author = {Morse, CB and Voillet, V and Bates, BM and Chiu, EY and Garcia, NM and Gottardo, R and Greenberg, PD and Anderson, KG}, title = {Development of a clinically relevant ovarian cancer model incorporating surgical cytoreduction to evaluate treatment of micro-metastatic disease.}, journal = {Gynecologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ygyno.2020.11.009}, pmid = {33229044}, issn = {1095-6859}, abstract = {OBJECTIVES: Mouse models of ovarian cancer commonly transfer large numbers of tumor cells into the peritoneal cavity to establish experimental metastatic disease, which may not adequately model early metastatic spread from a primary tumor site. We hypothesized we could develop an ovarian cancer model that predictably represents micro-metastatic disease.<br><br>METHODS: Murine ID8VEGF ovarian cancer cells were transduced to express enhanced luciferase (eLuc) to enable intravital detection of microscopic disease burden and injected beneath the ovarian bursa of C57Bl/6 mice. At 6 or 10 weeks after orthotopic injection, when mice had detectable metastases, hysterectomy and bilateral salpingo-oophorectomy was performed to remove all macroscopic disease, and survival monitored. Immunohistochemistry and gene expression profiling were performed on primary and metastatic tumors.<br><br>RESULTS: eLuc-transduced ID8VEGF cells were brighter than cells transduced with standard luciferase, enabling in vivo visualization of microscopic intra-abdominal metastases developing after orthotopic injection. Primary surgical cytoreduction removed the primary tumor mass but left minimal residual disease in all mice. Metastatic sites that developed following orthotopic injection were similar to metastatic human ovarian cancer sites. Gene expression and immune infiltration were similar between primary and metastatic mouse tumors. Surgical cytoreduction prolonged survival compared to no surgery, with earlier cytoreduction more beneficial than delayed, despite micro-metastatic disease in both settings.<br><br>CONCLUSIONS: Mice with primary ovarian tumors established through orthotopic injection develop progressively fatal metastatic ovarian cancer, and benefit from surgical cytoreduction to remove bulky disease. This model enables the analysis of therapeutic regimens designed to target and potentially eradicate established minimal residual disease.}, }
@article {pmid33228790, year = {2020}, author = {Takadera, M and Satomi, K and Szulzewsky, F and Cimino, PJ and Holland, EC and Yamamoto, T and Ichimura, K and Ozawa, T}, title = {Phenotypic characterization with somatic genome editing and gene transfer reveals the diverse oncogenicity of ependymoma fusion genes.}, journal = {Acta neuropathologica communications}, volume = {8}, number = {1}, pages = {203}, pmid = {33228790}, issn = {2051-5960}, support = {16K10775//KAKENHI/ ; 19K09518//KAKENHI/ ; 30-2//The Mother and Child Health Foundation/ ; }, abstract = {Recurrent RELA and YAP1 fusions are intimately associated with tumorigenesis in supratentorial ependymomas. Chromothripsis and focal copy number alterations involving 11q are hallmarks of these tumors. However, it is unknown whether the chromosomal alterations are a direct causal event resulting in fusion transcripts. In addition, the biological significance of the RELA fusion variants and YAP1 fusions is not yet fully characterized. In this study, we generated gene rearrangements on 11q with the CRISPR/Cas9 system and investigated the formation of oncogenic ependymoma fusion genes. Further, we examined the oncogenic potential of RELA fusion variants and YAP1 fusions in a lentiviral gene transfer model. We observed that endogenous RELA fusion events were successfully induced by CRISPR/Cas9-mediated genome rearrangement in cultured cells. In vivo genome editing in mouse brain resulted in the development of ependymoma-like brain tumors that harbored the Rela fusion gene. All RELA fusion variants tested, except a variant lacking the Rel homology domain, were able to induce tumor formation, albeit with different efficacy. Furthermore, expression of YAP1-FAM118B and YAP1-MAMLD1 fusions induced the formation of spindle-cell-like tumors at varying efficacy. Our results indicate that chromosomal rearrangements involving the Rela locus are the causal event for the formation of Rela fusion-driven ependymomas in mice. Furthermore, the type of RELA. fusion might affect the aggressiveness of tumors and that the Rel homology domain is essential for the oncogenic functions of RELA. fusions. The YAP1 fusion genes are also oncogenic when expressed in mice.}, }
@article {pmid33228787, year = {2020}, author = {Newman, KL and Rogers, JH and McCulloch, D and Wilcox, N and Englund, JA and Boeckh, M and Uyeki, TM and Jackson, ML and Starita, L and Hughes, JP and Chu, HY and , }, title = {Point-of-care molecular testing and antiviral treatment of influenza in residents of homeless shelters in Seattle, WA: study protocol for a stepped-wedge cluster-randomized controlled trial.}, journal = {Trials}, volume = {21}, number = {1}, pages = {956}, pmid = {33228787}, issn = {1745-6215}, support = {Seattle Flu Study//Gates Ventures/ ; }, abstract = {INTRODUCTION: Influenza is an important public health problem, but data on the impact of influenza among homeless shelter residents are limited. The primary aim of this study is to evaluate whether on-site testing and antiviral treatment of influenza in residents of homeless shelters reduces influenza spread in these settings.<br><br>METHODS AND ANALYSIS: This study is a stepped-wedge cluster-randomized trial of on-site testing and antiviral treatment for influenza in nine homeless shelter sites within the Seattle metropolitan area. Participants with acute respiratory illness (ARI), defined as two or more respiratory symptoms or new or worsening cough with onset in the prior 7 days, are eligible to enroll. Approximately 3200 individuals are estimated to participate from October to May across two influenza seasons. All sites will start enrollment in the control arm at the beginning of each season, with routine surveillance for ARI. Sites will be randomized at different timepoints to enter the intervention arm, with implementation of a test-and-treat strategy for individuals with two or fewer days of symptoms. Eligible individuals will be tested on-site with a point-of-care influenza test. If the influenza test is positive and symptom onset is within 48 h, participants will be administered antiviral treatment with baloxavir or oseltamivir depending upon age and comorbidities. Participants will complete a questionnaire on demographics and symptom duration and severity. The primary endpoint is the incidence of influenza in the intervention period compared to the control period, after adjusting for time trends.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04141917 . Registered 28 October 2019. Trial sponsor: University of Washington.}, }
@article {pmid33228398, year = {2020}, author = {LaMonte, MJ and Larson, JC and Manson, JE and Bellettiere, J and Lewis, CE and LaCroix, AZ and Bea, JW and Johnson, KC and Klein, L and Noel, CA and Stefanick, ML and Wactawski-Wende, J and Eaton, CB}, title = {Association of Sedentary Time and Incident Heart Failure Hospitalization in Postmenopausal Women.}, journal = {Circulation. Heart failure}, volume = {13}, number = {12}, pages = {e007508}, pmid = {33228398}, issn = {1941-3297}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; R01 HL130591/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: The 2018 US Physical Activity Guidelines recommend reducing sedentary behavior (SB) for cardiovascular health. SB's role in heart failure (HF) is unclear.<br><br>METHODS: We studied 80 982 women in the Women's Health Initiative Observational Study, aged 50 to 79 years, who were without known HF and reported ability to walk ≥1 block unassisted at baseline. Mean follow-up was 9 years for physician-adjudicated incident HF hospitalization (1402 cases). SB was assessed repeatedly by questionnaire. Time-varying total SB was categorized according to awake time spent sitting or lying down (≤6.5, 6.6-9.5, >9.5 h/d); sitting time (≤4.5, 4.6-8.5, >8.5 h/d) was also evaluated. Hazard ratios and 95% CI were estimated using Cox regression.<br><br>RESULTS: Controlling for age, race/ethnicity, education, income, smoking, alcohol, menopausal hormone therapy, and hysterectomy status, higher HF risk was observed across incremental tertiles of time-varying total SB (hazard ratios [95% CI], 1.00 [referent], 1.15 [1.01-1.31], 1.42 [1.25-1.61], trend P<0.001) and sitting time (1.00 [referent], 1.14 [1.01-1.28], 1.54 [1.34-1.78], trend P<0.001). The inverse trends remained significant after further controlling for comorbidities including time-varying myocardial infarction and coronary revascularization (hazard ratios: SB, 1.00, 1.11, 1.27; sitting, 1.00, 1.09, 1.37, trend P<0.001 each) and for baseline physical activity (hazard ratios: SB 1.00, 1.10, 1.24; sitting 1.00, 1.08, 1.33, trend P<0.001 each). Associations with SB exposures were not different according to categories of baseline age, race/ethnicity, body mass index, physical activity, physical functioning, diabetes, hypertension, or coronary heart disease.<br><br>CONCLUSIONS: SB was associated with increased risk of incident HF hospitalization in postmenopausal women. Targeted efforts to reduce SB could enhance HF prevention in later life.}, }
@article {pmid33227125, year = {2020}, author = {Noy, A and de Vos, S and Coleman, M and Martin, P and Flowers, CR and Thieblemont, C and Morschhauser, F and Collins, GP and Ma, S and Peles, S and Smith, SD and Barrientos, JC and Chong, E and Wu, S and Cheung, LW and Kwei, K and Hauns, B and Arango-Hisijara, I and Chen, R}, title = {Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.}, journal = {Blood advances}, volume = {4}, number = {22}, pages = {5773-5784}, pmid = {33227125}, issn = {2473-9537}, abstract = {Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.}, }
@article {pmid33225770, year = {2021}, author = {Vanderpool, RC and Huang, GC and Mollica, M and Gutierrez, AI and Maynard, CD}, title = {Cancer Information-seeking in an Age of COVID-19: Findings from the National Cancer Institute's Cancer Information Service.}, journal = {Health communication}, volume = {36}, number = {1}, pages = {89-97}, doi = {10.1080/10410236.2020.1847449}, pmid = {33225770}, issn = {1532-7027}, abstract = {Seeking cancer information is recognized as an important, life-saving behavior under normal circumstances. However, given the significant impact of COVID-19 on society, the healthcare system, and individuals and their families, it is important to understand how the pandemic has affected cancer information needs in a crisis context and, in turn, how public health agencies have responded to meeting the information needs of various audiences. Using data from the National Cancer Institute's Cancer Information Service (CIS) - a long-standing, multi-channel resource for trusted cancer information in English and Spanish - this descriptive analysis explored differences in cancer information-seeking among cancer survivors, caregivers, tobacco users, and members of the general public during the onset and continuation of the COVID-19 pandemic (February - September 2020), specifically comparing interactions that involved a discussion of COVID-19 to those that did not. During the study period, COVID-19 discussions were more likely to involve survivors or caregivers compared to tobacco users and the general public. Specific patterns emerged across the four user types and their respective discussions of COVID-19 related to language of service, point of CIS access, stage on the cancer continuum, subject of interaction, cancer site discussed, and referrals provided by the CIS. These results provide insights that may help public health agencies deliver, prioritize, and tailor their messaging and response to specific audiences based on heightened health information needs during a crisis.}, }
@article {pmid33225764, year = {2020}, author = {Crotty, E and Downey, K and Ferrerosa, L and Flores, C and Hegde, B and Raskin, S and Hwang, E and Vitanza, N and Okada, H}, title = {Considerations when treating high-grade pediatric glioma patients with immunotherapy.}, journal = {Expert review of neurotherapeutics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/14737175.2020.1855144}, pmid = {33225764}, issn = {1744-8360}, abstract = {INTRODUCTION: Children with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.<br><br>AREAS COVERED: The authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.<br><br>EXPERT OPINION: Adequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.}, }
@article {pmid33225342, year = {2020}, author = {Wilson, N and Zhao, N and Zhan, X and Koh, H and Fu, W and Chen, J and Li, H and Wu, MC and Plantinga, AM}, title = {MiRKAT: kernel machine regression-based global association tests for the microbiome.}, journal = {Bioinformatics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/bioinformatics/btaa951}, pmid = {33225342}, issn = {1367-4811}, abstract = {SUMMARY: Distance-based tests of microbiome beta diversity are an integral part of many microbiome analyses. MiRKAT enables distance-based association testing with a wide variety of outcome types, including continuous, binary, censored time-to-event, multivariate, correlated and high-dimensional outcomes. Omnibus tests allow simultaneous consideration of multiple distance and dissimilarity measures, providing higher power across a range of simulation scenarios. Two measures of effect size, a modified R-squared coefficient and a kernel RV coefficient, are incorporated to allow comparison of effect sizes across multiple kernels.<br><br>MiRKAT is available on CRAN as an R package.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.}, }
@article {pmid33225057, year = {2020}, author = {Abrams, K and Graves, SS and Parker, MH and Storb, R}, title = {CD94 Ex Vivo Cultures in a Bone Marrow Transplantation Setting.}, journal = {Transplantation direct}, volume = {6}, number = {12}, pages = {e632}, pmid = {33225057}, issn = {2373-8731}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, abstract = {Background: Complementary, marrow donor-derived peripheral blood T-lymphocyte infusions enable consistent hematopoietic engraftment in lethally irradiated dog leukocyte antigen (DLA)-haploidentical littermate recipients, but at the cost of severe graft versus host disease (GVHD). Here, we explored whether CD94-selected and in vitro-expanded natural killer (NK) cells could be substituted for T-lymphocytes for enhancing marrow engraftment without causing severe GVHD.<br><br>Methods: Five dogs were conditioned with 700 cGy total body irradiation followed by infusion of DLA-haploidentical donor marrow and CD94-selected, in vitro-expanded NK cells. NK cells were infused at a median of 140 000 (range 78 000-317 000) cells/kg.<br><br>Results: Four dogs rejected their marrow grafts, whereas 1 dog fully engrafted and developed GVHD. We observed an increase in peripheral blood NK cells after infusion of CD94-selected, ex vivo-expanded NK in 2 dogs. Peripheral blood lymphocyte counts peaked at day 7 or 8 posttransplant in the 4 rejecting dogs, whereas in the fully engrafted dog, lymphocyte counts remained stable at suboptimal levels.<br><br>Conclusions: Our study indicates NK cells can be expanded in vitro and safely infused into DLA-haploidentical recipients. Within the range of CD94-selected and expanded cells infused we concluded that they failed to both uniformly promote engraftment and avert GVHD.}, }
@article {pmid33222702, year = {2020}, author = {Gupta, S and Rose, CM and Buszkiewicz, J and Ko, LK and Mou, J and Cook, A and Aggarwal, A and Drewnowski, A}, title = {Characterising percentage energy from ultra-processed foods by participant demographics, diet quality and diet cost: findings from the Seattle Obesity Study (SOS) III.}, journal = {The British journal of nutrition}, volume = {}, number = {}, pages = {1-9}, doi = {10.1017/S0007114520004705}, pmid = {33222702}, issn = {1475-2662}, abstract = {Higher consumption of 'ultra-processed' (UP) foods has been linked to adverse health outcomes. The present paper aims to characterise percentage energy from UP foods by participant socio-economic status (SES), diet quality, self-reported food expenditure and energy-adjusted diet cost. Participants in the population-based Seattle Obesity Study III (n 755) conducted in WA in 2016-2017 completed socio-demographic and food expenditure surveys and the FFQ. Education and residential property values were measures of SES. Retail prices of FFQ component foods (n 378) were used to estimate individual-level diet cost. Healthy Eating Index (HEI-2015) and Nutrient Rich Food Index 9.3 (NRF9.3) were measures of diet quality. UP foods were identified following NOVA classification. Multivariable linear regressions were used to test associations between UP foods energy, socio-demographics, two estimates of food spending and diet quality measures. Higher percentage energy from UP foods was associated with higher energy density, lower HEI-2015 and NRF9.3 scores. The bottom decile of diet cost ($216·4/month) was associated with 67·5 % energy from UP foods; the top decile ($369·9/month) was associated with only 48·7 % energy from UP foods. Percentage energy from UP foods was inversely linked to lower food expenditures and diet cost. In multivariate analysis, percentage energy from UP foods was predicted by lower food expenditures, diet cost and education, adjusting for covariates. Percentage energy from UP foods was linked to lower food spending and lower SES. Efforts to reduce UP foods consumption, an increasingly common policy measure, need to take affordability, food expenditures and diet costs into account.}, }
@article {pmid33221175, year = {2020}, author = {Waqar, SN and Redman, MW and Arnold, SM and Hirsch, FR and Mack, PC and Schwartz, LH and Gandara, DR and Stinchcombe, TE and Leighl, NB and Ramalingam, SS and Tanna, SH and Raddin, RS and Minichiello, K and Bradley, JD and Kelly, K and Herbst, RS and Papadimitrakopoulou, VA}, title = {A Phase II Study of Telisotuzumab Vedotin in Patients With c-MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K, NCT03574753).}, journal = {Clinical lung cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cllc.2020.09.013}, pmid = {33221175}, issn = {1938-0690}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; UG1 CA189804/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA189858/CA/NCI NIH HHS/United States ; UG1 CA189997/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; UG1 CA233339/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Lung-MAP S1400K was designed to evaluate the response to telisotuzumab vedotin, an antibody-drug conjugate targeting c-MET, in patients with c-MET-positive squamous cell carcinoma (SCC).<br><br>PATIENTS AND METHODS: Patients with previously treated SCC with c-MET-positive tumors (H score ≥ 150, Ventana SP44 assay) were enrolled into 2 cohorts: Cohort 1 (immune checkpoint inhibitor-naive) and Cohort 2 (immune checkpoint inhibitor refractory). Telisotuzumab vedotin 2.7 mg/kg was administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Response assessments were performed every 6 weeks. The primary endpoint was response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival, overall survival, response within cohort, duration of response, and toxicities. Interim analysis was planned after 20 evaluable patients, with ≥ 3 responses needed to continue enrollment.<br><br>RESULTS: Forty-nine patients (14% of screened patients) were assigned to S1400K, 28 patients enrolled (15 in Cohort 1 and 13 in Cohort 2), and 23 were eligible. S1400K closed on December 21, 2018 owing to lack of efficacy. Two responses (response rate of 9%; 95% confidence interval, 0%-20%) were reported in cohort 1 (1 complete and 1 unconfirmed partial response), whereas 10 patients had stable disease, with a disease control rate of 52%. The median overall and progression-free survival was 5.6 and 2.4 months, respectively. There were 3 grade 5 events (2 pneumonitis, in Cohort 2, and 1 bronchopulmonary hemorrhage, in Cohort 1).<br><br>CONCLUSION: Telisotuzumab vedotin failed to meet the pre-specified response needed to justify continuing enrollment to S1400K. Pneumonitis was an unanticipated toxicity observed in patients with SCC.}, }
@article {pmid33220019, year = {2020}, author = {Patel, JL and Abedi, M and Cogle, CR and Erba, HP and Foucar, K and Garcia-Manero, G and Grinblatt, DL and Komrokji, RS and Kurtin, SE and Maciejewski, JP and Pollyea, DA and Revicki, DA and Roboz, GJ and Savona, MR and Scott, BL and Sekeres, MA and Steensma, DP and Thompson, MA and Dawn Flick, E and Kiselev, P and Louis, CU and Nifenecker, M and Swern, AS and George, TI}, title = {Real-world diagnostic testing patterns for assessment of ring sideroblasts and SF3B1 mutations in patients with newly diagnosed lower-risk myelodysplastic syndromes.}, journal = {International journal of laboratory hematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ijlh.13400}, pmid = {33220019}, issn = {1751-553X}, support = {//Bristol Myers Squibb/ ; }, abstract = {INTRODUCTION: The presence of ring sideroblasts (RS) and mutation of the SF3B1 gene are diagnostic of lower-risk (LR) myelodysplastic syndromes (MDS) and are correlated with favorable outcomes. However, information on testing and reporting in community-based clinical settings is scarce. This study from the Connect® MDS/AML Disease Registry aimed to compare the frequency of RS and SF3B1 reporting for patients with LR-MDS, before and after publication of the 2016 World Health Organization (WHO) MDS classification criteria.<br><br>METHODS: Ring sideroblasts assessment and molecular testing data were collected from patients with LR-MDS at enrollment in the Registry. Patients enrolled between December 2013 and the data cutoff of March 2020 were included in this analysis.<br><br>RESULTS: Among 489 patients with LR-MDS, 434 (88.8%) underwent RS assessment; 190 were assessed prior to the 2016 WHO guidelines (Cohort A), and 244 after (Cohort B). In Cohort A, 87 (45.8%) patients had RS identified; 29 (33.3%) patients had RS < 15%, none of whom underwent molecular testing for SF3B1. In Cohort B, 96 (39.3%) patients had RS identified; 31 (32.3%) patients had < 15% RS, with 13 undergoing molecular testing of which 10 were assessed for SF3B1.<br><br>CONCLUSIONS: In the Connect® MDS/AML Registry, only 32% of patients with <15% RS underwent SF3B1 testing after the publication of the WHO 2016 classification criteria. There was no change in RS assessment frequency before and after publication, despite the potential impact on diagnostic subtyping and therapy selection, suggesting an unmet need for education to increase testing rates for SF3B1 mutations.}, }
@article {pmid33219407, year = {2020}, author = {Scott, SR and O'Daffer, AG and Bradford, MC and Fladeboe, K and Lau, N and Steineck, A and Taylor, M and Yi-Frazier, JP and Rosenberg, AR}, title = {Adverse childhood experiences (ACEs) and medically traumatic events (TEs) in adolescents and young adults (AYAs) with cancer: a report from the Promoting Resilience in Stress Management (PRISM) randomized controlled trial.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00520-020-05888-x}, pmid = {33219407}, issn = {1433-7339}, support = {KL2TR000421/TR/NCATS NIH HHS/United States ; }, abstract = {OBJECTIVE: In adolescents and young adults (AYAs) with cancer, we examined (1) the distribution and type of traumatic events (TEs) experienced prior to baseline assessment and (2) how a resilience intervention, Promoting Resilience in Stress Management (PRISM), impacted changes in patient-reported outcomes (PROs) for AYAs with and without TEs.<br><br>METHODS: AYAs (12-25 years) within 1-10 weeks of diagnosis of new malignancy or ever diagnosed with advanced cancer were enrolled and randomly assigned to usual care (UC) with or without PRISM. To assess TEs, we screened medical records for traditionally defined adverse childhood experiences (ACEs) and medical traumatic events. Age-validated PROs assessed resilience, benefit-finding, hope, generic health-related quality of life (QoL), cancer-specific QoL, depression, and anxiety at enrollment and 6 months later. We calculated effect sizes (Cohen's d) for PRISM vs. UC effect on PRO score change at 6 months for 1+ TEs and 0 TE groups.<br><br>RESULTS: Ninety-two AYAs enrolled and completed baseline surveys (44-UC, 48-PRISM; N = 74 at 6 months, 38-UC, 36-PRISM); 60% experienced 1+ TEs. PROs at baseline were similar across groups. PRISM's effect on score change was greater (Cohen's d ≥ 0.5) for the 1+ TE group on domains of benefit-finding and hope; and similar (d < 0.5) on domains of resilience, depression, anxiety, and both generic and cancer-specific QoL.<br><br>CONCLUSIONS: In AYAs with cancer, TEs occurred at similar rates as the general population. PRISM may be particularly helpful for improving benefit-finding and hope for those who have experienced TEs.}, }
@article {pmid33219392, year = {2020}, author = {Dibay Moghadam, S and Navarro, SL and Shojaie, A and Randolph, TW and Bettcher, LF and Le, CB and Hullar, MA and Kratz, M and Neuhouser, ML and Lampe, PD and Raftery, D and Lampe, JW}, title = {Plasma lipidomic profiles after a low and high glycemic load dietary pattern in a randomized controlled crossover feeding study.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {16}, number = {12}, pages = {121}, pmid = {33219392}, issn = {1573-3890}, support = {U54 CA116847/CA/NCI NIH HHS/United States ; R01 CA192222/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; R01 GM114029/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, abstract = {BACKGROUND: Dietary patterns low in glycemic load are associated with reduced risk of cardiometabolic diseases. Improvements in serum lipid concentrations may play a role in these observed associations.<br><br>OBJECTIVE: We investigated how dietary patterns differing in glycemic load affect clinical lipid panel measures and plasma lipidomics profiles.<br><br>METHODS: In a crossover, controlled feeding study, 80 healthy participants (n = 40 men, n = 40 women), 18-45 y were randomized to receive low-glycemic load (LGL) or high glycemic load (HGL) diets for 28 days each with at least a 28-day washout period between controlled diets. Fasting plasma samples were collected at baseline and end of each diet period. Lipids on a clinical panel including total-, VLDL-, LDL-, and HDL-cholesterol and triglycerides were measured using an auto-analyzer. Lipidomics analysis using mass-spectrometry provided the concentrations of 863 species. Linear mixed models and lipid ontology enrichment analysis were implemented.<br><br>RESULTS: Lipids from the clinical panel were not significantly different between diets. Univariate analysis showed that 67 species on the lipidomics panel, predominantly in the triacylglycerol class, were higher after the LGL diet compared to the HGL (FDR < 0.05). Three species with FA 17:0 were lower after LGL diet with enrichment analysis (FDR < 0.05).<br><br>CONCLUSION: In the context of controlled eucaloric diets with similar macronutrient distribution, these results suggest that there are relative shifts in lipid species, but the overall pool does not change. Further studies are needed to better understand in which compartment the different lipid species are transported in blood, and how these shifts are related to health outcomes. This trial was registered at clinicaltrials.gov as NCT00622661.}, }
@article {pmid33218274, year = {2020}, author = {Kim, J and Beidler, P and Wang, H and Li, C and Quassab, A and Coles, C and Drescher, C and Carter, D and Lieber, A}, title = {Desmoglein-2 as a prognostic and biomarker in ovarian cancer.}, journal = {Cancer biology &amp; therapy}, volume = {21}, number = {12}, pages = {1154-1162}, pmid = {33218274}, issn = {1555-8576}, support = {R44 CA206607/CA/NCI NIH HHS/United States ; }, abstract = {Greater than 80% of all cancer cases are carcinomas, formed by the malignant transformation of epithelial cells. One of the key features of epithelial tumors is the presence of intercellular junctions, which link cells to one another and act as barriers to the penetration of molecules. This study assessed the expression of desmoglein-2, an epithelial junction protein, as a prognostic and diagnostic biomarker for ovarian cancer. Ovarian cancer sections were stained for DSG2 and signal intensity was correlated to cancer type and grade. DSG2 immunohistochemistry signals and mRNA levels were analyzed in chemo-resistant and chemo-sensitive cases. Ovarian cancer patient serum levels of shed DSG2 were correlated to disease-free and overall survival. Primary ovarian cancer cells were used to study DSG2 levels as they changed in response to cisplatin treatment. DSG2 expression was found to be positively correlated with cancer grade. Ovarian cancer patients with high serum levels of shed DSG2 fared significantly worse in both progression-free survival (median survival of 16 months vs. 26 months, p = .0023) and general survival (median survival of 37 months vs. undefined, p < .0001). A subgroup of primary chemotherapy-resistant cases had stronger DSG2 IHC/Western signals and higher DSG2 mRNA levels. Furthermore, our in vitro studies indicate that non-cytotoxic doses of cisplatin can enhance DSG2 expression, which, in turn, can contribute to chemo-resistance. We suggest that DSG2 can be used in stratifying patients, deciding on where to use aggressive treatment strategies, predicting chemoresistance, and as a companion diagnostic for treatments targeting DSG2.}, }
@article {pmid33217253, year = {2020}, author = {Carpenter, JS and Tisdale, JE and Chen, CX and Kovacs, R and Larson, JC and Guthrie, KA and Ensrud, KE and Newton, KM and LaCroix, AZ}, title = {A Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) Investigation of Self-Reported Menopausal Palpitation Distress.}, journal = {Journal of women's health (2002)}, volume = {}, number = {}, pages = {}, doi = {10.1089/jwh.2020.8586}, pmid = {33217253}, issn = {1931-843X}, abstract = {Background: Study to describe the degree of menopausal palpitation distress and its demographic, clinical, symptom, and quality-of-life (QOL) correlates. Analysis of existing, baseline, data from peri- and postmenopausal women, 42 to 62 years of age, who participated in the Menopause Strategies-Finding Lasting Answers for Symptoms and Health (MsFLASH) clinical trials testing interventions for vasomotor symptoms (n = 759). Up to 46.8% of menopausal women report having palpitations, yet the symptom is relatively understudied. Little is known about palpitation distress or its correlates. Materials and Methods: Degree of distress from &quot;heart racing or pounding&quot; was self-reported over the past two weeks as &quot;not at all,&quot; &quot;a little bit,&quot; &quot;moderately,&quot; &quot;quite a bit,&quot; or &quot;extremely.&quot; Other measures included self-report forms, clinic-verified body mass index (BMI), vasomotor symptom diaries, and validated symptom and QOL tools. Results: The percentage who reported palpitation distress was 19.6%, 25.2%, and 33.5% in the three trials or 25.0% overall. In multivariate analysis, the odds of reporting palpitation distress was lower in past smokers (odds ratio [OR] = 0.59 [95% confidence interval (CI) 0.38-0.90]) and current smokers (OR = 0.48 [0.27-0.87]) relative to never-smokers and lower with every 5 kg/m2 higher BMI (OR = 0.82 [0.69-0.98]).The odds of reporting palpitation distress was higher with every five point more severe insomnia (OR = 1.28 [1.05-1.54]), five point worse depressive symptoms (OR = 1.47 [1.11-1.95]), five point worse perceived stress (OR = 1.19 [1.01-1.39]), and one point worse menopausal QOL (OR = 1.29 [1.06-1.57]). Conclusions: Menopausal palpitation distress is common and associated with demographic, clinical, symptom, and QOL factors. Findings can be used for screening in clinical practice and to justify additional research on this understudied symptom.}, }
@article {pmid33215685, year = {2020}, author = {Choi, YG and Hanrahan, LP and Norton, D and Zhao, YQ}, title = {Simultaneous spatial smoothing and outlier detection using penalized regression, with application to childhood obesity surveillance from electronic health records.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13404}, pmid = {33215685}, issn = {1541-0420}, support = {2020R1G1A1A01006229//National Research Foundation of Korea/ ; P30CA015704/NH/NIH HHS/United States ; R21HD086754/NH/NIH HHS/United States ; S10OD020069/NH/NIH HHS/United States ; }, abstract = {Electronic health records (EHRs) have become a platform for data-driven granular-level surveillance in recent years. In this paper, we make use of EHRs for early prevention of childhood obesity. The proposed method simultaneously provides smooth disease mapping and outlier information for obesity prevalence that are useful for raising public awareness and facilitating targeted intervention. More precisely, we consider a penalized multilevel generalized linear model. We decompose regional contribution into smooth and sparse signals, which are automatically identified by a combination of fusion and sparse penalties imposed on the likelihood function. In addition, we weigh the proposed likelihood to account for the missingness and potential nonrepresentativeness arising from the EHR data. We develop a novel alternating minimization algorithm, which is computationally efficient, easy to implement, and guarantees convergence. Simulation studies demonstrate superior performance of the proposed method. Finally, we apply our method to the University of Wisconsin Population Health Information Exchange database.}, }
@article {pmid33213418, year = {2020}, author = {Jordahl, KM and Phipps, AI and Randolph, TW and Tinker, LF and Nassir, R and Hou, L and Anderson, GL and Kelsey, KT and White, E and Bhatti, P}, title = {Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk.}, journal = {BMC medical genetics}, volume = {21}, number = {1}, pages = {228}, pmid = {33213418}, issn = {1471-2350}, support = {125299-RSG-13-100-01-CCE//American Cancer Society/International ; R25 CA094880/CA/NCI NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL).<br><br>METHODS: Among 412 bladder cancer cases and 424 controls from the Women's Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking.<br><br>RESULTS: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766.<br><br>CONCLUSIONS: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.}, }
@article {pmid33212010, year = {2020}, author = {Krug, K and Jaehnig, EJ and Satpathy, S and Blumenberg, L and Karpova, A and Anurag, M and Miles, G and Mertins, P and Geffen, Y and Tang, LC and Heiman, DI and Cao, S and Maruvka, YE and Lei, JT and Huang, C and Kothadia, RB and Colaprico, A and Birger, C and Wang, J and Dou, Y and Wen, B and Shi, Z and Liao, Y and Wiznerowicz, M and Wyczalkowski, MA and Chen, XS and Kennedy, JJ and Paulovich, AG and Thiagarajan, M and Kinsinger, CR and Hiltke, T and Boja, ES and Mesri, M and Robles, AI and Rodriguez, H and Westbrook, TF and Ding, L and Getz, G and Clauser, KR and Fenyö, D and Ruggles, KV and Zhang, B and Mani, DR and Carr, SA and Ellis, MJ and Gillette, MA and , }, title = {Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.}, journal = {Cell}, volume = {183}, number = {5}, pages = {1436-1456.e31}, doi = {10.1016/j.cell.2020.10.036}, pmid = {33212010}, issn = {1097-4172}, abstract = {The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this &quot;proteogenomics&quot; approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.}, }
@article {pmid33211775, year = {2020}, author = {Müller, NF and Wüthrich, D and Goldman, N and Sailer, N and Saalfrank, C and Brunner, M and Augustin, N and Seth-Smith, HM and Hollenstein, Y and Syedbasha, M and Lang, D and Neher, RA and Dubuis, O and Naegele, M and Buser, A and Nickel, CH and Ritz, N and Zeller, A and Lang, BM and Hadfield, J and Bedford, T and Battegay, M and Schneider-Sliwa, R and Egli, A and Stadler, T}, title = {Characterising the epidemic spread of influenza A/H3N2 within a city through phylogenetics.}, journal = {PLoS pathogens}, volume = {16}, number = {11}, pages = {e1008984}, pmid = {33211775}, issn = {1553-7374}, abstract = {Infecting large portions of the global population, seasonal influenza is a major burden on societies around the globe. While the global source sink dynamics of the different seasonal influenza viruses have been studied intensively, its local spread remains less clear. In order to improve our understanding of how influenza is transmitted on a city scale, we collected an extremely densely sampled set of influenza sequences alongside patient metadata. To do so, we sequenced influenza viruses isolated from patients of two different hospitals, as well as private practitioners in Basel, Switzerland during the 2016/2017 influenza season. The genetic sequences reveal that repeated introductions into the city drove the influenza season. We then reconstruct how the effective reproduction number changed over the course of the season. While we did not find that transmission dynamics in Basel correlate with humidity or school closures, we did find some evidence that it may positively correlated with temperature. Alongside the genetic sequence data that allows us to see how individual cases are connected, we gathered patient information, such as the age or household status. Zooming into the local transmission outbreaks suggests that the elderly were to a large extent infected within their own transmission network. In the remaining transmission network, our analyses suggest that school-aged children likely play a more central role than pre-school aged children. These patterns will be valuable to plan interventions combating the spread of respiratory diseases within cities given that similar patterns are observed for other influenza seasons and cities.}, }
@article {pmid33208529, year = {2020}, author = {Kates, O and Starr, K and Bourassa, L}, title = {Closing the Brief Case: Nontoxigenic Corynebacterium diphtheriae in a Nonhealing Wound.}, journal = {Journal of clinical microbiology}, volume = {58}, number = {12}, pages = {}, doi = {10.1128/JCM.00507-20}, pmid = {33208529}, issn = {1098-660X}, }
@article {pmid33208528, year = {2020}, author = {Kates, O and Starr, K and Bourassa, L}, title = {The Brief Case: Nontoxigenic Corynebacterium diphtheriae in a Nonhealing Wound.}, journal = {Journal of clinical microbiology}, volume = {58}, number = {12}, pages = {}, pmid = {33208528}, issn = {1098-660X}, }
@article {pmid33208512, year = {2020}, author = {Deese, J and Philip, N and Lind, M and Ahmed, K and Batting, J and Beksinska, M and Edward, VA and Louw, CE and Onono, M and Palanee-Phillips, T and Smit, JA and Baeten, JM and Donnell, D and Mastro, TD and Mugo, NR and Nanda, K and Rees, H and Morrison, C}, title = {Sexually transmitted infections among women randomised to depot medroxyprogesterone acetate, a copper intrauterine device or a levonorgestrel implant.}, journal = {Sexually transmitted infections}, volume = {}, number = {}, pages = {}, doi = {10.1136/sextrans-2020-054590}, pmid = {33208512}, issn = {1472-3263}, abstract = {OBJECTIVES: Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods.<br><br>METHODS: We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16-35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression.<br><br>RESULTS: At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group (PR 0.83, 95% CI 0.72 to 0.95). Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups (PR 0.67, 95% CI 0.52 to 0.87).<br><br>CONCLUSIONS: The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use.}, }
@article {pmid33206462, year = {2020}, author = {Brown, ER and Hendrix, CW and van der Straten, A and Kiweewa, FM and Mgodi, NM and Palanee-Philips, T and Marzinke, MA and Bekker, LG and Soto-Torres, L and Hillier, SL and Baeten, JM and , }, title = {Greater dapivirine release from the dapivirine vaginal ring is correlated with lower risk of HIV-1 acquisition: a secondary analysis from a randomized, placebo-controlled trial.}, journal = {Journal of the International AIDS Society}, volume = {23}, number = {11}, pages = {e25634}, pmid = {33206462}, issn = {1758-2652}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1 AI106707/AI/NIAID NIH HHS/United States ; }, abstract = {INTRODUCTION: A vaginal ring containing 25 mg of the antiretroviral dapivirine has demonstrated efficacy in reducing women's risk of sexually acquiring HIV-1; however, imperfect ring use likely diluted efficacy estimates in clinical trials. The amount of dapivirine remaining in returned rings may reflect the extent of product use, permitting estimation of HIV protection in the context of consistent use.<br><br>METHODS: We measured the amount of dapivirine in returned rings from a placebo-controlled trial of the dapivirine vaginal ring conducted between August 2012 and June 2015 among 2629 African women. Phase I/II studies established that greater than 4 mg of dapivirine on average is released from the ring when used consistently over 28 days and ≤0.9 mg released suggested non-use. We assessed the relative risk reduction associated with levels of ring use using residual dapivirine in returned rings as a time-dependent covariate for HIV-1 infection in multivariable Cox models, including multiple exploratory analyses designed to estimate upper limits of efficacy given uncertainty in timing of HIV-1 acquisition. All models were adjusted for baseline covariates associated with HIV risk and adherence.<br><br>RESULTS: Residual dapivirine levels indicating at least some use (>0.9 mg released over a month) were associated with a 48% relative reduction in HIV-1 acquisition risk (95% confidence interval (CI): 21% to 66%; p = 0.002) compared to the placebo. Exploratory analyses accounting for potential misclassification in timing of HIV-1 acquisition estimated 75% to 91% HIV-1 risk reduction with> 4 mg released when compared to placebo. Results limited to the subgroup of women <25 years of age, who tended to have lower adherence, were generally consistent to those overall.<br><br>CONCLUSIONS: Residual dapivirine levels, an objective measure of adherence, were correlated with HIV-1 protection in a secondary analysis of a randomized trial. Periods of ring use were associated with approximately 50% protection, with exploratory analyses suggesting higher protection with more consistent use. The dapivirine vaginal ring is the first method to fulfil the promise of a fully reversible, long-acting, woman-initiated approach for discreet HIV-1 prevention.}, }
@article {pmid33205061, year = {2020}, author = {Li, S and Simoni, Y and Becht, E and Loh, CY and Li, N and Lachance, D and Koo, SL and Lim, TP and Tan, EKW and Mathew, R and Nguyen, A and Golovato, J and Berkson, JD and Prlic, M and Lee, B and Minot, SS and Nagarajan, N and Dey, N and Tan, DSW and Tan, IB and Newell, EW}, title = {Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer.}, journal = {Cell reports. Medicine}, volume = {1}, number = {3}, pages = {100039}, pmid = {33205061}, issn = {2666-3791}, support = {R01 AI123323/AI/NIAID NIH HHS/United States ; }, abstract = {Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show in vitro to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, Fusobacteria nucleatum, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy.}, }
@article {pmid33203990, year = {2020}, author = {Sari, IN and Yang, YG and Wijaya, YT and Jun, N and Lee, S and Kim, KS and Bajaj, J and Oehler, VG and Kim, SH and Choi, SY and Park, SH and Kim, DW and Reya, T and Han, J and Kwon, HY}, title = {AMD1 is required for the maintenance of leukemic stem cells and promotes chronic myeloid leukemic growth.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41388-020-01547-x}, pmid = {33203990}, issn = {1476-5594}, abstract = {Polyamines are critical elements in mammals, but it remains unknown whether adenosyl methionine decarboxylase (AMD1), a rate-limiting enzyme in polyamine synthesis, is required for myeloid leukemia. Here, we found that leukemic stem cells (LSCs) were highly differentiated, and leukemia progression was severely impaired in the absence of AMD1 in vivo. AMD1 was highly upregulated as chronic myeloid leukemia (CML) progressed from the chronic phase to the blast crisis phase, and was associated with the poor prognosis of CML patients. In addition, the pharmacological inhibition of AMD1 by AO476 treatment resulted in a robust reduction of the progression of leukemic cells both in vitro and in vivo. Mechanistically, AMD1 depletion induced loss of mitochondrial membrane potential and accumulation of reactive oxygen species (ROS), resulting in the differentiation of LSCs via oxidative stress and aberrant activation of unfolded protein response (UPR) pathway, which was partially rescued by the addition of polyamine. These results indicate that AMD1 is an essential element in the progression of myeloid leukemia and could be an attractive target for the treatment of the disease.}, }
@article {pmid33203692, year = {2020}, author = {Labadie, JD and Hua, X and Harrison, TA and Banbury, BL and Huyghe, JR and Sun, W and Shi, Q and Yothers, G and Alberts, SR and Sinicrope, FA and Goldberg, RM and George, TJ and Penney, KL and Phipps, AI and Cohen, SA and Peters, U and Chan, AT and Newcomb, PA}, title = {Genetic Predictors of Severe Skin Toxicity in Patients with Stage III Colon Cancer Treated with Cetuximab: NCCTG N0147 (Alliance).}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-1274}, pmid = {33203692}, issn = {1538-7755}, abstract = {BACKGROUND: Cetuximab, an EGFR inhibitor used to treat multiple cancer types, including colon cancer, causes severe skin toxicity in 5%-20% of patients, leading to decreased quality of life and treatment delays. Our understanding of which patients have an increased risk of severe toxicities is limited. We conducted a genome-wide association study to identify germline variants predictive of cetuximab-induced severe skin toxicity.<br><br>METHODS: Our study included 1,209 patients with stage III colon cancer randomized to receive cetuximab plus 5-fluorouracil and oxaliplatin as part of the NCCTG N0147 (Alliance) clinical trial. Skin toxicity outcomes were collected using the Common Toxicity Criteria for Adverse Events version 3.0. We performed genotyping, evaluating approximately 10 million genetic variants. We used logistic regression to evaluate the association of each genetic variant and severe (grade ≥ 3) skin toxicity, adjusting for age, sex, and genetic ancestry. Genome-wide significance was defined as P < 5 × 10-8.<br><br>RESULTS: Participants were predominantly middle-aged white men; 20% (n = 243) experienced severe skin toxicity. Two genetic variants in the retinoic acid receptor alpha (RARA) gene were significantly associated with severe skin toxicity [OR, 3.93; 95% confidence interval (CI), 2.47-6.25; P < 7.8 × 10-9]. Functional annotations indicate these variants are in the RARA promoter. Additional significantly associated variants were identified in chromosome 2 intergenic regions.<br><br>CONCLUSION: Identified variants could represent a potential target for risk stratification of patients with colon cancer receiving cetuximab.<br><br>IMPACT: Retinoids have shown promise in the treatment of cetuximab-induced skin toxicity, so follow-up work could evaluate whether individuals with the RARA variant would benefit from retinoid therapy.}, }
@article {pmid33203525, year = {2021}, author = {Watson, NL and Mull, KE and Bricker, JB}, title = {The association between frequency of e-cigarette use and long-term smoking cessation outcomes among treatment-seeking smokers receiving a behavioral intervention.}, journal = {Drug and alcohol dependence}, volume = {218}, number = {}, pages = {108394}, doi = {10.1016/j.drugalcdep.2020.108394}, pmid = {33203525}, issn = {1879-0046}, abstract = {INTRODUCTION: A growing body of literature suggests daily, but not non-daily, e-cigarette use is associated with greater odds of quitting combustible cigarettes in the general adult population. However, it is unknown if these findings generalize to treatment-seeking smokers who are receiving a behavioral intervention. Our primary aim was to examine whether frequency of e-cigarette use was associated with subsequent cessation among treatment-seeking smokers who are receiving a behavioral smoking cessation intervention.<br><br>METHODS: Participants (N = 2637) enrolled in a RCT of web-based smoking treatments reported their use of e-cigarettes at baseline, 3-, and 6-months. Three groups were created based on e-cigarette use: (1) non-users, (2) intermittent users, and (3) daily users. The primary outcome was complete-case, self-reported 30-day point prevalence abstinence at 12 months.<br><br>RESULTS: Compared to non-users, daily e-cigarette users were significantly less likely to be abstinent (21.39 % vs. 29.68 %; p = .006). Quit rates for intermittent users (24.56 %) were not significantly different from non-users (p = .092). Nicotine dependence moderated the results such that among smokers with low nicotine dependence, those who used e-cigarettes (intermittently or daily) were less likely to quit than non-users; these differences were not significant among those with high nicotine dependence. Post hoc analyses indicated that initiating daily e-cigarette use after baseline, but not daily e-cigarette use at baseline, was associated with lower odds of cessation.<br><br>CONCLUSIONS: Daily e-cig use may be associated with lower odds of quitting smoking among treatment-seeking smokers, particularly among those with lower nicotine dependence and who initiate daily use after beginning an intervention.}, }
@article {pmid33202017, year = {2020}, author = {Kvaskoff, M and Mahamat-Saleh, Y and Farland, LV and Shigesi, N and Terry, KL and Harris, HR and Roman, H and Becker, CM and As-Sanie, S and Zondervan, KT and Horne, AW and Missmer, SA}, title = {Endometriosis and cancer: a systematic review and meta-analysis.}, journal = {Human reproduction update}, volume = {}, number = {}, pages = {}, doi = {10.1093/humupd/dmaa045}, pmid = {33202017}, issn = {1460-2369}, abstract = {BACKGROUND: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.<br><br>OBJECTIVE AND RATIONALE: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.<br><br>SEARCH METHODS: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.<br><br>OUTCOMES: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.<br><br>WIDER IMPLICATIONS: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.}, }
@article {pmid33200828, year = {2020}, author = {Hill, JA and Menon, MP and Dhanireddy, S and Wurfel, MM and Green, M and Jain, R and Chan, JD and Huang, J and Bethune, D and Turtle, C and Johnston, C and Xie, H and Leisenring, WM and Nina Kim, H and Cheng, GS}, title = {Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, and safety.}, journal = {Journal of medical virology}, volume = {}, number = {}, pages = {}, pmid = {33200828}, issn = {1096-9071}, abstract = {Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation. We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a six-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab. We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced C-reactive protein, fibrinogen, and temperature, but there were no meaningful differences in time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% confidence interval [CI], 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias. Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.}, }
@article {pmid33200508, year = {2020}, author = {Mair, F and Liechti, T}, title = {Comprehensive Phenotyping of Human Dendritic Cells and Monocytes.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.a.24269}, pmid = {33200508}, issn = {1552-4930}, support = {//Intramural research program of the Vaccine Research Center, NIAID, NIH/ ; Intersect Fellowship Program for Computational Sci//American Association of Immunologists/ ; }, abstract = {Professional antigen-presenting cells (APCs), which include dendritic cells (DCs) and monocytes are essential for inducing and steering adaptive T-cell responses. Recent technological developments in single-cell analysis have significantly advanced our understanding of APC subset heterogeneity. To accurately resolve this functional diversity and to account for tissue-specific adaptation, novel phenotyping markers have been described more recently. While some of these largely overlap with traditionally used markers, more fine-grained phenotyping might be essential during inflammatory settings, where the traditional distinction between monocytes and dendritic cells has become blurred. Within this phenotype report, we provide a concise overview of traditional and recently described markers for the phenotyping of DCs and monocytes in the human system.}, }
@article {pmid33200182, year = {2020}, author = {Lichtenstein, AH and Petersen, K and Barger, K and Hansen, KE and Anderson, CAM and Baer, DJ and Lampe, JW and Rasmussen, H and Matthan, NR}, title = {Perspective: Design and Conduct of Human Nutrition Randomized Controlled Trials.}, journal = {Advances in nutrition (Bethesda, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1093/advances/nmaa109}, pmid = {33200182}, issn = {2156-5376}, abstract = {In the field of human nutrition, randomized controlled trials (RCTs) are considered the gold standard for establishing causal relations between exposure to nutrients, foods, or dietary patterns and prespecified outcome measures, such as body composition, biomarkers, or event rates. Evidence-based dietary guidance is frequently derived from systematic reviews and meta-analyses of these RCTs. Each decision made during the design and conduct of human nutrition RCTs will affect the utility and generalizability of the study results. Within the context of limited resources, the goal is to maximize the generalizability of the findings while producing the highest quality data and maintaining the highest levels of ethics and scientific integrity. The aim of this document is to discuss critical aspects of conducting human nutrition RCTs, including considerations for study design (parallel, crossover, factorial, cluster), institutional ethics approval (institutional review boards), recruitment and screening, intervention implementation, adherence and retention assessment, and statistical analyses considerations. Additional topics include distinguishing between efficacy and effectiveness, defining the research question(s), monitoring biomarker and outcome measures, and collecting and archiving data. Addressed are specific aspects of planning and conducting human nutrition RCTs, including types of interventions, inclusion/exclusion criteria, participant burden, randomization and blinding, trial initiation and monitoring, and the analysis plan.}, }
@article {pmid33199512, year = {2020}, author = {Gastman, B and Agarwal, PK and Berger, A and Boland, G and Broderick, S and Butterfield, LH and Byrd, D and Fecci, PE and Ferris, RL and Fong, Y and Goff, SL and Grabowski, MM and Ito, F and Lim, M and Lotze, MT and Mahdi, H and Malafa, M and Morris, CD and Murthy, P and Neves, RI and Odunsi, A and Pai, SI and Prabhakaran, S and Rosenberg, SA and Saoud, R and Sethuraman, J and Skitzki, J and Slingluff, CL and Sondak, VK and Sunwoo, JB and Turcotte, S and Yeung, CC and Kaufman, HL}, title = {Defining best practices for tissue procurement in immuno-oncology clinical trials: consensus statement from the Society for Immunotherapy of Cancer Surgery Committee.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33199512}, issn = {2051-1426}, abstract = {Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy.}, }
@article {pmid33199493, year = {2020}, author = {DeLucia, DC and Cardillo, TM and Ang, L and Labrecque, MP and Zhang, A and Hopkins, JE and De Sarkar, N and Coleman, I and da Costa, RMG and Corey, E and True, LD and Haffner, MC and Schweizer, MT and Morrissey, C and Nelson, PS and Lee, JK}, title = {Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5-SN38 Antibody-drug Conjugate in Neuroendocrine Prostate Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-20-3396}, pmid = {33199493}, issn = {1557-3265}, abstract = {PURPOSE: Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody-drug conjugate labetuzumab govitecan in prostate cancer.<br><br>EXPERIMENTAL DESIGN: The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models.<br><br>RESULTS: CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.<br><br>CONCLUSIONS: Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.}, }
@article {pmid33199356, year = {2020}, author = {Dela Cruz, EJ and Fiedler, TL and Liu, C and Munch, MM and Kohler, CM and Oot, AR and Wallis, JM and Wang, J and Frishman, A and Garcia, K and Wiser, A and Balkus, JE and Srinivasan, S and Golob, JL and Sycuro, LK and Marrazzo, JM and Hawn, TR and Fredricks, DN}, title = {Genetic variation in Toll-like receptor-5 and colonization with flagellated bacterial vaginosis-associated bacteria.}, journal = {Infection and immunity}, volume = {}, number = {}, pages = {}, doi = {10.1128/IAI.00060-20}, pmid = {33199356}, issn = {1098-5522}, abstract = {Bacterial vaginosis (BV) is a vaginal dysbiotic condition linked to negative gynecological and reproductive sequelae. Flagellated bacteria have been identified in women with BV, including Mobiluncus spp. and BV-associated bacterium-1 (BVAB1), an uncultivated, putatively flagellated species. The host response to flagellin mediated through toll-like receptor-5 (TLR5) has not been explored in BV. Using independent discovery and validation cohorts, we examined the hypothesis that TLR5 deficiency-defined by a dominant negative stop codon polymorphism rs5744168-is associated with an increased risk for BV and increased colonization with flagellated bacteria associated with BV (BVAB1, Mobiluncus curtisii, Mobiluncus mulieris). TLR5 deficiency was not associated with BV status and TLR5 deficient women had decreased colonization with BVAB1 in both cohorts. We stimulated HEK-hTLR5-overexpressing, NF-kB reporter cells with whole, heat-killed M. mulieris or M. curtisii, and with partially purified flagellin from these species; as BVAB1 is uncultivated, we used cervicovaginal lavage (CVL) supernatant from women colonized with BVAB1 for stimulation. While heat-killed M. mulieris and CVL from women colonized with BVAB1 stimulate a TLR5-mediated response, heat-killed M. curtisii did not. In contrast, partially purified flagellin from both Mobiluncus species stimulated a TLR5-mediated response in vitro. We observed no correlation between vaginal IL-8 and flagellated BVAB concentrations among TLR5 sufficient women. Inter-species variation in accessibility of flagellin recognition domains may be responsible for these observations as reflected in the potentially novel flagellin products encoded by Mobiluncus species versus those encoded by BVAB1.}, }
@article {pmid33197930, year = {2020}, author = {Emanuels, A and Heimonen, J and O'Hanlon, J and Kim, AE and Wilcox, N and McCulloch, DJ and Brandstetter, E and Wolf, CR and Logue, JK and Han, PD and Pfau, B and Newman, KL and Hughes, JP and Jackson, ML and Uyeki, TM and Boeckh, M and Starita, LM and Nickerson, DA and Bedford, T and Englund, JA and Chu, HY}, title = {Remote Household Observation for Non-influenza Respiratory Viral Illness.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1719}, pmid = {33197930}, issn = {1537-6591}, abstract = {BACKGROUND: Non-influenza respiratory viruses are responsible for a substantial burden of disease in the United States. Household transmission is thought to contribute significantly to subsequent transmission through the broader community. In the context of the COVID-19 pandemic, contactless surveillance methods are of particular importance.<br><br>METHODS: From November 2019 to April 2020, 303 households in the Seattle area were remotely monitored in a prospective longitudinal study for symptoms of respiratory viral illness. Enrolled participants reported weekly symptoms and submitted respiratory samples by mail in the event of an acute respiratory illness (ARI). Specimens were tested for fourteen viruses, including SARS-CoV-2, using RT-PCR. Participants completed all study procedures at home without physical contact with research staff.<br><br>RESULTS: In total, 1171 unique participants in 303 households were monitored for ARI. Of participating households, 128 (42%) included a child aged <5 years and 202 (67%) included a child aged 5-12 years. Of the 678 swabs collected during the surveillance period, 237 (35%) tested positive for one or more non-influenza respiratory viruses. Rhinovirus, common human coronaviruses, and respiratory syncytial virus were the most common. Four cases of SARS-CoV-2 were detected in three households.<br><br>CONCLUSIONS: This study highlights the circulation of respiratory viruses within households during the winter months during the emergence of the SARS-CoV-2 pandemic. Contactless methods of recruitment, enrollment and sample collection were utilized throughout this study, and demonstrate the feasibility of home-based, remote monitoring for respiratory infections.}, }
@article {pmid33197280, year = {2020}, author = {Togawa, K and Anderson, BO and Foerster, M and Galukande, M and Zietsman, A and Pontac, J and Anele, A and Adisa, C and Parham, G and Pinder, LF and McKenzie, F and Schüz, J and Dos-Santos-Silva, I and McCormack, V}, title = {Geospatial barriers to health care access for breast cancer diagnosis in sub-Saharan African settings: the African Breast Cancer - Disparities in Outcomes (ABC-DO) Cohort Study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33400}, pmid = {33197280}, issn = {1097-0215}, abstract = {We examined the geospatial dimension of delays to diagnosis of breast cancer in a prospective study of 1541 women newly diagnosed in the African Breast Cancer - Disparities in Outcomes (ABC-DO) Study. Women were recruited at cancer treatment facilities in Namibia, Nigeria, Uganda, and Zambia. The baseline interview included information used to generate the geospatial features: urban/rural residence, travel mode to treatment facility, and straight-line distances from home to first care provider and to diagnostic/treatment facility, categorized into country/ethnicity (population)-specific quartiles. These factors were investigated in relation to delay in diagnosis (≥3 months since first symptom) and late stage at diagnosis (TNM: III, IV) using logistic regression, adjusted for population group and sociodemographic characteristics. The median (interquartile range) distances to first provider and diagnostic and treatment facilities were 5 (1-37), 17 (3-105), and 62 (5-289) kms, respectively. The majority had a delay in diagnosis (74%) and diagnosis at late stage (64%). Distance to first provider was not associated with delay in diagnosis or late stage at diagnosis. Rural residence was associated with delay, but the association did not persist after adjustment for sociodemographic characteristics. Distance to the diagnostic/treatment facility was associated with delay (highest vs lowest quartile: Odds Ratio (OR)=1.56, 95% confidence interval (CI)=1.08-2.27) and late stage (overall: OR=1.47, CI=1.05-2.06; without Nigerian hospitals where mostly local residents were treated: OR=1.73, CI=1.18-2.54). These findings underscore the need of measures addressing the geospatial barriers to early diagnosis in sub-Saharan African settings, including providing transport or travel allowance and decentralizing diagnostic services.}, }
@article {pmid33193434, year = {2020}, author = {van Oers, NSC and Su, DM and Chidgey, AP and Dudakov, J}, title = {Editorial: New Insights Into Thymic Functions During Stress, Aging, and in Disease Settings.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {591936}, pmid = {33193434}, issn = {1664-3224}, support = {R01 AI114523/AI/NIAID NIH HHS/United States ; R21 AI144140/AI/NIAID NIH HHS/United States ; }, }
@article {pmid33191955, year = {2020}, author = {Sun, Y and Qi, L and Heng, F and Gilbert, PB}, title = {A Hybrid Approach for the Stratified Mark-Specific Proportional Hazards Model with Missing Covariates and Missing Marks, with Application to Vaccine Efficacy Trials.}, journal = {Journal of the Royal Statistical Society. Series C, Applied statistics}, volume = {69}, number = {4}, pages = {791-814}, pmid = {33191955}, issn = {0035-9254}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; }, abstract = {Deployment of the recently licensed CYD-TDV dengue vaccine requires understanding of how the risk of dengue disease in vaccine recipients depends jointly on a host biomarker measured after vaccination (neutralization titer - NAb) and on a &quot;mark&quot; feature of the dengue disease failure event (the amino acid sequence distance of the dengue virus to the dengue sequence represented in the vaccine). The CYD14 phase 3 trial of CYD-TDV measured NAb via case-cohort sampling and the mark in dengue disease failure events, with about a third missing marks. We addressed the question of interest by developing inferential procedures for the stratified mark-specific proportional hazards model with missing covariates and missing marks. Two hybrid approaches are investigated that leverage both augmented inverse probability weighting and nearest neighborhood hot deck multiple imputation. The two approaches differ in how the imputed marks are pooled in estimation. Our investigation shows that NNHD imputation can lead to biased estimation without properly selected neighborhood. Simulations show that the developed hybrid methods perform well with unbiased NNHD imputations from proper neighborhood selection. The new methods applied to CYD14 show that NAb is strongly inversely associated with risk of dengue disease in vaccine recipients, more strongly against dengue viruses with shorter distances.}, }
@article {pmid33191916, year = {2020}, author = {Henikoff, S and Henikoff, JG and Kaya-Okur, HS and Ahmad, K}, title = {Efficient chromatin accessibility mapping in situ by nucleosome-tethered tagmentation.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {33191916}, issn = {2050-084X}, support = {Henikoff/HHMI/Howard Hughes Medical Institute/United States ; Fred Hutch HCA Seed Network//Chan Zuckerberg Initiative/ ; R01 GM108699/GM/NIGMS NIH HHS/United States ; R01 HG010492/HG/NHGRI NIH HHS/United States ; R01 HG010492/NH/NIH HHS/United States ; R01 GM108699/NH/NIH HHS/United States ; }, abstract = {Chromatin accessibility mapping is a powerful approach to identify potential regulatory elements. A popular example is ATAC-seq, whereby Tn5 transposase inserts sequencing adapters into accessible DNA ('tagmentation'). CUT&amp;Tag is a tagmentation-based epigenomic profiling method in which antibody tethering of Tn5 to a chromatin epitope of interest profiles specific chromatin features in small samples and single cells. Here we show that by simply modifying the tagmentation conditions for histone H3K4me2 or H3K4me3 CUT&amp;Tag, antibody-tethered tagmentation of accessible DNA sites is redirected to produce chromatin accessibility maps that are indistinguishable from the best ATAC-seq maps. Thus, chromatin accessibility maps can be produced in parallel with CUT&amp;Tag maps of other epitopes with all steps from nuclei to amplified sequencing-ready libraries performed in single PCR tubes in the laboratory or on a home workbench. As H3K4 methylation is produced by transcription at promoters and enhancers, our method identifies transcription-coupled accessible regulatory sites.}, }
@article {pmid33191765, year = {2020}, author = {Seneviratne, HK and Tillotson, J and Lade, JM and Bekker, LG and Li, S and Pathak, S and Justman, J and Mgodi, N and Swaminathan, S and Sista, N and Farrior, J and Richardson, P and Hendrix, CW and Bumpus, NN}, title = {Metabolism of Long-Acting Rilpivirine Following Intramuscular Injection: HIV Prevention Trials Network Study 076 (HPTN 076).}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2020.0155}, pmid = {33191765}, issn = {1931-8405}, support = {R01 AI128781/AI/NIAID NIH HHS/United States ; R01 GM103853/GM/NIGMS NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; }, abstract = {A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in HIV maintenance therapy. We previously characterized RPV metabolism following oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV following injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect two metabolites following intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV and RPV N-glucuronide. Of the total of 80 individuals, 72 subjects exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. Additionally, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, 4 missense variants were detected for CYP3A4 while one missense variant and one frameshift variant were detected for CYP3A5. A total of 8 missense variants of UGT1A4 were detected, whereas 2 variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to overall understanding of metabolism following oral dosing versus injection.}, }
@article {pmid33191158, year = {2020}, author = {Beasley, JM and Rillamas-Sun, E and Tinker, LF and Wylie-Rosett, J and Mossavar-Rahmani, Y and Datta, M and Caan, BJ and LaCroix, AZ}, title = {Authors Response.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2020.10.015}, pmid = {33191158}, issn = {2212-2672}, }
@article {pmid33189694, year = {2020}, author = {Bak, A and Ho, RJ}, title = {Advancing Cell and Gene Therapeutic Products for Health Impact - Progress on Pharmaceutical Research, Development, Manufacturing and Controls.}, journal = {Journal of pharmaceutical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.xphs.2020.10.053}, pmid = {33189694}, issn = {1520-6017}, }
@article {pmid33188038, year = {2020}, author = {Simon, S and Voillet, V and Vignard, V and Wu, Z and Dabrowski, C and Jouand, N and Beauvais, T and Khammari, A and Braudeau, C and Josien, R and Adotevi, O and Laheurte, C and Aubin, F and Nardin, C and Rulli, S and Gottardo, R and Ramchurren, N and Cheever, M and Fling, SP and Church, CD and Nghiem, P and Dreno, B and Riddell, SR and Labarriere, N}, title = {PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33188038}, issn = {2051-1426}, abstract = {BACKGROUND: Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated.<br><br>METHODS: We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets.<br><br>RESULTS: We documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1 month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response.<br><br>CONCLUSIONS: Our results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.}, }
@article {pmid33186338, year = {2020}, author = {Montaño, MA and Alfaro, R and Ness, T and Ganoza, C and Gonzales, P and Sanchez, J and Lama, JR and Duerr, AC}, title = {Sexual Behavior and Sexually Transmitted Infection Outcomes Among Men Who Have Sex With Men and Transgender Women Participating in a Study of the Timing of Antiretroviral Therapy in Lima, Peru.}, journal = {Sexually transmitted diseases}, volume = {47}, number = {12}, pages = {825-831}, pmid = {33186338}, issn = {1537-4521}, support = {F31 MH114892/MH/NIMH NIH HHS/United States ; R01 DA032106/DA/NIDA NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: We assessed sexual behavior and incidence of sexually transmitted infections (STIs) among men who have sex with men and transgender women participating in Sabes, a study of an expanded treatment as prevention strategy focused on early diagnosis and treatment of HIV infection in Lima, Peru (2013-2017).<br><br>METHODS: Sabes participants were tested monthly for HIV to identify acute or early infections, and HIV-positive participants were randomized to receive antiretroviral therapy immediately (immediate arm) or after 24 weeks (deferred arm) during a 48-week follow-up period. Sexual behavior was assessed at randomization (baseline) and every 12 weeks thereafter. Participants were tested for urethral and rectal chlamydia and gonorrhea and for syphilis at baseline, 12, 24, and 48 weeks. We describe patterns of sexual behavior during the 48-week follow-up period and compare sexual behavior and STI incidence between study arms.<br><br>RESULTS: After randomization, 207 HIV-positive participants completed questionnaires and STI testing at 2 or more visits. After HIV diagnosis, participants in both arms reported increases in condom use with main and casual partners and decreased drug and alcohol use before or during anal sex. We observed no between-arm differences in sexual behavior. Deferred arm participants had higher incidence of chlamydia (incidence rate ratio, 2.33; 95% confidence interval, 1.14-4.77) but not gonorrhea or syphilis.<br><br>CONCLUSIONS: Despite reported increases in condom use, the overall high incidence of STIs reflects some ongoing condomless sex among HIV-positive men who have sex with men and transgender women, highlighting the importance of regular STI screening and counseling to support consistent condom use among HIV-positive individuals at risk for STIs.}, }
@article {pmid33184642, year = {2020}, author = {Best, CM and Riley, DV and Laha, TJ and Pflaum, H and Zelnick, LR and Hsu, S and Thummel, KE and Foster-Schubert, KE and Kuzma, JN and Cromer, G and Larson, I and Hagman, DK and Heshelman, K and Kratz, M and de Boer, IH and Hoofnagle, AN}, title = {Vitamin D in human serum and adipose tissue after supplementation.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqaa295}, pmid = {33184642}, issn = {1938-3207}, abstract = {BACKGROUND: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens.<br><br>OBJECTIVES: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials.<br><br>METHODS: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo.<br><br>RESULTS: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum.<br><br>CONCLUSIONS: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).}, }
@article {pmid33184632, year = {2020}, author = {Schmidt, KA and Cromer, G and Burhans, MS and Kuzma, JN and Hagman, DK and Fernando, I and Murray, M and Utzschneider, KM and Holte, S and Kraft, J and Kratz, M}, title = {The impact of diets rich in low-fat or full-fat dairy on glucose tolerance and its determinants: a randomized controlled trial.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajcn/nqaa301}, pmid = {33184632}, issn = {1938-3207}, abstract = {BACKGROUND: Dairy foods, particularly yogurt, and plasma biomarkers of dairy fat intake are consistently inversely associated with incident type 2 diabetes. Yet, few trials assessing the impact of dairy on glucose homeostasis include fermented or full-fat dairy foods.<br><br>OBJECTIVES: We aimed to compare the effects of diets rich in low-fat or full-fat milk, yogurt, and cheese on glucose tolerance and its determinants, with those of a limited dairy diet.<br><br>METHODS: In this parallel-design randomized controlled trial, 72 participants with metabolic syndrome completed a 4-wk wash-in period, limiting dairy intake to ≤3 servings/wk of nonfat milk. Participants were then randomly assigned to either continue the limited dairy diet, or switch to a diet containing 3.3 servings/d of either low-fat or full-fat dairy for 12 wk. Outcome measures included glucose tolerance (area under the curve glucose during an oral-glucose-tolerance test), insulin sensitivity, pancreatic β-cell function, systemic inflammation, liver-fat content, and body weight and composition.<br><br>RESULTS: In the per-protocol analysis (n = 67), we observed no intervention effect on glucose tolerance (P = 0.340). Both the low-fat and full-fat dairy diets decreased the Matsuda insulin sensitivity index (ISI) (means ± SDs -0.47 ± 1.07 and -0.25 ± 0.91, respectively) and as compared with the limited dairy group (0.00 ± 0.92) (P = 0.012 overall). Body weight also changed differentially (P = 0.006 overall), increasing on full-fat dairy (+1.0 kg; -0.2, 1.8 kg) compared with the limited dairy diet (-0.4 kg; -2.5, 0.7 kg), whereas the low-fat dairy diet (+0.3 kg; -1.1, 1.9 kg) was not significantly different from the other interventions. Intervention effects on the Matsuda ISI remained after adjusting for changes in adiposity. No intervention effects were detected for liver fat content or systemic inflammation. Findings in intent-to-treat analyses (n = 72) were consistent.<br><br>CONCLUSIONS: Contrary to our hypothesis, neither dairy diet improved glucose tolerance in individuals with metabolic syndrome. Both dairy diets decreased insulin sensitivity through mechanisms largely unrelated to changes in key determinants of insulin sensitivity.This trial was registered at clinicaltrials.gov as NCT02663544.}, }
@article {pmid33184492, year = {2020}, author = {Estey, E}, title = {New treatments for acute myeloid leukemia: how much has changed?.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-020-01084-2}, pmid = {33184492}, issn = {1476-5551}, }
@article {pmid33184181, year = {2020}, author = {Cao, J and O'Day, DR and Pliner, HA and Kingsley, PD and Deng, M and Daza, RM and Zager, MA and Aldinger, KA and Blecher-Gonen, R and Zhang, F and Spielmann, M and Palis, J and Doherty, D and Steemers, FJ and Glass, IA and Trapnell, C and Shendure, J}, title = {A human cell atlas of fetal gene expression.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6518}, pages = {}, doi = {10.1126/science.aba7721}, pmid = {33184181}, issn = {1095-9203}, support = {R56 DK119285/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R01 DK119285/DK/NIDDK NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; }, mesh = {Atlases as Topic ; Chromatin/*metabolism ; Fetus/*cytology/*metabolism ; *Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Humans ; Neurons/metabolism ; *Single-Cell Analysis ; Transcription Factors/metabolism ; }, abstract = {The gene expression program underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of gene expression and chromatin accessibility in fetal tissues. For gene expression, we applied three-level combinatorial indexing to >110 samples representing 15 organs, ultimately profiling ~4 million single cells. We leveraged the literature and other atlases to identify and annotate hundreds of cell types and subtypes, both within and across tissues. Our analyses focused on organ-specific specializations of broadly distributed cell types (such as blood, endothelial, and epithelial), sites of fetal erythropoiesis (which notably included the adrenal gland), and integration with mouse developmental atlases (such as conserved specification of blood cells). These data represent a rich resource for the exploration of in vivo human gene expression in diverse tissues and cell types.}, }
@article {pmid33184180, year = {2020}, author = {Domcke, S and Hill, AJ and Daza, RM and Cao, J and O'Day, DR and Pliner, HA and Aldinger, KA and Pokholok, D and Zhang, F and Milbank, JH and Zager, MA and Glass, IA and Steemers, FJ and Doherty, D and Trapnell, C and Cusanovich, DA and Shendure, J}, title = {A human cell atlas of fetal chromatin accessibility.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6518}, pages = {}, doi = {10.1126/science.aba7612}, pmid = {33184180}, issn = {1095-9203}, support = {T32 HL007828/HL/NHLBI NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; //Howard Hughes Medical Institute./International ; }, mesh = {Atlases as Topic ; Chromatin/*metabolism ; Fetus/*cytology/*metabolism ; *Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Humans ; Neurons/metabolism ; *Single-Cell Analysis ; Transcription Factors/metabolism ; }, abstract = {The chromatin landscape underlying the specification of human cell types is of fundamental interest. We generated human cell atlases of chromatin accessibility and gene expression in fetal tissues. For chromatin accessibility, we devised a three-level combinatorial indexing assay and applied it to 53 samples representing 15 organs, profiling ~800,000 single cells. We leveraged cell types defined by gene expression to annotate these data and cataloged hundreds of thousands of candidate regulatory elements that exhibit cell type-specific chromatin accessibility. We investigated the properties of lineage-specific transcription factors (such as POU2F1 in neurons), organ-specific specializations of broadly distributed cell types (such as blood and endothelial), and cell type-specific enrichments of complex trait heritability. These data represent a rich resource for the exploration of in vivo human gene regulation in diverse tissues and cell types.}, }
@article {pmid33180326, year = {2020}, author = {Ayeni, OA and Norris, SA and Joffe, M and Cubasch, H and Galukande, M and Zietsman, A and Parham, G and Adisa, C and Anele, A and Schüz, J and Anderson, BO and Foerster, M and Dos Santos Silva, I and McCormack, VA}, title = {Preexisting morbidity profile of women newly diagnosed with breast cancer in sub-Saharan Africa: African Breast Cancer-Disparities in Outcomes study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33387}, pmid = {33180326}, issn = {1097-0215}, support = {//Cancer Association of South Africa (CANSA) grant &quot;Down-staging and improving survival of breast cancer in South Africa&quot;/ ; NIH/R01-CA192627-01//NIH grant/ ; //South African Medical Research Council /University of the Witwatersrand Common Epithelial Cancer Research Centre/ ; IIR 13264158//Susan G. Komen for the Cure Foundation/ ; }, abstract = {The presence of preexisting morbidities poses a challenge to cancer patient care. There is little information on the profile and prevalence of multi-morbidities in breast cancer patients across middle income countries (MIC) to lower income countries (LIC) in sub-Saharan Africa (SSA). The African Breast Cancer-Disparities in Outcomes (ABC-DO) breast cancer cohort spans upper MICs South Africa and Namibia, lower MICs Zambia and Nigeria and LIC Uganda. At cancer diagnosis, seven morbidities were assessed: obesity, hypertension, diabetes, asthma/chronic obstructive pulmonary disease, heart disease, tuberculosis and HIV. Logistic regression models were used to assess determinants of morbidities and the influence of morbidities on advanced stage (stage III/IV) breast cancer diagnosis. Among 2189 women, morbidity prevalence was the highest for obesity (35%, country-specific range 15-57%), hypertension (32%, 15-51%) and HIV (16%, 2-26%) then for diabetes (7%, 4%-10%), asthma (4%, 2%-10%), tuberculosis (4%, 0%-8%) and heart disease (3%, 1%-7%). Obesity and hypertension were more common in upper MICs and in higher socioeconomic groups. Overall, 27% of women had at least two preexisting morbidities. Older women were more likely to have obesity (odds ratio: 1.09 per 10 years, 95% CI 1.01-1.18), hypertension (1.98, 1.81-2.17), diabetes (1.51, 1.32-1.74) and heart disease (1.69, 1.37-2.09) and were less likely to be HIV positive (0.64, 0.58-0.71). Multi-morbidity was not associated with stage at diagnosis, with the exception of earlier stage in obese and hypertensive women. Breast cancer patients in higher income countries and higher social groups in SSA face the additional burden of preexisting non-communicable diseases, particularly obesity and hypertension, exacerbated by HIV in Southern/Eastern Africa.}, }
@article {pmid33180325, year = {2020}, author = {Shim, YA and Weliwitigoda, A and Campbell, T and Dosanjh, M and Johnson, P}, title = {Splenic erythroid progenitors decrease TNF-α production by macrophages and reduce systemic inflammation in a mouse model of T cell-induced colitis.}, journal = {European journal of immunology}, volume = {}, number = {}, pages = {}, doi = {10.1002/eji.202048687}, pmid = {33180325}, issn = {1521-4141}, support = {MOP-77712/CAPMC/CIHR/Canada ; //Natural Sciences and Engineering Research Council/ ; }, abstract = {In inflammatory bowel disease (IBD), inflammation can occur beyond the intestine and spread systemically causing complications such as arthritis, cachexia, and anemia. Here, we determine the impact of CD45, a pan-leukocyte marker and tyrosine phosphatase, on IBD. Using a mouse model of T cell transfer colitis, CD25- CD45RBhigh CD4+ T cells were transferred into Rag1-deficient mice (RAGKO) and CD45-deficient RAGKO mice (CD45RAGKO). Weight loss and systemic wasting syndrome were delayed in CD45RAGKO mice compared to RAGKO mice, despite equivalent inflammation in the colon. CD45RAGKO mice had reduced serum levels of TNF-α, and reduced TNF-α production by splenic myeloid cells. CD45RAGKO mice also had increased numbers of erythroid progenitors in the spleen, which had previously been shown to be immunosuppressive. Adoptive transfer of these erythroid progenitors into RAGKO mice reduced their weight loss and TNF-α expression by splenic red pulp macrophages. In vitro, erythroid cells suppressed TNF-α expression in red pulp macrophages in a phagocytosis-dependent manner. These findings show a novel role for erythroid progenitors in suppressing the pro-inflammatory function of splenic macrophages and cachexia associated with IBD.}, }
@article {pmid33180106, year = {2020}, author = {Atallah, E and Schiffer, CA and Radich, JP and Weinfurt, KP and Zhang, MJ and Pinilla-Ibarz, J and Kota, V and Larson, RA and Moore, JO and Mauro, MJ and Deininger, MWN and Thompson, JE and Oehler, VG and Wadleigh, M and Shah, NP and Ritchie, EK and Silver, RT and Cortes, J and Lin, L and Visotcky, A and Baim, A and Harrell, J and Helton, B and Horowitz, M and Flynn, KE}, title = {Assessment of Outcomes After Stopping Tyrosine Kinase Inhibitors Among Patients With Chronic Myeloid Leukemia: A Nonrandomized Clinical Trial.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {33180106}, issn = {2374-2445}, support = {UG1 CA233328/CA/NCI NIH HHS/United States ; }, abstract = {Importance: Tyrosine kinase inhibitors (TKIs) have been associated with improved survival of patients with chronic myeloid leukemia (CML) but are also associated with adverse effects, especially fatigue and diarrhea. Discontinuation of TKIs is safe and is associated with the successful achievement of treatment-free remission (TFR) for some patients.<br><br>Objective: To evaluate molecular recurrence (MRec) and patient-reported outcomes (PROs) after TKI discontinuation for US patients with CML.<br><br>The Life After Stopping TKIs (LAST) study was a prospective single-group nonrandomized clinical trial that enrolled 172 patients from 14 US academic medical centers from December 18, 2014, to December 12, 2016, with a minimum follow-up of 3 years. Participants were adults with chronic-phase CML whose disease was well controlled with imatinib, dasatinib, nilotinib, or bosutinib. Statistical analysis was performed from August 13, 2019, to March 23, 2020.<br><br>Intervention: Discontinuation of TKIs.<br><br>Main Outcomes and Measures: Molecular recurrence, defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) by central laboratory testing, and PROs (Patient-Reported Outcomes Measurement Information System computerized adaptive tests) were monitored. Droplet digital polymerase chain reaction (ddPCR) was performed on samples with undetectable BCR-ABL1 by standard real-time quantitative polymerase chain reaction (RQ-PCR).<br><br>Results: Of 172 patients, 89 were women (51.7%), and the median age was 60 years (range, 21-86 years). Of 171 patients evaluable for molecular analysis, 112 (65.5%) stayed in major molecular response, and 104 (60.8%) achieved TFR. Undetectable BCR-ABL1 by either ddPCR or RQ-PCR at the time of TKI discontinuation (hazard ratio, 3.60; 95% CI, 1.99-6.50; P < .001) and at 3 months (hazard ratio, 5.86; 95% CI, 3.07-11.1; P < .001) was independently associated with MRec. Molecular recurrence for patients with detectable BCR-ABL1 by RQ-PCR was 50.0% (14 of 28), undetectable BCR-ABL1 by RQ-PCR but detectable by ddPCR was 64.3% (36 of 56), and undetectable BCR-ABL1 by both ddPCR and RQ-PCR was 10.3% (9 of 87) (P ≤ .001). Of the 112 patients in TFR at 12 months, 90 (80.4%) had a clinically meaningful improvement in fatigue, 39 (34.8%) had a clinically meaningful improvement in depression, 98 (87.5%) had a clinically meaningful improvement in diarrhea, 24 (21.4%) had a clinically meaningful improvement in sleep disturbance, and 5 (4.5%) had a clinically meaningful improvement in pain interference. Restarting a TKI resulted in worsening of PROs.<br><br>Conclusions and Relevance: In this study, TKI discontinuation was safe, and 60.8% of patients remained in TFR. Discontinuation of TKIs was associated with improvements in PROs. These findings should assist patients and physicians in their decision-making regarding discontinuation of TKIs. Detectable BCR-ABL1 by RQ-PCR or ddPCR at the time of TKI discontinuation was associated with higher risk of MRec; clinical application of this finding should be confirmed in other studies.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02269267.}, }
@article {pmid33180102, year = {2020}, author = {Fleury, ME and Farner, AM and Unger, JM}, title = {Association of the COVID-19 Outbreak With Patient Willingness to Enroll in Cancer Clinical Trials.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {33180102}, issn = {2374-2445}, }
@article {pmid33176741, year = {2020}, author = {Dembitz, V and Lalic, H and Kodvanj, I and Tomic, B and Batinic, J and Dubravcic, K and Batinic, D and Bedalov, A and Visnjic, D}, title = {5-aminoimidazole-4-carboxamide ribonucleoside induces differentiation in a subset of primary acute myeloid leukemia blasts.}, journal = {BMC cancer}, volume = {20}, number = {1}, pages = {1090}, pmid = {33176741}, issn = {1471-2407}, support = {IP-2016-06-4581//Hrvatska Zaklada za Znanost/ ; DOK-2018-01-9599//Hrvatska Zaklada za Znanost/ ; R01GM117446//Foundation for the National Institutes of Health/ ; GA KK01.1.1.01.0007//European Regional Development Fund/ ; }, abstract = {BACKGROUND: All-trans retinoic acid (ATRA)-based treatment of acute promyelocytic leukemia (APL) is the most successful pharmacological treatment of acute myeloid leukemia (AML). Recent development of inhibitors of mutated isocitrate dehydrogenase and dihydroorotate dehydrogenase (DHODH) has revived interest in differentiation therapy of non-APL AML. Our previous studies demonstrated that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induced differentiation of monocytic cell lines by activating the ATR/Chk1 via pyrimidine depletion. In the present study, the effects of AICAr on the viability and differentiation of primary AML blasts isolated from bone marrow of patients with non-APL AML were tested and compared with the effects of DHODH inhibitor brequinar and ATRA.<br><br>METHODS: Bone marrow samples were obtained from 35 patients and leukemia blasts were cultured ex vivo. The cell viability was assessed by MTT assay and AML cell differentiation was determined by flow cytometry and morphological analyses. RNA sequencing and partial data analysis were conducted using ClusterProfiler package. Statistical analysis was performed using GraphPad Prism 6.0.<br><br>RESULTS: AICAr is capable of triggering differentiation in samples of bone marrow blasts cultured ex vivo that were resistant to ATRA. AICAr-induced differentiation correlates with proliferation and sensitivity to DHODH inhibition. RNA-seq data obtained in primary AML blasts confirmed that AICAr treatment induced downregulation of pyrimidine metabolism pathways together with an upregulation of gene set involved in hematopoietic cell lineage.<br><br>CONCLUSION: AICAr induces differentiation in a subset of primary non-APL AML blasts, and these effects correlate with sensitivity to a well-known, potent DHODH inhibitor.}, }
@article {pmid33175831, year = {2020}, author = {Ralph, DK and Matsen, FA}, title = {Using B cell receptor lineage structures to predict affinity.}, journal = {PLoS computational biology}, volume = {16}, number = {11}, pages = {e1008391}, pmid = {33175831}, issn = {1553-7358}, support = {R01 GM113246/GM/NIGMS NIH HHS/United States ; }, abstract = {We are frequently faced with a large collection of antibodies, and want to select those with highest affinity for their cognate antigen. When developing a first-line therapeutic for a novel pathogen, for instance, we might look for such antibodies in patients that have recovered. There exist effective experimental methods of accomplishing this, such as cell sorting and baiting; however they are time consuming and expensive. Next generation sequencing of B cell receptor (BCR) repertoires offers an additional source of sequences that could be tapped if we had a reliable method of selecting those coding for the best antibodies. In this paper we introduce a method that uses evolutionary information from the family of related sequences that share a naive ancestor to predict the affinity of each resulting antibody for its antigen. When combined with information on the identity of the antigen, this method should provide a source of effective new antibodies. We also introduce a method for a related task: given an antibody of interest and its inferred ancestral lineage, which branches in the tree are likely to harbor key affinity-increasing mutations? We evaluate the performance of these methods on a wide variety of simulated samples, as well as two real data samples. These methods are implemented as part of continuing development of the partis BCR inference package, available at https://github.com/psathyrella/partis. Comments Please post comments or questions on this paper as new issues at https://git.io/Jvxkn.}, }
@article {pmid33175653, year = {2020}, author = {Clark, SE and Marcum, ZA and Radich, JP and Bansal, A}, title = {Predictors of tyrosine kinase inhibitor adherence trajectories in patients with newly diagnosed chronic myeloid leukemia.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {1078155220970616}, doi = {10.1177/1078155220970616}, pmid = {33175653}, issn = {1477-092X}, abstract = {INTRODUCTION: Although consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies.<br><br>METHODS: Newly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression.<br><br>RESULTS: Four broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups.<br><br>CONCLUSION: Select sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.}, }
@article {pmid33174580, year = {2020}, author = {Horowitz, LF and Rodriguez, AD and Au-Yeung, A and Bishop, KW and Barner, LA and Mishra, G and Raman, A and Delgado, P and Liu, JTC and Gujral, TS and Mehrabi, M and Yang, M and Pierce, RH and Folch, A}, title = {Microdissected &quot;cuboids&quot; for microfluidic drug testing of intact tissues.}, journal = {Lab on a chip}, volume = {}, number = {}, pages = {}, doi = {10.1039/d0lc00801j}, pmid = {33174580}, issn = {1473-0189}, abstract = {As preclinical animal tests often do not accurately predict drug effects later observed in humans, most drugs under development fail to reach the market. Thus there is a critical need for functional drug testing platforms that use human, intact tissues to complement animal studies. To enable future multiplexed delivery of many drugs to one small biopsy, we have developed a multi-well microfluidic platform that selectively treats cuboidal-shaped microdissected tissues or &quot;cuboids&quot; with well-preserved tissue microenvironments. We create large numbers of uniformly-sized cuboids by semi-automated sectioning of tissue with a commercially available tissue chopper. Here we demonstrate the microdissection method on normal mouse liver, which we characterize with quantitative 3D imaging, and on human glioma xenograft tumors, which we evaluate after time in culture for viability and preservation of the microenvironment. The benefits of size uniformity include lower heterogeneity in future biological assays as well as facilitation of their physical manipulation by automation. Our prototype platform consists of a microfluidic circuit whose hydrodynamic traps immobilize the live cuboids in arrays at the bottom of a multi-well plate. Fluid dynamics simulations enabled the rapid evaluation of design alternatives and operational parameters. We demonstrate the proof-of-concept application of model soluble compounds such as dyes (CellTracker, Hoechst) and the cancer drug cisplatin. Upscaling of the microfluidic platform and microdissection method to larger arrays and numbers of cuboids could lead to direct testing of human tissues at high throughput, and thus could have a significant impact on drug discovery and personalized medicine.}, }
@article {pmid33173205, year = {2020}, author = {Wilkins, LJ and Tosoian, JJ and Sundi, D and Ross, AE and Grimberg, D and Klein, EA and Chapin, BF and Nyame, YA}, title = {Surgical management of high-risk, localized prostate cancer.}, journal = {Nature reviews. Urology}, volume = {17}, number = {12}, pages = {679-690}, pmid = {33173205}, issn = {1759-4820}, abstract = {High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone. However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy. Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach. Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.}, }
@article {pmid33172885, year = {2020}, author = {Feng, Z and Pepe, MS}, title = {Adding Rigor to Biomarker Evaluations-EDRN Experience.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {29}, number = {12}, pages = {2575-2582}, doi = {10.1158/1055-9965.EPI-20-0240}, pmid = {33172885}, issn = {1538-7755}, abstract = {The cancer early-detection biomarker field was, compared with the therapeutic arena, in its infancy when the Early Detection Research Network (EDRN) was initiated in 2000. The EDRN has played a crucial role in changing the culture and the ways people conduct biomarker studies. The EDRN proposed biomarker developmental guidelines and biomarker pivotal trial study design standards, created biomarker reference sets and functioned as an unbiased broker for the field, implemented the most rigorous blinding policy in the biomarker field, developed an array of statistical and computational tools for early-detection biomarker evaluations, and developed a multidisciplinary team-science approach. We reviewed these contributions made by the EDRN and their impacts on maturing the field. Future challenges and opportunities in cancer early-detection biomarker translational research are discussed, particularly in strengthening biomarker discovery pipeline and conducting more efficient biomarker validation studies.See all articles in this CEBP Focus section, &quot;NCI Early Detection Research Network: Making Cancer Detection Possible.&quot;}, }
@article {pmid33171100, year = {2020}, author = {Su, Y and Chen, D and Yuan, D and Lausted, C and Choi, J and Dai, CL and Voillet, V and Duvvuri, VR and Scherler, K and Troisch, P and Baloni, P and Qin, G and Smith, B and Kornilov, SA and Rostomily, C and Xu, A and Li, J and Dong, S and Rothchild, A and Zhou, J and Murray, K and Edmark, R and Hong, S and Heath, JE and Earls, J and Zhang, R and Xie, J and Li, S and Roper, R and Jones, L and Zhou, Y and Rowen, L and Liu, R and Mackay, S and O'Mahony, DS and Dale, CR and Wallick, JA and Algren, HA and Zager, MA and ,  and Wei, W and Price, ND and Huang, S and Subramanian, N and Wang, K and Magis, AT and Hadlock, JJ and Hood, L and Aderem, A and Bluestone, JA and Lanier, LL and Greenberg, PD and Gottardo, R and Davis, MM and Goldman, JD and Heath, JR}, title = {Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19.}, journal = {Cell}, volume = {183}, number = {6}, pages = {1479-1495.e20}, doi = {10.1016/j.cell.2020.10.037}, pmid = {33171100}, issn = {1097-4172}, support = {R21 AI138258/AI/NIAID NIH HHS/United States ; R01 DA040395/DA/NIDA NIH HHS/United States ; UG3 TR002884/TR/NCATS NIH HHS/United States ; R01 AI068129/AI/NIAID NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; *COVID-19/blood/immunology ; Female ; *Genomics ; Humans ; Male ; Middle Aged ; *RNA-Seq ; *SARS-CoV-2/immunology/metabolism ; Severity of Illness Index ; *Single-Cell Analysis ; }, abstract = {We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated inflammatory signaling is accompanied by the loss of specific classes of metabolites and metabolic processes. Within this stressed plasma environment at moderate disease, multiple unusual immune cell phenotypes emerge and amplify with increasing disease severity. We condensed over 120,000 immune features into a single axis to capture how different immune cell classes coordinate in response to SARS-CoV-2. This immune-response axis independently aligns with the major plasma composition changes, with clinical metrics of blood clotting, and with the sharp transition between mild and moderate disease. This study suggests that moderate disease may provide the most effective setting for therapeutic intervention.}, }
@article {pmid33170935, year = {2020}, author = {Gupta, V and Kennedy, JA and Capo-Chichi, JM and Kim, S and Hu, ZH and Alyea, EP and Popat, UR and Sobecks, RM and Scott, BL and Gerds, AT and Salit, RB and Deeg, HJ and Nakamura, R and Saber, W}, title = {Genetic factors rather than blast reduction determine outcomes of allogeneic HCT in BCR-ABL-negative MPN in blast phase.}, journal = {Blood advances}, volume = {4}, number = {21}, pages = {5562-5573}, pmid = {33170935}, issn = {2473-9537}, support = {U01 AI126612/AI/NIAID NIH HHS/United States ; R21 HL140314/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U01 HL128568/HL/NHLBI NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; R01 CA215134/CA/NCI NIH HHS/United States ; R01 HL131731/HL/NHLBI NIH HHS/United States ; R01 HL126589/HL/NHLBI NIH HHS/United States ; R01 CA152108/CA/NCI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; R01 CA231141/CA/NCI NIH HHS/United States ; R01 HL129472/HL/NHLBI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 HL130388/HL/NHLBI NIH HHS/United States ; }, abstract = {There is a limited understanding of the clinical and molecular factors associated with outcomes of hematopoietic cell transplantation (HCT) in patients with BCR-ABL-negative myeloproliferative neoplasms in blast phase (MPN-BP). Using the Center for International Blood and Marrow Transplant Research database, we evaluated HCT outcomes in 177 patients with MPN-BP. Ninety-five (54%) had sufficient DNA for targeted next-generation sequencing of 49 genes clinically relevant in hematologic malignancies. At 5 years, overall survival (OS), cumulative incidence of relapse, and nonrelapse mortality of the study cohort was 18%, 61%, and 25%, respectively. In a multivariable model, poor-risk cytogenetics was associated with inferior OS (hazard ratio [HR], 1.71; 95% CI, 1.21-2.41) due to increased relapse (HR, 1.93; 95% CI, 1.32-2.82). Transplants using mobilized peripheral blood (PB) were associated with better OS (HR, 0.60; 95% CI, 0.38-0.96). No difference in outcomes was observed in patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Among the 95 patients with molecular data, mutation of TP53, present in 23%, was the only genetic alteration associated with outcomes. In a multivariate model, TP53-mutant patients had inferior OS (HR, 1.99; 95% CI, 1.14-3.49) and increased incidence of relapse (HR, 2.59; 95% CI, 1.41-4.74). There were no differences in the spectrum of gene mutations, number of mutations, or variant allele frequency between patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Genetic factors, namely cytogenetic alterations and TP53 mutation status, rather than degree of cytoreduction predict outcomes of HCT in MPN-BP. No meaningful benefit of conventional HCT was observed in patients with MPN-BP and mutated TP53.}, }
@article {pmid33170509, year = {2020}, author = {Chlebowski, RT and Aragaki, AK and Anderson, GL and Prentice, RL}, title = {Reply to The Women's Health Initiative; hormone replacement therapy; and surveillance, epidemiology, and end results data.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33260}, pmid = {33170509}, issn = {1097-0142}, support = {N01WH22110/WH/WHI NIH HHS/United States ; 24152//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32100-2//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32105-6//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32108-9//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 3211//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32111-13//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32115//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32118-32119//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 32122//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 42107-26//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 42129-32//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; 44221//the National Heart, Lung and Blood Institute, National Institutes of Health/ ; }, }
@article {pmid33169670, year = {2020}, author = {Kasinathan, B and Colmenares, SU and McConnell, H and Young, JM and Karpen, GH and Malik, HS}, title = {Innovation of heterochromatin functions drives rapid evolution of essential ZAD-ZNF genes in Drosophila.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {33169670}, issn = {2050-084X}, support = {/HHMI/Howard Hughes Medical Institute/United States ; R01 GM074108/GM/NIGMS NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; R01 GM117420/GM/NIGMS NIH HHS/United States ; F30 CA225077/CA/NCI NIH HHS/United States ; }, abstract = {Contrary to dogma, evolutionarily young and dynamic genes can encode essential functions. We find that evolutionarily dynamic ZAD-ZNF genes, which encode the most abundant class of insect transcription factors, are more likely to encode essential functions in Drosophila melanogaster than ancient, conserved ZAD-ZNF genes. We focus on the Nicknack ZAD-ZNF gene, which is evolutionarily young, poorly retained in Drosophila species, and evolves under strong positive selection. Yet we find that it is necessary for larval development in D. melanogaster. We show that Nicknack encodes a heterochromatin-localizing protein like its paralog Oddjob, also an evolutionarily dynamic yet essential ZAD-ZNF gene. We find that the divergent D. simulans Nicknack protein can still localize to D. melanogaster heterochromatin and rescue viability of female but not male Nicknack-null D. melanogaster. Our findings suggest that innovation for rapidly changing heterochromatin functions might generally explain the essentiality of many evolutionarily dynamic ZAD-ZNF genes in insects.}, }
@article {pmid33166790, year = {2020}, author = {Martin, AR and Patel, EU and Kirby, C and Astemborski, J and Kirk, GD and Mehta, SH and Marshall, K and Janes, H and Clayton, A and Corey, L and Hammer, SM and Sobieszczyk, ME and Arthos, J and Cicala, C and Redd, AD and Quinn, TC}, title = {The association of α4β7 expression with HIV acquisition and disease progression in people who inject drugs and men who have sex with men: Case control studies.}, journal = {EBioMedicine}, volume = {62}, number = {}, pages = {103102}, doi = {10.1016/j.ebiom.2020.103102}, pmid = {33166790}, issn = {2352-3964}, abstract = {BACKGROUND: α4β7 is a gut-homing integrin heterodimer that can act as a non-essential binding molecule for HIV. A previous study in heterosexual African women found that individuals with higher proportions of α4β7 expressing CD4+ T cells were more likely to become infected with HIV, as well as present with faster disease progression. It is unknown if this phenomenon is also observed in men who have sex with men (MSM) or people who inject drugs (PWID).<br><br>METHODS: MSM and transgender women who seroconverted as part of the HVTN 505 HIV vaccine trial and PWID who seroconverted during the ALIVE cohort study were selected as cases and matched to HIV-uninfected controls from the same studies (1:1 and 1:3, respectively). Pre-seroconversion PBMC samples from cases and controls in both studies were examined by flow cytometry to measure levels of α4β7 expression on CD4+ T cells. Multivariable conditional logistic regression was used to compare α4β7 expression levels between cases and controls. A Kaplan-Meier curve was used to examine the association of α4β7 expression pre-seroconversion with HIV disease progression.<br><br>FINDINGS: In MSM and transgender women (n = 103 cases, 103 controls), there was no statistically significant difference in the levels of α4β7 expression on CD4+ T cells between cases and controls (adjusted odds ratio [adjOR] =1.10, 95% confidence interval [CI]=0.94,1.29; p = 0.246). Interestingly, in PWID (n = 49 cases, 143 controls), cases had significantly lower levels of α4β7 expression compared to their matched controls (adjOR = 0.80, 95% CI = 0.68, 0.93; p = 0.004). Among HIV-positive PWID (n = 47), there was no significant association in HIV disease progression in individuals above or below the median level of α4β7 expression (log-rank p = 0.84).<br><br>INTERPRETATION: In contrast to findings in heterosexual women, higher α4β7 expression does not predict HIV acquisition or disease progression in PWID or MSM.<br><br>FUNDING: This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The study was also supported by extramural grants from NIAID T32AI102623 (E.U.P.), and UM1AI069470.}, }
@article {pmid33166406, year = {2020}, author = {Loh, KP and Tsang, M and LeBlanc, TW and Back, A and Duberstein, PR and Mohile, SG and Epstein, RM and Klepin, HD and Becker, MW and El-Jawahri, A and Lee, SJ}, title = {Decisional involvement and information preferences of patients with hematologic malignancies.}, journal = {Blood advances}, volume = {4}, number = {21}, pages = {5492-5500}, pmid = {33166406}, issn = {2473-9537}, support = {K99 CA237744/CA/NCI NIH HHS/United States ; }, abstract = {Understanding decisional involvement and information preferences in patients with hematologic malignancies may help to optimize physician-patient communication about treatment decisions and align the decision-making processes with patients' preferences. We described and examined factors associated with preferences of patients with hematologic malignancies for decisional involvement, information sources, and presentation of information. In a multicenter observational study, we recruited 216 patients with hematologic malignancies of any stage from September 2003 to June 2007. Patients were asked about their decisional involvement preferences (Control Preferences Scale), information sources (including most useful source of information), and preferences for their oncologists' presentation of treatment success information. We used multivariate logistic regressions to identify factors associated with decisional involvement preferences and usefulness of information sources (physicians vs nonphysicians). Patient-directed, shared, and physician-directed approaches were preferred in 34%, 38%, and 28% of patients, respectively. Physicians and computer/Internet were the most common information sources; 42% perceived physicians as the most useful source. On multivariate analysis, patients with less than a college education (vs postgraduate education) were less likely to perceive their physician as the most useful source (adjusted odds ratio [AOR], 0.46; 95% confidence interval (CI), 0.21-1.00), whereas patients with acute leukemia (vs other blood cancers) were more likely to perceive their physician as the most useful source (AOR, 2.49; 95% CI, 1.07-5.80). In terms of communicating treatment success rates, 70% preferred ≥1 method(s), and 88% preferred presentation in percentages. Our study suggests that decisional involvement and information preferences vary and should be assessed explicitly as part of each decision-making encounter.}, }
@article {pmid33166404, year = {2020}, author = {Moazzam, S and Onstad, L and O'Leary, H and Marshall, A and Osunkwo, I and Du, E and Dunn, T and Dunlap, J and Reed, B and Luger, S and Lee, SJ}, title = {Gender differences in question-asking at the 2019 American Society of Hematology Annual Meeting.}, journal = {Blood advances}, volume = {4}, number = {21}, pages = {5473-5479}, pmid = {33166404}, issn = {2473-9537}, abstract = {Attendance at professional conferences is an important component of career development, because conferences are a major forum for presenting new research, interacting with colleagues and networking. An extensive literature documents differences in the professional experiences of women and men, including experiences at professional conferences. We hypothesized that women are less likely than men to ask questions at conferences, thus forgoing opportunities for professional development. To address this issue, we analyzed the question-asking behavior of women and men at the 2019 Annual Meeting and Exposition of the American Society of Hematology. In all, 112 sessions (55% of those eligible) were randomly chosen for coding, yielding data on 577 presentations. Although approximately 50% of moderators and speakers were women, the proportion of questions asked by women was significantly lower compared with the estimated proportion of women attending the conference (23% vs 39%; P < .0001). Women were more likely to ask questions if another woman asked the first question or if the session topic was red cells. These results suggest that although women are represented equally as moderators and speakers, they are less likely to engage in the postpresentation discourse by asking questions. Encouraging women to speak up in professional situations and providing training on question-asking skills can help address this gender gap that potentially contributes to disparities in professional visibility and career advancement for women in hematology.}, }
@article {pmid33165566, year = {2020}, author = {Niang, MN and Sugimoto, JD and Diallo, A and Diarra, B and Ortiz, JR and Lewis, KDC and Lafond, KE and Halloran, ME and Widdowson, MA and Neuzil, KM and Victor, JC}, title = {Estimates of inactivated influenza vaccine effectiveness among children in Senegal: results from two consecutive cluster-randomized controlled trials in 2010 and 2011.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1689}, pmid = {33165566}, issn = {1537-6591}, abstract = {BACKGROUND: We report results of Years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal.<br><br>METHODS: We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months - 10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified-intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness.<br><br>RESULTS: We vaccinated 74% of 12,408 age-eligible children in Year 2 (June 2010-April 11) and 74% of 11,988 age-eligible children in Year 3 (April 2011-December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (Year 2) and 4.2 (Year 3) per 100 mITT child vaccinees of IPV villages. In Year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% CI: 32.3%-67.0%), and the population effectiveness was 36.0% (95% CI: 10.2%-54.4%) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI: 39.0%-68.9%). In Year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The Year 3 total effectiveness against LCI was -14.5% (95% CI: -81.2%-27.6%). Vaccine effectiveness varied by type/subtype of influenza in both years.<br><br>CONCLUSION: IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation.}, }
@article {pmid33164148, year = {2020}, author = {Mandal, R and Cano, R and Davis, CD and Hayashi, D and Jackson, SA and Jones, CM and Lampe, JW and Latulippe, ME and Lin, NJ and Lippa, KA and Piotrowski, P and Da Silva, SM and Swanson, KS and Wishart, DS}, title = {Workshop report: Toward the development of a human whole stool reference material for metabolomic and metagenomic gut microbiome measurements.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {16}, number = {11}, pages = {119}, pmid = {33164148}, issn = {1573-3890}, abstract = {INTRODUCTION: To date, there has been little effort to develop standards for metabolome-based gut microbiome measurements despite the significant efforts toward standard development for DNA-based microbiome measurements.<br><br>OBJECTIVES: The National Institute of Standards and Technology (NIST), The BioCollective (TBC), and the North America Branch of the International Life Sciences Institute (ILSI North America) are collaborating to extend NIST's efforts to develop a Human Whole Stool Reference Material for the purpose of method harmonization and eventual quality control.<br><br>METHODS: The reference material will be rationally designed for adequate quality assurance and quality control (QA/QC) for underlying measurements in the study of the impact of diet and nutrition on functional aspects of the host gut microbiome and relationships of those functions to health. To identify which metabolites deserve priority in their value assignment, NIST, TBC, and ILSI North America jointly conducted a workshop on September 12, 2019 at the NIST campus in Gaithersburg, Maryland. The objective of the workshop was to identify metabolites for which evidence indicates relevance to health and disease and to decide on the appropriate course of action to develop a fit-for-purpose reference material.<br><br>RESULTS: This document represents the consensus opinions of workshop participants and co-authors of this manuscript, and provides additional supporting information. In addition to developing general criteria for metabolite selection and a preliminary list of proposed metabolites, this paper describes some of the strengths and limitations of this initiative given the current state of microbiome research.<br><br>CONCLUSIONS: Given the rapidly evolving nature of gut microbiome science and the current state of knowledge, an RM (as opposed to a CRM) measured for multiple metabolites is appropriate at this stage. As the science evolves, the RM can evolve to match the needs of the research community. Ultimately, the stool RM may exist in sequential versions. Beneficial to this evolution will be a clear line of communication between NIST and the stakeholder community to ensure alignment with current scientific understanding and community needs.}, }
@article {pmid33163411, year = {2020}, author = {Milano, F and Emerson, RO and Salit, R and Guthrie, KA and Thur, LA and Dahlberg, A and Robins, HS and Delaney, C}, title = {Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation.}, journal = {Frontiers in oncology}, volume = {10}, number = {}, pages = {583349}, pmid = {33163411}, issn = {2234-943X}, abstract = {Introduction: Cord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.<br><br>Methods: All patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.<br><br>Results: Median age was 27 (range 1-58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).<br><br>Conclusions: Using a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.}, }
@article {pmid33162976, year = {2020}, author = {Yuan, S and Liu, Y and Till, B and Song, Y and Wang, Z}, title = {Pretreatment Peripheral B Cells Are Associated With Tumor Response to Anti-PD-1-Based Immunotherapy.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {563653}, pmid = {33162976}, issn = {1664-3224}, abstract = {Identification of reliable biomarkers to predict efficacy of immune checkpoint inhibitors and to monitor relapse in cancer patients receiving this therapy remains one of the main objectives of cancer immunotherapy research. We found that the pretreatment B cell number in the peripheral blood differed significantly between responders and non-responders to anti-PD-1-based immunotherapy. Patients with various cancer types achieving a clinical response had a significantly lower number of B cells compared with those with progressive disease. Patients who progressed from partial response to progressive disease exhibited a gradually increased number of circulating B cells. Our findings suggest that B cells represent a promising biomarker for anti-PD-1-based immunotherapy responses and inhibit the effect of PD-1 blockade immunotherapy. Thus, preemptive strategies targeting B cells may increase the efficacy of PD-1 blockade immunotherapy in patients with solid tumors.}, }
@article {pmid33161765, year = {2020}, author = {Honigberg, MC and Zekavat, SM and Niroula, A and Griffin, GK and Bick, AG and Pirruccello, JP and Nakao, T and Whitsel, EA and Farland, LV and Laurie, C and Kooperberg, C and Manson, JE and Gabriel, S and Libby, P and Reiner, AP and Ebert, BL and Natarajan, P}, title = {Premature Menopause, Clonal Hematopoiesis, and Coronary Artery Disease in Postmenopausal Women.}, journal = {Circulation}, volume = {}, number = {}, pages = {}, doi = {10.1161/CIRCULATIONAHA.120.051775}, pmid = {33161765}, issn = {1524-4539}, support = {DP5 OD029586/OD/NIH HHS/United States ; T32 HL094301/HL/NHLBI NIH HHS/United States ; }, abstract = {Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women's Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD). Results: The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.}, }
@article {pmid33160889, year = {2020}, author = {Diamantopoulos, LN and Holt, SK and Khaki, AR and Sekar, RR and Gadzinski, A and Nyame, YA and Vakar-Lopez, F and Tretiakova, MS and Psutka, SP and Gore, JL and Lin, DW and Schade, GR and Hsieh, AC and Lee, JK and Yezefski, T and Schweizer, MT and Cheng, HH and Yu, EY and True, LD and Montgomery, RB and Grivas, P and Wright, JL}, title = {Response to Neoadjuvant Chemotherapy and Survival in Micropapillary Urothelial Carcinoma: Data From a Tertiary Referral Center and the Surveillance, Epidemiology, and End Results (SEER) Program.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2020.10.002}, pmid = {33160889}, issn = {1938-0682}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Micropapillary urothelial carcinoma (MPC) is a rare urothelial carcinoma variant with conflicting data guiding clinical practice. In this study, we explored oncologic outcomes in relation to neoadjuvant chemotherapy (NAC) in a retrospective cohort of patients with MPC, alongside data from Surveillance, Epidemiology, and End Results (SEER)-Medicare.<br><br>PATIENTS AND METHODS: We retrospectively identified patients with MPC or conventional urothelial carcinoma (CUC) without any variant histology undergoing radical cystectomy (RC) in our institution (2003-2018). SEER-Medicare was also queried to identify patients diagnosed with MPC (2004-2015). Clinicopathologic data and treatment modalities were extracted. Overall survival (OS) was estimated with the Kaplan-Meier method. Mann-Whitney-Wilcoxon and chi-square tests were used for comparative analysis and Cox regression for identifying clinical covariates associated with OS.<br><br>RESULTS: Our institutional database yielded 46 patients with MPC and 457 with CUC. In SEER-Medicare, 183 patients with MPC were identified, and 63 (34%) underwent RC. In the institutional cohort, patients with MPC had significantly higher incidence of cN+ (17% vs. 8%), pN+ stage (30% vs. 17%), carcinoma-in-situ (43% vs. 25%), and lymphovascular invasion (30% vs. 16%) at RC versus those with CUC (all P < .05). Pathologic complete response (ypT0N0) to NAC was 33% for MPC and 35% for CUC (P = .899). Median OS was lower for institutional MPC versus CUC in univariate analysis (43.6 vs. 105.3 months, P = .006); however, MPC was not independently associated with OS in the multivariate model. Median OS was 25 months in the SEER MPC cohort for patients undergoing RC, while NAC was not associated with improved OS in that group.<br><br>CONCLUSION: Pathologic response to NAC was not significantly different between MPC and CUC, while MPC histology was not an independent predictor of OS. Further studies are needed to better understand biological mechanisms behind its aggressive features as well as the role of NAC in this histology variant.}, }
@article {pmid33160341, year = {2020}, author = {Laher, F and Salami, T and Hornschuh, S and Makhale, LM and Khunwane, M and Andrasik, MP and Gray, GE and Van Tieu, H and Dietrich, JJ}, title = {Willingness to use HIV prevention methods among vaccine efficacy trial participants in Soweto, South Africa: discretion is important.}, journal = {BMC public health}, volume = {20}, number = {1}, pages = {1669}, pmid = {33160341}, issn = {1471-2458}, support = {AI068614//National Institute of Allergy and Infectious Diseases/ ; OPP1148133//Bill and Melinda Gates Foundation (US)/ ; }, abstract = {BACKGROUND: Despite multiple available HIV prevention methods, the HIV epidemic continues to affect South Africa the most. We sought to understand willingness to use actual and hypothetical HIV prevention methods among participants enrolled in a preventative HIV vaccine efficacy trial in Soweto, South Africa.<br><br>METHODS: We conducted a qualitative study with 38 self-reporting HIV-uninfected and consenting 18-35 year olds participating in the HVTN 702 vaccine efficacy trial in Soweto. Using a semi-structured interview guide, five focus group discussions (FGDs) were held, stratified by age, gender and sexual orientation. The FGDs were composed of: (i) 10 heterosexual women aged 18-24 years; (ii) 9 heterosexual and bisexual women aged 25-35 years; (iii &amp; iv) heterosexual men aged 25-35 years with 7 in both groups; and (v) 5 men aged 18-35 years who have sex with men. FGDs were audio-recorded, transcribed verbatim, translated into English and analysed using thematic analysis.<br><br>RESULTS: We present five main themes: (i) long-lasting methods are preferable; (ii) condoms are well-known but not preferred for use; (iii) administration route of HIV prevention method is a consideration for the user; (iv) ideal HIV prevention methods should blend into the lifestyle of the user; and the perception that (v) visible prevention methods indicate sexual indiscretion.<br><br>CONCLUSIONS: The participants' candour about barriers to condom and daily oral pre-exposure prophylaxis (PrEP) use, and expressed preferences for long-lasting, discreet, lifestyle-friendly methods reveal a gap in the biomedical prevention market aiming to reduce sexually acquired HIV in South Africa. Product developers should consider long-acting injectable formulations, such as vaccines, passive antibodies and chemoprophylaxis, for HIV prevention technologies. Future innovations in HIV prevention products may need to address the desire for the method to blend easily into lifestyles, such as food-medication formulations.}, }
@article {pmid33159200, year = {2020}, author = {Imlay, H and Dasgupta, S and Boeckh, M and Stapleton, RD and Rubenfeld, GD and Chen, Y and Limaye, AP}, title = {Risk Factors for Cytomegalovirus Reactivation and Association with Outcomes in Critically Ill Adults with Sepsis: A Pooled Analysis of Prospective Studies.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaa697}, pmid = {33159200}, issn = {1537-6613}, support = {R56 AI140953/AI/NIAID NIH HHS/United States ; }, abstract = {We performed a multivariable analysis of potential risk factors (including CMV reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days [VFD], ICU-free days [ICUFD], hospital free days [HFD]) from pooled cohorts of two previous prospective studies of CMV seropositive adults with sepsis. CMV reactivation at any level, >100, >1,000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as endpoints for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.}, }
@article {pmid33158149, year = {2020}, author = {Brandão, A and Paulo, P and Maia, S and Pinheiro, M and Peixoto, A and Cardoso, M and Silva, MP and Santos, C and Eeles, RA and Kote-Jarai, Z and Muir, K and Ukgpcs Collaborators,  and Schleutker, J and Wang, Y and Pashayan, N and Batra, J and Apcb BioResource,  and Grönberg, H and Neal, DE and Nordestgaard, BG and Tangen, CM and Southey, MC and Wolk, A and Albanes, D and Haiman, CA and Travis, RC and Stanford, JL and Mucci, LA and West, CML and Nielsen, SF and Kibel, AS and Cussenot, O and Berndt, SI and Koutros, S and Sørensen, KD and Cybulski, C and Grindedal, EM and Park, JY and Ingles, SA and Maier, C and Hamilton, RJ and Rosenstein, BS and Vega, A and The Impact Study Steering Committee And Collaborators,  and Kogevinas, M and Wiklund, F and Penney, KL and Brenner, H and John, EM and Kaneva, R and Logothetis, CJ and Neuhausen, SL and Ruyck, K and Razack, A and Newcomb, LF and Canary Pass Investigators,  and Lessel, D and Usmani, N and Claessens, F and Gago-Dominguez, M and Townsend, PA and Roobol, MJ and The Profile Study Steering Committee,  and The Practical Consortium,  and Teixeira, MR}, title = {The CHEK2 Variant C.349A&gt;G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor.}, journal = {Cancers}, volume = {12}, number = {11}, pages = {}, pmid = {33158149}, issn = {2072-6694}, support = {CI-IPOP-16-2012//IPO-Porto Research Center/ ; HEALTH-F2-2009-223175//Canadian Institutes of Health Research, European Commission's Seventh Framework Programme/ ; C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, C16913/A6135/CRUK_/Cancer Research UK/United Kingdom ; No. 1 U19 CA 148537-01//The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative/ ; U19 CA 148537, X01HG007492/NH/NIH HHS/United States ; A8197/A16565/CRUK_/Cancer Research UK/United Kingdom ; NCI U01 CA188392/NH/NIH HHS/United States ; PEst-OE/SAU/ UI0776/2014, PTDC/DTP-PIC/1308/2014, UID/DTP/00776/2013/POCI-01-0145-FEDER-006868, SFRH/BD/71397/2010, SFRH/BD/73719/2010//Fundação para a Ciência e a Tecnologia/ ; }, abstract = {The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.}, }
@article {pmid33157031, year = {2020}, author = {Itani, OA and Zhong, X and Tang, X and Scott, BA and Yan, JY and Flibotte, S and Lim, Y and Hsieh, AC and Bruce, JE and Van Gilst, M and Crowder, CM}, title = {Coordinate Regulation of Ribosome and tRNA Biogenesis Controls Hypoxic Injury and Translation.}, journal = {Current biology : CB}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cub.2020.10.001}, pmid = {33157031}, issn = {1879-0445}, support = {R01 NS109088/NS/NINDS NIH HHS/United States ; }, abstract = {The translation machinery is composed of a myriad of proteins and RNAs whose levels must be coordinated to efficiently produce proteins without wasting energy or substrate. However, protein synthesis is clearly not always perfectly tuned to its environment, as disruption of translation machinery components can lengthen lifespan and stress survival. While much has been learned from bacteria and yeast about translational regulation, much less is known in metazoans. In a screen for mutations protecting C. elegans from hypoxic stress, we isolated multiple genes impacting protein synthesis: a ribosomal RNA helicase gene, tRNA biosynthesis genes, and a gene controlling amino acid availability. To define better the mechanisms by which these genes impact protein synthesis, we performed a second screen for suppressors of the conditional developmental arrest phenotype of the RNA helicase mutant and identified genes involved in ribosome biogenesis. Surprisingly, these suppressor mutations restored normal hypoxic sensitivity and protein synthesis to the tRNA biogenesis mutants, but not to the mutant reducing amino acid uptake. Proteomic analysis demonstrated that reduced tRNA biosynthetic activity produces a selective homeostatic reduction in ribosomal subunits, thereby offering a mechanism for the suppression results. Our study uncovers an unrecognized higher-order-translation regulatory mechanism in a metazoan whereby ribosome biogenesis genes communicate with genes controlling tRNA abundance matching the global rate of protein synthesis with available resources.}, }
@article {pmid33156064, year = {2020}, author = {Chou, EL and Pettinger, M and Haring, B and Allison, MA and Mell, MW and Hlatky, MA and Wactawski-Wende, J and Wild, RA and Shadyab, AH and Wallace, RB and Snetselaar, LG and Madsen, TE and Eagleton, MJ and Conrad, MF and Liu, S}, title = {Association of Premature Menopause With Risk of Abdominal Aortic Aneurysm in the Women's Health Initiative.}, journal = {Annals of surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/SLA.0000000000004581}, pmid = {33156064}, issn = {1528-1140}, abstract = {OBJECTIVE: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history.<br><br>SUMMARY OF BACKGROUND DATA: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women.<br><br>METHODS: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&amp;B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017.<br><br>RESULTS: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early menarche. Women with premature menopause were more likely to be overweight, Black, have ≥20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA.<br><br>CONCLUSIONS: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women.}, }
@article {pmid33155864, year = {2020}, author = {Schenk, JM and Newcomb, LF and Zhu, K and Zheng, Y and Lin, DW}, title = {Re: African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000001444}, doi = {10.1097/JU.0000000000001444}, pmid = {33155864}, issn = {1527-3792}, }
@article {pmid33155766, year = {2020}, author = {Granot-Hershkovitz, E and Tarraf, W and Kurniansyah, N and Daviglus, M and Isasi, CR and Kaplan, R and Lamar, M and Perreira, KM and Wassertheil-Smoller, S and Stickel, A and Thyagarajan, B and Zeng, D and Fornage, M and DeCarli, CS and González, HM and Sofer, T}, title = {APOE alleles' association with cognitive function differs across Hispanic/Latino groups and genetic ancestry in the study of Latinos-investigation of neurocognitive aging (HCHS/SOL).}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {}, number = {}, pages = {}, doi = {10.1002/alz.12205}, pmid = {33155766}, issn = {1552-5279}, support = {R01AG048642/AG/NIA NIH HHS/United States ; RF1AG054548/AG/NIA NIH HHS/United States ; RF1AG061022/AG/NIA NIH HHS/United States ; R21AG056952/AG/NIA NIH HHS/United States ; HHSN268201300001I/N01-HC-65233/HL/NHLBI NIH HHS/United States ; HHSN268201300004I/N01-HC-65234//University of Miami/ ; HHSN268201300002I/N01-HC-65235//Albert Einstein College of Medicine/ ; HHSN268201300003I/N01-HC-65236//University of Illinois at Chicago/ ; HHSN268201300005I/N01-HC-65237//San Diego State University/ ; /MD/NIMHD NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; /DK/NIDDK NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; //NIH Institution-Office of Dietary Supplements/ ; //Genetic Analysis Center/ ; //NHLBI/ ; HHSN268201300005C AM03/DE/NIDCR NIH HHS/United States ; MOD03/DE/NIDCR NIH HHS/United States ; R01AG048642/AG/NIA NIH HHS/United States ; RF1AG054548/AG/NIA NIH HHS/United States ; RF1AG061022/AG/NIA NIH HHS/United States ; R21AG056952/AG/NIA NIH HHS/United States ; HHSN268201300001I/N01-HC-65233/HL/NHLBI NIH HHS/United States ; /MD/NIMHD NIH HHS/United States ; /DC/NIDCD NIH HHS/United States ; /DE/NIDCR NIH HHS/United States ; /DK/NIDDK NIH HHS/United States ; /NS/NINDS NIH HHS/United States ; }, abstract = {INTRODUCTION: Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry-specific genetic effects.<br><br>METHODS: We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations.<br><br>RESULTS: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P-value = 0.03), with the strongest association in Cubans (OR = 1.46, P-value = 0.007). APOE-ε2 was associated with decreased risk of MCI (OR = 0.37, P-value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline.<br><br>DISCUSSION: Results suggest that APOE alleles' effects on cognitive outcomes differ across six Latino backgrounds and are modified by continental genetic ancestry.}, }
@article {pmid33154402, year = {2020}, author = {Amundsen, SK and Taylor, AF and Smith, GR}, title = {Chi hotspot control of RecBCD helicase-nuclease by long-range intramolecular signaling.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {19415}, pmid = {33154402}, issn = {2045-2322}, support = {R35 GM118120/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Repair of broken DNA by homologous recombination requires coordinated enzymatic reactions to prepare it for interaction with intact DNA. The multiple activities of enterobacterial RecBCD helicase-nuclease are coordinated by Chi recombination hotspots (5' GCTGGTGG 3') recognized during DNA unwinding. Chi is recognized in a tunnel in RecC but activates the RecB nuclease, > 25 Ǻ away. How the Chi-dependent signal travels this long distance has been unknown. We found a Chi hotspot-deficient mutant in the RecB helicase domain located > 45 Ǻ from both the Chi-recognition site and the nuclease active site. This unexpected observation led us to find additional mutations that reduced or eliminated Chi hotspot activity in each subunit and widely scattered throughout RecBCD. Each mutation alters the intimate contact between one or another pair of subunits in crystal or cryoEM structures of RecBCD bound to DNA. Collectively, these mutations span a path about 185 Ǻ long from the Chi recognition site to the nuclease active site. We discuss these surprising results in the context of an intramolecular signal transduction accounting for many previous observations.}, }
@article {pmid33152703, year = {2020}, author = {Horwitz, SM and Ansell, S and Ai, WZ and Barnes, J and Barta, SK and Clemens, MW and Dogan, A and Goodman, AM and Goyal, G and Guitart, J and Halwani, A and Haverkos, BM and Hoppe, RT and Jacobsen, E and Jagadeesh, D and Jones, A and Kim, YH and Mehta-Shah, N and Olsen, EA and Pro, B and Rajguru, SA and Rozati, S and Said, J and Shaver, A and Shustov, A and Sokol, L and Torka, P and Torres-Cabala, C and Wilcox, R and William, BM and Zain, J and Dwyer, MA and Sundar, H}, title = {NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {18}, number = {11}, pages = {1460-1467}, doi = {10.6004/jnccn.2020.0053}, pmid = {33152703}, issn = {1540-1413}, abstract = {Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.}, }
@article {pmid33152694, year = {2020}, author = {Nabors, LB and Portnow, J and Ahluwalia, M and Baehring, J and Brem, H and Brem, S and Butowski, N and Campian, JL and Clark, SW and Fabiano, AJ and Forsyth, P and Hattangadi-Gluth, J and Holdhoff, M and Horbinski, C and Junck, L and Kaley, T and Kumthekar, P and Loeffler, JS and Mrugala, MM and Nagpal, S and Pandey, M and Parney, I and Peters, K and Puduvalli, VK and Robins, I and Rockhill, J and Rusthoven, C and Shonka, N and Shrieve, DC and Swinnen, LJ and Weiss, S and Wen, PY and Willmarth, NE and Bergman, MA and Darlow, SD}, title = {Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {18}, number = {11}, pages = {1537-1570}, doi = {10.6004/jnccn.2020.0052}, pmid = {33152694}, issn = {1540-1413}, abstract = {The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.}, }
@article {pmid33152179, year = {2020}, author = {Soria, F and Black, PC and Fairey, AS and Cookson, MS and Yu, EY and Kassouf, W and Dall'Era, MA and Sridhar, SS and McGrath, JS and Wright, JL and Thorpe, AC and Morgan, TM and Daneshmand, S and Holzbeierlein, JM and Bivalacqua, TJ and North, S and Barocas, DA and Lotan, Y and Grivas, P and Stephenson, AJ and Shah, JB and van Rhijn, BW and Spiess, PE and Shariat, SF and Gontero, P}, title = {Neoadjuvant chemotherapy plus radical cystectomy versus radical cystectomy alone in clinical T2 bladder cancer without hydronephrosis.}, journal = {BJU international}, volume = {}, number = {}, pages = {}, doi = {10.1111/bju.15289}, pmid = {33152179}, issn = {1464-410X}, abstract = {OBJECTIVES: To assess the efficacy of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in a retrospective multicentre cohort of patients with cT2N0M0 bladder cancer (BCa) without preoperative hydronephrosis.<br><br>PATIENTS AND METHODS: This was a propensity-based analysis of 619 patients. Of these, 316 were treated with NAC followed by RC and 303 with upfront RC. After multiple imputations, inverse probability of treatment weighting (IPTW) was used to account for potential selection bias. Multivariable logistic regression analysis was performed to evaluate the impact of NAC on pathological complete response and downstaging at RC, while IPTW-adjusted Kaplan-Meier curves and Cox regression models were built to evaluate the impact of NAC on overall survival (OS).<br><br>RESULTS: After IPTW-adjusted analysis, standardised differences between groups were <15%. A complete response (pT0N0) at final pathology was achieved in 94 (30%) patients receiving NAC and nine (3%) undergoing upfront RC. Downstaging to non-muscle-invasive disease (<pT2N0M0) was observed in 174 (55%) patients after NAC and in 72 (24%) without NAC. On multivariable analysis, NAC was found to be an independent predictor of both pathological complete response and downstaging. No significant difference with respect to OS was observed between groups with a median follow-up of 18 months.<br><br>CONCLUSIONS: In patients with cT2N0 BCa and no preoperative hydronephrosis, NAC increased the rate of pathological complete response and downstaging.}, }
@article {pmid33152057, year = {2020}, author = {Reddy, P and Davies, S and Majhail, N and Sandmaier, B and Hari, P and Cutler, C}, title = {In response to &quot;American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults&quot;.}, journal = {Blood advances}, volume = {4}, number = {21}, pages = {5431-5432}, pmid = {33152057}, issn = {2473-9537}, }
@article {pmid33151772, year = {2020}, author = {Gralow, JR and Asirwa, FC and Bhatt, AS and Bourlon, MT and Chu, Q and Eniu, AE and Loehrer, PJ and Lopes, G and Shulman, LN and Close, J and Von Roenn, J and Tibbits, M and Pyle, D}, title = {Recommendations from the ASCO Academic Global Oncology Task Force.}, journal = {JCO global oncology}, volume = {6}, number = {}, pages = {1666-1673}, pmid = {33151772}, issn = {2687-8941}, abstract = {In recognition of the rising incidence and mortality of cancer in low- and middle-resource settings, as well as the increasingly international profile of its membership, ASCO has prioritized efforts to enhance its engagement at a global level. Among the recommendations included in the 2016 Global Oncology Leadership Task Force report to the ASCO Board of Directors was that ASCO should promote the recognition of global oncology as an academic field. The report suggested that ASCO could serve a role in transitioning global oncology from an informal field of largely voluntary activities to a more formal discipline with strong research and well-defined training components. As a result of this recommendation, in 2017, ASCO formed the Academic Global Oncology Task Force (AGOTF) to guide ASCO's contributions toward formalizing the field of global oncology. The AGOTF was asked to collect and analyze key issues and barriers toward the recognition of global oncology as an academic discipline, with an emphasis on training, research, and career pathways, and produce a set of recommendations for ASCO action. The outcome of the AGOTF was the development of recommendations designed to advance the status of global oncology as an academic discipline.}, }
@article {pmid33151547, year = {2020}, author = {Simon, MS and Hastert, TA and Barac, A and Banack, HR and Caan, BJ and Chlebowski, RT and Foraker, R and Hovsepyan, G and Liu, S and Luo, J and Manson, JE and Neuhouser, ML and Okwuosa, TM and Pan, K and Qi, L and Ruterbusch, JJ and Shadyab, AH and Thomson, CA and Wactawski-Wende, J and Waheed, N and Beebe-Dimmer, JL}, title = {Cardiometabolic risk factors and survival after cancer in the Women's Health Initiative.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33295}, pmid = {33151547}, issn = {1097-0142}, support = {N01WH22110/HL/NHLBI NIH HHS/United States ; 24152/HL/NHLBI NIH HHS/United States ; 32100-2/HL/NHLBI NIH HHS/United States ; 32105-6/HL/NHLBI NIH HHS/United States ; 32108-9/HL/NHLBI NIH HHS/United States ; 32111-13/HL/NHLBI NIH HHS/United States ; 32115/HL/NHLBI NIH HHS/United States ; 32118-32119/HL/NHLBI NIH HHS/United States ; 32122/HL/NHLBI NIH HHS/United States ; 42107-26/HL/NHLBI NIH HHS/United States ; 42129-32/HL/NHLBI NIH HHS/United States ; 44221/HL/NHLBI NIH HHS/United States ; P30CA022453/CA/NCI NIH HHS/United States ; //Blue Cross Blue Shield Foundation of Michigan/ ; }, abstract = {BACKGROUND: Cardiometabolic abnormalities are a leading cause of death among women, including women with cancer.<br><br>METHODS: This study examined the association between prediagnosis cardiovascular health and total and cause-specific mortality among 12,076 postmenopausal women who developed local- or regional-stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity-related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non-Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival.<br><br>RESULTS: After a median follow-up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all-cause mortality (HR, 1.99; 95% CI, 1.73-2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88-5.57), cancer-specific mortality (HR, 1.37; 95% CI, 1.1-1.72), and other-cause mortality (HR, 2.14; 95% CI, 1.70-2.69). A higher waist circumference was associated with greater all-cause mortality (HR, 1.17; 95% CI, 1.06-1.30) and cancer-specific mortality (HR, 1.22; 95% CI, 1.04-1.42).<br><br>CONCLUSIONS: Among postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all-cause, CVD, cancer-specific, and other-cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation.<br><br>LAY SUMMARY: This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.}, }
@article {pmid33151258, year = {2020}, author = {Jensen, K and Konnick, EQ and Schweizer, MT and Sokolova, AO and Grivas, P and Cheng, HH and Klemfuss, NM and Beightol, M and Yu, EY and Nelson, PS and Montgomery, B and Pritchard, CC}, title = {Association of Clonal Hematopoiesis in DNA Repair Genes With Prostate Cancer Plasma Cell-free DNA Testing Interference.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {33151258}, issn = {2374-2445}, abstract = {Importance: Cell-free DNA (cfDNA) testing is increasingly used in the treatment of patients with advanced prostate cancer. Clonal hematopoiesis of indeterminate potential (CHIP) can interfere with cfDNA testing and cause incorrect interpretation of results. There is an urgent need to better understand this problem following recent US Food and Drug Administration approval of poly(ADP) ribose polymerase inhibitors (PARPi) for metastatic prostate cancer based on variants in DNA repair genes that can be affected by CHIP.<br><br>Objective: To determine the prevalence of clinically relevant CHIP interference in prostate cancer cfDNA testing.<br><br>We report a case series of 69 patients with advanced prostate cancer (metastatic disease or with rising PSA following localized therapy) who had cfDNA variant testing with a large panel cancer next generation sequencing assay (UW-OncoPlexCT). To determine the source of variants in plasma, we tested paired cfDNA and whole blood control samples. The study was carried out in an academic medical center system reference laboratory.<br><br>Main Outcomes and Measures: Prevalence and gene spectrum of CHIP interference in patients with prostate cancer undergoing cfDNA testing.<br><br>Results: We detected CHIP variants at 2% or more variant fraction in cfDNA from 13 of 69 men with prostate cancer (19%; 95% CI, 10%-30%). Seven men (10%; 95% CI, 4%-20%) had CHIP variants in DNA repair genes used to determine PARPi candidacy, including ATM (n = 5), BRCA2 (n = 1), and CHEK2 (n = 1). Overall, CHIP variants accounted for almost half of the somatic DNA repair gene variants detected. Participant CHIP variants were exponentially correlated with older age (R2 = 0.82). CHIP interference variants could be distinguished from prostate cancer variants using a paired whole-blood control.<br><br>Conclusions and Relevance: In this case series, approximately 10% of men with advanced prostate cancer had CHIP interference in plasma cfDNA in DNA repair genes that are used for eligibility of PARPi therapy, most frequently in ATM. Clinical cfDNA testing should include a paired whole-blood control to exclude CHIP variants and avoid misdiagnosis.}, }
@article {pmid33149211, year = {2020}, author = {Tamatam, CM and Reddy, NM and Potteti, HR and Ankireddy, A and Noone, PM and Yamamoto, M and Kensler, TW and Reddy, SP}, title = {Preconditioning the immature lung with enhanced Nrf2 activity protects against oxidant-induced hypoalveolarization in mice.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {19034}, pmid = {33149211}, issn = {2045-2322}, support = {HL136946/HL/NHLBI NIH HHS/United States ; HL66109/HL/NHLBI NIH HHS/United States ; }, abstract = {Bronchopulmonary dysplasia (BPD) is a chronic disease of preterm babies with poor clinical outcomes. Nrf2 transcription factor is crucial for cytoprotective response, whereas Keap1-an endogenous inhibitor of Nrf2 signaling-dampens these protective responses. Nrf2-sufficient (wild type) newborn mice exposed to hyperoxia develop hypoalveolarization, which phenocopies human BPD, and Nrf2 deficiency worsens it. In this study, we used PND1 pups bearing bearing hypomorphic Keap1 floxed alleles (Keap1f/f) with increased levels of Nrf2 to test the hypothesis that constitutive levels of Nrf2 in the premature lung are insufficient to mitigate hyperoxia-induced hypoalveolarization. Both wildtype and Keap1f/f pups at PND1 were exposed to hyperoxia for 72 h and then allowed to recover at room air for two weeks (at PND18), sacrificed, and lung hypoalveolarization and inflammation assessed. Hyperoxia-induced lung hypoalveolarization was remarkably lower in Keap1f/f pups than in wildtype counterparts (28.9% vs 2.4%, wildtype vs Keap1f/f). Likewise, Keap1f/f pups were protected against prolonged (96 h) hyperoxia-induced hypoalveolarization. However, there were no differences in hyperoxia-induced lung inflammatory response immediately after exposure or at PND18. Lack of hypoalveolarization in Keap1f/f pups was accompanied by increased levels of expression of antioxidant genes and GSH as assessed immediately following hyperoxia. Keap1 knockdown resulted in upregulation of lung cell proliferation postnatally but had opposing effects following hyperoxia. Collectively, our study demonstrates that augmenting endogenous Nrf2 activation by targeting Keap1 may provide a physiological way to prevent hypoalveolarization associated with prematurity.}, }
@article {pmid33149114, year = {2020}, author = {Balle, C and Konstantinus, IN and Jaumdally, SZ and Havyarimana, E and Lennard, K and Esra, R and Barnabas, SL and Happel, AU and Moodie, Z and Gill, K and Pidwell, T and Karaoz, U and Brodie, E and Maseko, V and Gamieldien, H and Bosinger, SE and Myer, L and Bekker, LG and Passmore, JS and Jaspan, HB}, title = {Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {5578}, pmid = {33149114}, issn = {2041-1723}, support = {R01 AI094586/AI/NIAID NIH HHS/United States ; R01 HD083040/HD/NICHD NIH HHS/United States ; }, mesh = {Adolescent ; Africa South of the Sahara ; Contraceptive Devices, Female ; Contraceptives, Oral, Combined/administration &amp; dosage ; Cross-Over Studies ; Cytokines/*metabolism ; Female ; HIV Infections/*prevention &amp; control ; Hormonal Contraception/*adverse effects ; Humans ; Microbiota/*drug effects/genetics ; Norethindrone/administration &amp; dosage/analogs &amp; derivatives ; RNA, Ribosomal, 16S/genetics ; T-Lymphocytes/metabolism ; Vagina/*drug effects/metabolism/microbiology ; Young Adult ; }, abstract = {Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.}, }
@article {pmid33148263, year = {2020}, author = {Liu, Y and Du, Z and Ji, J and Li, J and Bi, D and Tang, F}, title = {Bidirectional association between serum carcinoembryonic antigen and metabolic syndrome among the Chinese male population: two cohort studies.}, journal = {Lipids in health and disease}, volume = {19}, number = {1}, pages = {233}, pmid = {33148263}, issn = {1476-511X}, support = {71804093//National Natural Science Foundation of China/ ; 2016WS0478//Shandong Provincial Medical and Health Science and Technology Development Project/ ; ZR2015HL102//Natural Science Foundation of Shandong Province/ ; 2016GSF201075//Key Technology Research and Development Program of Shandong/ ; 2019LJ005//Academic Promotion Programme of Shandong First Medical University/ ; 2019QL013//Academic Promotion Programme of Shandong First Medical University/ ; }, abstract = {PURPOSE: Previous studies have shown that serum carcinoembryonic antigen (CEA) is independently associated with metabolic syndrome (MetS). However, these studies were mainly cross-sectional analyses, and cause was not clarified. In the present study, two bidirectional cohort studies were conducted to investigate the bidirectional associations between CEA and MetS using a Chinese male sample cohort.<br><br>METHODS: The initial longitudinal cohort included 9629 Chinese males enrolled from January 2010 to December 2015. Two bidirectional cohorts were conducted in the study: subcohort A (from CEA to MetS, n = 6439) included participants without MetS at baseline to estimate the risk of developing incident MetS; subcohort B (from MetS to CEA, n = 8533) included participants without an elevated CEA level (Hyper-CEA) at baseline to examine the risk of developing incident Hyper-CEA. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.<br><br>RESULTS: In subcohort A, the incidence densities of MetS among participants with and without Hyper-CEA were 84.56 and 99.28 per 1000 person-years, respectively. No significant effects of Hyper-CEA on incident MetS were observed in subcohort A (HR, 0.89; 95% CI, 0.71 to 1.12; P = 0.326). In subcohort B, a higher incidence density of Hyper-CEA was found among participants with MetS (33.42 and 29.13 per 1000 person-years for those with and without MetS, respectively). For nonsmoking participants aged > 65 years, MetS increased the risk of incident Hyper-CEA (HR, 1.87; 95% CI, 1.09 to 3.20; P = 0.022).<br><br>CONCLUSION: For the direction of CEA on incident MetS, no significant association was observed. For the direction of MetS on incident Hyper-CEA, MetS in nonsmoking elderly men could increase the risk of incident Hyper-CEA, while this association was not found in other stratified participants. The clinical implications of the association between CEA and MetS should be interpreted with caution.}, }
@article {pmid33147337, year = {2020}, author = {Pasquini, MC and Hu, ZH and Curran, K and Laetsch, T and Locke, F and Rouce, R and Pulsipher, MA and Phillips, CL and Keating, A and Frigault, MJ and Salzberg, D and Jaglowski, S and Sasine, JP and Rosenthal, J and Ghosh, M and Landsburg, D and Margossian, S and Martin, PL and Kamdar, MK and Hematti, P and Nikiforow, S and Turtle, C and Perales, MA and Steinert, P and Horowitz, MM and Moskop, A and Pacaud, L and Yi, L and Chawla, R and Bleickardt, E and Grupp, S}, title = {Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma.}, journal = {Blood advances}, volume = {4}, number = {21}, pages = {5414-5424}, pmid = {33147337}, issn = {2473-9537}, support = {U01 AI126612/AI/NIAID NIH HHS/United States ; R21 HL140314/HL/NHLBI NIH HHS/United States ; U01 HL128568/HL/NHLBI NIH HHS/United States ; K12 CA087723/CA/NCI NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; R01 HL131731/HL/NHLBI NIH HHS/United States ; R01 CA152108/CA/NCI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; R01 CA231141/CA/NCI NIH HHS/United States ; R01 HL129472/HL/NHLBI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 HL130388/HL/NHLBI NIH HHS/United States ; U24 CA233032/CA/NCI NIH HHS/United States ; R01 CA215134/CA/NCI NIH HHS/United States ; }, abstract = {Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.}, }
@article {pmid33147073, year = {2020}, author = {Alberts, NM and Leisenring, WM and Flynn, JS and Whitton, J and Gibson, TM and Jibb, L and McDonald, A and Ford, J and Moraveji, N and Dear, BF and Krull, KR and Robison, LL and Stinson, JN and Armstrong, GT}, title = {Wearable Respiratory Monitoring and Feedback for Chronic Pain in Adult Survivors of Childhood Cancer: A Feasibility Randomized Controlled Trial From the Childhood Cancer Survivor Study.}, journal = {JCO clinical cancer informatics}, volume = {4}, number = {}, pages = {1014-1026}, pmid = {33147073}, issn = {2473-4276}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Approximately 40% of childhood cancer survivors experience chronic pain, with many also reporting pain-related disability. Given associations established in the general population among respiration, anxiety, and pain, continuous tracking and feedback of respiration may help survivors manage pain.<br><br>METHODS: A feasibility, nonblinded, randomized controlled trial (RCT) comparing wearable respiratory monitoring with a control group examined feasibility, acceptability, and preliminary efficacy among survivors of childhood cancer with chronic pain who were ≥ 18 years of age, able to speak and read English, lived in the United States, and had access to a smartphone and the Internet. The primary outcomes were pain interference, pain severity, anxiety, negative affect, and perceived stress. The intervention group (n = 32) received a wearable respiratory monitor, used the device, and completed an in-application breathing exercise daily for 30 days. The control group (n = 33) received psychoeducation after completion of the study.<br><br>RESULTS: Almost all participants in the intervention group (n = 31 of 32) and control group (n = 32 of 33) completed the study. Of those who completed the intervention, 90.3% wore the device for ≥ 50% of the trial. Posttreatment improvement for negative affect (Cohen d = 0.59; 95% CI, 0.09 to 1.10) was significantly greater in the intervention group compared with the control group. A follow-up study (n = 24) examined acceptability and feasibility of a second-generation device among those who completed the RCT. Most survivors (81.0%) wore the device daily during the trial and 85.7% reported satisfaction with the device and the application.<br><br>CONCLUSION: The results of this pilot study support the acceptability and feasibility of wearable respiratory monitoring among survivors of childhood cancer. Larger randomized trials are needed to assess efficacy and maintenance of this intervention for chronic pain.}, }
@article {pmid33146382, year = {2020}, author = {Etzioni, R and Nyame, YA}, title = {Prostate Cancer Screening Guidelines for Black Men: Spotlight on an Empty Stage.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaa172}, pmid = {33146382}, issn = {1460-2105}, }
@article {pmid33144283, year = {2020}, author = {Glubb, DM and Thompson, DJ and Aben, KK and Alsulimani, A and Amant, F and Annibali, D and Attia, J and Barricarte, A and Beckmann, MW and Berchuck, A and Bermisheva, M and Bernardini, MQ and Bischof, K and Bjørge, L and Bodelon, C and Brand, AH and Brenton, JD and Brinton, LA and Bruinsma, F and Buchanan, DD and Burghaus, S and Bützow, R and Cai, H and Carney, ME and Chanock, SJ and Chen, C and Chen, X and Chen, Z and Cook, LS and Cunningham, JM and De Vivo, I and DeFazio, A and Doherty, JA and Dork, T and du Bois, A and Dunning, AM and Durst, M and Edwards, T and Edwards, RP and Ekici, AB and Ewing, A and Fasching, PA and Ferguson, S and Flanagan, JM and Fostira, F and Fountzilas, G and Friedenreich, CM and Gao, B and Gaudet, MM and Gawełko, J and Gentry-Maharaj, A and Giles, GG and Glasspool, R and Goodman, MT and Gronwald, J and Harris, HR and Harter, P and Hein, A and Heitz, F and Hildebrandt, MAT and Hillemanns, P and Høgdall, E and Høgdall, CK and Holliday, EG and Huntsman, DG and Huzarski, T and Jakubowska, A and Jensen, A and Jones, ME and Karlan, BY and Karnezis, A and Kelley, JL and Khusnutdinova, E and Killeen, JL and Kjaer, SK and Klapdor, R and Köbel, M and Konopka, B and Konstantopoulou, I and Kopperud, RK and Koti, M and Kraft, P and Kupryjanczyk, J and Lambrechts, D and Larson, MC and Le Marchand, L and Lele, S and Lester, J and Li, AJ and Liang, D and Liebrich, C and Lipworth, L and Lissowska, J and Lu, L and Lu, KH and Macciotta, A and Mattiello, A and May, T and McAlpine, JN and McGuire, V and McNeish, IA and Menon, U and Modugno, F and Moysich, KB and Nevanlinna, H and Odunsi, K and Olsson, H and Orsulic, S and Osorio, A and Palli, D and Park-Simon, TW and Pearce, CL and Pejovic, T and Permuth, JB and Podgorska, A and Ramus, SJ and Rebbeck, TR and Riggan, MJ and Risch, HA and Rothstein, JH and Runnebaum, IB and Scott, RJ and Sellers, TA and Senz, J and Setiawan, VW and Siddiqui, N and Sieh, W and Spiewankiewicz, B and Sutphen, R and Swerdlow, AJ and Szafron, LM and Teo, SH and Thompson, PJ and Thomsen, LCV and Titus, L and Tone, A and Tumino, R and Turman, C and Vanderstichele, A and Velez Edwards, D and Vergote, I and Vierkant, RA and Wang, Z and Wang-Gohrke, S and Webb, PM and White, E and Whittemore, AS and Winham, SJ and Wu, X and Wu, AH and Yannoukakos, D and Spurdle, AB and O'Mara, TA}, title = {Cross-cancer genome-wide association study of endometrial cancer and epithelial ovarian cancer identifies genetic risk regions associated with risk of both cancers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-0739}, pmid = {33144283}, issn = {1538-7755}, abstract = {BACKGROUND: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.<br><br>METHODS: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.<br><br>RESULTS: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10-5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10-9). In addition, four novel sub-genome wide regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified (P < 5 × 10-7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.<br><br>CONCLUSION: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.<br><br>IMPACT: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.}, }
@article {pmid33143263, year = {2020}, author = {Epplein, M and Le Marchand, L and Cover, TL and Song, M and Blot, WJ and Peek, RM and Teras, LR and Visvanathan, K and Chen, Y and Sesso, HD and Zeleniuch-Jacquotte, A and Berndt, SI and Potter, JD and Ryser, MD and Haiman, CA and Wassertheil-Smoller, S and Tinker, LF and Waterboer, T and Butt, J}, title = {Association of Combined Sero-Positivity to Helicobacter pylori and Streptococcus gallolyticus with Risk of Colorectal Cancer.}, journal = {Microorganisms}, volume = {8}, number = {11}, pages = {}, pmid = {33143263}, issn = {2076-2607}, support = {R01 CA190428/CA/NCI NIH HHS/United States ; }, abstract = {Previously, we found that risk of colorectal cancer (CRC) is increased in individuals with serum antibody response to both Helicobacter pylori (HP) Vacuolating Cytotoxin (VacA) toxin or Streptococcus gallolyticus (SGG) pilus protein Gallo2178. In the present analysis, we tested the hypothesis that combined seropositivity to both antigens is a better indicator of CRC risk than seropositivity to single antigens. We used multiplex serologic assays to analyze pre-diagnostic serum for antibody responses from 4063 incident CRC cases and 4063 matched controls from 10 US cohorts. To examine whether combined SGG Gallo2178 and HP VacA sero-status was associated with CRC risk, we used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to dual sero-negative individuals, there was no increased risk for individuals sero-positive to SGG Gallo2178 only (OR: 0.93; 95% CI: 0.66-1.31) or to HP VacA only (OR: 1.08; 95% CI: 0.98-1.19). However, dual sero-positive individuals had a >50% increased odds of developing CRC (OR: 1.54; 95% CI: 1.16-2.04), suggesting an interaction between antibody responses to these two pathogens and CRC risk (pinteraction = 0.06). In conclusion, this study suggests that dual sero-positivity to HP VacA and SGG Gallo2178 is an indicator of increased risk of CRC.}, }
@article {pmid33139341, year = {2020}, author = {Davidsen, K and Sullivan, LB}, title = {Free Asparagine or Die: Cancer Cells Require Proteasomal Protein Breakdown to Survive Asparagine Depletion.}, journal = {Cancer discovery}, volume = {10}, number = {11}, pages = {1632-1634}, doi = {10.1158/2159-8290.CD-20-1251}, pmid = {33139341}, issn = {2159-8290}, abstract = {The chemotherapeutic enzyme asparaginase depletes systemic asparagine to kill cancers; however, its efficacy thus far is limited to a subset of leukemias. Hinze and colleagues identify that inhibiting proteasomal release of asparagine can sensitize colorectal cancers to asparagine depletion, providing a potential avenue to repurpose asparaginase for treatment of solid tumors.See related article by Hinze et al., p. 1690.}, }
@article {pmid33138708, year = {2021}, author = {Evins, AE and West, R and Benowitz, NL and Russ, C and Lawrence, D and McRae, T and Maravic, MC and Heffner, JL and Anthenelli, RM}, title = {Efficacy and Safety of Pharmacotherapeutic Smoking Cessation Aids in Schizophrenia Spectrum Disorders: Subgroup Analysis of EAGLES.}, journal = {Psychiatric services (Washington, D.C.)}, volume = {72}, number = {1}, pages = {7-15}, doi = {10.1176/appi.ps.202000032}, pmid = {33138708}, issn = {1557-9700}, abstract = {OBJECTIVE: This study aimed to evaluate the efficacy and safety of varenicline, bupropion, and nicotine replacement therapy (NRT) among smokers with schizophrenia spectrum disorders in post hoc analyses of Evaluating Adverse Events in a Global Smoking Cessation Study data.<br><br>METHODS: Smokers with schizophrenia spectrum disorder (N=390) and without a psychiatric illness (control group, N=4,028) were randomly assigned to receive varenicline, bupropion, NRT patch, or placebo for 12 weeks. Outcomes included abstinence rates during treatment and follow-up, number needed to treat (NNT) for abstinence, incidence of neuropsychiatric adverse events (NPSAEs), and temporal relationship between NPSAEs and abstinence status.<br><br>RESULTS: Smokers with schizophrenia smoked more and had greater dependence and fewer prior trials of cessation pharmacotherapy at baseline. At each time point, smokers with schizophrenia assigned to varenicline had significantly greater odds of abstinence compared with their matched placebo group, with NNT comparable to the control group. Bupropion and NRT increased odds of abstinence; confidence intervals (CIs) included 1 for some comparisons, and NNT for smokers with schizophrenia was greater than for the control group. No treatment was associated with significantly more NPSAEs, compared with placebo, in either cohort. The estimated NPSAE rate was 5% (95% CI=3.0-7.7) for smokers with schizophrenia and 1% (95% CI=0.6-2.1) for the control group. Over one-third of NPSAEs occurred during partial or full abstinence, suggesting a multifactorial nature.<br><br>CONCLUSIONS: For smokers with schizophrenia, varenicline led to significantly higher abstinence rates, and NNT was comparable to the control group. A significant proportion of NPSAEs occurred during early abstinence. No treatment significantly increased NPSAE prevalence.}, }
@article {pmid33137178, year = {2020}, author = {Perchetti, GA and Wilcox, N and Chu, HY and Katz, J and Khatry, SK and LeClerq, SC and Tielsch, JM and Jerome, KR and Englund, JA and Kuypers, J}, title = {Human Metapneumovirus Infection and Genotyping of Infants in Rural Nepal.}, journal = {Journal of the Pediatric Infectious Diseases Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/jpids/piaa118}, pmid = {33137178}, issn = {2048-7207}, abstract = {BACKGROUND: Acute respiratory tract infections are a serious clinical burden in infants; human metapneumovirus (HMPV) is an important etiological agent. We investigated genotypic variation and molecular epidemiological patterns among infants infected with HMPV in Sarlahi, Nepal, to better characterize infection in a rural, low-resource setting.<br><br>METHODS: Between May 2011 and April 2014, mid-nasal swabs were collected from 3528 infants who developed respiratory symptoms during a longitudinal maternal influenza vaccine study. Sequencing glycoprotein genes permitted genotyping and analyses among subtypes.<br><br>RESULTS: HMPV was detected by reverse-transcriptase polymerase chain reaction (RT-PCR) in 187 (5%) infants, with seasonality observed during fall and winter months. Phylogenetic investigation of complete and partial coding sequences for the F and G genes, respectively, revealed that 3 genotypes were circulating: A2, B1, and B2. HMPV-B was most frequently detected with a single type predominating each season. Both HMPV genotypes exhibited comparable median viral loads. Clinically significant differences between genotypes were limited to increased cough duration and general respiratory symptoms for type B.<br><br>CONCLUSIONS: In rural Nepal, multiple HMPV genotypes circulate simultaneously with an alternating predominance of a single genotype and definitive seasonality. No difference in viral load was detected by genotype and symptom severity was not correlated with RT-PCR cycle threshold or genotype.}, }
@article {pmid33136739, year = {2020}, author = {Moore, JR and Donnell, DJ and Boily, MC and Mitchell, KM and Delany-Moretlwe, S and Bekker, LG and Mgodi, NM and El-Sadr, W and Cohen, MS and Celum, CL and Dimitrov, D}, title = {Model-Based Predictions of HIV Incidence Among African Women Using HIV Risk Behaviors and Community-Level Data on Male HIV Prevalence and Viral Suppression.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {85}, number = {4}, pages = {423-429}, pmid = {33136739}, issn = {1944-7884}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical &quot;placebo arm&quot; for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP.<br><br>METHODS: Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study.<br><br>RESULTS: Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions.<br><br>CONCLUSIONS: We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.}, }
@article {pmid33136735, year = {2020}, author = {Moore, M and Boily, MC and Mitchell, KM and Donnell, DD and Cohen, MS and Dimitrov, DT}, title = {Identifying Regions of Greatest Need for Ending the HIV Epidemic: A Plan for America.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {85}, number = {4}, pages = {395-398}, doi = {10.1097/QAI.0000000000002477}, pmid = {33136735}, issn = {1944-7884}, abstract = {BACKGROUND: In the 2019 State of the Union Address, President Trump announced a plan for &quot;Ending the HIV Epidemic&quot; in the United States, with a goal to reduce new HIV infections by 90% by 2030. Phase I of the plan set an intermediate goal of a 75% reduction within 5 years, focusing on select states and counties.<br><br>METHODS: We assessed the feasibility of the first phase of the plan by estimating the fraction of HIV diagnoses that occur within the targeted region, using a statistical model to predict new HIV cases in each county. We suggested new areas that should be added to the current plan, prioritizing by both a &quot;Density Metric&quot; of new HIV cases and a &quot;Gap Metric&quot; quantifying shortcomings in antiretroviral therapy and pre-exposure prophylaxis uptake.<br><br>RESULTS: We found the current plan targets less than 60% of new diagnoses. The plan should be expanded to Puerto Rico, Florida, Georgia, Louisiana, and Maryland as well as parts of New York, North Carolina, Texas, and Virginia, areas which were prioritized by both metrics.<br><br>CONCLUSION: Many of the highest priority areas, both by density of HIV cases and by lack of viral suppression and pre-exposure prophylaxis use, were not covered by the original plan, particularly in the South. The current plan to end the HIV epidemic must be expanded to these areas to feasibly allow for a 75% reduction in new HIV cases within 5 years.}, }
@article {pmid33136468, year = {2020}, author = {Sopfe, J and Marsh, R and Ziniel, SI and Klosky, JL and Chow, EJ and Dorsey Holliman, B and Peterson, PN}, title = {Evaluation of the v2.0 Brief Profiles for Sexual Function and Satisfaction PROMIS in Adolescent and Young Adult Childhood Cancer Survivors.}, journal = {Journal of adolescent and young adult oncology}, volume = {}, number = {}, pages = {}, doi = {10.1089/jayao.2020.0166}, pmid = {33136468}, issn = {2156-535X}, abstract = {Purpose: Sexual dysfunction (SD) is a common, but often unrecognized potential late effect among childhood cancer survivors (CCS). Unfortunately, both patients and providers report low levels of routine screening and identify multiple barriers, including lack of knowledge, discomfort, and limited time. This is particularly true among CCS who are adolescent or young adult aged (AYA-CCS). One potential way to increase screening, detection, and treatment for SD among AYA-CCS is to employ patient-reported outcomes measures. While adult screening tools exist, no SD screening tool has been evaluated specifically among this younger population. Methods: This qualitative study used Think-Aloud and cognitive interviewing methods to obtain feedback from AYA-CCS on acceptability, usefulness, and validity of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) v2.0 Brief Profiles for Sexual Function and Satisfaction (SexFS Brief) in CCS now 15-24 years of age. Results: The SexFS Brief demonstrated acceptability, response process and content validity, and usefulness among AYA-CCS. There were no detectable differences by age or gender. This study did not reveal any necessary modification to the SexFS Brief for this population. Conclusion: The PROMIS SexFS Brief is an acceptable and useful tool, with demonstrated response process and content validity, and may facilitate improved screening and diagnosis of SD among AYA-CCS. Furthermore, this tool was viewed favorably by AYA-CCS as a way to reduce barriers such as discomfort and lack of knowledge on the part of patients. Further evaluation of its effectiveness and acceptability in a clinical setting is warranted.}, }
@article {pmid33136296, year = {2020}, author = {Nightingale, CL and Sterba, KR and McLouth, LE and Kent, EE and Dressler, EV and Dest, A and Snavely, AC and Adonizio, CS and Wojtowicz, M and Neuman, HB and Kazak, AE and Carlos, RC and Hudson, MF and Unger, JM and Kamen, CS and Weaver, KE}, title = {Caregiver engagement practices in National Cancer Institute Clinical Oncology Research Program settings: Implications for research to advance the field.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33296}, pmid = {33136296}, issn = {1097-0142}, support = {UCA189972B/CA/NCI NIH HHS/United States ; UG1 CA189867/CA/NCI NIH HHS/United States ; K07 CA190529/CA/NCI NIH HHS/United States ; P30 CA012197/CA/NCI NIH HHS/United States ; UG1 CA189828/CA/NCI NIH HHS/United States ; UL1TR001420/TR/NCATS NIH HHS/United States ; R25CA122061/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; 2UG1 CA189828/CA/NCI NIH HHS/United States ; 1UG1 CA189824/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Supportive care interventions have demonstrated benefits for both informal and/or family cancer caregivers and their patients, but uptake generally is poor. To the authors' knowledge, little is known regarding the availability of supportive care services in community oncology practices, as well as engagement practices to connect caregivers with these services.<br><br>METHODS: Questions from the National Cancer Institute Community Oncology Research Program (NCORP)'s 2017 Landscape Survey examined caregiver engagement practices (ie, caregiver identification, needs assessment, and supportive care service availability). Logistic regression was used to assess the relationship between the caregiver engagement outcomes and practice group characteristics.<br><br>RESULTS: A total of 204 practice groups responded to each of the primary outcome questions. Only 40.2% of practice groups endorsed having a process with which to systematically identify and document caregivers, although approximately 76% were routinely using assessment tools to identify caregiver needs and approximately 63.7% had supportive care services available to caregivers. Caregiver identification was more common in sites affiliated with a critical access hospital (odds ratio [OR], 2.44; P = .013), and assessments were less common in safety-net practices (OR, 0.41; P = .013). Supportive care services were more commonly available in the Western region of the United States, in practices with inpatient services (OR, 2.96; P = .012), and in practices affiliated with a critical access hospital (OR, 3.31; P = .010).<br><br>CONCLUSIONS: Although many practice groups provide supportive care services, fewer than one-half systematically identify and document informal cancer caregivers. Expanding fundamental engagement practices such as caregiver identification, assessment, and service provision will be critical to support recent calls to improve caregivers' well-being and skills to perform caregiving tasks.}, }
@article {pmid33134833, year = {2020}, author = {Cheung, YT and Liu, W and Brinkman, TM and Srivastava, D and Leisenring, WM and Howell, RM and Ullrich, NJ and Lommel, KM and Brouwers, P and Gibson, TM and Robison, LL and Armstrong, GT and Krull, KR}, title = {Prescription Psychoactive Medication Use in Adolescent Survivors of Childhood Cancer and Association With Adult Functional Outcomes.}, journal = {JNCI cancer spectrum}, volume = {4}, number = {5}, pages = {pkaa057}, pmid = {33134833}, issn = {2515-5091}, abstract = {Background: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years).<br><br>Methods: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes.<br><br>Results: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided P < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers.<br><br>Conclusion: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood.}, }
@article {pmid33134831, year = {2020}, author = {Geijsen, AJMR and Ulvik, A and Gigic, B and Kok, DE and van Duijnhoven, FJB and Holowatyj, AN and Brezina, S and van Roekel, EH and Baierl, A and Bergmann, MM and Böhm, J and Bours, MJL and Brenner, H and Breukink, SO and Bronner, MP and Chang-Claude, J and de Wilt, JHW and Grady, WM and Grünberger, T and Gumpenberger, T and Herpel, E and Hoffmeister, M and Huang, LC and Jedrzkiewicz, JD and Keulen, ETP and Kiblawi, R and Kölsch, T and Koole, JL and Kosma, K and Kouwenhoven, EA and Kruyt, FM and Kvalheim, G and Li, CI and Lin, T and Ose, J and Pickron, TB and Scaife, CL and Schirmacher, P and Schneider, MA and Schrotz-King, P and Singer, MC and Swanson, ER and van Duijvendijk, P and van Halteren, HK and van Zutphen, M and Vickers, K and Vogelaar, FJ and Wesselink, E and Habermann, N and Ulrich, AB and Ueland, PM and Weijenberg, MP and Gsur, A and Ulrich, CM and Kampman, E}, title = {Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.}, journal = {JNCI cancer spectrum}, volume = {4}, number = {5}, pages = {pkaa051}, pmid = {33134831}, issn = {2515-5091}, abstract = {Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.<br><br>Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.<br><br>Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.<br><br>Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.}, }
@article {pmid33134503, year = {2020}, author = {Radtke, S and Colonna, L and Perez, AM and Hoffman, M and Kean, LS and Kiem, HP}, title = {Isolation of a Highly Purified HSC-enriched CD34+CD90+CD45RA- Cell Subset for Allogeneic Transplantation in the Nonhuman Primate Large-animal Model.}, journal = {Transplantation direct}, volume = {6}, number = {8}, pages = {e579}, pmid = {33134503}, issn = {2373-8731}, support = {P51 OD010425/OD/NIH HHS/United States ; R01 AI135953/AI/NIAID NIH HHS/United States ; R33 AI116184/AI/NIAID NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a common treatment for patients suffering from different hematological disorders. Allo-HCT in combination with hematopoietic stem cell (HSC) gene therapy is considered a promising treatment option for millions of patients with HIV+ and acute myeloid leukemia. Most currently available HSC gene therapy approaches target CD34-enriched cell fractions, a heterogeneous mix of mostly progenitor cells and only very few HSCs with long-term multilineage engraftment potential. As a consequence, gene therapy approaches are currently limited in their HSC targeting efficiency, very expensive consuming huge quantities of modifying reagents, and can lead to unwanted side effects in nontarget cells. We have previously shown that purified CD34+CD90+CD45RA- cells are enriched for multipotent HSCs with long-term multilineage engraftment potential, which can reconstitute the entire hematopoietic system in an autologous nonhuman primate transplant model. Here, we tested the feasibility of transplantation with purified CD34+CD90+CD45RA- cells in the allogeneic setting in a nonhuman primate model.<br><br>Methods: To evaluate the feasibility of this approach, CD34+CD90+CD45RA- cells from 2 fully major histocompatibility complex-matched, full sibling rhesus macaques were sort-purified, quality controlled, and transplanted. Engraftment and donor chimerism were evaluated in the peripheral blood and bone marrow of both animals.<br><br>Results: Despite limited survival due to infectious complications, we show that the large-scale sort-purification and transplantation of CD34+CD90+CD45RA- cells is technically feasible and leads to rapid engraftment of cells in bone marrow in the allogeneic setting and absence of cotransferred T cells.<br><br>Conclusions: We show that purification of an HSC-enriched CD34+ subset can serve as a potential stem cell source for allo-HCTs. Most importantly, the combination of allo-HCT and HSC gene therapy has the potential to treat a wide array of hematologic and nonhematologic disorders.}, }
@article {pmid33133043, year = {2020}, author = {Wang, R and Gornalusse, GG and Kim, Y and Pandey, U and Hladik, F and Vojtech, L}, title = {Potent Restriction of Sexual Zika Virus Infection by the Lipid Fraction of Extracellular Vesicles in Semen.}, journal = {Frontiers in microbiology}, volume = {11}, number = {}, pages = {574054}, pmid = {33133043}, issn = {1664-302X}, support = {R01 DA040386/DA/NIDA NIH HHS/United States ; R21 AI129303/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; }, abstract = {Sexual Zika virus (ZIKV) transmission from men to women occurs less frequently than the often-detected high viral loads in semen would suggest, but worries that this transmission route predisposes to fetal damage in pregnant women remain. To better understand sexual ZIKV pathogenesis, we studied the permissiveness of the human female genital tract to infection and the effect of semen on this process. ZIKV replicates in vaginal tissues and primary epithelial cells from the vagina, ectocervix, and endocervix and induces an innate immune response, but also continues to replicate without cytopathic effect. Infection of genital cells and tissues is strongly inhibited by extracellular vesicles (EV) in semen at physiological vesicle-to-virus ratios. Liposomes with the same composition as semen EVs also impair infection, indicating that the EV's lipid fraction, rather than their protein or RNA cargo, is responsible for this anti-viral effect. Thus, EVs in semen potently restrict ZIKV transmission, but the virus propagates well once infection in the recipient mucosa has been established.}, }
@article {pmid33131544, year = {2020}, author = {Dixon, SB and Chow, EJ and Hjorth, L and Hudson, MM and Kremer, LCM and Morton, LM and Nathan, PC and Ness, KK and Oeffinger, KC and Armstrong, GT}, title = {The Future of Childhood Cancer Survivorship: Challenges and Opportunities for Continued Progress.}, journal = {Pediatric clinics of North America}, volume = {67}, number = {6}, pages = {1237-1251}, pmid = {33131544}, issn = {1557-8240}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; }, abstract = {As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.}, }
@article {pmid33131319, year = {2020}, author = {Graham, LS and Sokolova, AO and Khaki, AR and Wu, QV and Davidson, NE}, title = {Gender Differences in Faculty Rank and Subspecialty Choice among Academic Medical Oncologists.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/07357907.2020.1846191}, pmid = {33131319}, issn = {1532-4192}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {Gender parity within academic oncology is important. We hypothesized that gender differences exist in subspecialty choice and academic rank among medical oncologists. We performed a cross-sectional study of adult medical oncologists at the top 15 cancer centers. Gender, rank, subspecialty (breast, thoracic, gastrointestinal, and genitourinary) and board certification year were recorded. 570 medical oncologists were identified (60% men; 40% women). More women practice breast oncology (OR 3.1, p < 0.001), but less practice genitourinary oncology (OR 0.37, p < 0.001). 22% of women were full professors vs 34% of men (OR 0.55, p = 0.001). Gender differences persist in academic adult medical oncology.}, }
@article {pmid33130903, year = {2020}, author = {Vitanza, NA and Biery, MC and Myers, C and Ferguson, E and Zheng, Y and Girard, EJ and Przystal, JM and Park, G and Noll, A and Pakiam, F and Winter, CA and Morris, SM and Sarthy, J and Cole, BL and Leary, SES and Crane, C and Lieberman, NAP and Mueller, S and Nazarian, J and Gottardo, R and Brusniak, MY and Mhyre, AJ and Olson, JM}, title = {Optimal therapeutic targeting by HDAC inhibition in biopsy-derived treatment-naïve diffuse midline glioma models.}, journal = {Neuro-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1093/neuonc/noaa249}, pmid = {33130903}, issn = {1523-5866}, abstract = {BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis with less than 2% surviving 5-years post-diagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically-relevant DMG models to identify and validate other effective HDACi and their biomarkers of response.<br><br>METHODS: HDACi were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically-relevant radiation-resistance. RNA sequencing was performed to define and compare drug efficacy, and to map predictive biomarkers of response.<br><br>RESULTS: Quisinostat and romidepsin showed efficacy with a low nanomolar IC50 values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all three drugs at similar biologically effective doses, such as overexpression of TNNT1 and downregulation of COL20A1, identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (p <0.0001) inhibited in vivo tumor growth.<br><br>CONCLUSIONS: Our data highlights the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain-tumor-penetrant versions of potentially efficacious agents.}, }
@article {pmid33128769, year = {2021}, author = {van Rhee, F and Rossi, JF and Simpson, D and Fosså, A and Dispenzieri, A and Kuruvilla, J and Goh, YT and Cho, SG and Capra, M and Liu, T and Casper, C and Cavet, J and Wong, RS}, title = {Newly diagnosed and previously treated multicentric Castleman disease respond equally to siltuximab.}, journal = {British journal of haematology}, volume = {192}, number = {1}, pages = {e28-e31}, doi = {10.1111/bjh.17177}, pmid = {33128769}, issn = {1365-2141}, support = {//EUSA PHARMA/ ; //Janssen Research &amp; Development/ ; }, }
@article {pmid33128322, year = {2020}, author = {Goyal, A and Perelson, AS and Kandathil, AJ and Quinn, J and Balagopal, A and Ribeiro, RM}, title = {HIV influences clustering and intracellular replication of hepatitis C virus.}, journal = {Journal of viral hepatitis}, volume = {}, number = {}, pages = {}, doi = {10.1111/jvh.13429}, pmid = {33128322}, issn = {1365-2893}, support = {DA016078/DA/NIDA NIH HHS/United States ; R01 DA016078/DA/NIDA NIH HHS/United States ; AI116868//National Institute of Allergy and Infectious Diseases/ ; OD011095//NIH Office of the Director/ ; R01 AI078881/AI/NIAID NIH HHS/United States ; R01 AI116868/AI/NIAID NIH HHS/United States ; AI078881//National Institute of Allergy and Infectious Diseases/ ; AI028433//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {HCV and HIV coinfection is common and HIV leads to increased HCV viraemia and accelerated disease progression. However, the biological basis of this interaction remains poorly understood and little is known about the impact of HIV on HCV replication at the cellular level. We analysed HCV RNA, based on single-cell laser-capture microdissection, in liver biopsies from monoinfected (n = 4) and HCV/HIV-coinfected (n = 5) participants. HCV RNA was assayed in 3200 hepatocytes with information of spatial position. We compared HCV RNA levels and clustering properties of infection between mono- and coinfected participants, and developed a mathematical model of infection. Although the median plasma HCV RNA level and the fraction of infected cells were comparable in monoinfected (7.0 log10 IU/mL and ~ 30%) and coinfected (7.3 log10 IU/mL and ~ 40%) participants, the median HCV RNA per infected hepatocyte in monoinfected (2.8IU) was significantly lower than in coinfected (8.2IU) participants (p = .03). Clustering of infected cells was more prominent in monoinfected participants (91% of samples) than in coinfected participants (~48%), p = .0045, suggesting that spatial spread may be influenced by HIV coinfection. Interestingly, when clustering does occur, the size of clusters is similar in both types of infection. A mathematical model of infection suggested that HIV allows higher intracellular accumulation of HCV RNA by impeding the export of HCV RNA. Our observations show that HIV coinfection impacts intracellular accumulation of HCV RNA and the clustering of HCV-infected cells, but to a less extent the fraction of HCV-infected cells.}, }
@article {pmid33128203, year = {2020}, author = {van den Brandt, PA and Ziegler, RG and Wang, M and Hou, T and Li, R and Adami, HO and Agnoli, C and Bernstein, L and Buring, JE and Chen, Y and Connor, AE and Eliassen, AH and Genkinger, JM and Gierach, G and Giles, GG and Goodman, GG and Håkansson, N and Krogh, V and Le Marchand, L and Lee, IM and Liao, LM and Martinez, ME and Miller, AB and Milne, RL and Neuhouser, ML and Patel, AV and Prizment, A and Robien, K and Rohan, TE and Sawada, N and Schouten, LJ and Sinha, R and Stolzenberg-Solomon, RZ and Teras, LR and Tsugane, S and Visvanathan, K and Weiderpass, E and White, KK and Willett, WC and Wolk, A and Zeleniuch-Jacquotte, A and Smith-Warner, SA}, title = {Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s10654-020-00688-3}, pmid = {33128203}, issn = {1573-7284}, abstract = {Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.}, }
@article {pmid33128066, year = {2020}, author = {Buchanan, AL and Bessey, S and Goedel, WC and King, M and Murray, EJ and Friedman, S and Halloran, ME and Marshall, BDL}, title = {Disseminated Effects in Agent Based Models: A Potential Outcomes Framework and Application to Inform Pre-Exposure Prophylaxis Coverage Levels for HIV Prevention.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaa239}, pmid = {33128066}, issn = {1476-6256}, support = {DP1 DA034989/DA/NIDA NIH HHS/United States ; DP2 DA046856/DA/NIDA NIH HHS/United States ; F31 MH121112/MH/NIMH NIH HHS/United States ; R21 HD098733/HD/NICHD NIH HHS/United States ; }, abstract = {Pre-exposure prophylaxis (PrEP) for HIV prevention may not only benefit the individual who uses it, but also their uninfected sexual risk contacts. We developed an agent-based model using a novel trial emulation approach to quantify disseminated effects of PrEP use among men who have sex with men in Atlanta, USA from 2015 to 2017. Components (subsets of agents connected through partnerships in a sexual network, but not sharing partnerships with any other agents) were first randomized to an intervention coverage level or control, then within intervention components, eligible agents were randomized to PrEP. We estimated direct and disseminated (indirect) effects using randomization-based estimators and reported corresponding 95% simulation intervals across scenarios ranging from 10% to 90% coverage in the intervention components. A population of 11,245 agents was simulated with an average of 1,551 components identified. Comparing agents randomized to PrEP in 70% coverage components to control agents, there was a 15% disseminated risk reduction in HIV incidence (95% simulation intervals = 0.65, 1.05). Individuals not on PrEP may receive a protective benefit by being in a sexual network with higher PrEP coverage. Agent-based models are useful to evaluate possible direct and disseminated effects of HIV prevention modalities in sexual networks.}, }
@article {pmid33126877, year = {2020}, author = {Luyapan, J and Ji, X and Li, S and Xiao, X and Zhu, D and Duell, EJ and Christiani, DC and Schabath, MB and Arnold, SM and Zienolddiny, S and Brunnström, H and Melander, O and Thornquist, MD and MacKenzie, TA and Amos, CI and Gui, J}, title = {A new efficient method to detect genetic interactions for lung cancer GWAS.}, journal = {BMC medical genomics}, volume = {13}, number = {1}, pages = {162}, pmid = {33126877}, issn = {1755-8794}, support = {R01 LM012012/LM/NLM NIH HHS/United States ; RR170048//Cancer Prevention and Research Institute of Texas/International ; U19 CA203654/CA/NCI NIH HHS/United States ; T32 LM012204/LM/NLM NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Genome-wide association studies (GWAS) have proven successful in predicting genetic risk of disease using single-locus models; however, identifying single nucleotide polymorphism (SNP) interactions at the genome-wide scale is limited due to computational and statistical challenges. We addressed the computational burden encountered when detecting SNP interactions for survival analysis, such as age of disease-onset. To confront this problem, we developed a novel algorithm, called the Efficient Survival Multifactor Dimensionality Reduction (ES-MDR) method, which used Martingale Residuals as the outcome parameter to estimate survival outcomes, and implemented the Quantitative Multifactor Dimensionality Reduction method to identify significant interactions associated with age of disease-onset.<br><br>METHODS: To demonstrate efficacy, we evaluated this method on two simulation data sets to estimate the type I error rate and power. Simulations showed that ES-MDR identified interactions using less computational workload and allowed for adjustment of covariates. We applied ES-MDR on the OncoArray-TRICL Consortium data with 14,935 cases and 12,787 controls for lung cancer (SNPs = 108,254) to search over all two-way interactions to identify genetic interactions associated with lung cancer age-of-onset. We tested the best model in an independent data set from the OncoArray-TRICL data.<br><br>RESULTS: Our experiment on the OncoArray-TRICL data identified many one-way and two-way models with a single-base deletion in the noncoding region of BRCA1 (HR 1.24, P = 3.15 × 10-15), as the top marker to predict age of lung cancer onset.<br><br>CONCLUSIONS: From the results of our extensive simulations and analysis of a large GWAS study, we demonstrated that our method is an efficient algorithm that identified genetic interactions to include in our models to predict survival outcomes.}, }
@article {pmid33125909, year = {2020}, author = {Redman, MW and Papadimitrakopoulou, VA and Minichiello, K and Hirsch, FR and Mack, PC and Schwartz, LH and Vokes, E and Ramalingam, S and Leighl, N and Bradley, J and Miao, J and Moon, J and Highleyman, L and Miwa, C and LeBlanc, ML and Malik, S and Miller, VA and Sigal, EV and Adam, S and Wholley, D and Sigman, C and Smolich, B and Blanke, CD and Kelly, K and Gandara, DR and Herbst, RS}, title = {Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol.}, journal = {The Lancet. Oncology}, volume = {21}, number = {12}, pages = {1589-1601}, doi = {10.1016/S1470-2045(20)30475-7}, pmid = {33125909}, issn = {1474-5488}, support = {U10 CA180868/CA/NCI NIH HHS/United States ; UG1 CA233329/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA189858/CA/NCI NIH HHS/United States ; UG1 CA233340/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180858/CA/NCI NIH HHS/United States ; U10 CA180846/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: The Lung Cancer Master Protocol (Lung-MAP; S1400) is a completed biomarker-driven master protocol designed to address an unmet need for better therapies for squamous non-small-cell lung cancer. Lung-MAP (S1400) was created to establish an infrastructure for biomarker screening and rapid regulatory intent evaluation of targeted therapies and was the first biomarker-driven master protocol initiated with the US National Cancer Institute (NCI).<br><br>METHODS: Lung-MAP (S1400) was done within the National Clinical Trials Network of the NCI using a public-private partnership. Eligible patients were aged 18 years or older, had stage IV or recurrent squamous non-small-cell lung cancer, had previously been treated with platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The study included a screening component using the FoundationOne assay (Foundation Medicine, Cambridge, MA, USA) for next-generation sequencing, and a clinical trial component with biomarker-driven substudies and non-match substudies for patients who were ineligible for biomarker-driven substudies. Patients were pre-screened and received their substudy assignment upon progression, or they were screened at progression and received their substudy assignment upon completion of testing. Patients could enrol onto additional substudies after progression on a substudy. The study is registered with ClinicalTrials.gov, NCT02154490, and all research related to Lung-MAP (S1400) is completed.<br><br>FINDINGS: Between June 16, 2014, and Jan 28, 2019, 1864 patients enrolled and 1841 (98·9%) submitted tissue. 1674 (90·9%) of 1841 patients had biomarker results, and 1404 (83·9%) of 1674 patients received a substudy assignment. Of the assigned patients, 655 (46·7%) registered to a substudy. The biomarker-driven substudies evaluated taselisib (targeting PIK3CA alterations), palbociclib (cell cycle gene alterations), AZD4547 (FGFR alteration), rilotumumab plus erlotinib (MET), talazoparib (homologous recombination repair deficiency), and telisotuzumab vedotin (MET). The non-match substudies evaluated durvalumab, and nivolumab plus ipilimumab for anti-PD-1 or anti-PD-L1-naive disease, and durvalumab plus tremelimumab for anti-PD-1 or anti-PD-L1 relapsed disease. Combining data from the substudies, ten (7·0%) of 143 patients responded to targeted therapy, 53 (16·8%) of 315 patients responded to anti-PD-1 or anti-PD-L1 therapy for immunotherapy-naive disease, and three (5·4%) of 56 responded to docetaxel in the second line of therapy. Median overall survival was 5·9 months (95% CI 4·8-7·8) for the targeted therapy groups, 7·7 months (6·7-9·2) for the docetaxel groups, and 10·8 months (9·4-12·3) for the anti-PD-1 or anti-PD-L1-containing groups. Median progression-free survival was 2·5 months (95% CI 1·7-2·8) for the targeted therapy groups, 2·7 months (1·9-2·9) for the docetaxel groups, and 3·0 months (2·7-3·9) for the anti-PD-1 or anti-PD-L1-containing groups.<br><br>INTERPRETATION: Lung-MAP (S1400) met its goal to quickly address biomarker-driven therapy questions in squamous non-small-cell lung cancer. In early 2019, a new screening protocol was implemented expanding to all histological types of non-small-cell lung cancer and to add focus on immunotherapy combinations for anti-PD-1 and anti-PD-L1 therapy-relapsed disease. With these changes, Lung-MAP continues to meet its goal to focus on unmet needs in the treatment of advanced lung cancers.<br><br>FUNDING: US National Institutes of Health, and AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, and Pfizer through the Foundation for the National Institutes of Health.}, }
@article {pmid33121238, year = {2020}, author = {Petersdorf, EW and Gooley, T and Volt, F and Kenzey, C and Madrigal, A and McKallor, C and Querol, S and Rafii, H and Rocha, V and Tamouza, R and Chabannon, C and Ruggeri, A and Gluckman, E}, title = {Use of the HLA-B leader to optimize cord-blood transplantation.}, journal = {Haematologica}, volume = {Online ahead of print}, number = {}, pages = {0}, doi = {10.3324/haematol.2020.264424}, pmid = {33121238}, issn = {1592-8721}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; }, abstract = {Cord-blood transplantation (CBT) can cure life-threatening blood disorders. The HLA-B leader affects the success of unrelated donor transplantation but its role in CBT is unknown. We tested the hypothesis that the HLA-B leader influences CBT outcomes in unrelated single-unit cord-blood transplants performed by Eurocord/European Blood and Marrow Transplant (EBMT) centers between 1990 and 2018 with data reported to Eurocord. Among 4822 transplants, 2178 had one HLA-B mismatch of which 1013 were HLA-A and HLA-DRB1-matched. The leader (M or T) was determined for each HLA-B allele in patients and units to define the genotype. Among single HLA-B-mismatched transplants, the patient/unit mismatched alleles were defined as leader-matched if they encoded the same leader, or leader-mismatched if they encoded different leaders; the leader encoded by the matched (shared) allele was determined. The risks of GVHD, relapse, non-relapse mortality and overall mortality were estimated for various leaderdefined groups using multivariable regression models. Among the 1013 HLA-A, -DRB1- matched transplants with one HLA-B mismatch, increasing numbers of cord-blood unit M-leader alleles was associated with increased risk of relapse (hazard ratio [HR] for each increase in one M-leader allele 1.30, 95% confidence interval [CI] 1.05 to 1.60, P 0.02). Furthermore, leader mismatching together with an M-leader of the shared HLA-B allele lowered non-relapse mortality (HR 0.44, 95% CI 0.23 to 0.81; P 0.009) relative to leader-matching and a shared T-leader allele. The HLA-B leader may inform relapse and non-relapse mortality risk after CBT. Future patients might benefit from the appropriate selection of units that consider the leader.}, }
@article {pmid33119898, year = {2020}, author = {Pollyea, DA and Pratz, K and Letai, A and Jonas, BA and Wei, AH and Pullarkat, V and Konopleva, M and Thirman, MJ and Arellano, M and Becker, PS and Chyla, B and Hong, WJ and Jiang, Q and Potluri, J and DiNardo, CD}, title = {Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.26039}, pmid = {33119898}, issn = {1096-8652}, support = {//AbbVie/ ; }, abstract = {This analysis represents the longest-term follow-up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open-label, non-randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA; 75 mg/m2 ; days 1-7) or decitabine (DEC; 20 mg/m2 ; days 1-5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi]), response duration and overall survival (OS). The median follow-up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.}, }
@article {pmid33119874, year = {2020}, author = {Kohli, K and Pillarisetty, VG}, title = {Dendritic Cells in the Tumor Microenvironment.}, journal = {Advances in experimental medicine and biology}, volume = {1273}, number = {}, pages = {29-38}, doi = {10.1007/978-3-030-49270-0_2}, pmid = {33119874}, issn = {0065-2598}, abstract = {Dendritic cells (DCs) are professional antigen-presenting cells (APCs) of the immune system. They capture foreign antigens and can present them to lymphocytes, that is, T cells and B cells, to activate them. DCs are the most potent of all immune cells at inducing the adaptive immune system. Thus, the presence of DCs at the anatomical site of the immune challenge is imperative for the immune system to mount an effective immune response. From the anatomical site of the immune challenge, DCs cargo antigens to the draining lymph nodes, specialized immune organs where adaptive immunity is generated. DCs are heterogeneous as a type of immune cell, and various subsets of DCs have been reported and their functions described. In this chapter, we discuss various aspects of DC development and function. We further discuss how various tumor microenvironments can affect DC development, function, and migration, thus evading a strong adaptive immune response.}, }
@article {pmid33119476, year = {2020}, author = {Tung, NM and Robson, ME and Ventz, S and Santa-Maria, CA and Nanda, R and Marcom, PK and Shah, PD and Ballinger, TJ and Yang, ES and Vinayak, S and Melisko, M and Brufsky, A and DeMeo, M and Jenkins, C and Domchek, S and D'Andrea, A and Lin, NU and Hughes, ME and Carey, LA and Wagle, N and Wulf, GM and Krop, IE and Wolff, AC and Winer, EP and Garber, JE}, title = {TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {38}, number = {36}, pages = {4274-4282}, doi = {10.1200/JCO.20.02151}, pmid = {33119476}, issn = {1527-7755}, abstract = {PURPOSE: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2.<br><br>METHODS: Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).<br><br>RESULTS: Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone.<br><br>CONCLUSION: PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC.}, }
@article {pmid33119063, year = {2020}, author = {Hill, JA and Dalai, SC and Hong, DK and Ahmed, AA and Ho, C and Hollemon, D and Blair, L and Maalouf, J and Keane-Candib, J and Stevens-Ayers, T and Boeckh, M and Blauwkamp, TA and Fisher, CE}, title = {Liquid biopsy for invasive mold infections in hematopoietic cell transplant recipients with pneumonia through next-generation sequencing of microbial cell-free DNA in plasma.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1639}, pmid = {33119063}, issn = {1537-6591}, support = {K23 AI119133/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Non-invasive diagnostic options are limited for invasive mold infections (IMI). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT).<br><br>METHODS: We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq NGS in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of Proven/Probable Aspergillus IMI (n=51), Proven/Probable non-Aspergillus IMI (n=24), Possible IMI (n=20), and non-IMI controls (n=19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported.<br><br>RESULTS: Among 75 patients with Proven/Probable pulmonary IMI, mcfDNA-Seq detected ≥1 pathogenic mold in 38 patients (sensitivity, 51%; 95% CI, 39%-62%). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for Proven/Probable non-Aspergillus IMI (sensitivity, 79%; 95% CI, 56%-93%) compared to Aspergillus IMI (sensitivity, 31%; 95% CI, 19%-46%). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with Possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPV) of 81%-99%. The mcfDNA-seq assay was complementary to serum GMI testing; in combination, they were positive in 84% of individuals with Proven/Probable pulmonary IMI.<br><br>CONCLUSIONS: Non-invasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus.}, }
@article {pmid33117716, year = {2020}, author = {Zhang, Y and Ma, S and Wang, M and Shi, W and Hu, Y}, title = {Comprehensive Analysis of Prognostic Markers for Acute Myeloid Leukemia Based on Four Metabolic Genes.}, journal = {Frontiers in oncology}, volume = {10}, number = {}, pages = {578933}, pmid = {33117716}, issn = {2234-943X}, abstract = {Background: Metabolic reprogramming is the core characteristic of tumors during the development of tumors, and cancer cells can rely on metabolic changes to support their rapid growth. Nevertheless, an overall analysis of metabolic markers in acute myeloid leukemia (AML) is absent and urgently needed. Methods: Within this work, genetic expression, mutation data and clinical data of AML were queried from Genotype-Tissue Expression (GTEx) database, The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database. The tumor samples of TCGA were randomly divided into a training group (64 samples) and an internal validation group (64 samples) at one time, and the tumor samples of GEO served as two external validation groups (99 samples, 374 samples). According to the expression levels of survival-associated metabolic genes, we divided all TCGA tumor samples into high, medium and low metabolism groups, and evaluated the immune cell activity in the tumor microenvironment of the three metabolism groups by single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, we examined the mutations and prognostic effects of each model gene. Results: Four metabolism-related genes were screened and applied to construct a prognostic model for AML, giving excellent results. As for the area under the curve (AUC) value of receiver operating characteristic (ROC) curve, the training group was up to 0.902 (1-year), 0.81 (3-year), and 0.877 (5-year); and the internal and external validation groups also met the expected standards, showing high potency in predicting patient outcome. Univariate and multivariate prognostic analyses indicated that the riskScore obtained from our prognostic model was an independent prognostic factor. ssGSEA analysis revealed the high metabolism group had higher immune activity. Single and multiple gene survival analysis validated that each model gene had significant effects on the overall survival of AML patients. Conclusions: In our study, a high-efficiency prognostic prediction model was built and validated for AML patients. The results showed that metabolism-related genes could become potential prognostic biomarkers for AML.}, }
@article {pmid33115946, year = {2020}, author = {Brempelis, KJ and Cowan, CM and Kreuser, SA and Labadie, KP and Prieskorn, BM and Lieberman, NAP and Ene, CI and Moyes, KW and Chinn, H and DeGolier, KR and Matsumoto, LR and Daniel, SK and Yokoyama, JK and Davis, AD and Hoglund, VJ and Smythe, KS and Balcaitis, SD and Jensen, MC and Ellenbogen, RG and Campbell, JS and Pierce, RH and Holland, EC and Pillarisetty, VG and Crane, CA}, title = {Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.}, journal = {Journal for immunotherapy of cancer}, volume = {8}, number = {2}, pages = {}, pmid = {33115946}, issn = {2051-1426}, support = {R01 CA195718/CA/NCI NIH HHS/United States ; R25 NS079200/NS/NINDS NIH HHS/United States ; S10 OD016240/OD/NIH HHS/United States ; U54 CA193461/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies.<br><br>METHODS: Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies.<br><br>RESULTS: Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins.<br><br>CONCLUSIONS: Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics.}, }
@article {pmid33115722, year = {2020}, author = {Limaye, AP and Babu, TM and Boeckh, M}, title = {Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation.}, journal = {Clinical microbiology reviews}, volume = {34}, number = {1}, pages = {}, pmid = {33115722}, issn = {1098-6618}, abstract = {SUMMARYHosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.}, }
@article {pmid33114742, year = {2020}, author = {Ding, S and Laumaea, A and Benlarbi, M and Beaudoin-Bussières, G and Gasser, R and Medjahed, H and Pancera, M and Stamatatos, L and McGuire, AT and Bazin, R and Finzi, A}, title = {Antibody Binding to SARS-CoV-2 S Glycoprotein Correlates with but Does Not Predict Neutralization.}, journal = {Viruses}, volume = {12}, number = {11}, pages = {}, pmid = {33114742}, issn = {1999-4915}, mesh = {Animals ; Antibodies, Immobilized/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/*immunology ; Betacoronavirus/*immunology ; COVID-19 ; Cell Line ; Convalescence ; Coronavirus Infections/*immunology ; HEK293 Cells ; Humans ; Neutralization Tests ; Pandemics ; Pneumonia, Viral/*immunology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/*immunology ; Time Factors ; }, abstract = {Convalescent plasma from SARS-CoV-2 infected individuals and monoclonal antibodies were shown to potently neutralize viral and pseudoviral particles carrying the S glycoprotein. However, a non-negligent proportion of plasma samples from infected individuals, as well as S-specific monoclonal antibodies, were reported to be non-neutralizing despite efficient interaction with the S glycoprotein in different biochemical assays using soluble recombinant forms of S or when expressed at the cell surface. How neutralization relates to the binding of S glycoprotein in the context of viral particles remains to be established. Here, we developed a pseudovirus capture assay (VCA) to measure the capacity of plasma samples or antibodies immobilized on ELISA plates to bind to membrane-bound S glycoproteins from SARS-CoV-2 expressed at the surface of lentiviral particles. By performing VCA, ELISA, and neutralization assays, we observed a strong correlation between these parameters. However, while we found that plasma samples unable to capture viral particles did not neutralize, capture did not guarantee neutralization, indicating that the capacity of antibodies to bind to the S glycoprotein at the surface of pseudoviral particles is required but not sufficient to mediate neutralization. Altogether, our results highlight the importance of better understanding the inactivation of S by plasma and neutralizing antibodies.}, }
@article {pmid33113206, year = {2020}, author = {Foster, RH and Hayashi, RJ and Wang, M and Liu, W and Mohrmann, C and Howell, RM and Smith, SA and Gibson, TM and Srivastava, D and Green, DM and Oeffinger, KC and Leisenring, WM and Robison, LL and Armstrong, GT and Krull, KR and Hardy, KK}, title = {Psychological, educational, and social late effects in adolescent survivors of Wilms tumor: A report from the Childhood Cancer Survivor Study.}, journal = {Psycho-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/pon.5584}, pmid = {33113206}, issn = {1099-1611}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; CA21765//Cancer Center Support (CORE) Grant/ ; CA55727, GTA/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor.<br><br>METHODS: Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis.<br><br>RESULTS: Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40).<br><br>CONCLUSIONS: Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.}, }
@article {pmid33110068, year = {2020}, author = {Hurlburt, NK and Seydoux, E and Wan, YH and Edara, VV and Stuart, AB and Feng, J and Suthar, MS and McGuire, AT and Stamatatos, L and Pancera, M}, title = {Structural basis for potent neutralization of SARS-CoV-2 and role of antibody affinity maturation.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {5413}, pmid = {33110068}, issn = {2041-1723}, mesh = {Angiotensin-Converting Enzyme 2 ; Antibodies, Blocking/chemistry/immunology ; Antibodies, Monoclonal/chemistry/immunology ; Antibodies, Neutralizing/*chemistry/*immunology ; *Antibody Affinity ; Betacoronavirus/*immunology ; COVID-19 ; Coronavirus Infections/immunology ; Crystallography, X-Ray ; Epitopes, B-Lymphocyte ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Models, Molecular ; Pandemics ; Peptidyl-Dipeptidase A/chemistry/metabolism ; Pneumonia, Viral/immunology ; Protein Interaction Domains and Motifs ; Protein Subunits ; SARS-CoV-2 ; Somatic Hypermutation, Immunoglobulin ; Spike Glycoprotein, Coronavirus/chemistry/immunology ; }, abstract = {SARS-CoV-2 is a betacoronavirus virus responsible for the COVID-19 pandemic. Here, we determine the X-ray crystal structure of a potent neutralizing monoclonal antibody, CV30, isolated from a patient infected with SARS-CoV-2, in complex with the receptor binding domain. The structure reveals that CV30 binds to an epitope that overlaps with the human ACE2 receptor binding motif providing a structural basis for its neutralization. CV30 also induces shedding of the S1 subunit, indicating an additional mechanism of neutralization. A germline reversion of CV30 results in a substantial reduction in both binding affinity and neutralization potential indicating the minimal somatic mutation is needed for potently neutralizing antibodies against SARS-CoV-2.}, }
@article {pmid33110042, year = {2020}, author = {Nudy, M and Jiang, X and Aragaki, AK and Manson, JE and Shadyab, AH and Foy, AJ and Buerger, J and Kelsey, AM and LeBlanc, ES and Wild, RA and Wactawski-Wende, J and Stefanick, ML and Robbins, JA and Schnatz, PF}, title = {The severity of vasomotor symptoms and number of menopausal symptoms in postmenopausal women and select clinical health outcomes in the Women's Health Initiative Calcium and Vitamin D randomized clinical trial.}, journal = {Menopause (New York, N.Y.)}, volume = {27}, number = {11}, pages = {1265-1273}, doi = {10.1097/GME.0000000000001667}, pmid = {33110042}, issn = {1530-0374}, abstract = {OBJECTIVE: This study evaluated whether vasomotor symptom (VMS) severity and number of moderate/severe menopausal symptoms (nMS) were associated with health outcomes, and whether calcium and vitamin D (CaD) modified the risks.<br><br>METHODS: The Women's Health Initiative CaD study was a double blind, randomized, placebo-controlled trial, which tested 400 IU of 25-hydroxyvitamin-D and 1,000 mg of calcium per day in women aged 50 to 79 years. This study included 20,050 women (median follow-up of 7 y). The outcomes included hip fracture, colorectal cancer, invasive breast cancer, all-cause mortality, coronary heart disease, stroke, cardiovascular death, and total cardiovascular disease (CVD). MS included: hot flashes, night sweats, dizziness, heart racing, tremors, feeling restless, feeling tired, difficulty concentrating, forgetfulness, mood swings, vaginal dryness, breast tenderness, migraine, and waking up several times at night. Associations between VMS severity and nMS with outcomes were tested.<br><br>RESULTS: No association between VMS severity and any outcome were found. In contrast, nMS was associated with higher stroke (hazard ratio [HR] 1.40 95% confidence interval [CI] 1.04-1.89 for ≥ 2 MS vs none; HR 1.20 95% CI 0.89-1.63 for 1 MS vs none, P trend = 0.03) and total CVD (HR 1.35, 95% CI, 1.18-1.54 for ≥ 2 MS vs none; HR 0.99, 95% CI, 0.87-1.14 for 1 MS vs none P trend < 0.001). CaD did not modify any association.<br><br>CONCLUSION: Severity of VMS was not associated with any outcome. Having ≥2 moderate or severe MS was associated with an increased risk for CVD. The number of moderate/severe MS may be a marker for higher CVD risk. : Video Summary:http://links.lww.com/MENO/A669.}, }
@article {pmid33107562, year = {2020}, author = {Mitchell, CM and Srinivasan, S and Ma, N and Reed, SD and Wu, MC and Hoffman, NG and Valint, DJ and Proll, S and Fiedler, TL and Agnew, KJ and Guthrie, KA and Fredricks, DN}, title = {Bacterial communities associated with abnormal Nugent score are different in pre- versus postmenopausal women.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaa675}, pmid = {33107562}, issn = {1537-6613}, abstract = {Nugent score is the gold standard for bacterial vaginosis (BV) diagnosis but has not been validated in postmenopausal women. We compared relative abundances from 16S rRNA gene sequencing of vaginal microbiota with Nugent score in cohorts of premenopausal (n = 220) and postmenopausal (n = 144) women. In premenopausal women 33 taxa were significantly correlated with Nugent score, including the classic BV-associated taxa Gardnerella, Atopobium, Sneathia, Megasphaera and Prevotella. In postmenopausal women, 11 taxa were significantly associated with Nugent score, including Prevotella but no other BV-associated genera. High Nugent score should not be used to infer BV in postmenopausal women.}, }
@article {pmid33106923, year = {2020}, author = {Wrenn, ED and Moore, BM and Greenwood, E and McBirney, M and Cheung, KJ}, title = {Optimal, Large-Scale Propagation of Mouse Mammary Tumor Organoids.}, journal = {Journal of mammary gland biology and neoplasia}, volume = {}, number = {}, pages = {}, pmid = {33106923}, issn = {1573-7039}, support = {W81XWH-18-1-0098//U.S. Department of Defense/ ; R37CA234488/NH/NIH HHS/United States ; 1013355.01//Burroughs Wellcome Fund/ ; NA//Phi Beta Psi/ ; BCRF-18-035//Breast Cancer Research Foundation/ ; V2017-014//V Foundation for Cancer Research/ ; }, abstract = {Tumor organoids mimic the architecture and heterogeneity of in vivo tumors and enable studies of collective interactions between tumor cells as well as with their surrounding microenvironment. Although tumor organoids hold significant promise as cancer models, they are also more costly and labor-intensive to cultivate than traditional 2D cell culture. We sought to identify critical factors regulating organoid growth ex vivo, and to use these observations to develop a more efficient organoid expansion method. Using time-lapse imaging of mouse mammary tumor organoids in 3D culture, we observed that outgrowth potential varies non-linearly with initial organoid size. Maximal outgrowth occurred in organoids with a starting size between ~10 to 1000 cells. Based on these observations, we developed a suspension culture method that maintains organoids in the ideal size range, enabling expansion from 1 million to over 100 million cells in less than 2 weeks and less than 3 hours of hands-on time. Our method facilitates the rapid, cost-effective expansion of organoids for CRISPR based studies and other assays requiring a large amount of organoid starting material.}, }
@article {pmid33106847, year = {2020}, author = {Schoenherr, RM and Voytovich, UJ and Whiteaker, JR and Gadi, VK and Gralow, JR and Paulovich, AG}, title = {Quantification of Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 Protein Expression in Bone Biopsies by Targeted Mass Spectrometry without Acid Decalcification.}, journal = {Clinical chemistry}, volume = {66}, number = {11}, pages = {1459-1461}, doi = {10.1093/clinchem/hvaa220}, pmid = {33106847}, issn = {1530-8561}, }
@article {pmid33105471, year = {2020}, author = {Shelton, EM and Reeves, DB and Bender Ignacio, RA}, title = {Initiation of Antiretroviral Therapy during Primary HIV Infection: Effects on the Latent HIV Reservoir, Including on Analytic Treatment Interruptions.}, journal = {AIDS reviews}, volume = {23}, number = {3}, pages = {}, doi = {10.24875/AIDSRev.20000001}, pmid = {33105471}, issn = {1698-6997}, abstract = {Antiretroviral therapy (ART) inhibits HIV replication but does not eradicate the latent reservoir. The previous research suggests that earlier ART initiation provides benefit on limiting reservoir size, but timing and extent of this effect remain unclear. Analytic treatment interruption (ATI) may be used to demonstrate HIV remission, but whether early ART also improves likelihood or duration of even temporary virologic remission is unclear. This review seeks to answer both questions. We performed a systematic review and analysis following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and included 21 interventional or observational studies with sufficient HIV reservoir outcomes. We also aggregated reservoir outcomes and transformed data into approximate measurements of total HIV DNA per million peripheral blood mononuclear cells and analyzed the correlation between timing of ART initiation and reservoir size. People living with HIV who initiate ART in primary infection maintain smaller reservoirs on suppressive ART than those who initiate treatment during chronic infection. The reduction of reservoir is most pronounced when ART is started within 2 weeks of HIV acquisition. Across studies, we found a moderately strong association between longer time to ART initiation and reservoir size, which was strongest when measured after 1 year on ART (Pearson's r = 0.69, p = 0.0003). After ATI, larger pre-ATI reservoir size predicts shorter time to viral rebound. Early ART may also facilitate long-term control of viremia. Although achieving sustained HIV remission will require further interventions, initiating ART very early in infection could limit the extent of the reservoir and also lead to post-ATI control in rare cases.}, }
@article {pmid33105469, year = {2020}, author = {Strope, JD and Lochrin, SE and Sissung, TM and Kem, R and Chandrasekaran, P and Sharon, E and Price, DK and Uldrick, TS and Yarchoan, R and Figg, WD}, title = {Drug-drug Interactions in Patients with HIV and Cancer in Sub-Saharan Africa.}, journal = {AIDS reviews}, volume = {23}, number = {3}, pages = {}, doi = {10.24875/AIDSRev.20000005}, pmid = {33105469}, issn = {1698-6997}, abstract = {In Sub-Saharan Africa, the cancer burden is predicted to increase by > 85% by 2030, the largest increase worldwide. This region has a large HIV-positive population. Drug-drug interactions (DDIs) from concomitant use of multiple drugs increase the risk of drug toxicities, sub-optimal therapy, and drug resistance. With the increase in polypharmacy, involving antiretroviral (ARV), and anticancer drugs, there is a greater need for an appreciation of clinically relevant DDIs. Anticancer and ARV drugs studied in this review were from The World Health Organization's Model List of Essential Medicines 2017. We reviewed; drug package inserts, www.drugbank.ca and www.UpToDate.com, to evaluate pharmacokinetic interactions with cytochrome P450 (CYP450) and ABCB1. The DDIs between drugs were assessed using the University Of Liverpool, UK HIV Drug Interactions Checker, and the LexiComp Drug Interaction tool of www.UpToDate.com. About 70% of ARVs studied interact with CYP450, all involve CYP3A4, and 55% interact with ABCB1. About 65% of anticancer drugs interact with CYP450, 44% of which do so through CYP3A4. About 75% of anticancer drugs interact with ARV drugs, with nine absolute contraindications to concomitant therapy. There exist a substantial number of DDIs between ARV and anticancer drugs, primarily mediated through CYP450 enzymes. Dolutegravir based regimens offer the safest DDI profile for concurrent use with anticancer drugs. However, there are substantial gaps in our knowledge, and this study serves to highlight the need for additional research to better define these interactions and their effect on drug exposure, as attention to these DDIs is a relatively simple intervention that could lead to optimizing disease treatment.}, }
@article {pmid33105052, year = {2020}, author = {Jordan, SJ and Na, R and Weiderpass, E and Adami, HO and Anderson, KE and van den Brandt, PA and Brinton, LA and Chen, C and Cook, LS and Doherty, JA and Du, M and Friedenreich, CM and Gierach, GL and Goodman, MT and Krogh, V and Levi, F and Lu, L and Miller, AB and McCann, SE and Moysich, KB and Negri, E and Olson, SH and Petruzella, S and Palmer, JR and Parazzini, F and Pike, MC and Prizment, AE and Rebbeck, TR and Reynolds, P and Ricceri, F and Risch, HA and Rohan, TE and Sacerdote, C and Schouten, LJ and Serraino, D and Setiawan, VW and Shu, XO and Sponholtz, TR and Spurdle, AB and Stolzenberg-Solomon, RZ and Trabert, B and Wentzensen, N and Wilkens, LR and Wise, LA and Yu, H and La Vecchia, C and De Vivo, I and Xu, W and Zeleniuch-Jacquotte, A and Webb, PM}, title = {Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33360}, pmid = {33105052}, issn = {1097-0215}, support = {N01-CN-55424/CA/NCI NIH HHS/United States ; R01 CA74877/NH/NIH HHS/United States ; APP1061341//National Health and Medical Research Council/ ; P20-CA-57113//U.S. Public Health Service/ ; R03 CA169888/CA/NCI NIH HHS/United States ; R01-CA-55700//U.S. Public Health Service/ ; //Intramural Research Program of the National Cancer Institute/National Institutes of Health, Department of Health and Human Services, United States/ ; 521-2011-2955//Vetenskapsrådet/ ; //KWF Kankerbestrijding/ ; //Italian League Against Cancer/ ; P01-CA-33619//U.S. Public Health Service/ ; R01 CA39742/CA/NCI NIH HHS/United States ; /CAPMC/CIHR/Canada ; //Medical Research Council Canada/ ; GNT 1073898//National Health and Medical Research Council/ ; APP1073898//National Health and Medical Research Council/ ; APP339435//National Health and Medical Research Council/ ; P30 CA016087/CA/NCI NIH HHS/United States ; ID 1061778//National Health and Medical Research Council/ ; 2R01 CA082838/CA/NCI NIH HHS/United States ; //Canadian Breast Cancer Research Alliance/ ; R01 CA77398/CA/NCI NIH HHS/United States ; P30CA118100/CA/NCI NIH HHS/United States ; R35 CA39779/CA/NCI NIH HHS/United States ; RO3 CA135632/CA/NCI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; R01-CA-58598//U.S. Public Health Service/ ; //Health and Welfare Canada/ ; //Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; APP1061779//National Health and Medical Research Council/ ; R01 CA098346/CA/NCI NIH HHS/United States ; N01 HD 2 31/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA081212/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; CA11535/CA/NCI NIH HHS/United States ; R01 CA039742/CA/NCI NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 CA47749/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; 32.9495.88//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; R01 CA75977/CA/NCI NIH HHS/United States ; //National Cancer Institute of Canada/ ; R01 CA092585/CA/NCI NIH HHS/United States ; N01-CN-05223/CA/NCI NIH HHS/United States ; U01 CA182934/CA/NCI NIH HHS/United States ; 403031//Cancer Council Tasmania/ ; //Nova Scotia Department of Health/ ; P30CA016056/CA/NCI NIH HHS/United States ; //California Department of Public Health/ ; U01 CA164973/CA/NCI NIH HHS/United States ; 457636//Cancer Council Tasmania/ ; P01-CA77596/CA/NCI NIH HHS/United States ; //Alberta Heritage Foundation for Medical Research/ ; P30 CA14089/CA/NCI NIH HHS/United States ; //le Ministère de la Santé et des Services Soçiaux du Québec/ ; //Associazione Italiana per la Ricerca sul Cancro/ ; //Ontario Ministry of Health/ ; //Canadian Cancer Society/ ; R01 CA48774/CA/NCI NIH HHS/United States ; //Manitoba Health Services Commission/ ; OCS 1633-02-2005//Krebsforschung Schweiz Stiftung/ ; }, abstract = {A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.}, }
@article {pmid33104437, year = {2020}, author = {Persky, DO and Smith, SM and LeBlanc, ML and Friedberg, JW}, title = {Reply to E. Hawkes et al.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {38}, number = {35}, pages = {4222-4223}, doi = {10.1200/JCO.20.02856}, pmid = {33104437}, issn = {1527-7755}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; }, }
@article {pmid33104186, year = {2020}, author = {Fang, FC and Benson, CA and Del Rio, C and Edwards, KM and Fowler, VG and Fredricks, DN and Limaye, AP and Murray, BE and Naggie, S and Pappas, PG and Patel, R and Paterson, DL and Pegues, DA and Petri, WA and Schooley, RT}, title = {COVID-19 - Lessons Learned and Questions Remaining.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1654}, pmid = {33104186}, issn = {1537-6591}, abstract = {In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.}, }
@article {pmid33103025, year = {2020}, author = {Carbone, L and Vasan, S and Elam, R and Gupta, S and Tolaymat, O and Crandall, C and Wactawski-Wende, J and Johnson, KC}, title = {The Association of Methotrexate, Sulfasalazine, and Hydroxychloroquine Use With Fracture in Postmenopausal Women With Rheumatoid Arthritis: Findings From the Women's Health Initiative.}, journal = {JBMR plus}, volume = {4}, number = {10}, pages = {e10393}, pmid = {33103025}, issn = {2473-4039}, support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; HHSN268201100003I/HL/NHLBI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; }, abstract = {This study was conducted to evaluate the extent to which disease-modifying antirheumatic medications (DMARDs) used as part of a triple therapy for the treatment of rheumatoid arthritis (RA) including methotrexate, sulfasalazine, and hydroxychloroquine are associated with fractures in postmenopausal women with RA. Incident fractures following use of methotrexate, sulfasalazine, and/or hydroxychloroquine in postmenopausal women with RA in the Women's Health Initiative were estimated by Cox proportional hazards using hazard ratios (HRs) and 95% CIs after consideration of potential confounders. There were 1201 women with RA enrolled in the Women's Health Initiative included in these analyses, of which 74% were white, 17% were black, and 9% were of other or unknown race/ethnicity. Of the women with RA, 421 (35%) had not used methotrexate, sulfasalazine, or hydroxychloroquine, whereas 519 (43%) women had used methotrexate, 83 (7%) sulfasalazine, and 363 (30%) hydroxychloroquine alone or in combination at some time during study follow-up. Over a median length of 6.46 years of follow-up, in multivariable adjusted models, no statistically significant association was found between methotrexate (HR, 1.1; 95% CI, 0.8-1.6), sulfasalazine (HR, 0.6; 95% CI, 0.2-1.5), or hydroxychloroquine (HR, 1.0; 95% CI, 0.7-1.5) use and incident fractures or between combination therapy with methotrexate and sulfasalazine or methotrexate and hydroxychloroquine use (HR, 0.9; 95% CI, 0.5-1.6) and incident fractures. In conclusion, postmenopausal women with RA receiving any component of triple therapy should not be expected to have any substantial reduction in fracture risk from use of these DMARDs. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.}, }
@article {pmid33101740, year = {2020}, author = {Klocke, H and Dong, ZM and O'Brien, C and Burwick, N and Richard, RE and Wu, DY and Chauncey, TR and Graf, SA}, title = {Venetoclax and Decitabine for T/Myeloid Mixed-Phenotype Acute Leukemia Not Otherwise Specified (MPAL NOS).}, journal = {Case reports in hematology}, volume = {2020}, number = {}, pages = {8811673}, pmid = {33101740}, issn = {2090-6560}, abstract = {T/myeloid mixed-phenotype acute leukemia not otherwise specified (MPAL NOS) is an uncommon and aggressive leukemia without well-established treatment guidelines, particularly when relapsed. Venetoclax plus a hypomethylating agent offers a promising option in this situation since studies support its use in both acute myeloid and, albeit with fewer data to date, acute T-cell-lymphoblastic leukemias. We report the successful eradication of T/myeloid MPAL NOS relapsed after allogeneic stem cell transplant with venetoclax plus decitabine. A consolidative allogeneic stem cell transplant from a second donor was subsequently performed, and the patient remained without evidence of disease more than one year later. Further investigation is indicated to evaluate venetoclax combined with hypomethylating agents and/or other therapies for the management of T/myeloid MPAL NOS.}, }
@article {pmid33101525, year = {2020}, author = {Chen, YQ}, title = {Introduction to Special Issue on 'Statistical Methods for HIV/AIDS Research'.}, journal = {Statistics in biosciences}, volume = {}, number = {}, pages = {1-4}, pmid = {33101525}, issn = {1867-1764}, support = {R01 AI121259/AI/NIAID NIH HHS/United States ; R01 MH105857/MH/NIMH NIH HHS/United States ; R56 AI140953/AI/NIAID NIH HHS/United States ; }, }
@article {pmid33098265, year = {2020}, author = {Joshi, M and Grivas, P and Mortazavi, A and Monk, P and Clinton, SK and Sue-Ann Woo, M and Holder, SL and Drabick, JJ and Yin, M}, title = {Alterations of DNA damage response genes correlate with response and overall survival in anti-PD-1/PD-L1-treated advanced urothelial cancer.}, journal = {Cancer medicine}, volume = {9}, number = {24}, pages = {9365-9372}, doi = {10.1002/cam4.3552}, pmid = {33098265}, issn = {2045-7634}, support = {//OSU Startup Fund/ ; }, abstract = {DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti-PD-1/PD-L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti-PD-1/PD-L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum-based chemotherapy. DDR alterations (including ATM) were associated with a non-significantly higher ORR to PD-1/PD-L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non-significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20-1.38, p = 0.19). ATM alterations were associated with a non-significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65-19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD-1/PD-L1 blockade versus 24% ORR in patients with <3 DDR alterations. In summary, DDR alterations were associated with non-significantly higher ORR and longer OS for patients with advanced UC receiving anti-PD-1/PD-L1 agents. ATM alterations were associated with shorter OS.}, }
@article {pmid33097472, year = {2020}, author = {Goyal, A and Cardozo-Ojeda, EF and Schiffer, JT}, title = {Potency and timing of antiviral therapy as determinants of duration of SARS-CoV-2 shedding and intensity of inflammatory response.}, journal = {Science advances}, volume = {6}, number = {47}, pages = {}, pmid = {33097472}, issn = {2375-2548}, support = {R01 AI121129/AI/NIAID NIH HHS/United States ; 5R01AI121129-05/NH/NIH HHS/United States ; }, mesh = {Adenosine Monophosphate/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; Adoptive Transfer/*methods ; Alanine/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; Antibodies, Viral/*therapeutic use ; Antiviral Agents/pharmacokinetics/*therapeutic use ; Broadly Neutralizing Antibodies/*therapeutic use ; COVID-19/*drug therapy/immunology/virology ; Cell- and Tissue-Based Therapy/*methods ; Humans ; Hydrazines/*therapeutic use ; Killer Cells, Natural/immunology ; Models, Theoretical ; SARS-CoV-2/*physiology ; Time Factors ; Treatment Outcome ; Triazoles/*therapeutic use ; Viral Load/drug effects ; Virus Shedding/*drug effects ; }, abstract = {To affect the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies, or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop may decrease shedding duration and immune response intensity but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed before viral peak during presymptomatic infection could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration, not AUC, is most predictive of clinical severity.}, }
@article {pmid33096099, year = {2020}, author = {Corley, DA and Sedki, M and Ritzwoller, DP and Greenlee, RT and Neslund-Dudas, C and Rendle, KA and Honda, SA and Schottinger, JE and Udaltsova, N and Vachani, A and Kobrin, S and Li, CI and Haas, JS}, title = {Cancer Screening during COVID-19: A Perspective from NCI's PROSPR consortium.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2020.10.030}, pmid = {33096099}, issn = {1528-0012}, }
@article {pmid33095916, year = {2020}, author = {Sanchez, JI and Shankaran, V and Unger, JM and Madeleine, MM and Selukar, SR and Thompson, B}, title = {Inequitable access to surveillance colonoscopy among Medicare beneficiaries with surgically resected colorectal cancer.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33262}, pmid = {33095916}, issn = {1097-0142}, support = {T32 HS013853/HS/AHRQ HHS/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: After colorectal cancer (CRC) surgery, surveillance with colonoscopy is an important step for the early detection of local recurrence. Unfortunately, surveillance colonoscopy is underused, especially among racial/ethnic minorities. This study assesses the association between patient and neighborhood factors and receipt of surveillance colonoscopy.<br><br>METHODS: This retrospective, population-based cohort study used Surveillance, Epidemiology, and End Results-Medicare linked data (2009-2014). Beneficiaries with surgically resected stage II or III CRC between the ages of 66 and 85 years were identified, and multivariable logistic regression was used to assess the effect of factors on receipt of colonoscopy.<br><br>RESULTS: Overall, 57.5% of the patients received initial surveillance colonoscopy. After adjustments for all factors, Blacks and Hispanics had lower odds of receiving colonoscopy than non-Hispanic Whites (NHWs; 29.6% for Blacks; P = .002; 12.9% for Hispanics; P > .05). NHWs with Medicaid coverage had 35% lower odds of surveillance colonoscopy than NHWs without Medicaid coverage. Minority patients with Medicaid were more likely to receive colonoscopy than their racial/ethnic counterparts without Medicaid coverage (P > .05). Hispanics residing in neighborhoods with incomes of ≥$90,000 had significantly lower odds of surveillance colonoscopy than Hispanics residing in neighborhoods with incomes of $0 to $30,000.<br><br>CONCLUSIONS: Receipt of initial surveillance colonoscopy remains low, and there are acute disparities between Black and NHW patients. The association between factors that assess a patient's ability to access colonoscopy and actual receipt of colonoscopy suggests inequitable access to surveillance colonoscopy within and across racial/ethnic groups.}, }
@article {pmid33095855, year = {2020}, author = {Minab, R and Bu, W and Nguyen, H and Wall, A and Sholukh, AM and Huang, ML and Ortego, M and Krantz, EM and Irvine, M and Casper, C and Orem, J and McGuire, AT and Cohen, JI and Gantt, S}, title = {Maternal Epstein-Barr virus-specific antibodies and risk of infection in Ugandan infants.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaa654}, pmid = {33095855}, issn = {1537-6613}, abstract = {BACKGROUND: Epstein-Barr virus (EBV) infection is a major cause of malignancy worldwide. Maternal antibody is thought to prevent EBV infection because it is uncommon in early infancy. Maternal HIV infection is associated with an increased incidence of EBV infection in exposed infants, which we hypothesized results from impaired transfer of EBV-neutralizing maternal antibodies.<br><br>METHODS: Among Ugandan infants followed for EBV acquisition from birth, we measured antibody binding to EBV glycoproteins (e.g., gp350, gH/gL) involved in B cell and epithelial cell entry, as well as viral neutralization and antibody-dependent cellular cytotoxicity (ADCC) activity in plasma samples prior to infection. These serologic data were analyzed for differences between HIV-exposed uninfected (HEU) and unexposed (HUU) infants, and for associations with incident infant EBV infection.<br><br>RESULTS: HEU infants had significantly higher titers than HUU infants for all EBV-binding and neutralizing antibodies measured (p<0.01), but not ADCC activity, which was similar between groups. No antibody measure was associated with a decreased risk of EBV acquisition in the cohort.<br><br>CONCLUSIONS: Our findings indicate that in this cohort maternal antibody did not protect infants against EBV infection through viral neutralization. The identification of protective non-neutralizing antibody functions would be invaluable for the development of an EBV vaccine.}, }
@article {pmid33094113, year = {2020}, author = {Liu, C and Lan, K and Krantz, EM and Kim, HN and Zier, J and Bryson-Cahn, C and Chan, JD and Jain, R and Lynch, JB and Pergam, SA and Pottinger, PS and Sweet, A and Whimbey, E and Bryan, A}, title = {Improving Appropriate Diagnosis of Clostridioides difficile Infection Through an Enteric Pathogen Order Set With Computerized Clinical Decision Support: An Interrupted Time Series Analysis.}, journal = {Open forum infectious diseases}, volume = {7}, number = {10}, pages = {ofaa366}, pmid = {33094113}, issn = {2328-8957}, abstract = {Background: Inappropriate testing for Clostridioides difficile leads to overdiagnosis of C difficile infection (CDI). We determined the effect of a computerized clinical decision support (CCDS) order set on C difficile polymerase chain reaction (PCR) test utilization and clinical outcomes.<br><br>Methods: This study is an interrupted time series analysis comparing C difficile PCR test utilization, hospital-onset CDI (HO-CDI) rates, and clinical outcomes before and after implementation of a CCDS order set at 2 academic medical centers: University of Washington Medical Center (UWMC) and Harborview Medical Center (HMC).<br><br>Results: Compared with the 20-month preintervention period, during the 12-month postimplementation of the CCDS order set, there was an immediate and sustained reduction in C difficile PCR test utilization rates at both hospitals (HMC, -28.2% [95% confidence interval {CI}, -43.0% to -9.4%], P = .005; UWMC, -27.4%, [95% CI, -37.5% to -15.6%], P < .001). There was a significant reduction in rates of C difficile tests ordered in the setting of laxatives (HMC, -60.8% [95% CI, -74.3% to -40.1%], P < .001; UWMC, -37.3%, [95% CI, -58.2% to -5.9%], P = .02). The intervention was associated with an increase in the C difficile test positivity rate at HMC (P = .01). There were no significant differences in HO-CDI rates or in the proportion of patients with HO-CDI who developed severe CDI or CDI-associated complications including intensive care unit transfer, extended length of stay, 30-day mortality, and toxic megacolon.<br><br>Conclusions: Computerized clinical decision support tools can improve C difficile diagnostic test stewardship without causing harm. Additional studies are needed to identify key elements of CCDS tools to further optimize C difficile testing and assess their effect on adverse clinical outcomes.}, }
@article {pmid33093682, year = {2020}, author = {Overbaugh, J}, title = {Understanding protection from SARS-CoV-2 by studying reinfection.}, journal = {Nature medicine}, volume = {26}, number = {11}, pages = {1680-1681}, doi = {10.1038/s41591-020-1121-z}, pmid = {33093682}, issn = {1546-170X}, support = {AI138709//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/International ; }, mesh = {Antibodies, Viral/analysis/blood ; Biomedical Research/methods ; COVID-19/epidemiology/*immunology/prevention &amp; control/virology ; Contact Tracing ; Disease Susceptibility ; Humans ; Immunity/*physiology ; Pandemics ; *Reinfection/diagnosis/epidemiology/immunology ; SARS-CoV-2/immunology/*physiology ; }, }
@article {pmid33093209, year = {2020}, author = {Diab, A and Gem, H and Swanger, J and Kim, HY and Smith, K and Zou, G and Raju, S and Kao, M and Fitzgibbon, M and Loeb, KR and Rodriguez, CP and Méndez, E and Galloway, DA and Sidorova, JM and Clurman, BE}, title = {FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {45}, pages = {28287-28296}, pmid = {33093209}, issn = {1091-6490}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA193808/CA/NCI NIH HHS/United States ; R01 CA215647/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; }, abstract = {Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.}, }
@article {pmid33093162, year = {2020}, author = {Grady, WM and Yu, M and Markowitz, SD and Chak, A}, title = {Barrett's Esophagus and Esophageal Adenocarcinoma Biomarkers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {29}, number = {12}, pages = {2486-2494}, pmid = {33093162}, issn = {1538-7755}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; U54 CA143862/CA/NCI NIH HHS/United States ; P30 DK097948/DK/NIDDK NIH HHS/United States ; R01 CA194663/CA/NCI NIH HHS/United States ; P50 CA150964/CA/NCI NIH HHS/United States ; U01 CA086402/CA/NCI NIH HHS/United States ; R50 CA233042/CA/NCI NIH HHS/United States ; U01 CA182940/CA/NCI NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; U54 CA163060/CA/NCI NIH HHS/United States ; }, abstract = {Esophageal adenocarcinoma is a major cause of cancer-related morbidity and mortality in Western countries. The incidences of esophageal adenocarcinoma and its precursor Barrett's esophagus have increased substantially in the last four decades. Current care guidelines recommend that endoscopy be used for the early detection and monitoring of patients with Barrett's esophagus; however, the efficacy of this approach is unclear. To prevent the increasing morbidity and mortality from esophageal adenocarcinoma, there is a tremendous need for early detection and surveillance biomarker assays that are accurate, low-cost, and clinically feasible to implement. The last decade has seen remarkable advances in the development of minimally invasive molecular biomarkers, an effort led in large part by the Early Detection Research Network (EDRN). Advances in multi-omics analysis, the development of swallowable cytology collection devices, and emerging technology have led to promising assays that are likely to be implemented into clinical care in the next decade. In this review, an updated overview of the molecular pathology of Barrett's esophagus and esophageal adenocarcinoma and emerging molecular biomarker assays, as well as the role of EDRN in biomarker discovery and validation, will be discussed.See all articles in this CEBP Focus section, &quot;NCI Early Detection Research Network: Making Cancer Detection Possible.&quot;}, }
@article {pmid33093159, year = {2020}, author = {McDougall, JA and Cook, LS and Tang, MC and Linden, HM and Thompson, B and Li, CI}, title = {Determinants of Guideline-Discordant Breast Cancer Care.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-20-0985}, pmid = {33093159}, issn = {1538-7755}, abstract = {BACKGROUND: Evidence-based breast cancer treatment guidelines recommend the most appropriate course of therapy based on tumor characteristics and extent of disease. Evaluating the multilevel factors associated with guideline discordance is critical to identifying strategies to eliminate breast cancer survival disparities.<br><br>METHODS: We identified females diagnosed with a first primary, stage I-III breast cancer between the ages of 20-69 years of age from the population-based Seattle-Puget Sound Surveillance, Epidemiology, and End Results registry. Participants completed a survey about social support, utilization of patient support services, hypothesized barriers to care, and initiation of breast cancer treatment. We used logistic regression to estimate odds ratios and 95% confidence intervals (CI).<br><br>RESULTS: Among 1,390 participants, 10% reported guideline-discordant care. In analyses adjusted for patient-level sociodemographic factors, individuals who did not have someone to go with them to appointments or drive them home (OR 1.96; 95% CI, 1.09-3.59) and those who had problems talking to their doctors or their staff (OR 2.03; 95% CI, 1.13-3.64) were more likely to be guideline discordant than those with social support or without such problems, respectively. Use of patient support services was associated with a 43% lower odds of guideline discordance (OR 0.57; 95% CI, 0.36-0.88).<br><br>CONCLUSIONS: Although guideline discordance in this cohort of early-stage breast cancer survivors diagnosed <70 years of age was low, instrumental social support, patient support services, and communication with doctors and their staff emerged as potential multilevel intervention targets for improving breast cancer care delivery.<br><br>IMPACT: This study supports extending the reach of interventions designed to improve guideline concordance.}, }
@article {pmid33093149, year = {2020}, author = {Gao, C and Wisniewski, L and Liu, Y and Staal, B and Beddows, I and Plenker, D and Aldakkak, M and Hall, J and Barnett, D and Gouda, MK and Allen, P and Drake, R and Zureikat, A and Huang, Y and Evans, D and Singhi, A and Brand, RE and Tuveson, DA and Tsai, S and Haab, BB}, title = {Detection of Chemotherapy-resistant Pancreatic Cancer Using a Glycan Biomarker, sTRA.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-20-2475}, pmid = {33093149}, issn = {1557-3265}, abstract = {PURPOSE: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose.<br><br>EXPERIMENTAL DESIGN: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects.<br><br>RESULTS: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy.<br><br>CONCLUSIONS: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.}, }
@article {pmid33091364, year = {2020}, author = {Buchbinder, SP and McElrath, MJ and Dieffenbach, C and Corey, L}, title = {Use of adenovirus type-5 vectored vaccines: a cautionary tale.}, journal = {Lancet (London, England)}, volume = {396}, number = {10260}, pages = {e68-e69}, doi = {10.1016/S0140-6736(20)32156-5}, pmid = {33091364}, issn = {1474-547X}, mesh = {Adenoviridae/genetics ; *Adenovirus Vaccines ; Betacoronavirus ; COVID-19 ; COVID-19 Vaccines ; *Coronavirus Infections/prevention &amp; control ; Genetic Vectors ; Humans ; *Pandemics ; *Pneumonia, Viral ; SARS-CoV-2 ; Vaccines, Synthetic ; *Viral Vaccines ; }, }
@article {pmid33090897, year = {2020}, author = {Winestone, LE and Hochman, LL and Sharpe, JE and Alvarez, E and Becker, L and Chow, EJ and Reiter, JG and Ginsberg, JP and Silber, JH}, title = {Impact of Dependent Coverage Provision of the Affordable Care Act on Insurance Continuity for Adolescents and Young Adults With Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2000330}, doi = {10.1200/OP.20.00330}, pmid = {33090897}, issn = {2688-1535}, abstract = {PURPOSE: The 2010 Dependent Coverage Provision (DCP) of the Affordable Care Act (ACA) allowed enrollees to remain on their parents' health insurance until 26 years of age. We compared rates of insurance disenrollment among patients with cancer who were DCP-eligible at age 19 to those who were not eligible at age 19.<br><br>METHODS: Using OptumLabs Data Warehouse, which contains longitudinal, real-world, de-identified administrative claims for commercial enrollees, we examined patients born between 1982 and 1993 and diagnosed with cancer between 2000 and 2015. In the recent cohort, patients who turned 19 in 2010-2012 (DCP-eligible to stay on parents' insurance) were matched to patients who turned 19 in 2007-2009 (not DCP-eligible when turning 19). In an earlier control cohort, patients who turned 19 between 2004 and 2006 (not DCP-eligible) were matched to patients who turned 19 between 2001 and 2003 (not DCP-eligible). Patients were matched on cancer type, diagnosis date, demographics, and treatment characteristics. The time to loss of coverage was estimated using Cox models. Difference-in-difference between the recent and earlier cohorts was also evaluated.<br><br>RESULTS: A total of 2,829 patients who turned 19 years of age in 2010-2012 were matched to patients who turned 19 in 2007-2009. Median time to disenrollment was 26 months for younger patients versus 22 months for older patients (hazard ratio [HR], 0.85; 95% CI, 0.80 to 0.90; P = .001). In 8,978 patients who turned 19 between 2001 and 2006, median time to disenrollment was 20 months among both younger and older patients (HR, 0.99; 95% CI, 0.94 to 1.03; P = .59). The difference between the recent cohort and the earlier control cohort was a 15% greater reduction in coverage loss (P < .0001), favoring those turning 19 after the DCP went into effect.<br><br>CONCLUSION: In the vulnerable population of adolescent and young adult cancer survivors, the ACA may have lowered the insurance dropout rate.}, }
@article {pmid33090883, year = {2020}, author = {Lyman, GH and Kuderer, NM}, title = {Randomized Controlled Trials Versus Real-World Data in the COVID-19 Era: A False Narrative.}, journal = {Cancer investigation}, volume = {38}, number = {10}, pages = {537-542}, doi = {10.1080/07357907.2020.1841922}, pmid = {33090883}, issn = {1532-4192}, mesh = {COVID-19/diagnosis/*epidemiology/therapy/virology ; *Evidence-Based Medicine ; Humans ; Observational Studies as Topic/*standards ; Randomized Controlled Trials as Topic/*standards ; Research Design/*standards ; SARS-CoV-2/*isolation &amp; purification ; }, }
@article {pmid33090877, year = {2020}, author = {Mehrotra, DV and Janes, HE and Fleming, TR and Annunziato, PW and Neuzil, KM and Carpp, LN and Benkeser, D and Brown, ER and Carone, M and Cho, I and Donnell, D and Fay, MP and Fong, Y and Han, S and Hirsch, I and Huang, Y and Huang, Y and Hyrien, O and Juraska, M and Luedtke, A and Nason, M and Vandebosch, A and Zhou, H and Cohen, MS and Corey, L and Hartzel, J and Follmann, D and Gilbert, PB}, title = {Clinical Endpoints for Evaluating Efficacy in COVID-19 Vaccine Trials.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, pmid = {33090877}, issn = {1539-3704}, abstract = {Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.}, }
@article {pmid33090182, year = {2020}, author = {Nyame, YA and Underwood, W}, title = {Improving Pretreatment Risk Prognostication in Localized Prostate Cancer.}, journal = {JAMA oncology}, volume = {6}, number = {12}, pages = {1921-1922}, doi = {10.1001/jamaoncol.2020.4916}, pmid = {33090182}, issn = {2374-2445}, }
@article {pmid33089110, year = {2020}, author = {Garrett, ME and Itell, HL and Crawford, KHD and Basom, R and Bloom, JD and Overbaugh, J}, title = {Phage-DMS: A Comprehensive Method for Fine Mapping of Antibody Epitopes.}, journal = {iScience}, volume = {23}, number = {10}, pages = {101622}, pmid = {33089110}, issn = {2589-0042}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI120961/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; R01 AI138709/AI/NIAID NIH HHS/United States ; }, abstract = {Understanding the antibody response is critical to developing vaccine and antibody-based therapies and has inspired the recent development of new methods to isolate antibodies. Methods to define the antibody-antigen interactions that determine specificity or allow escape have not kept pace. We developed Phage-DMS, a method that combines two powerful approaches-immunoprecipitation of phage peptide libraries and deep mutational scanning (DMS)-to enable high-throughput fine mapping of antibody epitopes. As an example, we designed sequences encoding all possible amino acid variants of HIV Envelope to create phage libraries. Using Phage-DMS, we identified sites of escape predicted using other approaches for four well-characterized HIV monoclonal antibodies with known linear epitopes. In some cases, the results of Phage-DMS refined the epitope beyond what was determined in previous studies. This method has the potential to rapidly and comprehensively screen many antibodies in a single experiment to define sites essential for binding interactions.}, }
@article {pmid33088847, year = {2020}, author = {Long, DR and O'Reilly-Shah, V and Rustagi, AS and Bryson-Cahn, C and Jerome, KR and Weiss, NS and Sunshine, JE}, title = {Incidence of Health Care-Associated COVID-19 During Universal Testing of Medical and Surgical Admissions in a Large US Health System.}, journal = {Open forum infectious diseases}, volume = {7}, number = {10}, pages = {ofaa435}, doi = {10.1093/ofid/ofaa435}, pmid = {33088847}, issn = {2328-8957}, abstract = {Concerns about severe acute respiratory syndrome coronavirus 2 exposure in health care settings may cause patients to delay care. Among 2992 patients testing negative on admission to an academic, 3-hospital system, 8 tested positive during hospitalization or within 14 days postdischarge. Following adjudication of each instance, health care-associated infection incidence ranged from 0.8 to 5.0 cases per 10 000 patient-days.}, }
@article {pmid33085691, year = {2020}, author = {Du, Y and Du, Y and Yao, N}, title = {Patient-provider relationships in China: A qualitative study on the perspectives of healthcare students and junior professionals.}, journal = {PloS one}, volume = {15}, number = {10}, pages = {e0240747}, pmid = {33085691}, issn = {1932-6203}, mesh = {*Attitude of Health Personnel ; China ; *Delivery of Health Care ; Geography ; Humans ; *Physician-Patient Relations ; *Qualitative Research ; *Students ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Mistrust and conflicts in patient-provider relationships (PPR) have become prevalent in China. The frequency of verbal and physical violence against healthcare workers has been increasing, but few interventions seem to be effective. Limited prior research has focused on the perspectives of healthcare professionals in training. This paper aimed to understand their viewpoints and conceptualize potentially actionable areas for future policy interventions.<br><br>METHODS: We analyzed de-identified training registration data of a convenience sample of 151 healthcare students and 38 junior professionals from 20 provinces in China. One open-ended question in the registration form asked the participant to comment on PPRs in China. We used qualitative thematic coding to analyze the narrative data. All answers were categorized into three overarching frames: patients, providers, and external agencies/regulations. Frequently mentioned themes in each frame were evaluated to generate an overall theoretical framework.<br><br>FINDINGS: Although fewer than 25% indicated that current PPRs are &quot;good&quot; or acceptable, 98% of respondents were optimistic about the future improvement of these relationships. The leading factors of PPRs mentioned as patient-relevant were eroding trust in the physician, unrealistic expectations, and ineffective communication. The provider-relevant themes highlighted were poor service quality, ineffective communication, and heavy workload. Leading themes relevant to external agencies or regulations were dysfunctional administration system, negative media reports, and disparity in healthcare resource distribution.<br><br>INTERPRETATION: Healthcare professionals in training had a negative view of the current situation but had confidence in future improvement. Patient, provider, and societal factors all contributed to the tension between patients and providers. All aspects of the healthcare sector should be carefully considered when contemplating policy or social interventions to improve the patient-provider relationship.}, }
@article {pmid33085090, year = {2020}, author = {Hong, S and Brazauskas, R and Hebert, KM and Ganguly, S and Abdel-Azim, H and Diaz, MA and Beattie, S and Ciurea, SO and Szwajcer, D and Badawy, SM and Gratwohl, AA and LeMaistre, C and Aljurf, MDSM and Olsson, RF and Bhatt, NS and Farhadfar, N and Yared, JA and Yoshimi, A and Seo, S and Gergis, U and Beitinjaneh, AM and Sharma, A and Lazarus, H and Law, J and Ulrickson, M and Hashem, H and Schoemans, H and Cerny, J and Rizzieri, D and Savani, BN and Kamble, RT and Shaw, BE and Khera, N and Wood, WA and Hashmi, S and Hahn, T and Lee, SJ and Rizzo, JD and Majhail, NS and Saber, W}, title = {Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33232}, pmid = {33085090}, issn = {1097-0142}, support = {//Sanofi Genzyme/ ; N00014-18-1-2850//Office of Naval Research/ ; //AstraZeneca/ ; //Adaptive Biotechnologies/ ; //GlaxoSmithKline/ ; //Sobi, Inc/ ; //Novartis Oncology/ ; //Kyowa Kirin/ ; //Genzyme/ ; //OncoImmune, Inc/ ; //Orca Biosystems, Inc/ ; //Mesoblast/ ; //Regeneron Pharmaceuticals/ ; U24HL138660//The National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI)/ ; HHSH250201700006C//Health Resources and Services Administration (HRSA)/ ; //Kite Pharma/ ; //HistoGenetics/ ; //Daiichi Sankyo Co/ ; //Bluebird Bio/ ; HHSH250201700007C//Health Resources and Services Administration (HRSA)/ ; //Actinium Pharmaceuticals/ ; OT3HL147741/HL/NHLBI NIH HHS/United States ; //Millennium (the Takeda Oncology Co)/ ; //Janssen/Johnson &amp; Johnson/ ; //AlloVir/ ; //Jazz Pharmaceuticals/ ; //Adienne SA/ ; //Kiadis Pharma/ ; //Amgen/ ; //Medical College of Wisconsin/ ; //Novartis Pharmaceuticals Corporation/ ; //Gamida-Cell/ ; //Incyte Corporation/ ; //Pharmacyclics, LLC/ ; U24CA076518//The National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID)/ ; //Janssen Biotech/ ; U01HL128568/HL/NHLBI NIH HHS/United States ; //CytoSen Therapeutics/ ; //Viracor Eurofins/ ; //REGiMMUNE Corp/ ; //Astellas Pharma US/ ; //Takeda Oncology/ ; //AbbVie/ ; //Seattle Genetics/ ; //Celgene/ ; //Merck &amp; Company, Inc/ ; //Terumo BCT/ ; R01-CA215134/CA/NCI NIH HHS/United States ; R21HL140314/HL/NHLBI NIH HHS/United States ; //Bristol-Myers Squibb/ ; //Miltenyi Biotec/ ; //Anthem/ ; //Chimerix/ ; //Atara Biotherapeutics/ ; //Pfizer/ ; SC1MC31881-01-00//Health Resources and Services Administration (HRSA)/ ; //CSL Behring/ ; //Medac GmbH/ ; //Janssen Pharmaceuticals/ ; //Legend Biotech/ ; //Merck Sharp &amp; Dohme Corp/ ; P30 CA016672/NH/NIH HHS/United States ; R01 CA215134/CA/NCI NIH HHS/United States ; //Xenikos BV/ ; //Takeda Pharma/ ; N00014-18-1-2888//Office of Naval Research/ ; //Omeros Corporation/ ; K23 HL150232/HL/NHLBI NIH HHS/United States ; //Mallinckrodt LLC/ ; N00014-20-1-2705//Office of Naval Research/ ; //Magenta Therapeutics/ ; }, abstract = {BACKGROUND: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.<br><br>METHODS: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.<br><br>RESULTS: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.<br><br>CONCLUSIONS: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.}, }
@article {pmid33082277, year = {2020}, author = {Orozco, JJ and Kenoyer, AL and Lin, Y and O'Steen, S and Guel, R and Nartea, ME and Hernandez, AH and Hylarides, MD and Fisher, DR and Balkin, ER and Hamlin, DK and Wilbur, DS and Orcutt, KD and Wittrup, KD and Green, DJ and Gopal, AK and Till, BG and Sandmaier, B and Press, OW and Pagel, JM}, title = {Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA.}, journal = {Molecular cancer therapeutics}, volume = {19}, number = {12}, pages = {2575-2584}, pmid = {33082277}, issn = {1538-8514}, support = {R37 CA252070/CA/NCI NIH HHS/United States ; R01 CA154897/CA/NCI NIH HHS/United States ; R01 CA076287/CA/NCI NIH HHS/United States ; K01 CA188151/CA/NCI NIH HHS/United States ; K23 CA154874/CA/NCI NIH HHS/United States ; P01 CA044991/CA/NCI NIH HHS/United States ; R01 CA138720/CA/NCI NIH HHS/United States ; K24 CA184039/CA/NCI NIH HHS/United States ; }, abstract = {Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody streptavidin conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody constructs using 30F11 and BC8 antibodies, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (% ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1,200 μCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all nontreated controls required euthanasia because of tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen, 9.0 ± 1.5% ID/g and bone marrow, 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 μCi) of 90Y-DOTA-biotin had a survival advantage compared with untreated leukemic mice (median, 43 vs. 30 days, respectively; P < 0.0001). These data suggest bispecific antibody-mediated PRIT may be highly effective for leukemia therapy and translation to human studies.}, }
@article {pmid33082259, year = {2020}, author = {Outlaw, VK and Bovier, FT and Mears, MC and Cajimat, MN and Zhu, Y and Lin, MJ and Addetia, A and Lieberman, NAP and Peddu, V and Xie, X and Shi, PY and Greninger, AL and Gellman, SH and Bente, DA and Moscona, A and Porotto, M}, title = {Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain.}, journal = {mBio}, volume = {11}, number = {5}, pages = {}, pmid = {33082259}, issn = {2150-7511}, support = {R56 AI146980/AI/NIAID NIH HHS/United States ; R01 AI114736/AI/NIAID NIH HHS/United States ; R01 GM056414/GM/NIGMS NIH HHS/United States ; R01 AI121349/AI/NIAID NIH HHS/United States ; R01 NS091263/NS/NINDS NIH HHS/United States ; P30 CA013696/CA/NCI NIH HHS/United States ; }, mesh = {Amino Acid Sequence ; Animals ; Antiviral Agents/chemistry/*pharmacology ; Betacoronavirus/chemistry/*drug effects/physiology ; COVID-19 ; Chlorocebus aethiops ; Coronavirus Infections/prevention &amp; control/transmission ; HEK293 Cells ; Humans ; Lipopeptides/chemistry/*pharmacology ; Membrane Fusion/drug effects ; Middle East Respiratory Syndrome Coronavirus/chemistry/drug effects/physiology ; Pandemics/prevention &amp; control ; Pneumonia, Viral/prevention &amp; control/transmission ; Protein Domains ; Respiratory Mucosa/drug effects/virology ; SARS Virus/chemistry/drug effects/physiology ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/*chemistry ; Vero Cells ; Virus Internalization/*drug effects ; }, abstract = {The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.}, }
@article {pmid33080195, year = {2020}, author = {Sichel, SR and Salama, NR}, title = {Bacterial Cell Biology: It Takes Two to Tango.}, journal = {Current biology : CB}, volume = {30}, number = {20}, pages = {R1258-R1260}, doi = {10.1016/j.cub.2020.08.040}, pmid = {33080195}, issn = {1879-0445}, abstract = {Work identifying how stalk morphogenesis in a species of Alphaproteobacteria is controlled unveils an interesting mechanism that other bacteria may utilize to generate the variety of bacterial cell morphologies found across the bacterial domain.}, }
@article {pmid33080150, year = {2020}, author = {Tosoian, JJ and Trock, BJ and Morgan, TM and Salami, SS and Tomlins, SA and Spratt, DE and Siddiqui, J and Kunju, LP and Botbyl, R and Chopra, Z and Pandian, B and Eyrich, NW and Longton, G and Zheng, Y and Palapattu, GS and Wei, JT and Niknafs, YS and Chinnaiyan, AM}, title = {Use of the MyProstateScore (MPS) Test to Rule Out Clinically-Significant Cancer: Validation of a Straightforward Clinical Testing Approach.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000001430}, doi = {10.1097/JU.0000000000001430}, pmid = {33080150}, issn = {1527-3792}, abstract = {PURPOSE: The MyProstateScore (MPS) test was validated for improved detection of clinically-significant (Grade Group [GG] ≥2) prostate cancer relative to PSA-based risk calculators. We sought to validate an optimal MPS threshold for clinical use in ruling-out GG ≥2 cancer in men referred for biopsy.<br><br>MATERIALS AND METHODS: Biopsy-naïve men provided post-digital rectal examination (DRE) urine prior to biopsy. MPS was calculated using the validated, locked multivariable model including only serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The MPS threshold approximating 95% sensitivity for GG ≥2 cancer was identified in a training cohort, and performance was measured in two external validation cohorts. We assessed the (i) overall biopsy-referral population and (ii) population meeting guideline-based testing criteria (ie, PSA 3-10; or PSA <3 with suspicious DRE).<br><br>RESULTS: Validation cohorts were prospectively-enrolled from academic (n=977, median PSA 4.5 [IQR:3.1-6.0]) and community (n=548, median PSA 4.9 [IQR:3.7-6.8]) settings. In the overall validation population (n=1525), 338 men (22%) had GG ≥2 cancer on biopsy. The MPS threshold of 10 provided 97% sensitivity and 98% negative predictive value (NPV) for GG ≥2 cancer. MPS testing would have prevented 387 unnecessary biopsies (33%), while missing only ten GG ≥2 cancers (3.0%). In 1242 patients meeting guideline-based criteria, MPS ≤10 provided 96% sensitivity, 97% NPV, and would have prevented 32% of unnecessary biopsies, missing 3.7% of GG ≥2 cancers.<br><br>CONCLUSIONS: In a large, clinically-pertinent biopsy-referral population, MPS ≤10 provided exceptional sensitivity and NPV for ruling-out GG ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with PSA.}, }
@article {pmid33080007, year = {2020}, author = {Brodersen, LE and Gerbing, RB and Pardo, ML and Alonzo, TA and Paine, D and Fritschle, W and Hsu, FC and Pollard, JA and Aplenc, R and Kahwash, SB and Hirsch, B and Ramondi, S and Wells, D and Kolb, EA and Gamis, AS and Meshinchi, S and Loken, MR}, title = {Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.}, journal = {Blood advances}, volume = {4}, number = {20}, pages = {5050-5061}, pmid = {33080007}, issn = {2473-9537}, support = {U10 CA098413/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, abstract = {Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The &quot;difference from normal&quot; (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.}, }
@article {pmid33079579, year = {2020}, author = {Denduluri, N and Somerfield, MR and Chavez-MacGregor, M and Comander, AH and Dayao, Z and Eisen, A and Freedman, RA and Gopalakrishnan, R and Graff, SL and Hassett, MJ and King, TA and Lyman, GH and Maupin, GR and Nunes, R and Perkins, CL and Telli, ML and Trudeau, ME and Wolff, AC and Giordano, SH}, title = {Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2002510}, doi = {10.1200/JCO.20.02510}, pmid = {33079579}, issn = {1527-7755}, abstract = {PURPOSE: The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer.<br><br>METHODS: An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations.<br><br>RESULTS: The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab.<br><br>RECOMMENDATIONS: Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.Additional information can be found at www.asco.org/breast-cancer-guidelines.}, }
@article {pmid33079399, year = {2020}, author = {Lautz, TB and Chi, YY and Li, M and Wolden, SL and Casey, DL and Routh, JC and Granberg, CF and Binite, O and Rudzinski, ER and Hawkins, DS and Venkatramani, R and Rodeberg, DA}, title = {Benefit of delayed primary excision in rhabdomyosarcoma: A report from the Children's Oncology Group (COG).}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33275}, pmid = {33079399}, issn = {1097-0142}, support = {//St. Baldrick's Foundation/ ; //Seattle Children's Foundation/ ; U10CA180886/GF/NIH HHS/United States ; U10CA098413/GF/NIH HHS/United States ; U10CA098543/GF/NIH HHS/United States ; U10CA180899/GF/NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Most children with intermediate-risk rhabdomyosarcoma (RMS) have gross disease (group III) at the initiation of chemotherapy. Delayed primary excision (DPE) after induction chemotherapy allows for a reduction in adjuvant radiation dose, but with the risk of potential surgical morbidity. The objectives of this study were to compare outcomes in children with group III RMS who did and did not undergo DPE and to assess surgical morbidity.<br><br>METHODS: The study included 369 patients who had clinical group III RMS at sites amenable to DPE from intermediate-risk Children's Oncology Group studies D9803 (encouraged DPE) and ARST0531 (discouraged DPE).<br><br>RESULTS: The primary tumor site was bladder/prostate (136 patients; 37%), extremity (97 patients; 26%), trunk (24 patients; 7%), retroperitoneum (91 patients; 25%), or intrathoracic/perineum/perianal (21 patients; 6%). In total, 112 patients (53.9%) underwent DPE in D9803, and 26 patients (16.2%) underwent DPE in ARST0531 (P < .001), with loss of vital organ or function in 30 of 138 patients (22%). DPE allowed for a reduced radiation dose in 110 of 135 patients (81%; 51% were reduced to 36 Gy, and 30% were reduced to 42 Gy). Patients who underwent DPE had improved unadjusted overall survival (P = .013). In adjusted regression analysis, the risk of death (hazard ratio, 0.71; 95% CI 0.43-1.16) was similar for patients who did and did not undergo DPE and was improved for the subset of patients who had tumors of the trunk and retroperitoneum (hazard ratio, 0.44; 95% CI, 0.20-0.97).<br><br>CONCLUSIONS: Children with group III RMS have equivalent or improved outcomes with DPE and can receive a decreased radiation dose for definitive local control. The choice of local control modality should weigh the potential morbidity of surgery versus that of higher dose irradiation.}, }
@article {pmid33079308, year = {2020}, author = {Lüftner, D and Lyman, GH and Gonçalves, J and Pivot, X and Seo, M}, title = {Correction to: Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.}, journal = {Targeted oncology}, volume = {15}, number = {6}, pages = {805}, doi = {10.1007/s11523-020-00761-7}, pmid = {33079308}, issn = {1776-260X}, abstract = {The article Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.}, }
@article {pmid33077678, year = {2020}, author = {Haynes, BF and Corey, L and Fernandes, P and Gilbert, PB and Hotez, PJ and Rao, S and Santos, MR and Schuitemaker, H and Watson, M and Arvin, A}, title = {Prospects for a safe COVID-19 vaccine.}, journal = {Science translational medicine}, volume = {12}, number = {568}, pages = {}, doi = {10.1126/scitranslmed.abe0948}, pmid = {33077678}, issn = {1946-6242}, mesh = {Animals ; COVID-19 ; COVID-19 Vaccines ; Clinical Trials as Topic ; Coronavirus Infections/*immunology/prevention &amp; control ; Disease Models, Animal ; Drug Development ; Humans ; Pandemics ; Pneumonia, Viral/*immunology ; Vaccination ; Viral Vaccines/*adverse effects/*immunology ; }, abstract = {Rapid development of an efficacious vaccine against the viral pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of the coronavirus disease 2019 (COVID-19) pandemic, is essential, but rigorous studies are required to determine the safety of candidate vaccines. Here, on behalf of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group, we evaluate research on the potential risk of immune enhancement of disease by vaccines and viral infections, including coronavirus infections, together with emerging data about COVID-19 disease. Vaccine-associated enhanced disease has been rarely encountered with existing vaccines or viral infections. Although animal models of SARS-CoV-2 infection may elucidate mechanisms of immune protection, we need observations of enhanced disease in people receiving candidate COVID-19 vaccines to understand the risk of immune enhancement of disease. Neither principles of immunity nor preclinical studies provide a basis for prioritizing among the COVID-19 vaccine candidates with respect to safety at this time. Rigorous clinical trial design and postlicensure surveillance should provide a reliable strategy to identify adverse events, including the potential for enhanced severity of COVID-19 disease, after vaccination.}, }
@article {pmid33075743, year = {2020}, author = {Lau, N and Waldbaum, S and Parigoris, R and O'Daffer, A and Walsh, C and Colt, SF and Yi-Frazier, JP and Palermo, TM and McCauley, E and Rosenberg, AR}, title = {eHealth and mHealth Psychosocial Interventions for Youths With Chronic Illnesses: Systematic Review.}, journal = {JMIR pediatrics and parenting}, volume = {3}, number = {2}, pages = {e22329}, pmid = {33075743}, issn = {2561-6722}, support = {K12 HL137940/HL/NHLBI NIH HHS/United States ; L30 CA242720/CA/NCI NIH HHS/United States ; T32 CA092408/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: An estimated 12.8% of children and adolescents experience chronic health conditions that lead to poor quality of life, adjustment and coping issues, and concurrent mental health problems. Digital health deployment of psychosocial interventions to support youth with chronic illness has become increasingly popular with the advent of the technological advances in the digital age.<br><br>OBJECTIVE: Our objectives were to systematically review published efficacy studies of eHealth and mHealth (mobile health) psychosocial interventions for youths with chronic illnesses and review intervention theory and treatment components.<br><br>METHODS: PubMed, Embase, Web of Science, PsycInfo, and Cochrane Database of Systematic Reviews were searched for studies published from 2008 to 2019 of eHealth and mHealth psychosocial interventions designed for children and adolescents with chronic illnesses in which efficacy outcomes were reported. We excluded studies of interventions for caregivers, healthy youth, disease and medication management, and telehealth interventions that function solely as a platform to connect patients to providers via phone, text, or videoconference.<br><br>RESULTS: We screened 2551 articles and 133 relevant full-text articles. Sixteen efficacy studies with psychosocial and health outcomes representing 12 unique interventions met the inclusion criteria. Of the included studies, 12 were randomized controlled trials and 4 were prospective cohort studies with no comparison group. Most interventions were based in cognitive behavioral theory and designed as eHealth interventions; only 2 were designed as mHealth interventions. All but 2 interventions provided access to support staff via text, phone, email, or discussion forums. The significant heterogeneity in intervention content, intervention structure, medical diagnoses, and outcomes precluded meta-analysis. For example, measurement time points ranged from immediately postcompletion of the mHealth program to 18 months later, and we identified 39 unique outcomes of interest. The majority of included studies (11/16, 69%) reported significant changes in measured health and/or psychosocial posttreatment outcomes, with small to large effect sizes.<br><br>CONCLUSIONS: Although the available literature on the efficacy of eHealth and mHealth psychosocial interventions for youth with chronic illnesses is limited, preliminary research suggests some evidence of positive treatment responses. Future studies should continue to evaluate whether digital health platforms may be a viable alternative model of delivery to traditional face-to-face approaches.}, }
@article {pmid33075298, year = {2020}, author = {Leisman, DE and Ronner, L and Pinotti, R and Taylor, MD and Sinha, P and Calfee, CS and Hirayama, AV and Mastroiani, F and Turtle, CJ and Harhay, MO and Legrand, M and Deutschman, CS}, title = {Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.}, journal = {The Lancet. Respiratory medicine}, volume = {8}, number = {12}, pages = {1233-1244}, doi = {10.1016/S2213-2600(20)30404-5}, pmid = {33075298}, issn = {2213-2619}, support = {R00 HL141678/HL/NHLBI NIH HHS/United States ; R01 GM121102/GM/NIGMS NIH HHS/United States ; T32 GM008440/GM/NIGMS NIH HHS/United States ; K08 GM132794/GM/NIGMS NIH HHS/United States ; R35 HL140026/HL/NHLBI NIH HHS/United States ; }, mesh = {Biomarkers/blood ; COVID-19/*blood/immunology ; Cytokine Release Syndrome/*blood/immunology ; Humans ; Interleukin-6/*blood/immunology ; Respiratory Distress Syndrome/blood/immunology ; Sepsis/blood/immunology ; Severity of Illness Index ; }, abstract = {The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6-62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3-15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1-1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3-978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.}, }
@article {pmid33069767, year = {2021}, author = {Whaley, RE and Ameny, S and Arkatkar, T and Seese, A and Wall, A and Khan, I and Carter, JJ and Scherer, EM and Rawlings, DJ and Galloway, DA and McElrath, MJ and Cohen, KW and McGuire, AT}, title = {Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies.}, journal = {Journal of immunological methods}, volume = {488}, number = {}, pages = {112901}, doi = {10.1016/j.jim.2020.112901}, pmid = {33069767}, issn = {1872-7905}, abstract = {The isolation of human monoclonal antibodies (mAbs) arising from natural infection with human pathogens has proven to be a powerful technology, facilitating the understanding of the host response to infection at a molecular level. mAbs can reveal sites of vulnerability on pathogens and illuminate the biological function of the antigenic targets. Moreover, mAbs have the potential to be used directly for therapeutic applications such as passive delivery to prevent infection in susceptible target populations, and as treatment of established infection. The isolation of antigen-specific B cells from vaccine trials can also assist in deciphering whether the desired B cells are being targeted by a given vaccine. Several different processes have been developed to isolate mAbs, but all are generally labor-intensive and result in varying degrees of efficiency. Here, we describe the development of a cost-effective feeder cell line that stably expresses CD40-ligand, interleukin-2 and interleukin-21. Sorting of single B cells onto a layer of irradiated feeder cells sustained antibody production that permits functional screening of secreted antibodies in a manner that enables subsequent recovery of B cells for recombinant antibody cloning. As a proof of concept, we show that this approach can be used to isolate B cells that secrete antibodies that neutralize human papilloma virus (HPV) from participants of an HPV vaccine study.}, }
@article {pmid33067535, year = {2020}, author = {Signorelli, M and Mason, AG and Mul, K and Evangelista, T and Mei, H and Voermans, N and Tapscott, SJ and Tsonaka, R and van Engelen, BGM and van der Maarel, SM and Spitali, P}, title = {Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {17547}, pmid = {33067535}, issn = {2045-2322}, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is caused by the expression of DUX4 in skeletal muscles. A number of therapeutic approaches are being developed to antagonize the events preceding and following DUX4 expression that leads to muscular dystrophy. Currently, the possibility to evaluate treatment response in clinical trials is hampered by the lack of objective molecular biomarkers connecting the disease cause to clinical performance. In this study we employed RNA-seq to examine gene expression in PAXgene tubes obtained from two independent cohorts of FSHD patients. Analysis of gene expression profiles did not lead to the identification of genes or pathways differentially expressed in FSHD patients, or associated with disease severity. In particular, we did not find evidence that the DUX4 and PAX7 signatures were differentially expressed. On the other hand, we were able to improve patient classification by including single genes or groups of genes in classification models. The best classifier was ROPN1L, a gene known to be expressed in testis, coincidentally the typical location of DUX4 expression. These improvements in patient classification hold the potential to enrich the FSHD clinical trial toolbox.}, }
@article {pmid33067434, year = {2020}, author = {Böhme, J and Martinez, N and Li, S and Lee, A and Marzuki, M and Tizazu, AM and Ackart, D and Frenkel, JH and Todd, A and Lachmandas, E and Lum, J and Shihui, F and Ng, TP and Lee, B and Larbi, A and Netea, MG and Basaraba, R and van Crevel, R and Newell, E and Kornfeld, H and Singhal, A}, title = {Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {5225}, pmid = {33067434}, issn = {2041-1723}, support = {R01 HL081149/HL/NHLBI NIH HHS/United States ; U19 AI111224/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; BCG Vaccine/administration &amp; dosage/immunology ; CD8-Positive T-Lymphocytes/*drug effects/immunology/metabolism ; Diabetes Mellitus, Type 2/complications/*drug therapy/immunology/metabolism ; Female ; Guinea Pigs ; Humans ; Hypoglycemic Agents/*administration &amp; dosage ; Male ; Metformin/*administration &amp; dosage ; Mice ; Mycobacterium tuberculosis/drug effects/immunology/physiology ; Tuberculosis/etiology/immunology/microbiology/prevention &amp; control ; }, abstract = {Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3-/- mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.}, }
@article {pmid33067257, year = {2020}, author = {Eckel, AM and Deeg, HJ}, title = {Silver Lining: Reduced Relapse with Chronic GVHD after Transplant for MDS.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {26}, number = {24}, pages = {6404-6405}, doi = {10.1158/1078-0432.CCR-20-3583}, pmid = {33067257}, issn = {1557-3265}, abstract = {Chronic GVHD following hematopoietic cell transplantation is associated with reduced relapse incidence in patients with leukemias. This impact has been investigated in myelodysplastic syndrome, showing a beneficial impact of limited chronic GVHD on transplant outcomes in a cohort of more than 3,000 patients.See related article by Konuma et al., p. 6483.}, }
@article {pmid33065723, year = {2020}, author = {Parker, MH and Stone, D and Abrams, K and Johnson, M and Granot, N and Storb, R}, title = {Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD.}, journal = {Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1097/TP.0000000000003489}, pmid = {33065723}, issn = {1534-6080}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Chronic graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in transplant patients. We have previously shown that 3 doses of an anti-ICOS mAb transiently ameliorated symptoms and extended survival of dogs affected by chronic GVHD over that of control dogs. The purpose of this study was to specifically correlate changes in T-cell populations in the peripheral blood with anti-ICOS treatment and chronic GVHD progression and regression in order to reach a better understanding of the mechanism of the disease and prioritize future studies.<br><br>METHODS: Peripheral blood cells from canines transplanted with DLA-mismatched bone marrow and PBMC to generate chronic GVHD were analyzed by flow cytometry using a panel of antibodies specific to helper and cytolytic T cells.<br><br>RESULTS: Chronic GVHD was specifically associated with an increase in CD4ICOS cells, ICOS cells expressing IL-17A, and CD8 cells generating granzyme B. Treatment with anti-ICOS mAb at onset of chronic GVHD symptoms specifically targeted IL-17A-expressing cells, transiently relieved symptoms, and lengthened survival but was unable to reduce the percentage of CD8 T-cells expressing granzyme B.<br><br>CONCLUSIONS: These studies suggested a role for both CD4 and CD8 T cells in pathogenesis of chronic GVHD in the canine model. We propose that future studies should focus on further extending survival by developing a treatment that would control both CD4 and CD8 T cells.}, }
@article {pmid33064809, year = {2020}, author = {Slyker, JA and Guthrie, B and Pankau, M and Tapia, K and Wamalwa, D and Benki-Nugent, S and Ngugi, E and Huang, ML and Njuguna, I and Langat, A and John-Stewart, G and Lehman, D}, title = {Cytomegalovirus and Epstein-Barr virus viremia are associated with HIV DNA levels in the reservoir of Kenyan infants on antiretroviral therapy.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaa640}, pmid = {33064809}, issn = {1537-6613}, abstract = {Identifying determinants of HIV reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) co-infections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA-suppressed Kenyan children starting antiretroviral therapy (ART) before 7 months of age. Earlier acquisition of CMV and EBV, and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of ART, independent of HIV RNA levels over time. These data suggest delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation.}, }
@article {pmid33064153, year = {2019}, author = {Stoddard, BL and Black, ME}, title = {Letter to the Editor.}, journal = {Neuro-oncology}, volume = {21}, number = {9}, pages = {1210}, doi = {10.1093/neuonc/noz087}, pmid = {33064153}, issn = {1523-5866}, mesh = {Cytosine Deaminase ; *Glioma ; Humans ; Recombinant Proteins ; }, }
@article {pmid33064008, year = {2021}, author = {McCune, JS and McKiernan, JS and van Maarseveen, E and Huitema, ADR and Randolph, TW and Deeg, HJ and Nakamura, R and Baker, KS}, title = {Prediction of Acute Graft versus Host Disease and Relapse by Endogenous Metabolomic Compounds in Patients Receiving Personalized Busulfan-Based Conditioning.}, journal = {Journal of proteome research}, volume = {20}, number = {1}, pages = {684-694}, doi = {10.1021/acs.jproteome.0c00599}, pmid = {33064008}, issn = {1535-3907}, abstract = {Busulfan-based conditioning is the most commonly used high-dose conditioning regimen for allogeneic hematopoietic cell transplant (HCT). The alkylating agent busulfan has a narrow therapeutic index, with busulfan doses personalized to a target plasma exposure (targeted busulfan). Using a global pharmacometabonomics approach, we sought to identify novel biomarkers of relapse or acute graft versus host disease (GVHD) in a cohort of 84 patients receiving targeted busulfan before allogeneic HCT. A total of 763 endogenous metabolomic compounds (EMCs) were quantitated in 230 longitudinal blood samples before, during, and shortly after intravenous busulfan administration. We performed both univariate linear regression and pathway enrichment analyses using global testing. The cysteine/methionine pathway and the glycine, serine, and threonine metabolism pathway were most associated with relapse. The latter be explained by the fact that glutathione S-transferases conjugate both busulfan and glutathione, which contains glycine as a component. The d-arginine and d-ornithine metabolism pathway and arginine and proline metabolism pathway were most associated with acute GVHD. None of these associations were significant after correcting for false discovery rate (FDR) with a strict cutoff of FDR-adjusted p < 0.1. Although larger studies are needed to substantiate these findings, the results show that EMCs may be used as predictive biomarkers in HCT patients.}, }
@article {pmid33063663, year = {2020}, author = {Hays, M and Young, JM and Levan, PF and Malik, HS}, title = {A natural variant of the essential host gene MMS21 restricts the parasitic 2-micron plasmid in Saccharomyces cerevisiae.}, journal = {eLife}, volume = {9}, number = {}, pages = {}, pmid = {33063663}, issn = {2050-084X}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; R01 GM074108/GM/NIGMS NIH HHS/United States ; DGE-1256082//National Science Foundation/International ; /HHMI/Howard Hughes Medical Institute/United States ; }, abstract = {Antagonistic coevolution with selfish genetic elements (SGEs) can drive evolution of host resistance. Here, we investigated host suppression of 2-micron (2μ) plasmids, multicopy nuclear parasites that have co-evolved with budding yeasts. We developed SCAMPR (Single-Cell Assay for Measuring Plasmid Retention) to measure copy number heterogeneity and 2μ plasmid loss in live cells. We identified three S. cerevisiae strains that lack endogenous 2μ plasmids and reproducibly inhibit mitotic plasmid stability. Focusing on the Y9 ragi strain, we determined that plasmid restriction is heritable and dominant. Using bulk segregant analysis, we identified a high-confidence Quantitative Trait Locus (QTL) with a single variant of MMS21 associated with increased 2μ instability. MMS21 encodes a SUMO E3 ligase and an essential component of the Smc5/6 complex, involved in sister chromatid cohesion, chromosome segregation, and DNA repair. Our analyses leverage natural variation to uncover a novel means by which budding yeasts can overcome highly successful genetic parasites.}, }
@article {pmid33063025, year = {2020}, author = {Morrison, ML and Iwata, A and Wick, ML and VandenEkart, E and Insko, MA and Henning, DJ and Frare, C and Rice, SA and Drew, KL and Maier, RV and Roth, MB}, title = {Iodine Redistribution During Trauma, Sepsis, and Hibernation: An Evolutionarily Conserved Response to Severe Stress.}, journal = {Critical care explorations}, volume = {2}, number = {10}, pages = {e0215}, pmid = {33063025}, issn = {2639-8028}, abstract = {Objective: We performed these studies to learn how iodine in the form of free iodide behaves during stress.<br><br>Design: Prospective observational trial using samples obtained from human trauma patients and retrospective observational study using remnant samples from human sepsis patients and arctic ground squirrels. Preclinical interventional study using hind-limb ischemia and reperfusion injury in mice.<br><br>Setting: Level I trauma center emergency room and ICU and animal research laboratories.<br><br>Subjects: Adult human sepsis and trauma patients, wild-caught adult arctic ground squirrels, and sexually mature laboratory mice.<br><br>Interventions: Ischemia and reperfusion injury was induced in mice by temporary application of tourniquet to one hind-limb. Iodide was administered IV just prior to reperfusion.<br><br>Measurements and Main Results: Free iodide was measured using ion chromatography. Relative to iodide in plasma from normal donors, iodide was increased 17-fold in plasma from trauma patients and 26-fold in plasma from sepsis patients. In arctic ground squirrels, iodide increases over three-fold during hibernation. And during ischemia/reperfusion injury in mice, iodide accumulates in ischemic tissue and reduces both local and systemic tissue damage.<br><br>Conclusions: Iodide redistributes during stress and improves outcome after injury. Essential functions of iodide may have contributed to its evolutionary selection and be useful as a therapeutic intervention for human patients.}, }
@article {pmid33060197, year = {2020}, author = {Gordon, DE and Hiatt, J and Bouhaddou, M and Rezelj, VV and Ulferts, S and Braberg, H and Jureka, AS and Obernier, K and Guo, JZ and Batra, J and Kaake, RM and Weckstein, AR and Owens, TW and Gupta, M and Pourmal, S and Titus, EW and Cakir, M and Soucheray, M and McGregor, M and Cakir, Z and Jang, G and O'Meara, MJ and Tummino, TA and Zhang, Z and Foussard, H and Rojc, A and Zhou, Y and Kuchenov, D and Hüttenhain, R and Xu, J and Eckhardt, M and Swaney, DL and Fabius, JM and Ummadi, M and Tutuncuoglu, B and Rathore, U and Modak, M and Haas, P and Haas, KM and Naing, ZZC and Pulido, EH and Shi, Y and Barrio-Hernandez, I and Memon, D and Petsalaki, E and Dunham, A and Marrero, MC and Burke, D and Koh, C and Vallet, T and Silvas, JA and Azumaya, CM and Billesbølle, C and Brilot, AF and Campbell, MG and Diallo, A and Dickinson, MS and Diwanji, D and Herrera, N and Hoppe, N and Kratochvil, HT and Liu, Y and Merz, GE and Moritz, M and Nguyen, HC and Nowotny, C and Puchades, C and Rizo, AN and Schulze-Gahmen, U and Smith, AM and Sun, M and Young, ID and Zhao, J and Asarnow, D and Biel, J and Bowen, A and Braxton, JR and Chen, J and Chio, CM and Chio, US and Deshpande, I and Doan, L and Faust, B and Flores, S and Jin, M and Kim, K and Lam, VL and Li, F and Li, J and Li, YL and Li, Y and Liu, X and Lo, M and Lopez, KE and Melo, AA and Moss, FR and Nguyen, P and Paulino, J and Pawar, KI and Peters, JK and Pospiech, TH and Safari, M and Sangwan, S and Schaefer, K and Thomas, PV and Thwin, AC and Trenker, R and Tse, E and Tsui, TKM and Wang, F and Whitis, N and Yu, Z and Zhang, K and Zhang, Y and Zhou, F and Saltzberg, D and ,  and Hodder, AJ and Shun-Shion, AS and Williams, DM and White, KM and Rosales, R and Kehrer, T and Miorin, L and Moreno, E and Patel, AH and Rihn, S and Khalid, MM and Vallejo-Gracia, A and Fozouni, P and Simoneau, CR and Roth, TL and Wu, D and Karim, MA and Ghoussaini, M and Dunham, I and Berardi, F and Weigang, S and Chazal, M and Park, J and Logue, J and McGrath, M and Weston, S and Haupt, R and Hastie, CJ and Elliott, M and Brown, F and Burness, KA and Reid, E and Dorward, M and Johnson, C and Wilkinson, SG and Geyer, A and Giesel, DM and Baillie, C and Raggett, S and Leech, H and Toth, R and Goodman, N and Keough, KC and Lind, AL and ,  and Klesh, RJ and Hemphill, KR and Carlson-Stevermer, J and Oki, J and Holden, K and Maures, T and Pollard, KS and Sali, A and Agard, DA and Cheng, Y and Fraser, JS and Frost, A and Jura, N and Kortemme, T and Manglik, A and Southworth, DR and Stroud, RM and Alessi, DR and Davies, P and Frieman, MB and Ideker, T and Abate, C and Jouvenet, N and Kochs, G and Shoichet, B and Ott, M and Palmarini, M and Shokat, KM and García-Sastre, A and Rassen, JA and Grosse, R and Rosenberg, OS and Verba, KA and Basler, CF and Vignuzzi, M and Peden, AA and Beltrao, P and Krogan, NJ}, title = {Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.}, journal = {Science (New York, N.Y.)}, volume = {370}, number = {6521}, pages = {}, doi = {10.1126/science.abe9403}, pmid = {33060197}, issn = {1095-9203}, support = {R01 GM024485/GM/NIGMS NIH HHS/United States ; F30 AI143401/AI/NIAID NIH HHS/United States ; R01 AI143292/AI/NIAID NIH HHS/United States ; P01 AI120943/AI/NIAID NIH HHS/United States ; U19 AI135972/AI/NIAID NIH HHS/United States ; T32 GM007618/GM/NIGMS NIH HHS/United States ; R35 GM122481/GM/NIGMS NIH HHS/United States ; R01 HG009979/HG/NHGRI NIH HHS/United States ; K99 GM138753/GM/NIGMS NIH HHS/United States ; F32 CA239336/CA/NCI NIH HHS/United States ; P01 AI063302/AI/NIAID NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U19 AI135990/AI/NIAID NIH HHS/United States ; R01 NS089713/NS/NINDS NIH HHS/United States ; F32 GM137463/GM/NIGMS NIH HHS/United States ; R01 AI128214/AI/NIAID NIH HHS/United States ; R01 AI122747/AI/NIAID NIH HHS/United States ; R01 AI120694/AI/NIAID NIH HHS/United States ; P50 AI150476/AI/NIAID NIH HHS/United States ; F32 CA239333/CA/NCI NIH HHS/United States ; 133122P//The Laboratory for Genomics Research, which is a collaboration between the Innovative Genomics Institute of UC Berkeley/UCSF and GlaxoSmithKline/International ; }, mesh = {COVID-19/*metabolism ; Conserved Sequence ; Coronavirus Nucleocapsid Proteins/genetics/*metabolism ; Cryoelectron Microscopy ; *Host Microbial Interactions ; Humans ; Mitochondrial Membrane Transport Proteins/genetics/*metabolism ; Phosphoproteins/genetics/metabolism ; Protein Conformation ; *Protein Interaction Maps ; SARS Virus/*metabolism ; SARS-CoV-2/*metabolism ; Severe Acute Respiratory Syndrome/*metabolism ; }, abstract = {The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.}, }
@article {pmid33059593, year = {2020}, author = {Golob, JL and Minot, SS}, title = {In silico benchmarking of metagenomic tools for coding sequence detection reveals the limits of sensitivity and precision.}, journal = {BMC bioinformatics}, volume = {21}, number = {1}, pages = {459}, pmid = {33059593}, issn = {1471-2105}, support = {AI134808//NIH / NIAID/ ; New Investigator Award//ASBMT/ ; }, mesh = {Algorithms ; *Benchmarking ; *Computer Simulation ; Humans ; *Metagenome ; Metagenomics ; Microbiota/genetics ; Open Reading Frames/*genetics ; Predictive Value of Tests ; }, abstract = {BACKGROUND: High-throughput sequencing can establish the functional capacity of a microbial community by cataloging the protein-coding sequences (CDS) present in the metagenome of the community. The relative performance of different computational methods for identifying CDS from whole-genome shotgun sequencing is not fully established.<br><br>RESULTS: Here we present an automated benchmarking workflow, using synthetic shotgun sequencing reads for which we know the true CDS content of the underlying communities, to determine the relative performance (sensitivity, positive predictive value or PPV, and computational efficiency) of different metagenome analysis tools for extracting the CDS content of a microbial community. Assembly-based methods are limited by coverage depth, with poor sensitivity for CDS at < 5X depth of sequencing, but have excellent PPV. Mapping-based techniques are more sensitive at low coverage depths, but can struggle with PPV. We additionally describe an expectation maximization based iterative algorithmic approach which we show to successfully improve the PPV of a mapping based technique while retaining improved sensitivity and computational efficiency.<br><br>CONCLUSION: Our benchmarking approach reveals the trade-offs of assembly versus alignment-based approaches and the relative performance of specific implementations when one wishes to extract the protein coding capacity of microbial communities.}, }
@article {pmid33058866, year = {2020}, author = {Guo, X and Lin, W and Wen, W and Huyghe, J and Bien, S and Cai, Q and Harrison, T and Chen, Z and Qu, C and Bao, J and Long, J and Yuan, Y and Wang, F and Bai, M and Abecasis, GR and Albanes, D and Berndt, SI and Bézieau, S and Bishop, DT and Brenner, H and Buch, S and Burnett-Hartman, A and Campbell, PT and Castellví-Bel, S and Chan, AT and Chang-Claude, J and Chanock, SJ and Cho, SH and Conti, DV and Chapelle, A and Feskens, EJM and Gallinger, SJ and Giles, GG and Goodman, PJ and Gsur, A and Guinter, M and Gunter, MJ and Hampe, J and Hampel, H and Hayes, RB and Hoffmeister, M and Kampman, E and Kang, HM and Keku, TO and Kim, HR and Le Marchand, L and Lee, SC and Li, CI and Li, L and Lindblom, A and Lindor, N and Milne, RL and Moreno, V and Murphy, N and Newcomb, PA and Nickerson, DA and Offit, K and Pearlman, R and Pharoah, PDP and Platz, EA and Potter, JD and Rennert, G and Sakoda, LC and Schafmayer, C and Schmit, SL and Schoen, RE and Schumacher, FR and Slattery, ML and Su, YR and Tangen, CM and Ulrich, CM and van Duijnhoven, FJB and Van Guelpen, B and Visvanathan, K and Vodicka, P and Vodickova, L and Vymetalkova, V and Wang, X and White, E and Wolk, A and Woods, MO and Casey, G and Hsu, L and Jenkins, MA and Gruber, SB and Peters, U and Zheng, W}, title = {Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2020.08.062}, pmid = {33058866}, issn = {1528-0012}, support = {R37 CA227130/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.<br><br>METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.<br><br>RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.<br><br>CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.}, }
@article {pmid33058280, year = {2020}, author = {Rout, ED and Moore, AR and Burnett, RC and Labadie, JD and Hughes, KL and Navin, PA and Yoshimoto, JA and Avery, PR and Avery, AC}, title = {Polyclonal B-cell lymphocytosis in English bulldogs.}, journal = {Journal of veterinary internal medicine}, volume = {34}, number = {6}, pages = {2622-2635}, pmid = {33058280}, issn = {1939-1676}, support = {D18CA-413//Morris Animal Foundation/ ; }, abstract = {BACKGROUND: English bulldogs disproportionally develop an expansion of small B-cells, which has been interpreted as B-cell chronic lymphocytic leukemia (BCLL). However, clonality testing in these cases has often not been supportive of neoplasia.<br><br>HYPOTHESIS: English bulldogs have a syndrome of nonneoplastic B-cell expansion.<br><br>ANIMALS: Eighty-four English bulldogs with small-sized CD21+ B-cell lymphocytosis in the blood as determined by flow cytometry.<br><br>METHODS: This is a retrospective study. We characterized this syndrome by assessing B-cell clonality, clinical presentation, flow cytometric features, and immunoglobulin gammopathy patterns. We identified 84 cases with CD21+ lymphocytosis among 195 English bulldogs with blood samples submitted to the Colorado State University-Clinical Immunology laboratory for immunophenotyping between 2010 and 2019. Flow cytometry features were compared to normal B-cells and BCLL cases. PCR for antigen receptor rearrangements (PARR) by multiple immunoglobulin primers was performed to assess B-cell clonality. A subset of cases with gammopathy were examined by protein electrophoresis, immunofixation, and immunoglobulin subclass ELISA quantification.<br><br>RESULTS: Seventy percent (58/83) of cases had polyclonal or restricted polyclonal immunoglobulin gene rearrangements, suggesting nonmalignant B-cell expansion. The median age of all dogs in the study was 6.8 years and 74% were male. The median (range) lymphocyte count was 22 400/μL (2000-384 400/μL) and B-cells had low expression of class II MHC and CD25. Splenomegaly or splenic masses were detected in 57% (26/46) of cases and lymphadenopathy in 11% (7/61). Seventy-one percent (52/73) of cases had hyperglobulinemia and 77% (23/30) with globulin characterization had IgA ± IgM polyclonal or restricted polyclonal gammopathy patterns.<br><br>Polyclonal B-cell lymphocytosis in English bulldogs is characterized by low B-cell class II MHC and CD25 expression, splenomegaly and hyperglobulinemia consisting of increased IgA ± IgM. We hypothesize that this syndrome has a genetic basis.}, }
@article {pmid33058221, year = {2020}, author = {Haddad, N and Delyon, J and Trabelsi Messai, S and Herms, F and Leccia, MT and Lebbe, C and Whitney, J and Bhatia, S and Basset-Seguin, N}, title = {Clinical response to immune checkpoint inhibition in patients with advanced skin cancers receiving concurrent ruxolitinib therapy for haematological malignancy.}, journal = {The British journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjd.19604}, pmid = {33058221}, issn = {1365-2133}, }
@article {pmid33057201, year = {2020}, author = {Bick, AG and Weinstock, JS and Nandakumar, SK and Fulco, CP and Bao, EL and Zekavat, SM and Szeto, MD and Liao, X and Leventhal, MJ and Nasser, J and Chang, K and Laurie, C and Burugula, BB and Gibson, CJ and Lin, AE and Taub, MA and Aguet, F and Ardlie, K and Mitchell, BD and Barnes, KC and Moscati, A and Fornage, M and Redline, S and Psaty, BM and Silverman, EK and Weiss, ST and Palmer, ND and Vasan, RS and Burchard, EG and Kardia, SLR and He, J and Kaplan, RC and Smith, NL and Arnett, DK and Schwartz, DA and Correa, A and de Andrade, M and Guo, X and Konkle, BA and Custer, B and Peralta, JM and Gui, H and Meyers, DA and McGarvey, ST and Chen, IY and Shoemaker, MB and Peyser, PA and Broome, JG and Gogarten, SM and Wang, FF and Wong, Q and Montasser, ME and Daya, M and Kenny, EE and North, KE and Launer, LJ and Cade, BE and Bis, JC and Cho, MH and Lasky-Su, J and Bowden, DW and Cupples, LA and Mak, ACY and Becker, LC and Smith, JA and Kelly, TN and Aslibekyan, S and Heckbert, SR and Tiwari, HK and Yang, IV and Heit, JA and Lubitz, SA and Johnsen, JM and Curran, JE and Wenzel, SE and Weeks, DE and Rao, DC and Darbar, D and Moon, JY and Tracy, RP and Buth, EJ and Rafaels, N and Loos, RJF and Durda, P and Liu, Y and Hou, L and Lee, J and Kachroo, P and Freedman, BI and Levy, D and Bielak, LF and Hixson, JE and Floyd, JS and Whitsel, EA and Ellinor, PT and Irvin, MR and Fingerlin, TE and Raffield, LM and Armasu, SM and Wheeler, MM and Sabino, EC and Blangero, J and Williams, LK and Levy, BD and Sheu, WH and Roden, DM and Boerwinkle, E and Manson, JE and Mathias, RA and Desai, P and Taylor, KD and Johnson, AD and ,  and Auer, PL and Kooperberg, C and Laurie, CC and Blackwell, TW and Smith, AV and Zhao, H and Lange, E and Lange, L and Rich, SS and Rotter, JI and Wilson, JG and Scheet, P and Kitzman, JO and Lander, ES and Engreitz, JM and Ebert, BL and Reiner, AP and Jaiswal, S and Abecasis, G and Sankaran, VG and Kathiresan, S and Natarajan, P}, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, number = {7831}, pages = {763-768}, pmid = {33057201}, issn = {1476-4687}, support = {DP5 OD029586/OD/NIH HHS/United States ; R01 HL139731/HL/NHLBI NIH HHS/United States ; U54 GM115428/GM/NIGMS NIH HHS/United States ; R01 HL133040/HL/NHLBI NIH HHS/United States ; T32 HL129982/HL/NHLBI NIH HHS/United States ; R01 HL148050/HL/NHLBI NIH HHS/United States ; R01 HL113323/HL/NHLBI NIH HHS/United States ; R01 HL091357/HL/NHLBI NIH HHS/United States ; R01 HL055673/HL/NHLBI NIH HHS/United States ; K01 HL135405/HL/NHLBI NIH HHS/United States ; F30 HL149180/HL/NHLBI NIH HHS/United States ; K01 HL136700/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; P01 HL132825/HL/NHLBI NIH HHS/United States ; R01 HL138737/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; UM1 HG008895/HG/NHGRI NIH HHS/United States ; }, abstract = {Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.}, }
@article {pmid33057025, year = {2020}, author = {Zhao, X and Qiao, D and Yang, C and Kasela, S and Kim, W and Ma, Y and Shrine, N and Batini, C and Sofer, T and Taliun, SAG and Sakornsakolpat, P and Balte, PP and Prokopenko, D and Yu, B and Lange, LA and Dupuis, J and Cade, BE and Lee, J and Gharib, SA and Daya, M and Laurie, CA and Ruczinski, I and Cupples, LA and Loehr, LR and Bartz, TM and Morrison, AC and Psaty, BM and Vasan, RS and Wilson, JG and Taylor, KD and Durda, P and Johnson, WC and Cornell, E and Guo, X and Liu, Y and Tracy, RP and Ardlie, KG and Aguet, F and VanDenBerg, DJ and Papanicolaou, GJ and Rotter, JI and Barnes, KC and Jain, D and Nickerson, DA and Muzny, DM and Metcalf, GA and Doddapaneni, H and Dugan-Perez, S and Gupta, N and Gabriel, S and Rich, SS and O'Connor, GT and Redline, S and Reed, RM and Laurie, CC and Daviglus, ML and Preudhomme, LK and Burkart, KM and Kaplan, RC and Wain, LV and Tobin, MD and London, SJ and Lappalainen, T and Oelsner, EC and Abecasis, GR and Silverman, EK and Barr, RG and ,  and ,  and Cho, MH and Manichaikul, A}, title = {Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {5182}, pmid = {33057025}, issn = {2041-1723}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; R01 HL077612/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R21 HL129924/HL/NHLBI NIH HHS/United States ; R01 HL137927/HL/NHLBI NIH HHS/United States ; U01 HL117626/HL/NHLBI NIH HHS/United States ; R01 HL131565/HL/NHLBI NIH HHS/United States ; R01 HL147148/HL/NHLBI NIH HHS/United States ; R01 HL089856/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; R01 HL135142/HL/NHLBI NIH HHS/United States ; R21 HL121457/HL/NHLBI NIH HHS/United States ; R35 HL135818/HL/NHLBI NIH HHS/United States ; R01 HL098433/HL/NHLBI NIH HHS/United States ; HHSN268201500015C/HL/NHLBI NIH HHS/United States ; R01 HL142028/HL/NHLBI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; K01 HL129039/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; K23 HL130627/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; African Americans/*genetics ; Aged ; Aged, 80 and over ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics ; Calcium-Binding Proteins/genetics ; Feasibility Studies ; Female ; Follow-Up Studies ; *Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Lung/physiopathology ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein Inhibitors of Activated STAT/genetics ; Pulmonary Disease, Chronic Obstructive/ethnology/*genetics/physiopathology ; Respiratory Physiological Phenomena/*genetics ; Small Ubiquitin-Related Modifier Proteins/genetics ; *Whole Genome Sequencing ; }, abstract = {Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.}, }
@article {pmid33054121, year = {2020}, author = {Tam, CS and Robak, T and Ghia, P and Kahl, BS and Walker, P and Janowski, W and Simpson, D and Shadman, M and Ganly, PS and Laurenti, L and Opat, S and Tani, M and Ciepluch, H and Verner, E and Šimkovič, M and Österborg, A and Trněný, M and Tedeschi, A and Paik, JC and Kuwahara, SB and Feng, S and Ramakrishnan, V and Cohen, A and Huang, J and Hillmen, P and Brown, JR}, title = {Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion.}, journal = {Haematologica}, volume = {Online ahead of print}, number = {}, pages = {}, doi = {10.3324/haematol.2020.259432}, pmid = {33054121}, issn = {1592-8721}, abstract = {Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.}, }
@article {pmid33054118, year = {2020}, author = {Stephens, DM and Boucher, K and Kander, E and Parikh, SA and Parry, EM and Shadman, M and Pagel, JM and Cooperrider, J and Rhodes, J and Mato, A and Winter, A and Hill, B and Gaballa, S and Danilov, A and Phillips, T and Brander, DM and Smith, SM and Davids, M and Rogers, K and Glenn, MJ and Byrd, JC}, title = {Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration.}, journal = {Haematologica}, volume = {Online ahead of print}, number = {}, pages = {}, doi = {10.3324/haematol.2020.256388}, pmid = {33054118}, issn = {1592-8721}, support = {R35 CA197734/CA/NCI NIH HHS/United States ; }, abstract = {Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.}, }
@article {pmid33054108, year = {2020}, author = {Granot, N and Storb, R}, title = {History of hematopoietic cell transplantation: challenges and progress.}, journal = {Haematologica}, volume = {Online ahead of print}, number = {}, pages = {2716-2729}, pmid = {33054108}, issn = {1592-8721}, support = {P01 CA078902/CA/NCI NIH HHS/United States ; P01 HL122173/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.}, }
@article {pmid33054092, year = {2020}, author = {Hongjiao Li,  and Yi Wang,  and Xingchen Pang,  and Chenglian Xie,  and H Joachim Deeg,  and Hui Wang,  and Ting Wan,  and Jinpeng Wu,  and Feng Guan,  and Xiang Li, }, title = {Elevated TWIST1 expression in myelodysplastic syndromes/acute myeloid leukemia reduces efficacy of hypomethylating therapy with decitabine.}, journal = {Haematologica}, volume = {105}, number = {10}, pages = {e502}, pmid = {33054092}, issn = {1592-8721}, }
@article {pmid33053450, year = {2020}, author = {Camacho-Bydume, C and Wang, T and Sees, JA and Fernandez-Viña, M and Abid, MB and Askar, M and Beitinjaneh, A and Brown, V and Castillo, P and Chhabra, S and Gadalla, SM and Hsu, JM and Kamoun, M and Lazaryan, A and Nishihori, T and Page, K and Schetelig, J and Fleischhauer, K and Marsh, SGE and Paczesny, S and Spellman, SR and Lee, SJ and Hsu, KC}, title = {Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2020.10.010}, pmid = {33053450}, issn = {1523-6536}, abstract = {Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.}, }
@article {pmid33053332, year = {2020}, author = {Lin, YR and Parks, KR and Weidle, C and Naidu, AS and Khechaduri, A and Riker, AO and Takushi, B and Chun, JH and Borst, AJ and Veesler, D and Stuart, A and Agrawal, P and Gray, M and Pancera, M and Huang, PS and Stamatatos, L}, title = {HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors.}, journal = {Immunity}, volume = {53}, number = {4}, pages = {840-851.e6}, pmid = {33053332}, issn = {1097-4180}, support = {P01 AI138212/AI/NIAID NIH HHS/United States ; R01 AI104384/AI/NIAID NIH HHS/United States ; }, abstract = {Activating precursor B cell receptors of HIV-1 broadly neutralizing antibodies requires specifically designed immunogens. Here, we compared the abilities of three such germline-targeting immunogens against the VRC01-class receptors to activate the targeted B cells in transgenic mice expressing the germline VH of the VRC01 antibody but diverse mouse light chains. Immunogen-specific VRC01-like B cells were isolated at different time points after immunization, their VH and VL genes were sequenced, and the corresponding antibodies characterized. VRC01 B cell sub-populations with distinct cross-reactivity properties were activated by each immunogen, and these differences correlated with distinct biophysical and biochemical features of the germline-targeting immunogens. Our study indicates that the design of effective immunogens to activate B cell receptors leading to protective HIV-1 antibodies will require a better understanding of how the biophysical properties of the epitope and its surrounding surface on the germline-targeting immunogen influence its interaction with the available receptor variants in vivo.}, }
@article {pmid33052755, year = {2020}, author = {Piccart, MJ and Hilbers, FS and Bliss, JM and Caballero, C and Frank, ES and Renault, P and Naït Kaoudjt, R and Schumacher, E and Spears, PA and Regan, MM and Gelber, RD and Davidson, NE and Norton, L and Winer, EP and , }, title = {Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {38}, number = {34}, pages = {4120-4129}, doi = {10.1200/JCO.20.01382}, pmid = {33052755}, issn = {1527-7755}, abstract = {An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.}, }
@article {pmid33051337, year = {2020}, author = {Bast, RC and Lu, Z and Han, CY and Lu, KH and Anderson, KS and Drescher, CW and Skates, SJ}, title = {Biomarkers and Strategies for Early Detection of Ovarian Cancer.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {29}, number = {12}, pages = {2504-2512}, pmid = {33051337}, issn = {1538-7755}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA217685/CA/NCI NIH HHS/United States ; U01 CA152990/CA/NCI NIH HHS/United States ; P50 CA083639/CA/NCI NIH HHS/United States ; U01 CA200462/CA/NCI NIH HHS/United States ; }, abstract = {Early detection of ovarian cancer remains an important unmet medical need. Effective screening could reduce mortality by 10%-30%. Used individually, neither serum CA125 nor transvaginal sonography (TVS) is sufficiently sensitive or specific. Two-stage strategies have proven more effective, where a significant rise above a woman's baseline CA125 prompts TVS and an abnormal sonogram prompts surgery. Two major screening trials have documented that this strategy has adequate specificity, but sensitivity for early-stage (I-II) disease must improve to have a greater impact on mortality. To improve the first stage, different panels of protein biomarkers have detected cases missed by CA125. Autoantibodies against TP53 have detected 20% of early-stage ovarian cancers 8 months before elevation of CA125 and 22 months before clinical diagnosis. Panels of autoantibodies and antigen-autoantibody complexes are being evaluated with the goal of detecting >90% of early-stage ovarian cancers, alone or in combination with CA125, while maintaining 98% specificity in control subjects. Other biomarkers, including micro-RNAs, ctDNA, methylated DNA, and combinations of ctDNA alterations, are being tested to provide an optimal first-stage test. New technologies are also being developed with greater sensitivity than TVS to image small volumes of tumor.See all articles in this CEBP Focus section, &quot;NCI Early Detection Research Network: Making Cancer Detection Possible.&quot;}, }
@article {pmid33051252, year = {2020}, author = {Li, Y and Bai, L and Yu, H and Cai, D and Wang, X and Huang, B and Peng, S and Huang, M and Cao, G and Kaz, AM and Grady, WM and Wang, J and Luo, Y}, title = {Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer.}, journal = {Cancer research}, volume = {80}, number = {23}, pages = {5203-5215}, doi = {10.1158/0008-5472.CAN-20-1590}, pmid = {33051252}, issn = {1538-7445}, abstract = {DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. SIGNIFICANCE: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.}, }
@article {pmid33049206, year = {2020}, author = {Kugel, S and Hingorani, SR}, title = {Cholesterol Biosynthesis Influences Subtype Specificity and Plasticity in Pancreas Cancer.}, journal = {Cancer cell}, volume = {38}, number = {4}, pages = {443-445}, doi = {10.1016/j.ccell.2020.09.010}, pmid = {33049206}, issn = {1878-3686}, abstract = {Cellular plasticity contributes to intratumoral heterogeneity, metastatic spread, and treatment resistance of cancers. In this issue of Cancer Cell, Gabitova-Cornell et al. identify the potential to inadvertently develop an undifferentiated and more aggressive pancreas cancer with agents commonly prescribed to manage heart disease risk.}, }
@article {pmid33049057, year = {2020}, author = {Bleakley, M}, title = {Naive T-cell depletion in stem cell transplantation.}, journal = {Blood advances}, volume = {4}, number = {19}, pages = {4980}, doi = {10.1182/bloodadvances.2020001888}, pmid = {33049057}, issn = {2473-9537}, abstract = {Allogeneic hematopoietic stem cell transplantation (HCT) is curative in many patients with advanced hematopoietic malignancies. Donor T cells not only facilitate engraftment and protect against opportunistic pathogens and residual disease, but can also cause graft-versus-host disease (GVHD), with significant morbidity and mortality. Complete T-cell depletion can not only substantially reduce GVHD rates but can also delay immune reconstitution and increase rates of opportunistic infections and relapse. Murine models have shown that naive T cells (TNs) consistently cause severe GVHD, whereas memory T cells cause milder or no GVHD and have critical graft-versus-tumor function. Informed by experiments performed in murine models of HCT, clinical trials are being conducted to evaluate TN-depleted peripheral blood stem cell (PBSC) grafts. These trials are showing very low rates of chronic GVHD and of serious acute GVHD in the HLA-matched HCT setting, with lower frequencies of opportunistic infections than after fully T-cell-depleted HCT and no apparent increase in relapse rates. Randomized clinical trials are ongoing, comparing standard unselected HCT with TN-depleted PBSCs and other promising GVHD-reduction strategies. Correlative laboratory studies will clarify how antitumor function is retained in TN-depleted HCT and inform strategies to further augment graft-versus-leukemia in patients at a high risk of relapse. TN depletion of donor lymphocyte infusions and of haploidentical stem cell grafts is also being investigated.}, }
@article {pmid33049054, year = {2020}, author = {Voso, MT and Larson, RA and Jones, D and Marcucci, G and Prior, T and Krauter, J and Heuser, M and Lavorgna, S and Nomdedeu, J and Geyer, SM and Walker, A and Wei, AH and Sierra, J and Sanz, MA and Brandwein, JM and de Witte, TM and Jansen, JH and Niederwieser, D and Appelbaum, FR and Medeiros, BC and Tallman, MS and Schlenk, RF and Ganser, A and Amadori, S and Cheng, Y and Chen, Y and Pallaud, C and Du, L and Piciocchi, A and Ehninger, G and Byrd, J and Thiede, C and Döhner, K and Stone, RM and Döhner, H and Bloomfield, CD and Lo-Coco, F}, title = {Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.}, journal = {Blood advances}, volume = {4}, number = {19}, pages = {4945-4954}, pmid = {33049054}, issn = {2473-9537}, support = {UG1 CA233290/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA233180/CA/NCI NIH HHS/United States ; UG1 CA233338/CA/NCI NIH HHS/United States ; U24 CA196171/CA/NCI NIH HHS/United States ; U10 CA180867/CA/NCI NIH HHS/United States ; }, abstract = {The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.}, }
@article {pmid33049053, year = {2020}, author = {van der Ploeg, K and Le Luduec, JB and Stevenson, PA and Park, S and Gooley, TA and Petersdorf, EW and Shaffer, BC and Hsu, KC}, title = {HLA-A alleles influencing NK cell function impact AML relapse following allogeneic hematopoietic cell transplantation.}, journal = {Blood advances}, volume = {4}, number = {19}, pages = {4955-4964}, pmid = {33049053}, issn = {2473-9537}, support = {R01 AI125651/AI/NIAID NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; K23 HL140134/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {HLA-B allotypes exhibiting the Bw4 epitope trigger variable inhibitory signaling of KIR3DL1 receptor types, where strong inhibitory HLA-B and KIR3DL1 allele combinations are associated with increased risk for relapse of acute myelogenous leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). Several HLA-A allotypes also exhibit the Bw4 epitope. Studies with natural killer (NK) cell clones have demonstrated NK inhibition via KIR3DL1 by HLA-A Bw4+ allotypes, but did not delineate strengths of inhibition or hierarchies of NK education. Using primary NK cells from healthy donors, we demonstrate that HLA-A*23, HLA-A*24, and HLA-A*32 proteins are expressed at different densities and exhibit different capacities to educate and inhibit KIR3DL1-expressing NK cells in vitro. Among the HLA-A Bw4+ allotypes, HLA-A*24 and HLA-A*32 demonstrate the strongest inhibitory capacity. To determine if HLA-A allotypes with strong inhibitory capacity have similar negative impact in allogeneic HCT as HLA-B Bw4+ allotypes, we performed a retrospective analysis of 1729 patients with AML who received an allogeneic HCT from a 9/10 or 10/10 HLA allele-matched unrelated donor. Examination of the donor-recipient pairs whose Bw4 epitope was exclusively contributed from HLA-A*24 and A*32 allotypes revealed that patients with HLA-A*24 who received an allograft from a KIR3DL1+ donor experienced a higher risk of disease relapse (hazard ratio, 1.65; 95% confidence interval, 1.17-2.32; P = .004) when compared with patients without a Bw4 epitope. These findings indicate that despite weak affinity interactions with KIR3DL1, common HLA-A allotypes with the Bw4 epitope can interact with KIR3DL1+ donor NK cells with clinically meaningful impact and provide additional insight to donor NK alloreactivity in HLA-matched HCT.}, }
@article {pmid33049000, year = {2020}, author = {Montes de Oca, M and de Labastida Rivera, F and Winterford, C and Frame, TCM and Ng, SS and Amante, FH and Edwards, CL and Bukali, L and Wang, Y and Uzonna, JE and Kuns, RD and Zhang, P and Kabat, A and Klein Geltink, RI and Pearce, EJ and Hill, GR and Engwerda, CR}, title = {IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection.}, journal = {PLoS pathogens}, volume = {16}, number = {10}, pages = {e1008994}, pmid = {33049000}, issn = {1553-7374}, abstract = {Inflammation is critical for controlling pathogens, but also responsible for symptoms of infectious diseases. IL-27 is an important regulator of inflammation and can limit development of IFNγ-producing Tbet+ CD4+ T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4+ T cells, but the underlying mechanisms of these immunoregulatory pathways are not clear. Here we studied the role of IL-27 signalling in experimental visceral leishmaniasis (VL) caused by infection of C57BL/6 mice with the human pathogen Leishmania donovani. We found IL-27 signalling was critical for the development of IL-10-producing Th1 (Tr1) cells during infection. Furthermore, in the absence of IL-27 signalling, there was improved control of parasite growth, but accelerated splenic pathology characterised by the loss of marginal zone macrophages. Critically, we discovered that IL-27 signalling limited glycolysis in Th1 cells during infection that in turn attenuated inflammation. Furthermore, the modulation of glycolysis in the absence of IL-27 signalling restricted tissue pathology without compromising anti-parasitic immunity. Together, these findings identify a novel mechanism by which IL-27 mediates immune regulation during disease by regulating cellular metabolism.}, }
@article {pmid33048842, year = {2020}, author = {Coelho, CH and Nadakal, ST and Gonzales Hurtado, P and Morrison, R and Galson, JD and Neal, J and Wu, Y and King, CR and Price, V and Miura, K and Wong-Madden, S and Alamou Doritchamou, JY and Narum, DL and MacDonald, NJ and Snow-Smith, M and Vignali, M and Taylor, JJ and Lefranc, MP and Trück, J and Long, CA and Sagara, I and Fried, M and Duffy, PE}, title = {Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing.}, journal = {JCI insight}, volume = {5}, number = {22}, pages = {}, pmid = {33048842}, issn = {2379-3708}, abstract = {Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. Here, we develop an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. Using proteomic tools coupled with bulk immunosequencing data, we determined human antigen-binding fragment [F(ab')2] peptide sequences from plasma IG of adults who received 4 doses of Pfs25-EPA/Alhydrogel. Specifically, Pfs25 antigen-specific F(ab')2 peptides (Pfs25-IG) were aligned to cDNA sequences of IG heavy (IGH) chain complementarity determining region 3 from a data set generated by total peripheral B cell immunosequencing of the entire vaccinated population. IGHV4 was the most commonly identified IGHV subgroup of Pfs25-IG, a pattern that was corroborated by V heavy/V light chain sequencing of Pfs25-specific single B cells from 5 vaccinees and by matching plasma Pfs25-IG peptides and V-(D)-J sequences of Pfs25-specific single B cells from the same donor. Among 13 recombinant human mAbs generated from IG sequences of Pfs25-specific single B cells, a single IGHV4 mAb displayed strong neutralizing activity, reducing the number of P. falciparum oocysts in infected mosquitoes by more than 80% at 100 μg/mL. Our approach characterizes the human plasma Ab repertoire in response to the Pfs25-EPA/Alhydrogel vaccine and will be useful for studying circulating Abs in response to other vaccines as well as those induced during infections or autoimmune disorders.}, }
@article {pmid33048379, year = {2020}, author = {Richard, MA and Brown, AL and Belmont, JW and Scheurer, ME and Arroyo, VM and Foster, KL and Kern, KD and Hudson, MM and Leisenring, WM and Okcu, MF and Sapkota, Y and Yasui, Y and Morton, LM and Chanock, SJ and Robison, LL and Armstrong, GT and Bhatia, S and Oeffinger, KC and Lupo, PJ and Kamdar, KY}, title = {Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.33258}, pmid = {33048379}, issn = {1097-0142}, support = {//St. Baldrick's Foundation/ ; CA21765/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; U24 CA55727/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; 6314-11//Leukemia and Lymphoma Society/ ; //Micaela's Army Foundation/ ; U01 CA195547/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL.<br><br>METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors.<br><br>RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age.<br><br>CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.}, }
@article {pmid33046887, year = {2020}, author = {Galletti, G and De Simone, G and Mazza, EMC and Puccio, S and Mezzanotte, C and Bi, TM and Davydov, AN and Metsger, M and Scamardella, E and Alvisi, G and De Paoli, F and Zanon, V and Scarpa, A and Camisa, B and Colombo, FS and Anselmo, A and Peano, C and Polletti, S and Mavilio, D and Gattinoni, L and Boi, SK and Youngblood, BA and Jones, RE and Baird, DM and Gostick, E and Llewellyn-Lacey, S and Ladell, K and Price, DA and Chudakov, DM and Newell, EW and Casucci, M and Lugli, E}, title = {Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans.}, journal = {Nature immunology}, volume = {21}, number = {12}, pages = {1552-1562}, doi = {10.1038/s41590-020-0791-5}, pmid = {33046887}, issn = {1529-2916}, support = {ERC_StG_2014 PERSYST 640511//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; IG21567//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PE-2016-02363915//Ministero della Salute (Ministry of Health, Italy)/ ; C17199/A18246/A29202//Cancer Research UK (CRUK)/ ; 100326/Z/12/Z//Wellcome Trust (Wellcome)/ ; }, abstract = {T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.}, }
@article {pmid33046529, year = {2020}, author = {Addetia, A and Lin, MJ and Peddu, V and Roychoudhury, P and Jerome, KR and Greninger, AL}, title = {Sensitive Recovery of Complete SARS-CoV-2 Genomes from Clinical Samples by Use of Swift Biosciences' SARS-CoV-2 Multiplex Amplicon Sequencing Panel.}, journal = {Journal of clinical microbiology}, volume = {59}, number = {1}, pages = {}, pmid = {33046529}, issn = {1098-660X}, mesh = {COVID-19/diagnosis ; COVID-19 Nucleic Acid Testing/*methods ; Gene Library ; Genome, Viral/*genetics ; Humans ; Phylogeny ; RNA, Viral/genetics ; SARS-CoV-2/*genetics ; Whole Genome Sequencing/*methods ; }, }
@article {pmid33046443, year = {2020}, author = {Rusert, JM and Juarez, EF and Brabetz, S and Jensen, J and Garancher, A and Chau, LQ and Tacheva-Grigorova, SK and Wahab, S and Udaka, YT and Finlay, D and Seker-Cin, H and Reardon, B and Gröbner, S and Serrano, J and Ecker, J and Qi, L and Kogiso, M and Du, Y and Baxter, PA and Henderson, JJ and Berens, ME and Vuori, K and Milde, T and Cho, YJ and Li, XN and Olson, JM and Reyes, I and Snuderl, M and Wong, TC and Dimmock, DP and Nahas, SA and Malicki, D and Crawford, JR and Levy, ML and Van Allen, EM and Pfister, SM and Tamayo, P and Kool, M and Mesirov, JP and Wechsler-Reya, RJ}, title = {Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.}, journal = {Cancer research}, volume = {80}, number = {23}, pages = {5393-5407}, pmid = {33046443}, issn = {1538-7445}, support = {P30 CA030199/CA/NCI NIH HHS/United States ; R01 CA159859/CA/NCI NIH HHS/United States ; R01 NS096368/NS/NINDS NIH HHS/United States ; }, abstract = {Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.}, }
@article {pmid33045387, year = {2020}, author = {Farhadfar, N and Burns, LJ and Mupfudze, T and Shaw, BE and Bollard, CM and Devine, SM and Horowitz, MM and Jones, RJ and Murthy, HS and Wingard, JR and Lee, SJ}, title = {Hematopoietic Cell Transplantation: Practice Predictions for the Year 2023.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.bbmt.2020.10.006}, pmid = {33045387}, issn = {1523-6536}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, abstract = {Research priorities are best determined by the most pressing scientific questions, in the context of current knowledge. However, definitive research studies take time, while real-world experience accumulates. Adoption of new practices before adequate comparison with current treatments threatens successful study conduct and may expose patients to what ultimately turns out to be inferior treatment. We conducted a survey to understand the hematopoietic cell transplantation (HCT) community's predictions about future practice trends in the HCT field and results of ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials to gauge how the HCT community views the treatments being studied. The survey was distributed between February and March 2019 to an electronic mailing list of HCT clinicians practicing in the United States maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR). Of 986 clinicians surveyed, 315 responded (32%). They predicted an increase in the number of HCTs performed for malignant hematologic diseases and benign diseases such as sickle cell, autoimmune, and genetic disorders. The majority (63%) predicted that matched related donors will remain the preferred donor source for adult HCT recipients in 2023, but 21% predicted haploidentical (haplo) donors and 17% predicted matched unrelated donors would be the preferred source. Most respondents (65%) predicted a decrease in the use of umbilical cord blood (UCB) as a graft source for HCT. Most respondents also predicted that calcineurin-based graft-versus-host disease (GVHD) prophylaxis would be replaced by post-transplantation cyclophosphamide (PTCy) (55%), biomarker use would become standard practice to guide GVHD therapy (73%), and steroids would be combined with other agents as first-line therapy for newly diagnosed acute (53%) and chronic GVHD (54%). In ongoing BMT CTN trials in which outcomes are not yet known, 60% to 92% of respondents had an opinion about which arm they thought would be superior. However, not all respondents predicted the same outcome, with 44% to 88% choosing the same arm. There was no clear relationship between the proportion predicting the same arm would win and accrual to the trial. Survey respondents were optimistic about an increasing volume of transplantation procedures, and they also expected significant changes in HCT practice over the next few years, including wider adoption of PTCy GVHD prophylaxis, increased use of biomarkers to guide GVHD therapy, and decreased use of UCB HCT. The degree of equipoise in the community about the relative efficacy of therapies being studied did not seem to affect accrual to current BMT CTN trials, but this is an area that needs further investigation.}, }
@article {pmid33044955, year = {2020}, author = {Karcher, MD and Carvalho, LM and Suchard, MA and Dudas, G and Minin, VN}, title = {Estimating effective population size changes from preferentially sampled genetic sequences.}, journal = {PLoS computational biology}, volume = {16}, number = {10}, pages = {e1007774}, pmid = {33044955}, issn = {1553-7358}, support = {R01 AI107034/AI/NIAID NIH HHS/United States ; R01 LM012080/LM/NLM NIH HHS/United States ; U54 GM111274/GM/NIGMS NIH HHS/United States ; }, abstract = {Coalescent theory combined with statistical modeling allows us to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. When sequences are sampled serially through time and the distribution of the sampling times depends on the effective population size, explicit statistical modeling of sampling times improves population size estimation. Previous work assumed that the genealogy relating sampled sequences is known and modeled sampling times as an inhomogeneous Poisson process with log-intensity equal to a linear function of the log-transformed effective population size. We improve this approach in two ways. First, we extend the method to allow for joint Bayesian estimation of the genealogy, effective population size trajectory, and other model parameters. Next, we improve the sampling time model by incorporating additional sources of information in the form of time-varying covariates. We validate our new modeling framework using a simulation study and apply our new methodology to analyses of population dynamics of seasonal influenza and to the recent Ebola virus outbreak in West Africa.}, }
@article {pmid33044876, year = {2020}, author = {Marchand, A and Kervarrec, T and Bhatia, S and Samimi, M}, title = {Pembrolizumab and other immune checkpoint inhibitors in locally advanced or metastatic Merkel Cell Carcinoma: safety and efficacy.}, journal = {Expert review of anticancer therapy}, volume = {20}, number = {12}, pages = {1093-1106}, doi = {10.1080/14737140.2021.1835477}, pmid = {33044876}, issn = {1744-8328}, abstract = {INTRODUCTION: Merkel Cell Carcinoma (MCC) is a rare aggressive skin cancer, mostly affecting elderly patients. Until recently, patients with advanced disease were treated with cytotoxic chemotherapies despite rapid chemoresistance and high toxicity. As with other cancers, immune checkpoint inhibitors (CPI), including pembrolizumab, allow durable responses with a manageable safety profile in these patients.<br><br>AREAS COVERED: This review describes the rationale for using PD-1/PD-L1 inhibitors in MCC, as well as efficacy and safety results from the three open-label trials investigating pembrolizumab or other PD-1/PD-L1 inhibitors in patients with advanced MCC. Real-life experience and predictive pre-treatment biomarkers are discussed to assess which patients are likely to be candidates for such strategies. Ongoing fields of research include the use of CPI in the adjuvant or neoadjuvant setting and combined strategies in refractory patients. Expert Opinion: CPI have become the standard of care for frontline treatment in patients with advanced MCC. Earlier introduction of CPI in the disease course, including neo-adjuvant and adjuvant settings, is likely to improve the outcomes further. Given the rarity of this cancer, we still need to harmonize efforts in order to conduct large-scale trials and efficiently identify best optimal care.}, }
@article {pmid33043613, year = {2021}, author = {Alshiekh, S and Maziarz, M and Geraghty, DE and Larsson, HE and Agardh, D}, title = {High-resolution genotyping indicates that children with type 1 diabetes and celiac disease share three HLA class II loci in DRB3, DRB4 and DRB5 genes.}, journal = {HLA}, volume = {97}, number = {1}, pages = {44-51}, pmid = {33043613}, issn = {2059-2310}, support = {//Skåne County Council's Research and Development Foundation/ ; //Swedish Research Foundation; Skåne University Hospital Foundation./ ; }, abstract = {Type 1 diabetes (T1D) and celiac disease (CD) share common genetic loci, mainly within the human leukocyte antigen (HLA) class II complex. Extended genotyping of HLA class II alleles and their potential risk for developing both diseases remains to be studied. The present study compared extended HLA-class II gene polymorphisms in children with T1D, CD, and a subgroup diagnosed with both diseases (T1D w/CD). Next-generation targeted sequencing (NGTS) of HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1, and DPB1 alleles from DNA collected from 68 T1D, 219 CD, and seven T1D w/CD patients were compared with 636 HLA-genotyped Swedish children from the general population selected as controls. In comparison to controls, the DRB4*01:03:01 allele occurred more frequently in T1D w/CD (odds ratio (OR) = 7.84; 95% confidence interval (95% CI) = (2.24, 34.5), P = 0.0002) and T1D (OR = 3.86; 95% CI, (2.69, 5.55), P = 1.07 × 10-14), respectively. The DRB3*01:01:02 allele occurred more frequently in CD as compared to controls (OR = 7.87; 95% CI, (6.17, 10.03), P = 4.24 × 10-71), but less frequently in T1D (OR = 2.59; 95% CI, (1.76, 3.81), P = 7.29 × 10-07) and T1D w/CD (OR = 0.87; 95% CI, (0.09, 3.96), P ≤ 0.999). The frequency of the DRB4*01:03:01-DRB1*04:01:01-DQA1*03:01:01-DQB1*03:02:01 (DR4-DQ8) haplotype was higher in T1D w/CD (OR = 12.88; 95% CI (4.35, 38.14) P = 3.75 × 10-9), and moderately higher in T1D (OR = 2.13; 95% CI (1.18, 3.83) P = 0.01) compared with controls, but comparable in CD (OR = 1.45; 95% CI (0.94, 2.21), P = 0.08) and controls. Children with T1D and CD are associated with DRB4*01:03:01, DRB3*01:01:02, and DRB3*02:02:01 of which DRB4*01:03:01 confers the strongest risk allele for developing T1D w/CD.}, }
@article {pmid33043428, year = {2020}, author = {Williamson, BD and Gilbert, PB and Carone, M and Simon, N}, title = {Nonparametric variable importance assessment using machine learning techniques.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13392}, pmid = {33043428}, issn = {1541-0420}, support = {DP5 OD019820/OD/NIH HHS/United States ; F31 AI140836/AI/NIAID NIH HHS/United States ; R01 AI029168/AI/NIAID NIH HHS/United States ; UM1AI068635//National Institute of Allergy and Infectious Diseases/ ; F31AI140836//National Institute of Allergy and Infectious Diseases/ ; DP5OD019820//National Institute of Allergy and Infectious Diseases/ ; R01AI029168//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {In a regression setting, it is often of interest to quantify the importance of various features in predicting the response. Commonly, the variable importance measure used is determined by the regression technique employed. For this reason, practitioners often only resort to one of a few regression techniques for which a variable importance measure is naturally defined. Unfortunately, these regression techniques are often suboptimal for predicting the response. Additionally, because the variable importance measures native to different regression techniques generally have a different interpretation, comparisons across techniques can be difficult. In this work, we study a variable importance measure that can be used with any regression technique, and whose interpretation is agnostic to the technique used. This measure is a property of the true data-generating mechanism. Specifically, we discuss a generalization of the analysis of variance variable importance measure and discuss how it facilitates the use of machine learning techniques to flexibly estimate the variable importance of a single feature or group of features. The importance of each feature or group of features in the data can then be described individually, using this measure. We describe how to construct an efficient estimator of this measure as well as a valid confidence interval. Through simulations, we show that our proposal has good practical operating characteristics, and we illustrate its use with data from a study of risk factors for cardiovascular disease in South Africa.}, }
@article {pmid33042443, year = {2020}, author = {Connelly, ZM and Jin, R and Zhang, J and Yang, S and Cheng, S and Shi, M and Cates, JM and Shi, R and DeGraff, DJ and Nelson, PS and Liu, Y and Morrissey, C and Corey, E and Yu, X}, title = {FOXA2 promotes prostate cancer growth in the bone.}, journal = {American journal of translational research}, volume = {12}, number = {9}, pages = {5619-5629}, pmid = {33042443}, issn = {1943-8141}, abstract = {Bone metastasis frequently occurs in advanced-stage prostate cancer (PCa) patients. Understanding the mechanisms that promote PCa-mediated bone destruction is important for the identification of therapeutic targets against this lethal disease. We found that forkhead box A2 (FOXA2) is expressed in a subset of PCa bone metastasis specimens. To determine the functional role of FOXA2 in PCa metastasis, we knocked down the expression of FOXA2 in PCa PC3 cells, which can grow in bones and elicit an osteolytic reaction. The PC3/FOXA2-knockdown cells generated fewer bone lesions following intra-tibial injection compared to control cells. Further, we found that FOXA2 knockdown decreased the expression of PTHLH, which encodes PTHrP, a well-established factor that regulates bone remodeling. These results indicate that FOXA2 is involved in PCa bone metastasis.}, }
@article {pmid33038964, year = {2020}, author = {Kuderer, NM and Wulff-Burchfield, E and Rubinstein, SM and Grivas, P and Warner, JL}, title = {Cancer and COVID-19 - Authors' reply.}, journal = {Lancet (London, England)}, volume = {396}, number = {10257}, pages = {1067-1068}, pmid = {33038964}, issn = {1474-547X}, mesh = {Betacoronavirus ; COVID-19 ; Cohort Studies ; *Coronavirus Infections ; Humans ; *Neoplasms ; *Pandemics ; *Pneumonia, Viral ; SARS-CoV-2 ; }, }
@article {pmid33038280, year = {2020}, author = {Dimou, NL and Papadimitriou, N and Mariosa, D and Johansson, M and Brennan, P and Peters, U and Chanock, SJ and Purdue, M and Bishop, DT and Gago-Dominquez, M and Giles, GG and Moreno, V and Platz, EA and Tangen, CM and Wolk, A and Zheng, W and Wu, X and Campbell, PT and Giovannucci, E and Lin, Y and ,  and Gunter, MJ and Murphy, N}, title = {Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.33338}, pmid = {33038280}, issn = {1097-0215}, support = {//Funding information for this article is available after the Acknowledgement section./ ; }, abstract = {Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10-8). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.}, }
@article {pmid33038127, year = {2020}, author = {Patel, S and Issaka, RB and Chen, E and Somsouk, M}, title = {Colorectal Cancer Screening and COVID-19.}, journal = {The American journal of gastroenterology}, volume = {}, number = {}, pages = {}, pmid = {33038127}, issn = {1572-0241}, }
@article {pmid33037989, year = {2020}, author = {Chow, EJ and Doody, DR and Di, C and Armenian, SH and Baker, KS and Bricker, JB and Gopal, AK and Hagen, AM and Ketterl, TG and Lee, SJ and Reding, KW and Schenk, JM and Syrjala, KL and Taylor, SA and Wang, G and Neuhouser, ML and Mendoza, JA}, title = {Feasibility of a behavioral intervention using mobile health applications to reduce cardiovascular risk factors in cancer survivors: a pilot randomized controlled trial.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11764-020-00949-w}, pmid = {33037989}, issn = {1932-2267}, support = {R01 CA215134/CA/NCI NIH HHS/United States ; CA015704/CA/NCI NIH HHS/United States ; CA215134/CA/NCI NIH HHS/United States ; CA204378/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Determine the feasibility of a remotely delivered mobile health (mHealth)-supported intervention to improve diet and physical activity in hematologic malignancy survivors.<br><br>METHODS: Pilot randomized controlled trial of a 16-week intervention for improving diet and physical activity: individualized goal-setting (daily steps, sodium, saturated fat, added sugar intake) per feedback from mHealth trackers (Fitbit for activity; Healthwatch360 for diet), supplemented by a Facebook peer support group. Controls accessed the trackers without goal-setting or peer support. Everyone received standardized survivorship counseling with tailored advice from a clinician. Actigraphy and food frequency questionnaires assessed activity and diet at baseline and follow-up.<br><br>RESULTS: Forty-one participants (51.2% male; median age 45.1 years; 7.0 years from treatment) were randomized (24 intervention; 17 control). Fitbit and Healthwatch360 use were more common among intervention versus control participants (75.0% versus 70.6% and 50.0% versus 17.7% of eligible days, respectively). Most intervention participants (66.7%) engaged with Facebook; overall, 91.7% interacted with the study's mHealth applications. While no comparisons in activity or dietary outcomes between intervention versus control group met statistical significance, the intervention was associated with greater reductions in the targeted dietary factors and improvements in Healthy Eating Index-2015 score, moderate-vigorous physical activity time, and daily steps. Participant retention at 6 months was 90.2%.<br><br>CONCLUSIONS: An intervention for cardiovascular risk reduction based on individualized goal-setting enhanced by mHealth and social media peer support was feasible and acceptable among cancer survivors.<br><br>Effective and easily disseminated strategies that improve diet and physical activity in this population are needed.<br><br>TRIAL REGISTRATION: Registered in ClinicalTrials.gov (NCT03574012) on June 29, 2018.}, }
@article {pmid33037320, year = {2020}, author = {Rozot, V and Nemes, E and Geldenhuys, H and Musvosvi, M and Toefy, A and Rantangee, F and Makhethe, L and Erasmus, M and Bilek, N and Mabwe, S and Finak, G and Fulp, W and Ginsberg, AM and Hokey, DA and Shey, M and Gurunathan, S and DiazGranados, C and Bekker, LG and Hatherill, M and Scriba, TJ and , }, title = {Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines.}, journal = {Communications biology}, volume = {3}, number = {1}, pages = {563}, pmid = {33037320}, issn = {2399-3642}, abstract = {We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection.}, }
@article {pmid33037203, year = {2020}, author = {Bauer, M and Nascakova, Z and Mihai, AI and Cheng, PF and Levesque, MP and Lampart, S and Hurwitz, R and Pfannkuch, L and Dobrovolna, J and Jacobs, M and Bartfeld, S and Dohlman, A and Shen, X and Gall, AA and Salama, NR and Töpfer, A and Weber, A and Meyer, TF and Janscak, P and Müller, A}, title = {The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress.}, journal = {Nature communications}, volume = {11}, number = {1}, pages = {5117}, pmid = {33037203}, issn = {2041-1723}, mesh = {Adaptor Proteins, Signal Transducing/genetics/*metabolism ; Bacterial Proteins/metabolism ; Cell Line, Tumor ; DNA/chemistry/genetics ; DNA Damage ; DNA Replication/drug effects ; Floxuridine ; Glycosyltransferases/metabolism ; Helicobacter Infections/metabolism/microbiology ; Helicobacter pylori/metabolism/*pathogenicity ; Host-Pathogen Interactions/physiology ; Humans ; Lipopolysaccharides/metabolism ; Mutation ; NF-kappa B/genetics/*metabolism ; Protein Kinases/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Stomach Neoplasms/genetics/microbiology/pathology ; }, abstract = {Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.}, }
@article {pmid33035616, year = {2020}, author = {Park, J and Frizzell, H and Zhang, H and Cao, S and Hughes, SM and Hladik, F and Koelle, DM and Woodrow, KA}, title = {Flt3-L enhances trans-epithelial migration and antigen presentation of dendritic cells adoptively transferred to genital mucosa.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jconrel.2020.10.012}, pmid = {33035616}, issn = {1873-4995}, abstract = {Dendritic cells (DCs) play a critical role in shaping adaptive immunity. Systemic transfer of DCs by intravenous injection has been widely investigated to inform the development of immunogenic DCs for use as cellular therapies. Adoptive transfer of DCs to mucosal sites has been limited but serves as a valuable tool to understand the role of the microenvironment on mucosal DC activation, maturation and antigen presentation. Here, we show that chitosan facilitates transmigration of DCs across the vaginal epithelium in the mouse female reproductive tract (FRT). In addition, ex vivo programming of DCs with fms-related tyrosine kinase 3 ligand (Flt3-L) was found to enhance translocation of intravaginally administered DCs to draining lymph nodes (dLNs) and stimulate in vivo proliferation of both antigen-specific CD4+ and CD8+ T cells (cross-presentation). Mucosal priming with chitosan and DC programming may hold great promise to enhance efficacy of DC-based vaccination to the female genital mucosa.}, }
@article {pmid33035459, year = {2020}, author = {Gounder, M and Schöffski, P and Jones, RL and Agulnik, M and Cote, GM and Villalobos, VM and Attia, S and Chugh, R and Chen, TW and Jahan, T and Loggers, ET and Gupta, A and Italiano, A and Demetri, GD and Ratan, R and Davis, LE and Mir, O and Dileo, P and Van Tine, BA and Pressey, JG and Lingaraj, T and Rajarethinam, A and Sierra, L and Agarwal, S and Stacchiotti, S}, title = {Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.}, journal = {The Lancet. Oncology}, volume = {21}, number = {11}, pages = {1423-1432}, doi = {10.1016/S1470-2045(20)30451-4}, pmid = {33035459}, issn = {1474-5488}, mesh = {Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/adverse effects ; Benzamides/*administration &amp; dosage/adverse effects/pharmacokinetics ; Doxorubicin/administration &amp; dosage/adverse effects/pharmacokinetics ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Progression-Free Survival ; Pyridones/*administration &amp; dosage/adverse effects/pharmacokinetics ; SMARCB1 Protein/*genetics ; Sarcoma/*drug therapy/genetics/pathology ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma.<br><br>METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing.<br><br>FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.<br><br>INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941).<br><br>FUNDING: Epizyme.}, }
@article {pmid33035296, year = {2020}, author = {Armstrong, WS and Agwu, AL and Barrette, EP and Ignacio, RB and Chang, JJ and Colasanti, JA and Floris-Moore, M and Haddad, M and MacLaren, L and Weddle, A}, title = {Innovations in HIV care delivery during the COVID-19 pandemic: Policies to strengthen the Ending the Epidemic Initiative - A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaa1532}, pmid = {33035296}, issn = {1537-6591}, abstract = {The goal of the Ending the HIV Epidemic Initiative is to reduce new infections in the US by 90% by 2030. Success will require fundamentally changing HIV prevention and care delivery to engage more persons with HIV and at-risk of HIV in treatment. While the COVID-19 pandemic reduced in-person visits to care facilities and led to concern about interruptions in care, it also accelerated growth of alternative options, bolstered by additional funding support. These included the use of telehealth, medication delivery to the home and increased flexibility facilitating access to Ryan White HIV/AIDS Program services. While the outcomes of these programs must be studied, many have improved accessibility during the pandemic. As the pandemic wanes, long term policy changes are needed to preserve these options for those who benefit from them. These new care paradigms may provide a roadmap for progress for those with other chronic health issues as well.}, }
@article {pmid33033531, year = {2019}, author = {Huang, Y and Dasgupta, S}, title = {Likelihood-Based Methods for Assessing Principal Surrogate Endpoints in Vaccine Trials.}, journal = {Statistics in biosciences}, volume = {11}, number = {3}, pages = {504-523}, pmid = {33033531}, issn = {1867-1764}, support = {R01 GM106177/GM/NIGMS NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; }, abstract = {When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study design with a close-out placebo vaccination (CPV) component. The estimated likelihood approach, which separates the estimation of biomarker distribution from the maximization of the estimated likelihood, has often been adopted. Here we develop a likelihood-based approach that jointly estimates the two parts and describe the methods for selecting auxiliary variables as risk predictors and/or biomarker predictors. Through numerical studies, we observe that in a standard trial design without a CPV component, the two methods achieve similar performance in estimation of the risk model and the marker model. However, for trials augmented with a CPV component, using the likelihood-based method achieves better estimation performance compared to the estimated likelihood method. Moreover, in the presence of a large number of covariates from which to select, the ML method achieves comparable or better performance compared to the EL method in both designs. While the CPV component has not yet been implemented in existing vaccine trials, our results have applications in the planning of future vaccine trials. We illustrate the method using data from a dengue vaccine trial.}, }
@article {pmid33033018, year = {2020}, author = {Chu, HY and Boeckh, M and Englund, JA and Famulare, M and Lutz, B and Nickerson, DA and Rieder, M and Starita, LM and Adler, A and Brandstetter, E and Frazer, CD and Han, PD and Gulati, RK and Hadfield, J and Jackson, M and Kiavand, A and Kimball, LE and Lacombe, K and Newman, K and Sibley, TR and Logue, JK and Lyon, VR and Wolf, CR and Zigman Suchsland, M and Shendure, J and Bedford, T}, title = {The Seattle Flu Study: a multiarm community-based prospective study protocol for assessing influenza prevalence, transmission and genomic epidemiology.}, journal = {BMJ open}, volume = {10}, number = {10}, pages = {e037295}, pmid = {33033018}, issn = {2044-6055}, abstract = {INTRODUCTION: Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterise, and potentially contain new and emerging influenza strains at both an individual and population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.<br><br>METHODS AND ANALYSIS: Starting in the 2018-2019 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modelling platforms are in development to characterise the regional spread of influenza and other respiratory pathogens.<br><br>ETHICS AND DISSEMINATION: The study was approved by the University of Washington's Institutional Review Board (STUDY00006181). Results will be disseminated through talks at conferences, peer-reviewed publications and on the study website (www.seattleflu.org).}, }
@article {pmid33032661, year = {2020}, author = {Manrique-Saide, P and Dean, NE and Halloran, ME and Longini, IM and Collins, MH and Waller, LA and Gomez-Dantes, H and Lenhart, A and Hladish, TJ and Che-Mendoza, A and Kirstein, OD and Romer, Y and Correa-Morales, F and Palacio-Vargas, J and Mendez-Vales, R and Pérez, PG and Pavia-Ruz, N and Ayora-Talavera, G and Vazquez-Prokopec, GM}, title = {The TIRS trial: protocol for a cluster randomized controlled trial assessing the efficacy of preventive targeted indoor residual spraying to reduce Aedes-borne viral illnesses in Merida, Mexico.}, journal = {Trials}, volume = {21}, number = {1}, pages = {839}, pmid = {33032661}, issn = {1745-6215}, support = {U01AI148069//National Institute of Allergy and Infectious Diseases/ ; R01 AI139761/AI/NIAID NIH HHS/United States ; U54 GM111274/NH/NIH HHS/United States ; R37 AI0032042/NH/NIH HHS/United States ; DFID:30041-105//Innovative Vector Control Consortium/ ; }, abstract = {BACKGROUND: Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces.<br><br>METHODS/DESIGN: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2-15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A &quot;fried egg&quot; design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the &quot;yolk,&quot; the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1-2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons.<br><br>DISCUSSION: The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04343521 . Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1).<br><br>PRIMARY SPONSOR: National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).}, }
@article {pmid33031748, year = {2020}, author = {Feofanova, EV and Chen, H and Dai, Y and Jia, P and Grove, ML and Morrison, AC and Qi, Q and Daviglus, M and Cai, J and North, KE and Laurie, CC and Kaplan, RC and Boerwinkle, E and Yu, B}, title = {A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.}, journal = {American journal of human genetics}, volume = {107}, number = {5}, pages = {849-863}, pmid = {33031748}, issn = {1537-6605}, support = {HHSN268201300005C/HL/NHLBI NIH HHS/United States ; HHSN268201300004C/HL/NHLBI NIH HHS/United States ; HHSN268201300001C/HL/NHLBI NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; R01 HL087641/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; R01 DK120870/DK/NIDDK NIH HHS/United States ; R01 HG009974/HG/NHGRI NIH HHS/United States ; R01 HL059367/HL/NHLBI NIH HHS/United States ; R01 HL086694/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; HHSN268201700002C/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; HHSN268201300003C/HG/NHGRI NIH HHS/United States ; R01 HL142003/HL/NHLBI NIH HHS/United States ; HHSN268201700005C/HL/NHLBI NIH HHS/United States ; HHSN268201700001C/HL/NHLBI NIH HHS/United States ; HHSN268201700003C/HL/NHLBI NIH HHS/United States ; R01 HL141824/HL/NHLBI NIH HHS/United States ; HHSN268201700004C/HL/NHLBI NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Chromans/metabolism ; Cohort Studies ; Coronary Disease/diagnosis/ethnology/*genetics/metabolism ; Cytochrome P450 Family 4/genetics/metabolism ; Diabetes Mellitus, Type 2/diagnosis/ethnology/*genetics/metabolism ; Female ; Gene Expression ; *Genetic Predisposition to Disease ; *Genome, Human ; Genome-Wide Association Study ; Hispanic Americans ; Humans ; Male ; Membrane Transport Proteins/genetics/metabolism ; Metabolome/*genetics ; Middle Aged ; Phenotype ; Polymorphism, Single Nucleotide ; Propionates/metabolism ; Public Health ; *Quantitative Trait Loci ; Quantitative Trait, Heritable ; Vitamin E/metabolism ; }, abstract = {Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.}, }
@article {pmid33031539, year = {2020}, author = {Chow, VA and Gopal, AK and Gauthier, J and Tseng, YD and Turtle, CJ and Maloney, DG and Shadman, M}, title = {Axicabtagene ciloleucel for relapsed or refractory lymphoma after prior treatment with a different CD19-directed CAR T-cell therapy.}, journal = {Blood advances}, volume = {4}, number = {19}, pages = {4869-4872}, pmid = {33031539}, issn = {2473-9537}, }
@article {pmid33031159, year = {2020}, author = {Ganapathi, SS and Havard, ME and Ferguson, M and Cole, BL and Millard, NE and Vitanza, NA}, title = {Extramedullary Hematopoiesis in the Dura Mater During Treatment of a CNS Embryonal Tumor.}, journal = {Journal of pediatric hematology/oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPH.0000000000001962}, pmid = {33031159}, issn = {1536-3678}, abstract = {Extramedullary hematopoiesis (EMH) is hematopoiesis occurring outside of the bone marrow. It has been reported to develop in abdominal organs or lymph nodes after chemotherapy. Here, the authors describe a patient with a localized central nervous system embryonal tumor who, during intensive chemotherapy, developed dural nodules. Biopsy revealed these nodules to be EMH. Without a pathologic diagnosis, this may have been considered disease progression, altering the patient's treatment plan. This report intends to serve as a reminder that EMH should be included in the differential diagnosis of suspicious lesions and highlights the importance of their biopsy because of potential management implications.}, }
@article {pmid33030979, year = {2020}, author = {Palmieri, R and Othus, M and Halpern, AB and Percival, MM and Godwin, CD and Becker, PS and Walter, RB}, title = {Accuracy of SIE/SIES/GITMO Consensus Criteria for Unfitness to Predict Early Mortality After Intensive Chemotherapy in Adults With AML or Other High-Grade Myeloid Neoplasm.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {38}, number = {35}, pages = {4163-4174}, doi = {10.1200/JCO.20.01392}, pmid = {33030979}, issn = {1527-7755}, abstract = {PURPOSE: With increasing therapeutic alternatives available, there is growing interest in tools that accurately identify patients most suitable for intensive acute myeloid leukemia (AML) chemotherapy. Nowadays, conceptual criteria proposed by an Italian panel of experts are widely used for this purpose. How accurately these Ferrara criteria predict fitness for intensive chemotherapy is unknown.<br><br>PATIENTS AND METHODS: We assessed the fitness of adults undergoing intensive AML therapy based on Ferrara criteria and determined the accuracy of this assessment for early mortality and survival prediction.<br><br>RESULTS: Among 655 adults who received curative-intent induction or reinduction chemotherapy with 7 days of standard-dose cytarabine and 3 days of an anthracycline (&quot;7+3&quot;) CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone), or reduced-dose CLAG-M, 197 (30%) met at least one of the criteria defining unfitness for intensive chemotherapy (F-unfit). Compared with F-fit patients, the overall survival of F-unfit patients was significantly shorter (median, 4.8 months; 95% CI, 3.6 to 6.5 months v 36.8 months; 95% CI, 27.4 to 73.0 months; P < .001). When used alone, the Ferrara unfitness assessment was more accurate in predicting day 28 and day 100 mortality than the treatment-related mortality score we developed previously (used binary, ≤ 13.1 v > 13.1), as indicated by area under the receiver operating characteristic curve (AUC) values of 0.76 and 0.79 versus 0.66 and 0.62. The predictive accuracy of the Ferrara unfitness assessment could be significantly improved by including additional covariates such as performance status and albumin, yielding AUCs as high as 0.84-0.85 for the prediction of day 28 or day 100 mortality. Prediction of overall survival was less accurate, yielding a c-statistic value as high as 0.75 in multivariable models.<br><br>CONCLUSION: Ferrara unfitness criteria provide a good prediction tool for shorter-term mortality after intensive AML chemotherapy. Our data may serve as a benchmark for expected outcomes with intensive chemotherapy in F-fit and F-unfit patients.}, }
@article {pmid33030517, year = {2020}, author = {Short, NJ and Zhou, S and Fu, C and Berry, DA and Walter, RB and Freeman, SD and Hourigan, CS and Huang, X and Nogueras Gonzalez, G and Hwang, H and Qi, X and Kantarjian, H and Ravandi, F}, title = {Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {33030517}, issn = {2374-2445}, abstract = {Importance: Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.<br><br>Objective: To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.<br><br>Data Sources: Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.<br><br>Study Selection: Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non-English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded.<br><br>Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling.<br><br>Main Outcomes and Measures: Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.<br><br>Results: Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization.<br><br>Conclusions and Relevance: The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.}, }
@article {pmid33029725, year = {2020}, author = {McKay, RR and Hafron, JM and Ferro, C and Wilfehrt, HM and Fitch, K and Flanders, SC and Fabrizio, MD and Schweizer, MT}, title = {A Retrospective Observational Analysis of Overall Survival with Sipuleucel-T in Medicare Beneficiaries Treated for Advanced Prostate Cancer.}, journal = {Advances in therapy}, volume = {37}, number = {12}, pages = {4910-4929}, pmid = {33029725}, issn = {1865-8652}, abstract = {INTRODUCTION: Since sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.<br><br>METHODS: This retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes.<br><br>RESULTS: The model included 6044 eligible men (average age 75-78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (n, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (n, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527-0.651) and 0.56 (0.494-0.627) for the any-line and first-line cohorts, respectively.<br><br>CONCLUSION: This analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.}, }
@article {pmid33028949, year = {2020}, author = {Suzuki, T and Uruno, A and Yumoto, A and Taguchi, K and Suzuki, M and Harada, N and Ryoke, R and Naganuma, E and Osanai, N and Goto, A and Suda, H and Browne, R and Otsuki, A and Katsuoka, F and Zorzi, M and Yamazaki, T and Saigusa, D and Koshiba, S and Nakamura, T and Fukumoto, S and Ikehata, H and Nishikawa, K and Suzuki, N and Hirano, I and Shimizu, R and Oishi, T and Motohashi, H and Tsubouchi, H and Okada, R and Kudo, T and Shimomura, M and Kensler, TW and Mizuno, H and Shirakawa, M and Takahashi, S and Shiba, D and Yamamoto, M}, title = {Author Correction: Nrf2 contributes to the weight gain of mice during space travel.}, journal = {Communications biology}, volume = {3}, number = {1}, pages = {566}, doi = {10.1038/s42003-020-01292-7}, pmid = {33028949}, issn = {2399-3642}, abstract = {An amendment to this paper has been published and can be accessed via a link at the top of the paper.}, }
@article {pmid33028713, year = {2020}, author = {Stinn, T and Kuntz, S and Varon, D and Huang, ML and Selke, S and Njikan, S and Ford, ES and Dragavon, J and Coombs, RW and Johnston, C and Bull, ME}, title = {Subclinical Genital Herpes Shedding in HIV/Herpes Simplex Virus 2-Coinfected Women during Antiretroviral Therapy Is Associated with an Increase in HIV Tissue Reservoirs and Potentially Promotes HIV Evolution.}, journal = {Journal of virology}, volume = {95}, number = {1}, pages = {}, pmid = {33028713}, issn = {1098-5514}, support = {K08 AI148588/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI124770/AI/NIAID NIH HHS/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; }, abstract = {Antigen (Ag)-specific immune responses to chronic infections, such as herpes simplex virus type 2 (HSV-2) in HIV/HSV-coinfected persons, may sustain HIV tissue reservoirs by promoting T-cell proliferation but are poorly studied in women on antiretroviral therapy (ART). Mixed anogenital swabs and cervical secretions were self-collected by nine HIV/HSV-2-coinfected women during ART for 28 days to establish subclinical HSV DNA shedding rates and detection of HIV RNA by real-time PCR. Typical herpes lesion site biopsy (TLSB) and cervical biopsy specimens were collected at the end of the daily sampling period. Nucleic acids (NA) isolated from biopsy specimens had HIV quantified and HIV envC2-V5 single-genome amplification (SGA) and T-cell receptor (TCR) repertoires assessed. Women had a median CD4 count of 537 cells/μl (IQR: 483 to 741) at enrollment and HIV plasma viral loads of <40 copies/ml. HSV DNA was detected on 12% of days (IQR: 2 to 25%) from anogenital specimens. Frequent subclinical HSV DNA shedding was associated with increased HIV DNA tissue concentrations and increased divergence from the most recent common ancestor (MRCA), an indicator of HIV replication. Distinct predominant TCR clones were detected in cervical and TLSB specimens in a woman with frequent HSV DNA shedding, with mixing of minor variants between her tissues. In contrast, more limited TCR repertoire mixing was observed in two women with less frequent subclinical HSV DNA shedding. Subclinical HSV shedding in HIV/HSV-coinfected women during ART may sustain HIV tissue reservoirs via Ag exposure or HIV replication. This study provides evidence supporting further study of interventions targeting suppression of Ag-specific immune responses as a component of HIV cure strategies.IMPORTANCE Persons with HIV infection are frequently coinfected with chronic herpesviruses, which periodically replicate and produce viable herpes virions, particularly in anogenital and cervical tissues. Persistent protein expression results in proliferation of CD8+ and CD4+ T cells, and the latter could potentially expand and sustain HIV tissue reservoirs. We found HSV genital shedding rates were positively correlated with HIV DNA concentrations and HIV divergence from ancestral sequences in tissues. Our work suggests that immune responses to common coinfections, such as herpesviruses, may sustain HIV tissue reservoirs during suppressive ART, suggesting future cure strategies should study interventions to suppress replication or reactivation of chronic herpes infections.}, }
@article {pmid33028263, year = {2020}, author = {Lloyd, EC and Sallis, HM and Verplanken, B and Haase, AM and Munafò, MR}, title = {Understanding the nature of association between anxiety phenotypes and anorexia nervosa: a triangulation approach.}, journal = {BMC psychiatry}, volume = {20}, number = {1}, pages = {495}, pmid = {33028263}, issn = {1471-244X}, support = {ES/J50015X/1//Economic and Social Research Council/ ; MC_UU_00011/7//MRC/ ; }, abstract = {BACKGROUND: Evidence from observational studies suggests an association between anxiety disorders and anorexia nervosa (AN), but causal inference is complicated by the potential for confounding in these studies. We triangulate evidence across a longitudinal study and a Mendelian randomization (MR) study, to evaluate whether there is support for anxiety disorder phenotypes exerting a causal effect on AN risk.<br><br>METHODS: Study One assessed longitudinal associations of childhood worry and anxiety disorders with lifetime AN in the Avon Longitudinal Study of Parents and Children cohort. Study Two used two-sample MR to evaluate: causal effects of worry, and genetic liability to anxiety disorders, on AN risk; causal effects of genetic liability to AN on anxiety outcomes; and the causal influence of worry on anxiety disorder development. The independence of effects of worry, relative to depressed affect, on AN and anxiety disorder outcomes, was explored using multivariable MR. Analyses were completed using summary statistics from recent genome-wide association studies.<br><br>RESULTS: Study One did not support an association between worry and subsequent AN, but there was strong evidence for anxiety disorders predicting increased risk of AN. Study Two outcomes supported worry causally increasing AN risk, but did not support a causal effect of anxiety disorders on AN development, or of AN on anxiety disorders/worry. Findings also indicated that worry causally influences anxiety disorder development. Multivariable analysis estimates suggested the influence of worry on both AN and anxiety disorders was independent of depressed affect.<br><br>CONCLUSIONS: Overall our results provide mixed evidence regarding the causal role of anxiety exposures in AN aetiology. The inconsistency between outcomes of Studies One and Two may be explained by limitations surrounding worry assessment in Study One, confounding of the anxiety disorder and AN association in observational research, and low power in MR analyses probing causal effects of genetic liability to anxiety disorders. The evidence for worry acting as a causal risk factor for anxiety disorders and AN supports targeting worry for prevention of both outcomes. Further research should clarify how a tendency to worry translates into AN risk, and whether anxiety disorder pathology exerts any causal effect on AN.}, }
@article {pmid33027813, year = {2020}, author = {Godwin, CD and Zhou, Y and Othus, M and Asmuth, MM and Shaw, C and Gardner, KM and Wood, BL and Walter, RB and Estey, E}, title = {Acute Myeloid Leukemia Measurable Residual Disease Detection by Flow Cytometry in Peripheral Blood Versus Bone Marrow.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2020006219}, pmid = {33027813}, issn = {1528-0020}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid33025002, year = {2020}, author = {Prentice, RL and Aragaki, AK and Chlebowski, RT and Rossouw, JE and Anderson, GL and Stefanick, ML and Wactawski-Wende, J and Kuller, LH and Wallace, R and Johnson, KC and Shadyab, AH and Gass, M and Manson, JAE}, title = {Randomized Trial Evaluation of Benefits and Risks of Menopausal Hormone Therapy Among Women Aged 50-59.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaa210}, pmid = {33025002}, issn = {1476-6256}, abstract = {The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy post-menopausal women aged 50-79 at 40 U.S. clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens, and 16,608 participants with uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over an 18-year (median) follow-up period (1993-2016) risk for a global index, defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality, is reduced with conjugated equine estrogens with hazard ratio (95% confidence interval) of 0.82 (0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (0.95, 1.19) were non-significant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.}, }
@article {pmid33023656, year = {2020}, author = {Petitprez, F and Levy, S and Sun, CM and Meylan, M and Linhard, C and Becht, E and Elarouci, N and Tavel, D and Roumenina, LT and Ayadi, M and Sautès-Fridman, C and Fridman, WH and de Reyniès, A}, title = {The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression.}, journal = {Genome medicine}, volume = {12}, number = {1}, pages = {86}, pmid = {33023656}, issn = {1756-994X}, abstract = {Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer's disease.}, }
@article {pmid33022830, year = {2020}, author = {Wenger, DS and Triplette, M and Shahrir, S and Akgun, KM and Wongtrakool, C and Brown, ST and Kim, JW and Soo Hoo, GW and Rodriguez-Barradas, MC and Huang, L and Feemster, LC and Zifodya, J and Crothers, K}, title = {Associations of marijuana with markers of chronic lung disease in people living with HIV.}, journal = {HIV medicine}, volume = {}, number = {}, pages = {}, doi = {10.1111/hiv.12966}, pmid = {33022830}, issn = {1468-1293}, support = {HL007287/HL/NHLBI NIH HHS/United State