tbuckley/cabot-search huggingface dataset:
Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era
Authors: Dunhui Li, Frank L. Mastaglia, Sue Fletcher, Steve D. Wilton
Journal: Medicinal Research Reviews (2020)

Abstract Parkinson's disease (PD) is one of the most common neurodegenerative disorders that manifest various motor and nonmotor symptoms. Although currently available therapies can alleviate some of the symptoms, the disease continues to progress, leading eventually to severe motor and cognitive decline and reduced life expectancy. The past two decades have witnessed rapid progress in our understanding of the molecular and genetic pathogenesis of the disease, paving the way for the development of new therapeutic approaches to arrest or delay the neurodegenerative process. As a result of these advances, biomarker‐driven subtyping is making it possible to stratify PD patients into more homogeneous subgroups that may better respond to potential genetic‐molecular pathway targeted disease‐modifying therapies. Therapeutic nucleic acid oligomers can bind to target gene sequences with very high specificity in a base‐pairing manner and precisely modulate downstream molecular events. Recently, nucleic acid therapeutics have proven effective in the treatment of a number of severe neurological and neuromuscular disorders, drawing increasing attention to the possibility of developing novel molecular therapies for PD. In this review, we update the molecular pathogenesis of PD and discuss progress in the use of antisense oligonucleotides, small interfering RNAs, short hairpin RNAs, aptamers, and microRNA‐based therapeutics to target critical elements in the pathogenesis of PD that could have the potential to modify disease progression. In addition, recent advances in the delivery of nucleic acid compounds across the blood–brain barrier and challenges facing PD clinical trials are also reviewed.
Abstract A28: Deregulation of KMT2D promotes squamous differentiation in a mouse model of muscle-invasive bladder cancer
Authors: Lijie Rong, Cory Abate-Shen
Journal: Clinical Cancer Research (2020)

Abstract Cell differentiation and plasticity is precisely controlled by specific gene expression programs coordinate with chromatin remodeling, which are often deregulated during tumorigenesis. While divergent histopathologic differentiation in bladder cancer is prevalent and may affect clinical outcome, the underlying mechanisms are not well understood. Here, we aim to elucidate mechanisms for alteration of the histopathologic and molecular features of muscle-invasive bladder cancer (MIBC) by interrogating the functional role of chromatin-remodeling genes using relevant genetically engineered mouse models (GEMMs). High frequency of mutations in chromatin-remodeling genes encoding COMPASS-like chromatin-remodeling complex members has been identified in human MIBC. These genes include “writers” that create histone post-translational modification, such as the lysine methyltransferase KMT2D (MLL2/4), and “erasers” that remove these modifications, such as the lysine demethylase KDM6A (UTX). We have generated GEMMs that enable bladder-specific conditional inactivation of individual chromatin-remodeling genes in combination with loss of function of Trp53 and Pten, which leads to MIBC. Interestingly, bladder tumors from GEMMs having inactivation of Kmt2d along with Trp53 and Pten (e.g., Kmt2d;Trp53;Pten mice) develop a variant histologic phenotype that is not observed in tumors from either the Trp53;Pten or Kdm6a;Trp53;Pten mice. Specifically, these Kmt2d-inactivated tumors share histopathologic features in common with human urothelial carcinoma that display squamous differentiation. Furthermore, expression profiling of these Kmt2d;Trp53;Pten bladder tumors identified a unique set of differentially expressed genes that are enriched for genes representing squamous differentiation in other nonbladder cancers. Our findings suggest that deregulated Kmt2d expression promotes squamous differentiation in MIBC, at least in context of Trp53;pten coinactivation. Citation Format: Lijie Rong, Cory Abate-Shen. Deregulation of KMT2D promotes squamous differentiation in a mouse model of muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A28.
NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis
Authors: Ruy Andrade Louzada, Raphaël Corre, Rabii Ameziane El Hassani, Lydia Meziani, Madeleine Jaillet, Aurélie Cazes, Bruno Crestani, Eric Deutsch, Corinne Dupuy
Journal: European Respiratory Journal (2020)

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-β1/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular hydrogen peroxide (H2O2--)-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.Our in vivo data (idiopathic pulmonary fibrosis patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1+/- and DUOX1-/-) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.These findings highlight a role for DUOX1-derived H2O2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.
Recurrent <i>MVD</i> mutation in European patients with disseminated porokeratosis
Authors: M. Saleva‐Stateva, K. Technau‐Hafsi, L. Frommherz, G. Grüninger, S. Jägle, L. Dourmishev, L. Miteva, J. Fischer, C. Has
Journal: British Journal of Dermatology (2020)
Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis (vol 21, pg 636, 2020)
Authors: Antoine Roquilly, Cedric Jacqueline, Marion Davieau, Alice Molle, Abderrahmane Sadek, Cynthia Fourgeux, Paul Rooze, Alexis Broquet, Barbara Misme-Aucouturier, Tanguy Chaumette, Mickael Vourc'h, Raphael Cinotti, Nadege Marec, Vanessa Gauttier, Hamish Eg McWilliam, Frederic Altare, Jeremie Poschmann, Jose A Villadangos, Karim Asehnoune
Journal: Nature Immunology (2020)
Clinical Implications of Body Mass Index in Metastatic Breast Cancer Patients Treated With Abemaciclib and Endocrine Therapy
Authors: Maria Alice Franzoi, Daniel Eiger, Lieveke Ameye, Noam Ponde, Rafael Caparica, Claudia De Angelis, Mariana Brandão, Christine Desmedt, Serena Di Cosimo, Nuria Kotecki, Matteo Lambertini, Ahmad Awada, Martine Piccart, Evandro de Azambuja
Journal: JNCI Journal of the National Cancer Institute (2020)

There are limited data regarding the impact of body mass index (BMI) on outcomes in advanced breast cancer, especially in patients treated with endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors.A pooled analysis of individual patient-level data from MONARCH 2 and 3 trials was performed. Patients were classified according to baseline BMI into underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (≥30 kg/m2) and divided into 2 treatment groups: abemaciclib + ET vs placebo + ET. The primary endpoint was progression-free survival (PFS) according to BMI in each treatment group. Secondary endpoints were response rate, adverse events according to BMI, and loss of weight (≥5% from baseline) during treatment.This analysis included 1138 patients (757 received abemaciclib + ET and 381 placebo + ET). There was no difference in PFS between BMI categories in either group, although normal-weight patients presented a numerically higher benefit with abemaciclib + ET (Pinteraction = .07). Normal and/or underweight patients presented higher overall response rate in the abemaciclib + ET group compared with overweight and/or obese patients (49.4% vs 41.6%, odds ratio = 0.73, 95% confidence interval = 0.54 to 0.99) as well as higher neutropenia frequency (51.0% vs 40.4%, P = .004). Weight loss was more frequent in the abemaciclib + ET group (odds ratio = 3.23, 95% confidence interval = 2.09 to 5.01).Adding abemaciclib to ET prolongs PFS regardless of BMI, showing that overweight or obese patients also benefit from this regimen. Our results elicit the possibility of a better effect of abemaciclib in normal and/or underweight patients compared with overweight and/or obese patients. More studies analyzing body composition parameters in patients under treatment with cyclin-dependent kinase 4/6 inhibitors may further clarify this hypothesis.
A review of current phase III clinical trials of plaque psoriasis: under‐representation of nonwhite participants and need for reform
Authors: V.D. Reddy, B.A. Myers, S.Y. Chan, Q.G. Thibodeaux, N.D. Brownstone, T. Bhutani, W. Liao, J.C. Lester, J.Y. Koo
Journal: British Journal of Dermatology (2020)
Increased Palmitoylation Modulates Cytoskeletal Regulators to Enhance CXCR4-Mediated Motility of Malignant B Cells
Authors: Andrea Haerzschel, Dunja Baatout, Valeska Berg, Manuela Paunovic, Karin Oberascher, Hubert Kerschbaum, Richard Greil, Michael J. Hallek, Tanja N. Hartmann, Lukas P. Frenzel
Journal: Blood (2017)
A seventeenth-century Mycobacterium tuberculosis genome supports a Neolithic emergence of the Mycobacterium tuberculosis complex
Authors: Susanna Sabin, Alexander Herbig, Åshild J. Vågene, Torbjörn Ahlström, Gracijela Bozovic, Caroline Arcini, Denise Kühnert, Kirsten I. Bos
Journal: Genome biology (2020)

Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor followed human migrations out of Africa approximately 70,000 years before present. However, studies using ancient genomes as calibration points have yielded much younger dates of less than 6000 years. Here, we aim to address this discrepancy through the analysis of the highest-coverage and highest-quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605-d. 1679).A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Genomic enrichment enabled the reconstruction of a 141-fold coverage M. tuberculosis genome. In utilizing this high-quality, high-coverage seventeenth-century genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent.The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate a most recent common ancestor date for the MTBC of between 2190 and 4501 before present and for Lineage 4 of between 929 and 2084 before present using multiple models, confirming a Neolithic emergence for the MTBC.
Novel Mutations in RASGRP1 Are Associated with Immune Dysregulation and Predispose to EBV-Induced Lymphoma
Authors: Ido Somekh, Benjamin Marquardt, Yanshan Liu, Meino Rohlfs, Shirly Frizinsky, Ekrem Unal, Daniel Kotlarz, Raz Somech, Christoph Klein
Journal: Blood (2017)
Duplication on Chromosome 14q Identified in Familial Predisposition to Myeloid Malignancies and Myeloproliferative Neoplasms
Authors: Christopher N Hahn, Amilia Wee, Milena Babic, Jinghua Feng, Paul Wang, Monika M Kutyna, Sarah Moore, Anna L Brown, Richard D'Andrea, Deepak Singhal, Andreas Schreiber, Pratyush Giri, David M Ross, Devendra K Hiwase, Hamish S Scott
Journal: Blood (2017)
Splenic Infarct As an Harbinger for Sickle Cell Traits in High Altitude
Authors: Velu Nair, Uday Yanamandra, Rajan Kapoor, Rajiv Kumar, Satya Ranjan Das, Ajay Sharma, Singh Jasjit, Suman Pramanik, Sanjeevan Sharma, Tarun Verma
Journal: Blood (2017)
Saving Office Practice
Authors: Harold C. Sox
Journal: Annals of Internal Medicine (2003)

Editorials5 August 2003Saving Office PracticeHarold C. Sox, MD, EditorHarold C. Sox, MD, EditorSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-139-3-200308050-00012 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail This editorial is about the office practice of adult medicine. Office practice has been hurting for at least a decade. Medical students are taking notice, and more of them are choosing clinical specialties in which office practice plays a relatively small role. Leaders of internal medicine and family practice are concerned (1) but are uncertain about how to facilitate the change that must occur in individual practices scattered over a large and diverse country. An analysis of all of the problems confronting office practice isn't suitable for a brief essay, so I focus on a specific piece of the problem: ...References1. Showstack J, Sox HC, eds. The future of primary care. Ann Intern Med. 2003; 138(part 2):241-72. Google Scholar2. Reed M, Ginsburg P. Behind the Times: Physician Income 1995-99. Center for Studying Health System Change. Data Bulletin. March 2003; no. 24. Google Scholar3. Trude S. So much to do, so little time: physician capacity constraints, 1997-2001. Center for Studying Health System Change. Tracking Report. May 2003; no. 8. Google Scholar4. 2001 Patient Care Physician Survey. Physician Socioeconomic Statistics. Chicago: American Medical Assoc; 2003. Google Scholar5. Medical Group Management Association. Cost Survey: 2002 Report Based on 2001 Data. Salary costs in 2001. Accessed at www.mgma.com/surveys on 25 Google Scholar6. Center for Studying Health System Change. Community Tracking Study Physician Survey. Accessed at ctsonline.s-3.com/psurvey.asp on 21 May 2003. Google Scholar Author, Article, and Disclosure InformationAffiliations: Corresponding Author: Customer Service, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSaving Office Practice Alan R. Ertle Saving Office Practice Scott Matthew Bolhack Saving Office Practice Peter Basch Saving Office Practice Harold C. Sox Metrics Cited byDiversification by the Audit Office and Its Impact on Audit QualitySaving Office PracticeAlan R. Ertle, MD, MPH, MBASaving Office PracticeScott Matthew Bolhack, MDSaving Office PracticePeter Basch, MDDissatisfaction with Medical Practice 5 August 2003Volume 139, Issue 3Page: 227-228KeywordsElectronic medical recordsHealth Insurance Portability and Accountability ActHealth careHealth care utilizationInformation technologyPatient advocacyPatientsPrimary care physiciansResearch designRunning ePublished: 5 August 2003 Issue Published: 5 August 2003 Copyright & PermissionsCopyright © 2003 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The potential public health consequences of COVID-19 on malaria in Africa
Authors: Ellie Sherrard-Smith, Alexandra B. Hogan, Arran Hamlet, Oliver J. Watson, Charlie Whittaker, Peter Winskill, Fatima Ali, Audu B. Mohammad, Perpetua Uhomoibhi, Ibrahim Maikore, Nnenna Ogbulafor, Jamilu Nikau, Mara D. Kont, Joseph D. Challenger, Robert Verity, Ben Lambert, Matthew Cairns, Bhargavi Rao, Marc Baguelin, Lilith K. Whittles, John A. Lees, Sangeeta Bhatia, Edward S. Knock, Lucy Okell, Hannah C. Slater, Azra C. Ghani, Patrick G. T. Walker, Okefu Oyale Okoko, Thomas S. Churcher
Journal: Nature Medicine (2020)

The burden of malaria is heavily concentrated in sub-Saharan Africa (SSA) where cases and deaths associated with COVID-19 are rising1. In response, countries are implementing societal measures aimed at curtailing transmission of SARS-CoV-22,3. Despite these measures, the COVID-19 epidemic could still result in millions of deaths as local health facilities become overwhelmed4. Advances in malaria control this century have been largely due to distribution of long-lasting insecticidal nets (LLINs)5, with many SSA countries having planned campaigns for 2020. In the present study, we use COVID-19 and malaria transmission models to estimate the impact of disruption of malaria prevention activities and other core health services under four different COVID-19 epidemic scenarios. If activities are halted, the malaria burden in 2020 could be more than double that of 2019. In Nigeria alone, reducing case management for 6 months and delaying LLIN campaigns could result in 81,000 (44,000-119,000) additional deaths. Mitigating these negative impacts is achievable, and LLIN distributions in particular should be prioritized alongside access to antimalarial treatments to prevent substantial malaria epidemics.
Racial Disproportionality in Covid Clinical Trials
Authors: Daniel B. Chastain, Sharmon P. Osae, Andrés F. Henao-Martínez, Carlos Franco-Paredes, Joeanna S. Chastain, Henry N. Young
Journal: New England Journal of Medicine (2020)

Racial Disproportionality in Covid Clinical Trials To provide the necessary data for generalizing efficacy and safety outcomes across racial groups, Covid-19 clinical trials must prioritize inclusi...
Epigenomic and Transcriptomic Dynamics During Human Heart Organogenesis
Authors: Jennifer VanOudenhove, Tara N. Yankee, Andrea Wilderman, Justin Cotney
Journal: Circulation Research (2020)

There is growing evidence that common variants and rare sequence alterations in regulatory sequences can result in birth defects or predisposition to disease. Congenital heart defects are the most common birth defect and have a clear genetic component, yet only a third of cases can be attributed to structural variation in the genome or a mutation in a gene. The remaining unknown cases could be caused by alterations in regulatory sequences.
Using a real-world network to model localized COVID-19 control strategies
Authors: Josh A. Firth, Joel Hellewell, Petra Klepac, Stephen Kissler, Mark Jit, Katherine E. Atkins, Samuel Clifford, C. Julian Villabona-Arenas, Sophie R. Meakin, Charlie Diamond, Nikos I. Bosse, James D. Munday, Kiesha Prem, Anna M. Foss, Emily S. Nightingale, Kevin van Zandvoort, Nicholas G. Davies, Hamish P. Gibbs, Graham Medley, Amy Gimma, Stefan Flasche, David Simons, Megan Auzenbergs, Timothy W. Russell, Billy J. Quilty, Eleanor M. Rees, Quentin J. Leclerc, W. John Edmunds, Sebastian Funk, Rein M. G. J. Houben, Gwenan M. Knight, Sam Abbott, Fiona Yueqian Sun, Rachel Lowe, Damien C. Tully, Simon R. Procter, Christopher I. Jarvis, Akira Endo, Kathleen O’Reilly, Jon C. Emery, Thibaut Jombart, Alicia Rosello, Arminder K. Deol, Matthew Quaife, Stéphane Hué, Yang Liu, Rosalind M. Eggo, Carl A. B. Pearson, Adam J. Kucharski, Lewis G. Spurgin
Journal: Nature Medicine (2020)
Mechanisms Regulating Muscle Protein Synthesis in CKD
Authors: Liping Zhang, Qin Chen, Zihong Chen, Ying Wang, Jorge L. Gamboa, Talat Alp Ikizler, Giacomo Garibotto, William E. Mitch
Journal: Journal of the American Society of Nephrology (2020)

CKD induces loss of muscle proteins partly by suppressing muscle protein synthesis. Muscles of mice with CKD have increased expression of nucleolar protein 66 (NO66), as do muscle biopsy specimens from patients with CKD or those undergoing hemodialysis. Inflammation stimulates NO66 expression and changes in NF-κB mediate the response.Subtotal nephrectomy created a mouse model of CKD with BUN >80 mg/dl. Crossing NO66flox/flox with MCK-Cre mice bred muscle-specific NO66 (MCK-NO66) knockout mice. Experiments assessed the effect of removing NO66.Muscle-specific NO66 knockout in mice blocks CKD-induced loss of muscle mass and improves protein synthesis. NO66 suppression of ribosomal biogenesis via demethylase activity is the mechanism behind these responses. In muscle cells, expression of NO66, but not of demethylase-dead mutant NO66, decreased H3K4me3 and H3K36me3 and suppressed pre-rRNA expression. Knocking out NO66 increased the enrichment of H3K4me3 and H3K36me3 on ribosomal DNA. In primary muscle cells and in muscles of mice without NO66, ribosomal RNA, pre-rRNA, and protein synthesis all increased.CKD suppresses muscle protein synthesis via epigenetic mechanisms that NO66 mediates. Blocking NO66 could suggest strategies that counter CKD-induced abnormal muscle protein catabolism.
All that glisters is not COVID: Low prevalence of seroconversion against SARS-CoV-2 in a pediatric cohort of patients with chilblain-like lesions
Authors: Marco Denina, Francesco Pellegrino, Francesco Morotti, Paola Coppo, Ilaria Maria Bonsignori, Silvia Garazzino, Paolo Ravanini, Maria Avolio, Rossana Cavallo, Luigi Bertolotti, Enrico Felici, Gabriela Acucella, Davide Montin, Ivana Rabbone, Francesco Licciardi
Journal: Journal of the American Academy of Dermatology (2020)
The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma
Authors: Raul Caso, Francisco Sanchez-Vega, Kay See Tan, Brooke Mastrogiacomo, Jian Zhou, Gregory D. Jones, Bastien Nguyen, Nikolaus Schultz, James G. Connolly, Whitney S. Brandt, Matthew J. Bott, Gaetano Rocco, Daniela Molena, James M. Isbell, Yuan Liu, Marty W. Mayo, Prasad S. Adusumilli, William D. Travis, David R. Jones
Journal: Journal of Thoracic Oncology (2020)