tbuckley/cabot-search huggingface dataset:
Serotonin is elevated in COVID-19-associated diarrhoea
Authors: Seeun Ha, Byungchang Jin, Brooke Clemmensen, Paul Park, Sumaiya Mahboob, Vadim Gladwill, Farah Madhani Lovely, Andres Gottfried-Blackmore, Aida Habtezion, Subhash Verma, Seungil Ro
Journal: Gut (2021)

<h3>Abstract</h3> Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer’s disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-α. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.
Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
Authors: Harshabad Singh, Yvonne Y. Li, Liam F. Spurr, Atul B. Shinagare, Ritika Abhyankar, Emma Reilly, Lauren K. Brais, Anwesha Nag, Matthew D. Ducar, Aaron R. Thorner, Geoffrey I. Shapiro, Rachel B. Keller, Cheta Siletti, Jeffrey W. Clark, Anna F. Farago, Jessica J. Lin, George D. Demetri, Rahul Gujrathi, Matthew H. Kulke, Laura E. MacConaill, Azra H. Ligon, Ewa Sicinska, Matthew L. Meyerson, Jeffrey A. Meyerhardt, Andrew D. Cherniack, Brian M. Wolpin, Kimmie Ng, Marios Giannakis, Jason L. Hornick, James M. Cleary
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer. Experimental Design: We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results. Results: We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy. Conclusions: RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging‐Induced Osteoarthritis in Mice
Authors: P. M. Moon, Z. Y. Shao, G. Wambiekele, C. T. G. Appleton, D. W. Laird, S. Penuela, F. Beier
Journal: Arthritis & Rheumatology (2021)

Objective Osteoarthritis (OA) results in pathologic changes in the joint tissue. The mechanisms driving disease progression remain largely unclear, and thus disease‐modifying treatments are lacking. Pannexin 3 (Panx3) was identified as a potential mediator of cartilage degeneration in OA, and our previous study in mice indicated that deletion of the Panx3 gene delayed surgically induced cartilage degeneration. This study was undertaken to examine the role of Panx3 in other OA subtypes, particularly primary OA during aging, in a mouse model of aging‐induced OA. Methods Wild‐type (WT) and Panx3 −/− C57BL/6J (Black‐6) mice, ages 18–24 months, were analyzed by micro–computed tomography to investigate bone mineral density and body composition. Joints were harvested from the mice, and histopathologic analysis of the joint tissue for OA development was conducted with a specific focus on changes in articular cartilage, subchondral bone, and synovial tissue. Results Global loss of Panx3 in aging mice was not associated with increased mortality or changes in body composition. Mice lacking Panx3 had shorter appendicular skeletons than WT mice, but overall the body compositions appeared quite similar. Panx3 deletion dramatically accelerated cartilage degeneration and subchondral bone thickening with aging in both 18‐month‐old and 24‐month‐old mice, while promoting synovitis in 18‐month‐old mice. Conclusion These observations in a mouse model of OA suggest that Panx3 has a protective role against the development of primary aging‐associated OA. It appears that Panx3 has opposing context‐specific roles in joint health following traumatic injury versus that associated with aging. These data strongly suggest that there are differences in the molecular pathways driving different subtypes of OA, and therefore a detailed understanding of these pathways could directly improve strategies for OA diagnosis, therapy, and research.
MO01.28 A Phase 1b/2, Open-Label Study of Bintrafusp Alfa with Chemotherapy in Patients with Stage IV Non-Small Cell Lung Cancer
Authors: F. Barlesi, S. Hiret, C. Rolfo, I. Grenga, A. Koenig, Y. Vugmeyster, L. Horn
Journal: Journal of Thoracic Oncology (2021)
Elastic fibers during aging and disease
Authors: Andrea Heinz
Journal: Ageing Research Reviews (2021)

Elastic fibers are essential constituents of the extracellular matrix of higher vertebrates and endow several tissues and organs including lungs, skin and blood vessels with elasticity and resilience. During the human lifespan, elastic fibers are exposed to a variety of enzymatic, chemical and biophysical influences, and accumulate damage due to their low turnover. Aging of elastin and elastic fibers involves enzymatic degradation, oxidative damage, glycation, calcification, aspartic acid racemization, binding of lipids and lipid peroxidation products, carbamylation and mechanical fatigue. These processes can trigger an impairment or loss of elastic fiber function and are associated with severe pathologies. There are different inherited or acquired pathological conditions, which influence the structure and function of elastic fibers and microfibrils predominantly in the cardiorespiratory system and skin. Inherited elastic-fiber pathologies have a direct or indirect impact on elastic-fiber formation due to mutations in the fibrillin genes (fibrillinopathies), in the elastin gene (elastinopathies) or in genes encoding proteins that are associated with microfibrils or elastic fibers. Acquired elastic-fiber pathologies appear age-related or as a result of multiple factors impairing tissue homeostasis. This review gives an overview on the fate of elastic fibers over the human lifespan in health and disease.
Signaling Microdomains in the Spotlight: Visualizing Compartmentalized Signaling Using Genetically Encoded Fluorescent Biosensors
Authors: Jin-Fan Zhang, Sohum Mehta, Jin Zhang
Journal: The Annual Review of Pharmacology and Toxicology (2021)

How cells muster a network of interlinking signaling pathways to faithfully convert diverse external cues to specific functional outcomes remains a central question in biology. Through their ability to convert dynamic biochemical activities to rapid and precise optical readouts, genetically encoded fluorescent biosensors have become instrumental in unraveling the molecular logic controlling the specificity of intracellular signaling. In this review, we discuss how the use of genetically encoded fluorescent biosensors to visualize dynamic signaling events within their native cellular context is elucidating the different strategies employed by cells to organize signaling activities into discrete compartments, or signaling microdomains, to ensure functional specificity.
Interferons in cancer immunoediting: sculpting metastasis and immunotherapy response
Authors: Michelle von Locquenghien, Catalina Rozalén, Toni Celià-Terrassa
Journal: Journal of Clinical Investigation (2021)

Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.
Persistent Opioid Use May Be a Failure of Pain Management Rather Than Prescribing—Reply
Authors: Chase R. Brown, Peter Groeneveld, Nimesh Desai
Journal: JAMA Cardiology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Association of Coloproctology of Great Britain and Ireland response to: “Have large increases in fast track referrals improved bowel cancer outcomes in the UK?”
Authors: Michael Davies, Jim Teirnan
Journal: BMJ (2021)

Thompson and colleagues raise concern that a series of UK Department of Health policies have led to an inexorable rise in referrals of people with bowel symptoms rather than an improvement in survival from colorectal cancer.1 The small percentage of people with serious disease are hidden in this tsunami of referrals, which overwhelms the investigative processes and weakens the ability to improve survival rates.

Using the fecal immunological …
Genetic Association of a Gain‐of‐Function <i>IFNGR1</i> Polymorphism and the Intergenic Region <i>LNCAROD/DKK1</i> With Behçet’s Disease
Authors: Lourdes Ortiz Fernández, Patrick Coit, Vuslat Yilmaz, Sibel P. Yentür, Fatma Alibaz‐Oner, Kenan Aksu, Eren Erken, Nursen Düzgün, Gokhan Keser, Ayse Cefle, Ayten Yazici, Andac Ergen, Erkan Alpsoy, Carlo Salvarani, Bruno Casali, Bünyamin Kısacık, Ina Kötter, Jörg Henes, Muhammet Çınar, Arne Schaefer, Rahime M. Nohutcu, Alexandra Zhernakova, Cisca Wijmenga, Fujio Takeuchi, Shinji Harihara, Toshikatsu Kaburaki, Meriam Messedi, Yeong‐Wook Song, Timuçin Kaşifoğlu, F. David Carmona, Joel M. Guthridge, Judith A. James, Javier Martin, María Francisca González Escribano, Güher Saruhan‐Direskeneli, Haner Direskeneli, Amr H. Sawalha
Journal: Arthritis & Rheumatology (2021)

Objective Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population. Methods A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray‐24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed. Results We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1 (rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10 −9 ) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10 −8 ). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide‐stimulated monocytes. In addition, our results replicated the association ( P &lt; 5 × 10 −8 ) of 6 previously identified susceptibility loci in Behçet’s disease: IL10 , IL23R , IL12A‐AS1 , CCR3 , ADO , and LACC1 , reinforcing the notion that these loci are strong genetic factors in Behçet’s disease shared across ancestries. We also identified &gt;30 genetic susceptibility loci with a suggestive level of association ( P &lt; 5 × 10 −5 ), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated. Conclusion We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.
Cardioprotective effects of an early invasive strategy for non–ST-segment elevationacute coronary syndromes: Are we all becoming “interventional” cardiologists?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Ravi K Yarlagadda, William E Boden
Journal: Journal of the American College of Cardiology (2002)
P87.02 AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC
Authors: B. Besse, E. Felip, E.S. Kim, C. Clifford, M. Louie-Gao, A. Yagui-Beltran, S. Popat
Journal: Journal of Thoracic Oncology (2021)
Abstract 16299: Fontan Patients With Heart Failure and Preserved Ejection Fraction Have Similar Functional Health Status to Fontan Patients With Reduced Ejection Fraction
Authors: Shahryar M Chowdhury, Kimberly McHugh, Stephanie Gaydos, Carolyn L Taylor, Eric M Graham, Arni Nutting, Andrew M Atz
Journal: Circulation (2018)

Introduction: Patients with Fontan physiology often report abnormal functional health status despite evidence of normal ejection fraction on non-invasive imaging. The objective of this study was to...
Longitudinal associations between ambient air pollution and insulin sensitivity: results from the KORA cohort study
Authors: Siqi Zhang, Sarah Mwiberi, Regina Pickford, Susanne Breitner, Cornelia Huth, Wolfgang Koenig, Wolfgang Rathmann, Christian Herder, Michael Roden, Josef Cyrys, Annette Peters, Kathrin Wolf, Alexandra Schneider
Journal: The Lancet Planetary Health (2021)

BackgroundImpaired insulin sensitivity could be an intermediate step that links exposure to air pollution to the development of type 2 diabetes. However, longitudinal associations of air pollution with insulin sensitivity remain unclear. Our study investigated the associations of long-term air pollution exposure with the degree and rate of change of insulin sensitivity.MethodsIn this longitudinal study, we analysed data from the Cooperative Health Research in the Region of Augsburg (KORA) cohort from Augsburg, Germany, which recruited participants aged 25–74 years in the survey between 1999 and 2001 (KORA S4), with two follow-up examinations in 2006–08 (KORA F4) and 2013–14 (KORA FF4). Serum concentrations of fasting insulin and glucose, and homoeostasis model assessment of insulin resistance (HOMA-IR, a surrogate measure of insulin sensitivity) and β-cell function (HOMA-B, a surrogate marker for fasting insulin secretion) were assessed at up to three visits between 1999 and 2014. Annual average air pollutant concentrations at the residence were estimated by land-use regression models. We examined the associations of air pollution with repeatedly assessed biomarker levels using mixed-effects models, and we assessed the associations with the annual rate of change in biomarkers using quantile regression models.FindingsAmong 9620 observations from 4261 participants in the KORA cohort, we included 6008 (62·5%) observations from 3297 (77·4%) participants in our analyses. Per IQR increment in annual average air pollutant concentrations, HOMA-IR significantly increased by 2·5% (95% CI 0·3 to 4·7) for coarse particulate matter, by 3·1% (0·9 to 5·3) for PM2·5, by 3·6% (1·0 to 6·3) for PM2·5absorbance, and by 3·2% (0·6 to 5·8) for nitrogen dioxide, and borderline significantly increased by 2·2% (–0·1 to 4·5) for ozone, whereas it did not significantly increase for the whole range of ultrafine particles. Similar positive associations in slightly smaller magnitude were observed for HOMA-B and fasting insulin levels. In addition, air pollutant concentrations were positively associated with the annual rate of change in HOMA-IR, HOMA-B, and fasting insulin. Neither the level nor the rate of change of fasting glucose were associated with air pollution exposure.InterpretationOur study indicates that long-term air pollution exposure could contribute to the development of insulin resistance, which is one of the key factors in the pathogenesis of type 2 diabetes.FundingGerman Federal Ministry of Education and Research.
Enhanced drug delivery to the reproductive tract using nanomedicine reveals therapeutic options for prevention of preterm birth
Authors: Hannah C. Zierden, Jairo I. Ortiz, Kevin DeLong, Jingqi Yu, Gaoshan Li, Peter Dimitrion, Sabrine Bensouda, Victoria Laney, Anna Bailey, Nicole M. Anders, Morgan Scardina, Mala Mahendroo, Sam Mesiano, Irina Burd, Gunter Wagner, Justin Hanes, Laura M. Ensign
Journal: Science Translational Medicine (2021)

Vaginally delivered nanoformulations of progesterone and histone deacetylase inhibitors prevent inflammation-induced preterm birth in mice.
­­Speaking truth to power
Authors: Fiona Godlee
Journal: BMJ (2021)

These are people who have bravely called out wrongdoing or have paved a compelling path for doing right, often through their writings in The BMJ.At the end of last year the prize went to Allyson Pollock, who is interviewed this week. 1 Why should we prize these people so highly?Because it takes determination, diligence, and skill to speak out effectively, to use data and judgment, to avoid the easy resort to polemic or personal attack, and to balance necessary criticism with constructive ideas.
Genomic and phenotypic characterization of Investigator Global Assessment (IGA) scale-based endotypes in atopic dermatitis
Authors: Sandra P. Smieszek, Bartlomiej Przychodzen, Sarah E. Welsh, Jennifer L. Brzezynski, Alyssa R. Kaden, Michael Mohrman, Jingyuan Wang, Changfu Xiao, Sonja Ständer, Gunther Birznieks, Christos Polymeropoulos, Mihael H. Polymeropoulos
Journal: Journal of the American Academy of Dermatology (2021)
Covid 19: Widening divisions will take time to heal
Authors: Fiona Godlee
Journal: BMJ (2021)

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DF-MDA: An effective diffusion-based computational model for predicting miRNA-disease association
Authors: Hao-Yuan Li, Zhu-Hong You, Lei Wang, Xin Yan, Zheng-Wei Li
Journal: Molecular Therapy (2021)

It is reported that microRNAs (miRNAs) play an important role in various human diseases. However, the mechanisms of miRNA in these diseases have not been fully understood. Therefore, detecting potential miRNA-disease associations has far-reaching significance for pathological development and the diagnosis and treatment of complex diseases. In this study, we propose a novel diffusion-based computational method, DF-MDA, for predicting miRNA-disease association based on the assumption that molecules are related to each other in human physiological processes. Specifically, we first construct a heterogeneous network by integrating various known associations among miRNAs, diseases, proteins, long non-coding RNAs (lncRNAs), and drugs. Then, more representative features are extracted through a diffusion-based machine-learning method. Finally, the Random Forest classifier is adopted to classify miRNA-disease associations. In the 5-fold cross-validation experiment, the proposed model obtained the average area under the curve (AUC) of 0.9321 on the HMDD v3.0 dataset. To further verify the prediction performance of the proposed model, DF-MDA was applied in three significant human diseases, including lymphoma, lung neoplasms, and colon neoplasms. As a result, 47, 46, and 47 out of top 50 predictions were validated by independent databases. These experimental results demonstrated that DF-MDA is a reliable and efficient method for predicting potential miRNA-disease associations.
Peter George Higgins
Authors: Jenny Harries, Katherine Harries
Journal: BMJ (2021)

Peter George Higgins was born in Kettering on 11 July 1926 to a non-medical family. His grandfather was a vicar, and his father was a sales manager in the shoe trade. He had one elder brother who suffered severe brain trauma at birth, resulting in lifelong epileptic seizures and social constraints. Peter could remember, as a very young child, the hard work of pushing his brother in a pram across fields to a distant farm to obtain unpasteurised milk for what was then considered the latest “treatment” for his brother’s condition. The family moved to Stopsley, Bedfordshire, where Peter attended first junior school, then Luton Grammar Schoo,l and where he met his future wife, Marjorie Simpson, who was a pupil at the parallel Luton Girls’ High School and a member of Luton Girls’ Choir. Whether inspired by his early view of illness through his brother’s trauma, or from the associated need to strike out independently from a difficult home environment, he moved to London to study medicine at Westminster Medical School, qualifying in 1950.

Peter set out initially on a career in paediatrics, completing house physician roles at Westminster Hospital’s children’s department and subsequently at Addenbrooke’s in Cambridge. In 1952 he joined the Royal Air Force, …