tbuckley/cabot-search huggingface dataset:
Intestinal <i>Cetobacterium</i> and acetate modify glucose homeostasis via parasympathetic activation in zebrafish
Authors: Anran Wang, Zhen Zhang, Qianwen Ding, Yalin Yang, Jérôme Bindelle, Chao Ran, Zhigang Zhou
Journal: Gut Microbes (2021)

The capability of carbohydrate utilization in fish is limited compared to mammals. It has scientific and practical significance to improve the ability of fish to use carbohydrates. The efficiency of dietary carbohydrate utilization varies among fish with different feeding habits, which are associated with differential intestinal microbiota. In this study, we found that zebrafish fed with omnivorous diet (OD) and herbivorous diet (HD) showed better glucose homeostasis compared with carnivorous diet (CD) fed counterpart and the differential glucose utilization efficiency was attributable to the intestinal microbiota. The commensal bacterium Cetobacterium somerae, an acetate producer, was enriched in OD and HD groups, and administration of C. somerae in both adult zebrafish and gnotobiotic larval zebrafish models resulted in improved glucose homeostasis and increased insulin expression, supporting a causative role of C. somerae enrichment in glucose homeostasis in fish. The enrichment of C. somerae was constantly associated with higher acetate levels, and dietary supplementation of acetate promotes glucose utilization in zebrafish, suggesting a contribution of acetate in the function of C. somerae. Furthermore, we found that the beneficial effect of both acetate and C. somerae on glucose homeostasis was mediated through parasympathetic activation. Overall, this work highlights the existence of a C. somerae-brain axis in the regulation of glucose homeostasis in fish and suggests a role of acetate in mediating the axis function. Our results suggest potential strategies for improvement of fish carbohydrate utilization.
Abstract 13191: Increased Extracellular Sodium and Intercellular Cleft Separation Synergistically Prolong Repolarization in the Long-qt Syndrome Type 3
Authors: Xiaobo Wu, Gregory HOEKER, David Ryan King, Robert G Gourdie, Seth Weinberg, Steven Poelzing
Journal: Circulation (2020)

Introduction: Long-QT syndrome type 3 (LQT3) is caused by a gain-of-function mutation in the cardiac sodium channel that increases the late sodium current and prolongs repolarization. We previously suggested that narrowing the perinexus which is adjacent gap junction conceals the LQT3 phenotype by depleting extracellular sodium ([Na]) within this nanodomain and curtails the late current and repolarization. However, it is unknown if elevating bulk [Na] alone modulates action potential duration (APD) in widened perinexi to unmask LQT3. Hypothesis: Elevated [Na] and widened perinexi synergistically prolong APD in LQT3. Methods: The dependence of APD on [Na] and perinexal width was explored with a computational model and in Langendorff-perfused guinea pig hearts. The late sodium current was induced with ATXII (7nM). Perfusate [Na] changed from 145 (145Na) to 160 mM (160Na). Perinexal expansion was induced with βadp1 (1uM). APD was quantified from whole-heart optical maps. Perinexal width was quantified by transmission electron microscopy. Results: A computational model, including preferential sodium channel location at the intercalated disk, predicts that combination of elevated [Na] and widened perinexus prolongs APD greater than summing the effect of the individual interventions alone. Therefore, the combination is synergistic and not additive. Isolated heart experiments are consistent with the model. Specifically, ATXII+βadp1 significantly widens perinexal width from 27.8±4.1 to 49.7±9.3 nm and prolongs APD by 18.1±5.1ms with 600ms pacing relative to ATXII alone. In the presence of ATXII, 160Na significantly prolongs APD by 12.0±5.8ms relative to 145Na. Furthermore, the combination of both interventions is synergistic. Specifically, in the presence of ATXII, 160Na+βadp1 significantly prolongs APD more than the sum of the individual effects (49.9±7.5ms vs. 30.2±5.4ms). Conclusions: The data demonstrate that in LQT3, enhancing sodium and perinexal width concurrently prolong APD more than the individual effects alone. This synergistic effect suggests that maintaining reduced plasma sodium level can be a simple and effective method to conceal LQT3, even in the presence of perinexal expansion associated with osmotically induced stress.
Author Correction: Reopening businesses and risk of COVID-19 transmission (npj Digital Medicine, (2021), 4, 1, (51), 10.1038/s41746-021-00420-9)
Authors: A. O’Donoghue, T. Dechen, W. Pavlova, M. Boals, G. Moussa, M. Madan, A. Thakkar, F. J. DeFalco, J. P. Stevens
Journal: npj Digital Medicine (2021)
Reply to Satoshi Funada, Takashi Yoshioka, and Yan Luo’s Letter to the Editor re: Cosimo De Nunzio, Benjamin Brucker, Thomas Bschleipfer, et al. Beyond Antimuscarinics: A Review of Pharmacological and Interventional Options for Overactive Bladder Management in Men. Eur Urol 2021;79:492–504
Authors: Cosimo De Nunzio, Benjamin Brucker, Thomas Bschleipfer, Jean-Nicolas Cornu, Marcus J. Drake, Ferdinando Fusco, Stavros Gravas, Matthias Oelke, Benoit Peyronnet, Manuela Tutolo, Gommert van Koeveringe, Stephan Madersbacher
Journal: European Urology (2021)
Charles L Christian: model physician scientist and mentor
Authors: Mary K Crow
Journal: Annals of the Rheumatic Diseases (2021)

Dr Charles L Christian arrived in New York City in 1953, having grown up in Wichita, Kansas, and graduating from medical school at Case Western Reserve in Cleveland, Ohio. In New York, Dr Christian embarked on training in internal medicine at Columbia’s Presbyterian Hospital where he met an individual who would shape the course of his career, Dr Charles Ragan, a founder of the Arthritis Foundation. Dr Christian, or Chuck as he was usually called, went on to shape the developing field of rheumatology, advancing understanding of our most complex diseases as an investigator, master clinician, mentor and academic leader. During an era when the cellular and humoral features of the immune system were just coming into focus, Chuck performed laboratory experiments with precision and creativity to achieve new understanding of three significant diseases: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and vasculitis. Review of his publications from the 1950s and 1960s provides a window into a time when figures were hand drawn and papers often had a single author. While the tools of technology that we rely on today were not available to Chuck, his insights have had a sustained impact on how we understand and treat autoimmune rheumatic diseases (table 1). His talents and his dedication to patients, colleagues, science and medicine supported a lifetime of remarkable contributions.

View this table:

Table 1 
Charles L Christian, MD: major scientific contributions



Dr Christian’s research addressing immunologic mechanisms in RA was inspired by Dr Ragan, who with Dr Harry M. Rose can be credited with the discovery of rheumatoid factor. Dr Ragan was Chairman of the Department of Medicine at Columbia University College of Physicians & Surgeons at the time Chuck joined their faculty as a young physician. In 1957, in a paper published with Dr Ragan, and in a single-author study published in Journal …
Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial
Authors: Yvo J.M. Op den Kamp, Marlies de Ligt, Bas Dautzenberg, Esther Kornips, Russell Esterline, Matthijs K.C. Hesselink, Joris Hoeks, Vera B. Schrauwen-Hinderling, Bas Havekes, Jan Oscarsson, Esther Phielix, Patrick Schrauwen
Journal: Diabetes Care (2021)

SGTL2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes. The underlying mechanism may involve caloric restriction-like metabolic effects due to urinary glucose loss. We investigated the effects of dapagliflozin on 24-h energy metabolism and insulin sensitivity in patients with type 2 diabetes.There were 26 patients with type 2 diabetes randomized to a 5-week double-blind, crossover study with a 6- to 8-week washout. Indirect calorimetry was used to measure 24-h energy metabolism and the respiratory exchange ratio (RER), both by whole-room calorimetry and by ventilated hood during a two-step euglycemic-hyperinsulinemic clamp. Results are presented as the differences in least squares mean (95% CI) between treatments.Evaluable patients (n = 24) had a mean (SD) age of 64.2 (4.6) years, BMI of 28.1 (2.4) kg/m2, and HbA1c of 6.9% (0.7) (51.7 [6.8] mmol/mol). Rate of glucose disappearance was unaffected by dapagliflozin, whereas fasting endogenous glucose production (EGP) increased by dapagliflozin (+2.27 [1.39, 3.14] μmol/kg/min, P < 0.0001). Insulin-induced suppression of EGP (-1.71 [-2.75, -0.63] μmol/kg/min, P = 0.0036) and plasma free fatty acids (-21.93% [-39.31, -4.54], P = 0.016) was greater with dapagliflozin. Twenty-four-hour energy expenditure (-0.11 [-0.24, 0.03] MJ/day) remained unaffected by dapagliflozin, but dapagliflozin reduced the RER during daytime and nighttime, resulting in an increased day-to-nighttime difference in the RER (-0.010 [-0.017, -0.002], P = 0.016). Dapagliflozin treatment resulted in a negative 24-h energy and fat balance (-20.51 [-27.90, -13.12] g/day).Dapagliflozin treatment for 5 weeks resulted in major adjustments of metabolism mimicking caloric restriction, increased fat oxidation, improved hepatic and adipose insulin sensitivity, and improved 24-h energy metabolism.
Prognostic Value of Cardiac CT Delayed Enhancement Imaging in Patients With Suspected Coronary Artery Disease
Authors: Yoshitaka Goto, Kakuya Kitagawa, Satoshi Nakamura, Masafumi Takafuji, Shiro Nakamori, Naoki Nagasawa, Tairo Kurita, Kaoru Dohi, Hajime Sakuma
Journal: JACC. Cardiovascular imaging (2021)
Abstract 12968: Association of Achieved Hemoglobin A1c and Cardiovascular Outcome in Type 2 Diabetic Patients With Coronary Artery Disease
Authors: Shinichiro Ueda, Takeshi Morimoto, Akihiro Tokushige, Michio Shimabukuro, Takanori Yasu, Osamu Arasaki, Taku Inoue, Koichi Node
Journal: Circulation (2018)

Introduction: There remains debate in terms of appropriate target of blood glucose levels particularly in type 2 diabetic patients with long history of diabetes and co-morbidities. We explored the ...
Nonserious Infections in Patients With Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis
Authors: Katie Bechman, Kapil Halai, Mark Yates, Sam Norton, Andrew P. Cope, Kimme L. Hyrich, James B. Galloway
Journal: Arthritis & Rheumatology (2021)

Objective To describe the frequency and predictors of nonserious infections (NSI) and compare incidence across biologic agents within the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR‐RA). Methods The BSRBR‐RA is a prospective observational cohort study. An NSI was defined as an infection that did not require hospitalization or intravenous therapy. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered “at risk” from the date of initiation of biologic treatment for up to 3 years. Drug exposure was defined by agent: tumor necrosis factor inhibitor (TNFi), interleukin‐6 (IL‐6) inhibitor, B cell depletion (rituximab), or conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) alone. A multiple‐failure Cox model was used with multivariable adjustment. Missing data were addressed using multiple imputation. Results There were 17,304 NSI in 8,145 patients, with an event rate of 27.0 per person per year (95% confidence interval [95% CI] 26.6–27.4). Increasing age, female sex, comorbidity burden, glucocorticoid therapy, higher Disease Activity Score in 28 joints, and higher Health Assessment Questionnaire disability index were associated with an increased risk of NSI. There was a significant reduction in NSI risk with csDMARDs compared to biologic treatments. Compared to TNFi, IL‐6 inhibition and rituximab were associated with a higher NSI risk (adjusted hazard ratio 1.45 [95% CI 1.29–1.63] and adjusted hazard ratio 1.28 [95% CI 1.14–1.45], respectively), while the csDMARD cohort had a lower risk (adjusted hazard ratio 0.64 [95% CI 0.59–0.70]). Within the TNFi class, adalimumab was associated with a higher NSI risk than etanercept (adjusted hazard ratio 1.11 [95% CI 1.05–1.17]). Conclusion NSI occur frequently in RA, and predictors mirror those reported with serious infections. All biologics are associated with a greater risk of NSI, with differences observed between agents. While unmeasured confounding must be considered, the magnitude of effect is large, and a relationship between NSI and targeted immunomodulatory therapy likely exists.
Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC
Authors: James E. Frampton
Journal: Drugs (2021)

Entrectinib (Rozlytrek®) is an orally active, CNS-penetrant, small-molecule, selective inhibitor of the tropomyosin receptor tyrosine kinases TRKA/B/C [encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1/2/3, respectively], the proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and the anaplastic lymphoma kinase gene (ALK). It is approved for the treatment of adults and paediatric patients aged ≥ 12 years with NTRK fusion-positive (NTRK+) solid tumours and adults with ROS1 fusion-positive (ROS1+) non-small-cell lung cancer (NSCLC). In trials in adults, entrectinib induced clinically meaningful and durable systemic responses in tyrosine kinase inhibitor (TKI)-naïve patients with locally-advanced or metastatic NTRK+ solid tumours or ROS1+ NSCLC, irrespective of the presence or absence of CNS metastases at baseline. Moreover, entrectinib demonstrated substantial intracranial efficacy in patients with baseline CNS metastases. Entrectinb efficacy in paediatric patients was established on the basis of extrapolation of clinical trial data from adults with NTRK+ solid tumours and children and adolescents aged < 21 years with recurrent or refractory NTRK+ CNS/solid tumours. Entrectinib was generally well tolerated, with a manageable safety profile. Thus, entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases.
2007 George L. Duff Memorial Lecture—The Immune Response in Atherosclerosis
Authors: Göran K. Hansson
Journal: Circulation (2007)

Immune responses participate in every phase of atherosclerosis. Indeed, atherosclerosis can be viewed as an immune/inflammatory response to lipoprotein retention in the artery wall. There is increasing evidence that both adaptive and innate immunity tightly regulate the atherosclerotic process. Specific antigens and pathogen-like molecular patterns initiate the 2 aspects of immunity by ligating T- and B-cell receptors and pattern recognition receptors, respectively. Effector responses of vascular immune reactions include macrophage activation, cellular immunity, antibody formation, and vascular inflammation. Whereas experimental studies in gene-targeted models have identified major roles for innate immunity and Th1 responses in plaque initiation and progression, clinical, epidemiological and genetic studies suggest that plaque activation, rupture, and atherothrombosis also depend on immune reactions. This lecture will focus on the role of immune mechanisms in the formation and activation of atherosclerotic plaques.
Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
Authors: Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrícia Bento, Inigo Barrio-Hernandez, Lars Rönnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O’Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas
Journal: Nature Medicine (2021)
Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study
Authors: Élie Azoulay, Pedro Castro, Adel Maamar, Victoria Metaxa, Alice Gallo de Moraes, Louis Voigt, Florent Wallet, Kada Klouche, Muriel Picard, Anne-Sophie Moreau, Andry Van De Louw, Amélie Seguin, Djamel Mokart, Sanjay Chawla, Julien Leroy, Boris Böll, Nahema Issa, Bruno Levy, Pleun Hemelaar, Sara Fernandez, Laveena Munshi, Philippe Bauer, Peter Schellongowski, Michael Joannidis, Gabriel Moreno-Gonzalez, Gennadii Galstian, Michael Darmon, Sandrine Valade, Lara Zafrani, Eric Mariotte, Virginie Lemiale, Bertrand Arnulf, Nicolas Boissel, Catherine Thieblemont, Florence Rabian, Stéphanie Harel, Roberta Di Blasi, Julio Delgado, Valentin Ortiz, Didier Blaise, Sabine Fürst, Faezeh Legrand, Christian Chabannon, Edouard Forcade, François-Xavier Gros, Cécile Borel, Anne Huynh, Christian Récher, Jakob Rudzki, Kevin Rakszawski, Pierre Sesques, Emmanuel Bachy, Gilles Salles, Miguel A Perales, Philipp Wohlfarth, Thomas Staudingert, Ulrich Jäger, Guillaume Cartron, Nathalie Fégueux, Patrice Ceballos, Laura Platon, Thomas Gastinne, Benoit Tessoulin, Amandine Le Bourgeois, Olga Gavrilina, Anna Sureda, Alberto Mussetti, Jorge Garcia Borrega, Peter Borchmann, Yi Lin, Reuben Benjamin, Sophie de Guibert, Quentin Quelven, Ibrahim Yakoub-Agha, David Beauvais, Marie-Therese Rubio
Journal: The Lancet Haematology (2021)
Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance
Authors: Rana R. McKay, Lucia Kwak, Jett P. Crowdis, Jamie M. Sperger, Shuang G. Zhao, Wanling Xie, Lillian Werner, Rosina T. Lis, Zhenwei Zhang, Xiao X. Wei, Joshua M. Lang, Eliezer M. Van Allen, Rupal S. Bhatt, Evan Y. Yu, Peter S. Nelson, Glenn J. Bubley, R. Bruce Montgomery, Mary-Ellen Taplin
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. Patients and Methods: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. Results: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression. Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
Association Between <i>KRAS</i> Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Lova Sun, Miles Hsu, Roger B. Cohen, Corey J. Langer, Ronac Mamtani, Charu Aggarwal
Journal: JAMA Oncology (2021)

Conflict of Interest Disclosures: Dr Odisho reported personal fees from VSee, LLC outside the submitted work.Dr Hong reported a
MicroRNAs as theranostic markers in cardiac allograft transplantation: from murine models to clinical practice
Authors: Jan Novák, Táňa Macháčková, Jan Krejčí, Julie Bienertová-Vašků, Ondřej Slabý
Journal: Theranostics (2021)

Congestive heart failure affects about 23 million people worldwide, and cardiac allograft transplantation remains one of the last options for patients with terminal refractory heart failure. Besides the infectious or oncological complications, the prognosis of patients after heart transplantation is affected by acute cellular or antibody-mediated rejection and allograft vasculopathy development. Current monitoring of both conditions requires the performance of invasive procedures (endomyocardial biopsy sampling and coronary angiography or optical coherence tomography, respectively) that are costly, time-demanding, and non-comfortable for the patient. Within this narrative review, we focus on the potential pathophysiological and clinical roles of microRNAs (miRNAs, miRs) in the field of cardiac allograft transplantation. Firstly, we provide a general introduction about the status of cardiac allograft function monitoring and the discovery of miRNAs as post-transcriptional regulators of gene expression and clinically relevant biomarkers found in the extracellular fluid. After this general introduction, information from animal and human studies are summarized to underline the importance of miRNAs both in the pathophysiology of the rejection process, the possibility of its modulation by altering miRNAs levels, and last but not least, about the use of miRNAs in the clinical practice to diagnose or predict the rejection occurrence.
Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial
Authors: Keith J Chappell, Francesca L Mordant, Zheyi Li, Danushka K Wijesundara, Paula Ellenberg, Julia A Lackenby, Stacey T M Cheung, Naphak Modhiran, Michael S Avumegah, Christina L Henderson, Kym Hoger, Paul Griffin, Jillian Bennet, Luca Hensen, Wuji Zhang, Thi H O Nguyen, Sara Marrero-Hernandez, Kevin J Selva, Amy W Chung, Mai H Tran, Peter Tapley, James Barnes, Patrick C Reading, Suellen Nicholson, Stavroula Corby, Thomas Holgate, Bruce D Wines, P Mark Hogarth, Katherine Kedzierska, Damian F J Purcell, Charani Ranasinghe, Kanta Subbarao, Daniel Watterson, Paul R Young, Trent P Munro
Journal: The Lancet Infectious Diseases (2021)