tbuckley/cabot-search huggingface dataset:
PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma
Authors: Adnan Shami Shah, Xiaofu Cao, Andrew C. White, Jeremy M. Baskin
Journal: Cancer Research (2021)

Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1-S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation. SIGNIFICANCE: This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.
Genome-Scale Profiling Reveals Noncoding Loci Carry Higher Proportions of Concordant Data
Authors: Robert Literman, Rachel Schwartz
Journal: Molecular Biology and Evolution (2021)

Abstract Many evolutionary relationships remain controversial despite whole-genome sequencing data. These controversies arise, in part, due to challenges associated with accurately modeling the complex phylogenetic signal coming from genomic regions experiencing distinct evolutionary forces. Here, we examine how different regions of the genome support or contradict well-established relationships among three mammal groups using millions of orthologous parsimony-informative biallelic sites (PIBS) distributed across primate, rodent, and Pecora genomes. We compared PIBS concordance percentages among locus types (e.g. coding sequences (CDS), introns, intergenic regions), and contrasted PIBS utility over evolutionary timescales. Sites derived from noncoding sequences provided more data and proportionally more concordant sites compared with those from CDS in all clades. CDS PIBS were also predominant drivers of tree incongruence in two cases of topological conflict. PIBS derived from most locus types provided surprisingly consistent support for splitting events spread across the timescales we examined, although we find evidence that CDS and intronic PIBS may, respectively and to a limited degree, inform disproportionately about older and younger splits. In this era of accessible wholegenome sequence data, these results:1) suggest benefits to more intentionally focusing on noncoding loci as robust data for tree inference and 2) reinforce the importance of accurate modeling, especially when using CDS data.
Tumor Necrosis Factor Inhibitors Reduce Spinal Radiographic Progression in Patients With Radiographic Axial Spondyloarthritis: A Longitudinal Analysis From the Alberta Prospective Cohort
Authors: Alexandre Sepriano, Sofia Ramiro, Stephanie Wichuk, Praveena Chiowchanwisawakit, Joel Paschke, Désirée van der Heijde, Robert Landewé, Walter P. Maksymowych
Journal: Arthritis & Rheumatology (2021)

Objective To investigate whether tumor necrosis factor inhibitors (TNFi) impact spinal radiographic progression in patients with axial spondyloarthritis (SpA) and whether this is coupled to their effect on inflammation. Methods Patients with axial SpA fulfilling the modified New York criteria were included in a prospective cohort (the ALBERTA Follow Up Research Cohort in Ankylosing Spondylitis Treatment). Spine radiographs, performed every 2 years for up to 10 years, were scored by 2 central readers, using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The indirect effect of TNFi on mSASSS was evaluated with generalized estimating equations by testing the interaction between TNFi and Ankylosing Spondylitis Disease Activity Score (ASDAS) at the start of each 2‐year interval (t). If significant, the association between ASDAS at t and mSASSS at the end of the interval (t+1) was assessed in 1) patients treated with TNFi at all visits, 2) patients treated with TNFi at some visits, and 3) patients who were never treated with TNFi. In addition, the association between TNFi at t and mSASSS at t+1 (adjusting for ASDAS at t) was also tested (direct effect). Results In total, 314 patients were included. A gradient was seen for the effect of ASDAS at t on mSASSS at t+1 (interaction P = 0.10), with a higher progression in patients never treated with TNFi (β = 0.41 [95% confidence interval (95% CI) 0.13, 0.68]) compared to those continuously treated (β = 0.16 [95% CI 0.00, 0.31]) (indirect effect). However, TNFi also directly slowed progression, as treated patients had on average an mSASSS 0.85 units lower at t+1 compared to untreated patients (β = −0.85 [95% CI −1.35, −0.35]). Conclusion Our findings indicate that TNFi reduce spinal radiographic progression in patients with radiographic axial SpA, which might be partially uncoupled from their effects on inflammation as measured by the ASDAS.
In Defense of TNT: A Dynamite Strategy
Authors: Andrea Cercek, Paul B. Romesser, Christopher H. Crane, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2021)

In Defense of TNT: A Dynamite StrategyIn their critique of total neoadjuvant therapy (TNT) for rectal cancer, Drs Shi and Mamon 1 state that "there have been few randomized studies comparing TNT to current standards of care."Actually, there have been no adequately sized randomized studies comparing TNT with the older approach of neoadjuvant chemoradiation plus postoperative chemotherapy, and, as Shi and Mamon 1 correctly note, there never will be.As they further note, TNT is, and has been for many years, a fully acceptable option in NCCN guidelines and is, by definition, a standard of care.The logic and available nonrandomized data are sufficiently compelling that the NCI Gastrointestinal Steering Committee unanimously endorsed the NRG GI-002, a chemo-first TNT platform study, as the standard to which new experimental agents are investigated.
Association of the Gut Microbiome and Metabolome with Wheeze Frequency in Childhood Asthma
Authors: Kathleen Lee-Sarwar, Sandra Dedrick, Babak Momeni, Rachel Kelly, Robert Zeiger, George O'Connor, Megan Sandel, Leonard Bacharier, Avraham Beigelman, Nancy Laranjo, Diane Gold, Jessica Lasky-Su, Augusto Litonjua, Yang-Yu Liu, Scott Weiss
Journal: Journal of Allergy and Clinical Immunology (2021)
Predictive Value of Cardiopulmonary Exercise Testing Parameters in Ambulatory Advanced Heart Failure
Authors: Anuradha Lala, Keyur B Shah, David E Lanfear, Jennifer T Thibodeau, Maryse Palardy, Amrut V Ambardekar, Dennis M McNamara, Wendy C Taddei-Peters, J Timothy Baldwin, Neal Jeffries, Shokoufeh Khalatbari, Cathie Spino, Blair Richards, Douglas L Mann, Garrick C Stewart, Keith D Aaronson, Donna M Mancini
Journal: JACC Heart Failure (2021)
Prevalence and Co-occurrence of Alcohol, Nicotine, and Other Substance Use Disorder Diagnoses Among US Transgender and Cisgender Adults
Authors: Jaclyn M. W. Hughto, Emily K. Quinn, Michael S. Dunbar, Adam J. Rose, Theresa I. Shireman, Guneet K. Jasuja
Journal: JAMA Network Open (2021)

Substance use disorders are a major source of morbidity and mortality in the United States. National data comparing the prevalence of substance use disorder diagnoses (SUDDs) among transgender and cisgender individuals are lacking in the United States. To investigate the prevalence of SUDDs among transgender and cisgender adults and to identify within-group and between-group differences by age, gender, and geographic location. This cross-sectional study used the OptumLabs Data Warehouse to analyze deidentified claims from approximately 74 million adults aged 18 years or older enrolled in commercial or Medicare Advantage insurance plans in 2017. A total of 15 637 transgender adults were identified based on a previously developed algorithm using a combination of International Classification of Diseases, Tenth Revision (ICD-10) transgender-related diagnosis and procedure codes and sex-discordant hormone prescriptions. A cohort of 46 911 cisgender adults was matched to the transgender cohort in a 3:1 ratio based on age and geographic location. SUDDs, based on ICD-10 codes, were assessed overall and compared between transgender and cisgender cohorts and by geographic region (ie, Northeast, Midwest, South, and West); age groups (eg, 18-25, 26-30, 31-35 years), and gender (ie, transfeminine [TF; assigned male sex at birth, identify along feminine gender spectrum], transmasculine [TM; assigned female sex at birth, identify along masculine gender spectrum], male, and female). In this study of 15 637 transgender adults (4955 [31.7%] TM) and 46 911 cisgender adults (23 247 [50.4%] men), most (8627 transgender adults [55.2%]; 51 762 cisgender adults [55.2%]) were aged between 18 and 40 years, and 6482 transgender adults (41.5%) and 19 446 cisgender adults (41.5%) lived in the South. Comparing transgender to cisgender groups, significant differences were found in the prevalence of a nicotine (2594 [16.6%] vs 2551 [5.4%]; P < .001), alcohol (401 [2.6%] vs 438 [0.9%]; P < .001), and drug (678 [4.3%] vs 549 [1.2%]; P < .001) SUDDs. Among transgender adults, cannabis was the most prevalent drug SUDD (321 [2.1%]), followed by opioid SUDD (205 [1.3%]) and cocaine SUDD (81 [0.5%]), whereas among cisgender adults, cannabis and opioid SUDDs were equally prevalent (cannabis, 186 [0.4%]; opioid, 207 [0.4%]), followed by cocaine SUDD (59 [0.1%]). In this study, the prevalence of SUDDs was significantly elevated among transgender adults relative to their cisgender peers. These findings underscore the need for culturally tailored clinical interventions to treat substance use disorder in transgender populations.
Evaluation in the Primary Care of Patients with Type 2 Diabetes and Their Risk of Hospitalization in Mexico
Authors: José Esteban Fernández-Gárate, Leticia Manuel-Apolinar, Jessie N. Zurita-Cruz, María de Lourdes Basurto Acevedo, María Luisa Arellano Flores, Roberto Alejandro Correa González, Nelly González Cisneros
Journal: Metabolism (2021)
Multicenter Consistency Assessment of Valvular Flow Quantification With Automated Valve Tracking in 4D Flow CMR
Authors: Joe F. Juffermans, Savine C.S. Minderhoud, Johan Wittgren, Anton Kilburg, Amir Ese, Benjamin Fidock, Yu-Cong Zheng, Jun-Mei Zhang, Carmen P.S. Blanken, Hildo J. Lamb, Jelle J. Goeman, Marcus Carlsson, Shihua Zhao, R. Nils Planken, Pim van Ooij, Liang Zhong, Xiuyu Chen, Pankaj Garg, Tilman Emrich, Alexander Hirsch, Johannes Töger, Jos J.M. Westenberg
Journal: JACC. Cardiovascular imaging (2021)
Antiviral therapy in the palliative setting of HCC (BCLC-B and -C)
Authors: Maria Reig, Giuseppe Cabibbo
Journal: Journal of Hepatology (2021)

The potential impact of direct-acting antivirals (DAAs) in patients with Barcelona Clinic Liver Cancer (BCLC)-B/C stage hepatocellular carcinoma (HCC) is understudied. Patients with HCC have been systematically excluded from randomised controlled trials evaluating the effectiveness of DAAs. Thus, the benefits of DAAs in patients with HCC are less well defined. The presence of active HCC before the initiation of DAA treatment is reported to be a predictor of DAA failure, and studies in patients without HCC have demonstrated that improvements in cirrhosis complications were lower or absent after DAA failure. Even if viral eradication is achieved using DAAs, reversal of liver function impairment may take longer than the development of end-stage cancer status. Additionally, the impact of DAAs on HCC recurrence is still a controversial topic. Thus, the decision of whether to use DAAs should be made on a patient-by-patient basis, and each patient should be informed of all the potential risks and benefits associated with their usage. This document summarises the current data on the usage of DAAs in BCLC-B/C patients, discusses the concept of "the point of no return" in the setting of DAAs, and proposes tools for deciding the best option for each patient profile. If liver function improvement overlaps with symptomatic HCC progression, the benefits of DAAs could be minimised, worsened, or fully counterbalanced. If the BCLC stage is defined using only liver dysfunction, the decision to prioritise DAA treatment should be based on the option (or lack thereof) of liver transplantation and/or the HCC stage. We propose applying a shared decision-making approach, informing each patient of all the potential risks and benefits of the proposed medical intervention.
Abstract PO022: Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease
Authors: Erik Dvergsten, Sanja Karovic, Vasiliki Thomeas-McEwing, Danielle Kimble, Pingzhen Guo, Hao Yang, Binsheng Zhao, Lawrence H. Schwartz, Michael L. Maitland
Journal: Clinical Cancer Research (2021)

Abstract Evolutionary biology-based methods to characterize human cancer increasingly inform screening, surveillance, and early stage disease treatment strategies. Advanced metastatic disease presents distinct challenges in research and effective treatment. We have established the Advanced Solid Tumor Registry at the Inova Schar Cancer Institute to systematically track quantitative behavior of advanced solid tumors in a “real world” treatment setting. The study supports collection of serial: plasma samples for ctDNA analysis, computed tomography digital images and semi-automated segmentation of lesions for tumor burden volume measurement, and collection of tumor marker measures among patients receiving routine, longitudinal treatment in a community oncology practice. At submission, the study has enrolled 53 patients, 6 with recurrent metastatic endometrial cancer. Study operations have been enhanced by development of R code and workflow to enable graphical display for individual patients in clinically relevant time. In addition to enhancing clinical decision-making for the individual patients, the collective endometrial cancer patient data currently cover 207 patient-months of observation, 119 circulating marker time-points, 73 CT scans, 27 individual lesions, and 20 different courses of treatment. Treatments included palliative radiation, and: cytotoxic, hormonal, immune-, and targeted therapeutics. We propose this registry represents a new tool to support application of evolutionary science-based methods to clinical care and reciprocally to collect “real world” data with sufficient detail to inform computational science assumptions and inferences in multi-scale modeling projects. In this pilot study, individual cases effectively display multiple observations relevant to understanding treatment response in advanced metastatic disease in the clinical care environment. This project was supported, in part, by R01-CA194783. Citation Format: Erik Dvergsten, Sanja Karovic, Vasiliki Thomeas-McEwing, Danielle Kimble, Pingzhen Guo, Hao Yang, Binsheng Zhao, Lawrence H. Schwartz, Michael L. Maitland. Multidimensional longitudinal assessment of patients under treatment for advanced endometrial cancer: a new tool to advance research on human disease [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO022.
Thresholds of Glycemia and the Outcomes of COVID-19 Complicated With Diabetes: A Retrospective Exploratory Study Using Continuous Glucose Monitoring
Authors: Yun Shen, Xiaohong Fan, Lei Zhang, Yaxin Wang, Cheng Li, Jingyi Lu, Bingbing Zha, Yueyue Wu, Xiaohua Chen, Jian Zhou, Weiping Jia
Journal: Diabetes Care (2021)

OBJECTIVE Although elevated glucose levels are reported to be associated with adverse outcomes of coronavirus disease 2019 (COVID-19), the optimal range of glucose in patients with COVID-19 and diabetes remains unknown. This study aimed to investigate the threshold of glycemia and its association with the outcomes of COVID-19. RESEARCH DESIGN AND METHODS Glucose levels were assessed through intermittently scanned continuous glucose monitoring in 35 patients for an average period of 10.2 days. The percentages of time above range (TAR), time below range (TBR), time in range (TIR), and coefficient of variation (CV) were calculated. Composite adverse outcomes were defined as either the need for admission to the intensive care unit, need for mechanical ventilation, or morbidity with critical illness. RESULTS TARs using thresholds from 160 to 200 mg/dL were significantly associated with composite adverse outcomes after adjustment of covariates. Both TBR (&amp;lt;70 mg/dL) and TIR (70–160 mg/dL), but not mean sensor glucose level, were significantly associated with composite adverse outcomes and prolonged hospitalization. The multivariate-adjusted odds ratios of the CV of sensor glucose across tertiles for composite adverse outcomes of COVID-19 were 1.00, 1.18, and 25.2, respectively. CONCLUSIONS Patients with diabetes and COVID-19 have an increased risk of adverse outcomes with glucose levels &amp;gt;160 mg/dL and &amp;lt;70 mg/dL and a high CV. Therapies that improve these metrics of glycemic control may result in better prognoses for these patients.
Variability of Postprandial Glycemia Reflecting by 1,5 anhydro-D-sorbitol in Patients with Insulin Resistance and Prediabetes
Authors: Dinara Sheryazdanova, Yelena Laryushina, Viktoriya Parakhina, Anna Shalygina, Natalya Vassilyeva, Alexandr Marchenko
Journal: Metabolism (2021)
Failure to Advance Access to Kidney Transplantation over Two Decades in the United States
Authors: Jesse D. Schold, Sumit Mohan, Anne Huml, Laura D. Buccini, John R. Sedor, Joshua J. Augustine, Emilio D. Poggio
Journal: Journal of the American Society of Nephrology (2021)

Extensive research and policies have been developed to improve access to kidney transplantation among patients with ESKD. Despite this, wide variation in transplant referral rates exists between dialysis facilities.To evaluate the longitudinal pattern of access to kidney transplantation over the past two decades, we conducted a retrospective cohort study of adult patients with ESKD initiating ESKD or placed on a transplant waiting list from 1997 to 2016 in the United States Renal Data System. We used cumulative incidence models accounting for competing risks and multivariable Cox models to evaluate time to waiting list placement or transplantation (WLT) from ESKD onset.Among the study population of 1,309,998 adult patients, cumulative 4-year WLT was 29.7%, which was unchanged over five eras. Preemptive WLT (prior to dialysis) increased by era (5.2% in 1997-2000 to 9.8% in 2013-2016), as did 4-year WLT incidence among patients aged 60-70 (13.4% in 1997-2000 to 19.8% in 2013-2016). Four-year WLT incidence diminished among patients aged 18-39 (55.8%-48.8%). Incidence of WLT was substantially lower among patients in lower-income communities, with no improvement over time. Likelihood of WLT after dialysis significantly declined over time (adjusted hazard ratio, 0.80; 95% confidence interval, 0.79 to 0.82) in 2013-2016 relative to 1997-2000.Despite wide recognition, policy reforms, and extensive research, rates of WLT following ESKD onset did not seem to improve in more than two decades and were consistently reduced among vulnerable populations. Improving access to transplantation may require more substantial interventions.
Correction: Simultaneous COVID-19 in Monozygotic Twins
Authors: Davide Lazzeroni, MD, Pietro Concari, MD, Luca Moderato, PhD
Journal: Annals of Internal Medicine (2021)

Corrections2 February 2021Correction: Simultaneous COVID-19 in Monozygotic TwinsFREEThis correction concerns the following article:LettersMay 2021Simultaneous COVID-19 in Monozygotic TwinsFREEDavide Lazzeroni, MD, Pietro Concari, MD, and Luca Moderato, PhDDavide Lazzeroni, MDIRCCS Fondazione Don Carlo Gnocchi, Milan, Italy, Pietro Concari, MDSuzzara Hospital, Mantova, Italy, and Luca Moderato, PhDGuglielmo da Saliceto Hospital, Piacenza, Italyhttps://doi.org/10.7326/L21-0013 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In the article by Lazzeroni and colleagues (1), the authors assumed the twins were identical because they had concordant phenotypes, and there is a high correlation between phenotype and genotype in identical-looking twins. As a result, the authors referred to the twins as “homozygous.” Since publication, additional information has shown that the twins had the same placenta at birth, and genetic testing has confirmed that the twins share the same genotype. Some clinical texts use the terms homozygous and monozygotic interchangeably to indicate that twins are identical. However, the more precise meaning of homozygous refers to having identical alleles of the same gene. In contrast, monozygotic refers to originating from the same zygote and is the preferred technical term for identical twins. In response to comments, the authors agree that homozygous can be misinterpreted. Therefore, the term homozygous has been replaced with the term monozygotic in the title and in the text of the article. In addition, the authors have learned that information about the twins' marital status was misleading, so this information has been removed from the Table.Please note that the comments posted to the article have not been corrected and reflect the term homozygous.Reference1. Lazzeroni D, Concari P, Moderato L. Simultaneous COVID-19 in monozygotic twins [Letter]. Ann Intern Med. 2020. doi:10.7326/L20-1207 LinkGoogle Scholar Comments0 CommentsSign In to Submit A Comment PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSimultaneous COVID-19 in Monozygotic Twins Davide Lazzeroni , Pietro Concari , and Luca Moderato Metrics March 2021Volume 174, Issue 3Page: 436KeywordsAllelesBirthCOVID-19Genetic testingMonozygotic twinsPhenotypesPlacentaTwins ePublished: 2 February 2021 Issue Published: March 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
PM2RA: A Framework for Detecting and Quantifying Relationship Alterations in Microbial Community
Authors: Zhi Liu, Kai Mi, Zhenjiang Zech Xu, Qiankun Zhang, Xingyin Liu
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract The dysbiosis of gut microbiota is associated with the pathogenesis of human diseases. However, observing shifts in the microbe abundance cannot fully reveal underlying perturbations. Examining the relationship alterations (RAs) in the microbiome between health and disease statuses provides additional hints about the pathogenesis of human diseases, but no methods were designed to detect and quantify the RAs between different conditions directly. Here, we present profile monitoring for microbial relationship alteration (PM2RA), an analysis framework to identify and quantify the microbial RAs. The performance of PM2RA was evaluated with synthetic data, and it showed higher specificity and sensitivity than the co-occurrence-based methods. Analyses of real microbial datasets showed that PM2RA was robust for quantifying microbial RAs across different datasets in several diseases. By applying PM2RA, we identified several novel or previously reported microbes implicated in multiple diseases. PM2RA is now implemented as a web-based application available at http://www.pm2ra-xingyinliulab.cn/.