tbuckley/cabot-search huggingface dataset:
Profiling SARS-CoV-2 mutation fingerprints that range from the viral pangenome to individual infection quasispecies
Authors: Billy T. Lau, Dmitri Pavlichin, Anna C. Hooker, Alison Almeda, Giwon Shin, Jiamin Chen, Malaya K. Sahoo, Chun Hong Huang, Benjamin A. Pinsky, Ho Joon Lee, Hanlee P. Ji
Journal: Genome Medicine (2021)

Abstract Background The genome of SARS-CoV-2 is susceptible to mutations during viral replication due to the errors generated by RNA-dependent RNA polymerases. These mutations enable the SARS-CoV-2 to evolve into new strains. Viral quasispecies emerge from de novo mutations that occur in individual patients. In combination, these sets of viral mutations provide distinct genetic fingerprints that reveal the patterns of transmission and have utility in contact tracing. Methods Leveraging thousands of sequenced SARS-CoV-2 genomes, we performed a viral pangenome analysis to identify conserved genomic sequences. We used a rapid and highly efficient computational approach that relies on k-mers, short tracts of sequence, instead of conventional sequence alignment. Using this method, we annotated viral mutation signatures that were associated with specific strains. Based on these highly conserved viral sequences, we developed a rapid and highly scalable targeted sequencing assay to identify mutations, detect quasispecies variants, and identify mutation signatures from patients. These results were compared to the pangenome genetic fingerprints. Results We built a k-mer index for thousands of SARS-CoV-2 genomes and identified conserved genomics regions and landscape of mutations across thousands of virus genomes. We delineated mutation profiles spanning common genetic fingerprints (the combination of mutations in a viral assembly) and a combination of mutations that appear in only a small number of patients. We developed a targeted sequencing assay by selecting primers from the conserved viral genome regions to flank frequent mutations. Using a cohort of 100 SARS-CoV-2 clinical samples, we identified genetic fingerprints consisting of strain-specific mutations seen across populations and de novo quasispecies mutations localized to individual infections. We compared the mutation profiles of viral samples undergoing analysis with the features of the pangenome. Conclusions We conducted an analysis for viral mutation profiles that provide the basis of genetic fingerprints. Our study linked pangenome analysis with targeted deep sequenced SARS-CoV-2 clinical samples. We identified quasispecies mutations occurring within individual patients and determined their general prevalence when compared to over 70,000 other strains. Analysis of these genetic fingerprints may provide a way of conducting molecular contact tracing.
Erratum. Clinical Translation of Cardiovascular Outcome Trials in Type 2 Diabetes: Is There More or Is There Less Than Meets the Eye? Diabetes Care 2021;44:641–646
Authors: Ele Ferrannini, Julio Rosenstock
Journal: Diabetes Care (2021)

In the reference list of this article, reference 7 was incorrect and is replaced as follows:

7. Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with …
Beyond association: successes and challenges in linking non-coding genetic variation to functional consequences that modulate Alzheimer’s disease risk
Authors: Gloriia Novikova, Shea J. Andrews, Alan E. Renton, Edoardo Marcora
Journal: Molecular Neurodegeneration (2021)

Abstract Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of people worldwide; however, no disease-modifying treatments are currently available. Genome-wide association studies (GWASs) have identified more than 40 loci associated with AD risk. However, most of the disease-associated variants reside in non-coding regions of the genome, making it difficult to elucidate how they affect disease susceptibility. Nonetheless, identification of the regulatory elements, genes, pathways and cell type/tissue(s) impacted by these variants to modulate AD risk is critical to our understanding of disease pathogenesis and ability to develop effective therapeutics. In this review, we provide an overview of the methods and approaches used in the field to identify the functional effects of AD risk variants in the causal path to disease risk modification as well as describe the most recent findings. We first discuss efforts in cell type/tissue prioritization followed by recent progress in candidate causal variant and gene nomination. We discuss statistical methods for fine-mapping as well as approaches that integrate multiple levels of evidence, such as epigenomic and transcriptomic data, to identify causal variants and risk mechanisms of AD-associated loci. Additionally, we discuss experimental approaches and data resources that will be needed to validate and further elucidate the effects of these variants and genes on biological pathways, cellular phenotypes and disease risk. Finally, we discuss future steps that need to be taken to ensure that AD GWAS functional mapping efforts lead to novel findings and bring us closer to finding effective treatments for this devastating disease.
Antioxidant activity of mesenchymal stem cell-derived extracellular vesicles restores hippocampal neurons following seizure damage
Authors: Qiang Luo, Panpan Xian, Tian Wang, Shengxi Wu, Tangna Sun, Wenting Wang, Bo Wang, Hao Yang, Yanping Yang, Han Wang, Weiping Liu, Qianfa Long
Journal: Theranostics (2021)

Oxidative stress is a critical event in neuronal damage following seizures. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been shown to be promising nanotherapeutic agents in neurological disorders. However, the mechanism underlying MSC-EVs therapeutic efficacy for oxidative stress-induced neuronal damage remains poorly understood. Methods: We investigated the antioxidant and restoration activities of MSC-EVs on hippocampal neurons in response to H2O2 stimulation in vitro and seizures in vivo. We also explored the potential underlying mechanism by injecting adeno-associated virus (AAV)-nuclear factor erythroid-derived 2, like 2 (Nrf2), a key antioxidant mediator, in animal models. Results: MSC-EVs were enriched in antioxidant miRNAs and exhibited remarkable antioxidant activity evident by increased ferric ion-reducing antioxidant ability, catalase, superoxide dismutase, and glutathione peroxidase activities and decreased reactive oxygen species (ROS) generation, DNA/lipid/protein oxidation, and stress-associated molecular patterns in cultured cells and mouse models. Notably, EV administration exerted restorative effects on the hippocampal neuronal structure and associated functional impairments, including dendritic spine alterations, electrophysiological disturbances, calcium transients, mitochondrial changes, and cognitive decline after oxidative stress in vitro or in vivo. Mechanistically, we found that the Nrf2 signaling pathway was involved in the restorative effect of EV therapy against oxidative neuronal damage, while AAV-Nrf2 injection attenuated the antioxidant activity of MSC-EVs on the seizure-induced hippocampal injury. Conclusions: We have shown that MSC-EVs facilitate the reconstruction of hippocampal neurons associated with the Nrf2 defense system in response to oxidative insults. Our study highlights the clinical value of EV-therapy in neurological disorders such as seizures.
Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial
Authors: Roberto Orecchia, Umberto Veronesi, Patrick Maisonneuve, Viviana Enrica Galimberti, Roberta Lazzari, Paolo Veronesi, Barbara Alicja Jereczek-Fossa, Federica Cattani, Claudia Sangalli, Alberto Luini, Pietro Caldarella, Marco Venturino, Daniele Sances, Stefano Zurrida, Giuseppe Viale, Maria Cristina Leonardi, Mattia Intra
Journal: The Lancet Oncology (2021)
Computational methods for cancer driver discovery: A survey
Authors: Vu Viet Hoang Pham, Lin Liu, Cameron Bracken, Gregory Goodall, Jiuyong Li, Thuc Duy Le
Journal: Theranostics (2021)

Identifying the genes responsible for driving cancer is of critical importance for directing treatment.Accordingly, multiple computational tools have been developed to facilitate this task.Due to the different methods employed by these tools, different data considered by the tools, and the rapidly evolving nature of the field, the selection of an appropriate tool for cancer driver discovery is not straightforward.This survey seeks to provide a comprehensive review of the different computational methods for discovering cancer drivers.We categorise the methods into three groups; methods for single driver identification, methods for driver module identification, and methods for identifying personalised cancer drivers.In addition to providing a "one-stop" reference of these methods, by evaluating and comparing their performance, we also provide readers the information about the different capabilities of the methods in identifying biologically significant cancer drivers.The biologically relevant information identified by these tools can be seen through the enrichment of discovered cancer drivers in GO biological processes and KEGG pathways and through our identification of a small cancer-driver cohort that is capable of stratifying patient survival.
Transfusion- Related Iron Overload (TRIO) Is Associated with Delayed Engraftment and Increased Non Relapse Mortality (NRM) in Patients Undergoing Umbilical Cord Blood (UCB) Hematopoietic Cell Transplantation (HCT)
Authors: Monzr M. Al Malki, Joo Y. Song, Dongyun Yang, Thai Cao, Ibrahim Aldoss, Sally Mokhtari, Sanjeet Dadwal, Ketevan Gendzekhadze, Anna B Pawlowska, Maryam Ameri, Guido Marcucci, Chatchada Karanes, Pablo Parker, David S. Snyder, David Senitzer, Auayporn P. Nademanee, Stephen J. Forman, Ryotaro Nakamura, Vinod Pullarkat
Journal: Blood (2017)
Transfusion Dependence at Day +100 Predicts Poorer Outcomes in Patients Undergoing Allogeneic Stem Cell Transplantation for Myelofibrosis
Authors: Tania Jain, Katie L. Kunze, Daniel K. Partain, Heidi Kosiorek, Vivek Roy, Nandita Khera, James L. Slack, Mrinal M. Patnaik, William J. Hogan, Pierre Noel, Veena D. S. Fauble, Jose F. Leis, Lisa Sproat, Ruben A Mesa, Jeanne Palmer
Journal: Blood (2017)
The CLL International Prognostic Index predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL
Authors: Sameer A. Parikh, Kari G. Rabe, Neil E. Kay, Timothy G. Call, Wei Ding, Jose F. Leis, Saad S. Kenderian, Eli Muchtar, Yucai Wang, Amber B. Koehler, Susan M. Schwager, Connie E. Lesnick, Geffen Kleinstern, Daniel Van Dyke, Curtis A. Hanson, Esteban Braggio, Susan L. Slager, Tait D. Shanafelt
Journal: Blood (2021)
Predictive Value of Bowel Ultrasound in Crohn’s Disease: A 12-Month Prospective Study
Authors: Mariangela Allocca, Vincenzo Craviotto, Stefanos Bonovas, Federica Furfaro, Alessandra Zilli, Laurent Peyrin-Biroulet, Gionata Fiorino, Silvio Danese
Journal: Clinical Gastroenterology and Hepatology (2021)
Real-World Effectiveness of Human Papillomavirus Vaccination Against Cervical Cancer
Authors: Susanne K Kjaer, Christian Dehlendorff, Federica Belmonte, Louise Baandrup
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background The primary goal of human papillomavirus (HPV) vaccination is to reduce morbidity and mortality from HPV-associated disease, especially cervical cancer. We determined the real-world effectiveness of HPV vaccination against cervical cancer. Methods The study included women aged 17-30 years living in Denmark October 2006-December 2019. From nationwide registries, information on HPV vaccination and cervical cancer diagnoses were retrieved. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for cervical cancer according to vaccination status were estimated using Poisson regression with HPV vaccination treated as a time-varying variable and stratified by age at vaccination. We adjusted for attained age, education, and ethnicity. To address the effect of prevalent disease, different buffer periods were used, with 1-year buffer period as primary analysis. Results The cohort comprised 867 689 women. At baseline, 36.3% were vaccinated at age 16 years and younger, and during follow-up, 19.3% and 2.3% were vaccinated at ages 17-19 years and 20-30 years, respectively. For women vaccinated at ages 16 years and younger or 17-19 years, the IRRs of cervical cancer were 0.14 (95% CI = 0.04 to 0.53) and 0.32 (95% CI = 0.08 to 1.28), respectively, compared with unvaccinated women. In women aged 20-30 years at vaccination, the incidence rate was higher than among unvaccinated women (IRR = 1.19, 95% CI = 0.80 to 1.79) but slightly decreased with increasing buffer period (IRR = 0.85, 95% CI = 0.55 to 1.32, with 4-year buffer period). Conclusion HPV vaccine effectiveness against cervical cancer at the population level is high among girls vaccinated younger than age 20 years. The lack of immediate effect in women vaccinated at age 20-30 years points to the importance of early age at vaccination.
PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity
Authors: Shuang Qu, Zichen Jiao, Geng Lu, Bing Yao, Ting Wang, Weiwei Rong, Jiahan Xu, Ting Fan, Xinlei Sun, Rong Yang, Jun Wang, Yongzhong Yao, Guifang Xu, Xin Yan, Tao Wang, Hongwei Liang, Ke Zen
Journal: Genome biology (2021)

Abstract Background Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. Results Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. Conclusions In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.
Central Nervous System Relapse in HIV Positive Patients Affected By Diffuse Large B Cell Lymphoma. IsÂ the CNS-IPI Score Useful in This Population?
Authors: Luisa Verga, Davide Dalu, Rossella Renso, Andrea Aroldi, Ilaria De Benedetto, Filippo Brioschi, Claudia Zeroli, Paola Vitiello, Fulvio Crippa, Elisa Suardi, Raffaella Epifani, Omar Giglio, Maurizio Mena, Chiara Bombonati, Elisa Colella, Andrea Gori, Carlo Gambacorti-Passerini, Alessandra Bandera
Journal: Blood (2017)
A Young Patient With Hives and Chest Pain
Authors: Maxim Ben-Yakov, Vigil James, Brant Slomovic
Journal: JAMA Cardiology (2021)

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AFLAP: assembly-free linkage analysis pipeline using k-mers from genome sequencing data
Authors: Kyle Fletcher, Lin Zhang, Juliana Gil, Rongkui Han, Keri Cavanaugh, Richard Michelmore
Journal: Genome biology (2021)

Abstract Our assembly-free linkage analysis pipeline (AFLAP) identifies segregating markers as k-mers in the raw reads without using a reference genome assembly for calling variants and provides genotype tables for the construction of unbiased, high-density genetic maps without a genome assembly. AFLAP is validated and contrasted to a conventional workflow using simulated data. AFLAP is applied to whole genome sequencing and genotype-by-sequencing data of F1, F2, and recombinant inbred populations of two different plant species, producing genetic maps that are concordant with genome assemblies. The AFLAP-based genetic map for Bremia lactucae enables the production of a chromosome-scale genome assembly.
The long noncoding RNA <i>lnc-HLX-2-7</i> is oncogenic in Group 3 medulloblastomas
Authors: Keisuke Katsushima, Bongyong Lee, Haritha Kunhiraman, Cuncong Zhong, Rabi Murad, Jun Yin, Ben Liu, Alexandra Garancher, Ignacio Gonzalez-Gomez, Hector L Monforte, Stacie Stapleton, Rajeev Vibhakar, Chetan Bettegowda, Robert J Wechsler-Reya, George Jallo, Eric Raabe, Charles G Eberhart, Ranjan J Perera
Journal: Neuro-Oncology (2020)

Abstract Background Medulloblastoma (MB) is an aggressive brain tumor that predominantly affects children. Recent high-throughput sequencing studies suggest that the noncoding RNA genome, in particular long noncoding RNAs (lncRNAs), contributes to MB subgrouping. Here we report the identification of a novel lncRNA, lnc-HLX-2-7, as a potential molecular marker and therapeutic target in Group 3 MBs. Methods Publicly available RNA sequencing (RNA-seq) data from 175 MB patients were interrogated to identify lncRNAs that differentiate between MB subgroups. After characterizing a subset of differentially expressed lncRNAs in vitro and in vivo, lnc-HLX-2-7 was deleted by CRISPR/Cas9 in the MB cell line. Intracranial injected tumors were further characterized by bulk and single-cell RNA-seq. Results Lnc-HLX-2-7 is highly upregulated in Group 3 MB cell lines, patient-derived xenografts, and primary MBs compared with other MB subgroups as assessed by quantitative real-time, RNA-seq, and RNA fluorescence in situ hybridization. Depletion of lnc-HLX-2-7 significantly reduced cell proliferation and 3D colony formation and induced apoptosis. Lnc-HLX-2-7–deleted cells injected into mouse cerebellums produced smaller tumors than those derived from parental cells. Pathway analysis revealed that lnc-HLX-2-7 modulated oxidative phosphorylation, mitochondrial dysfunction, and sirtuin signaling pathways. The MYC oncogene regulated lnc-HLX-2-7, and the small-molecule bromodomain and extraterminal domain family‒bromodomain 4 inhibitor Jun Qi 1 (JQ1) reduced lnc-HLX-2-7 expression. Conclusions Lnc-HLX-2-7 is oncogenic in MB and represents a promising novel molecular marker and a potential therapeutic target in Group 3 MBs.
Annals Graphic Medicine - Should I PrEP? Barriers to HIV-Related Preventive Care Faced by Black MSM
Authors: Annabel Kuhn, Theresa Maatman
Journal: Annals of Internal Medicine (2021)

Web ExclusivesApril 2021Annals Graphic Medicine - Should I PrEP? Barriers to HIV-Related Preventive Care Faced by Black MSMFREEAnnabel Kuhn, MDand Theresa Maatman, MDAnnabel Kuhn, MDMedical College of Wisconsin, Milwaukee, Wisconsin (A.K., T.M.)Search for more papers by this authorand Theresa Maatman, MDMedical College of Wisconsin, Milwaukee, Wisconsin (A.K., T.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0086 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Medical College of Wisconsin, Milwaukee, Wisconsin (A.K., T.M.)Disclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G20-0086.Author/Illustrator Information: Annabel Kuhn, MD, will graduate from the Medical College of Wisconsin in May 2021 and will be a psychiatry resident at Harvard South Shore (e-mail, [email protected]edu). Theresa Maatman, MD, is an assistant professor at the Medical College of Wisconsin. She studies the use of comics in medical education as both a content delivery mechanism and a communication tool.This article was published at Annals.org on 13 April 2021. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byTodurujo na Kadurok (empowering youth): study protocol of an HIV self-testing and edutainment comic cluster randomised trial among refugee youth in a humanitarian setting in UgandaMixed-methods findings from the Ngutulu Kagwero (agents of change) participatory comic pilot study on post-rape clinical care and sexual violence prevention with refugee youth in a humanitarian setting in Uganda April 2021Volume 174, Issue 4Page: W37-W44 ePublished: 13 April 2021 Issue Published: April 2021 Copyright & PermissionsCopyright © 2021 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...