tbuckley/cabot-search huggingface dataset:
Fusing the Genetic Landscape of Infantile High-Grade Gliomas
Authors: Frank Szulzewsky, Patrick J. Cimino
Journal: Cancer Discovery (2020)

Abstract Summary: In this issue of Cancer Discovery, Clarke and colleagues define the genetic landscape of infantile cerebral high-grade gliomas, which frequently contain alterations in the MAPK pathway, as well as recurrent gene fusions in receptor tyrosine kinases (ALK, ROS1, MET) and neurotrophic receptor kinases (NTRK1–3). Combining their multi-omic profiling data with functional preclinical and clinical studies, this large multi-institutional study provides strong rationale for future classification and molecular subtype–specific therapeutic management of infantile high-grade glioma. See related article by Clarke et al., p. 942.
A single-center, retrospective record review of malignancy prevalence in patients with dermatomyositis with anti-transcription intermediary factor 1γ antibodies via line immunoassay versus immunoprecipitation
Authors: Skylar Westerdahl, Christopher M. Hull, Jennie T. Clarke, Christopher B. Hansen, Jamie L.W. Rhoads
Journal: Journal of the American Academy of Dermatology (2020)
Increased Risk of Myocardial Infarction Among Patients With Type 2 Diabetes Who Carry the Common rs10830963 Variant in the <i>MTNR1B</i> Gene
Authors: Xiao Tan, Christian Benedict
Journal: Diabetes Care (2020)

OBJECTIVE The common MTNR1B single nucleotide polymorphism rs10830963 associates with risk of type 2 diabetes (T2D). Here, we examine the association between this gene variant and the risk of myocardial infarction (MCI) among patients with T2D. MCI is a main cause of death and disability among such individuals. RESEARCH DESIGN AND METHODS Data from the UK Biobank cohort were used in order to examine the association between rs10830963 and incidence of MCI (fatal and nonfatal) among 13,655 participants with probable T2D during a follow-up period of 6.8 years. RESULTS Assuming an additive genetic model, a positive association was found between the rs10830963 variant in the MTNR1B gene and the risk for incident MCI during the 6.8-year follow-up (adjusted hazard ratio per G allele 1.19 [95% CI 1.02, 1.40], P = 0.03). CONCLUSIONS The rs10830963 polymorphism may be a useful genetic marker for MCI in patients with T2D.
Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance
Authors: Tomoyuki Uchihara, Keisuke Miyake, Atsuko Yonemura, Yoshihiro Komohara, Rumi Itoyama, Mayu Koiwa, Tadahito Yasuda, Kota Arima, Kazuto Harada, Kojiro Eto, Hiromitsu Hayashi, Masaaki Iwatsuki, Shiro Iwagami, Yoshifumi Baba, Naoya Yoshida, Masakazu Yashiro, Mari Masuda, Jaffer A. Ajani, Patrick Tan, Hideo Baba, Takatsugu Ishimoto
Journal: Cancer Research (2020)

Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of β1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics. SIGNIFICANCE: This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing β1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/16/3222/F1.large.jpg.
Specific ablation of CD4<sup>+</sup> T-cells promotes heart regeneration in juvenile mice
Authors: Jiatao Li, Cai Liang, Kevin Y. Yang, Xiuzhen Huang, Mao Ying Han, Xisheng Li, Vicken W. Chan, Kathleen S. Chan, Di Liu, Zhan-Peng Huang, Bin Zhou, Kathy O. Lui
Journal: Theranostics (2020)

Unlike adult cardiomyocytes, neonatal cardiomyocytes can readily proliferate that contributes to a transient regenerative potential after myocardial injury in mice. We have recently reported that CD4+ regulatory T-cells promote this process; however, the role of other CD4+ T-cell subsets as well as CD8+ T-cells in postnatal heart regeneration has been less studied. Methods: by comparing the regenerating postnatal day (P) 3 and the non-regenerating P8 heart after injury, we revealed the heterogeneity of CD4+ and CD8+ T-cells in the myocardium through single cell analysis. We also specifically ablated CD4+ and CD8+ T-cells using the lytic anti-CD4 and -CD8 monoclonal antibodies, respectively, in juvenile mice at P8 after myocardial injury. Results: we observe significantly more CD4+FOXP3- conventional T-cells in the P8 heart when compared to that of the P3 heart within a week after injury. Surprisingly, such a difference is not seen in CD8+ T-cells that appear to have no function as their depletion does not reactivate heart regeneration. On the other hand, specific ablation of CD4+ T-cells contributes to mitigated cardiac fibrosis and increased cardiomyocyte proliferation after injury in juvenile mice. Single-cell transcriptomic profiling reveals a pro-fibrotic CD4+ T-cell subset in the P8 but not P3 heart. Moreover, there are likely more Th1 and Th17 cells in the P8 than P3 heart. We further demonstrate that cytokines of Th1 and Th17 cells can directly reduce the proliferation and increase the apoptosis of neonatal cardiomyocytes. Moreover, ablation of CD4+ T-cells can directly or indirectly facilitate the polarization of macrophages away from the pro-fibrotic M2-like signature in the juvenile heart. Nevertheless, ablation of CD4+ T-cells alone does not offer the same protection in the adult heart after myocardial infarction, suggesting a developmental change of immune cells including CD4+ T-cells in the regulation of age-related mammalian heart repair. Conclusions: our results demonstrate that ablation of CD4+ but not CD8+ T-cells promotes heart regeneration in juvenile mice; and CD4+ T-cells play a distinct role in the regulation of heart regeneration and repair during development.
Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia
Authors: Dirk J. Blom, Mariko Harada-Shiba, Paolo Rubba, Daniel Gaudet, John J.P. Kastelein, Min-Ji Charng, Robert Pordy, Stephen Donahue, Shazia Ali, Yuping Dong, Nagwa Khilla, Poulabi Banerjee, Marie Baccara-Dinet, Robert S. Rosenson
Journal: Journal of the American College of Cardiology (2020)

Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment.This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH.This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment.Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period.In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).
New Diagnostic Agent Detects Tau Pathology in the Brain
Authors: Rebecca Voelker
Journal: JAMA (2020)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction
Authors: Wei Cao, Liling Wu, Xiaodong Zhang, Jing Zhou, Jian Wang, Zhichen Yang, Huanjuan Su, Youhua Liu, Christopher S. Wilcox, Fan Fan Hou
Journal: Journal of the American Society of Nephrology (2020)

Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)-dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown.A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance.By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice.5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.
Increased Internet Search Interest for GI Symptoms May Predict COVID-19 Cases in US Hotspots
Authors: Imama Ahmad, Ryan Flanagan, Kyle Staller
Journal: Clinical Gastroenterology and Hepatology (2020)

Google Trends is an online tool that allows measurement of search term popularity on Google, spatially and temporally. While not an epidemiological tool for determining incidence, it can estimate the popularity of a certain disease by search volume over time.1,2 It has previously correlated well with infectious disease incidence and has demonstrated utility in disease forecasting, especially with influenza data.3 We utilized Google Trends to investigate whether search interest in common gastrointestinal (GI) symptoms would correlate with coronavirus disease 2019 (COVID-19) incidence data.
Introductions and early spread of SARS-CoV-2 in France, 24 January to 23 March 2020
Authors: Fabiana Gámbaro, Sylvie Behillil, Artem Baidaliuk, Flora Donati, Mélanie Albert, Andreea Alexandru, Maud Vanpeene, Méline Bizard, Angela Brisebarre, Marion Barbet, Fawzi Derrar, Sylvie van der Werf, Vincent Enouf, Etienne Simon-Loriere
Journal: Eurosurveillance (2020)

Following SARS-CoV-2 emergence in China, a specific surveillance was implemented in France. Phylogenetic analysis of sequences retrieved through this surveillance suggests that detected initial introductions, involving non-clade G viruses, did not seed local transmission. Nevertheless, identification of clade G variants subsequently circulating in the country, with the earliest from a patient who neither travelled to risk areas nor had contact with travellers, suggests that SARS-CoV-2 might have been present before the first recorded local cases.
COVID-19 and the practice of rheumatology in Africa: big changes to services from the shockwave of a pandemic
Authors: Richard Oluyinka Akintayo, Akpabio Akpabio, Asgar Kalla, Dzifa Dey, Angela Migowa, Hakeem Olaosebikan, Rachid Bahiri, Yasser El Miedany, Djohra Hadef, Wafa Hamdi, Omondi Oyoo, Samy Slimani, Abubakar Yerima, Yassmin Taha, Adewale Adebajo, Olufemi Adelowo, Mohammed Tikly, Imad Ghozlani, Kawther Ben Abdelghani, Nermeen Ahmed Fouad, Doaa Mosad, Dalia El Mikkawy, Mohamed Hassan Abu-Zaid, Rasha A Abdel-Magied
Journal: Annals of the Rheumatic Diseases (2020)

The onset of the COVID-19 pandemic has led to far-reaching changes in the delivery of healthcare services across Africa. A number of drugs used in the management of rheumatic diseases have been touted to have roles to play in the treatment and/or exacerbation of COVID-19 symptoms and this has resulted in significant changes in the practice of rheumatology. The global rheumatology community has risen to this challenge by demonstrating collaborative partnership, resulting in the establishment of the global rheumatology registry to collect data on rheumatic patients infected with COVID-19.1 In view of the study by Gianfrancesco et al ,2 an online survey consisting of 40 practice and experience questions ((online supplementary file 1) and (online supplementary file 2)) was created by the COVID-19 African Rheumatology Study Group which was formed through the network of the African League of Associations for Rheumatology (AFLAR). The aim of the study was to identify the changes in rheumatology practice and patient behaviour, as well as to highlight key concerns of rheumatologists across Africa resulting from the ongoing COVID-19 pandemic.### Supplementary data

[annrheumdis-2020-218273supp001.pdf] 

### Supplementary data

[annrheumdis-2020-218273supp002.pdf] 

A total of 554 completed responses were received from 20 African countries. There were 431 (77.8%) responses from Northern Africa, 43 (7.8%) from West Africa, 6 (1%) from Central Africa, 20 (3.6%) from East Africa and 54 (9.8%) from Southern Africa. The scope of practice was adult only in 296 (53.4%), paediatric only in 15 (2.7%) and both in 243 (43.9%). A total of 288 (52.9%) of the respondents practised in academic institutions, while 162 (29.2%) practised primarily in a private setting. Forty-four (7.9%) were using hydroxychloroquine (HCQ) more than before, 19 (3.4%) admitted to have prescribed HCQ to prevent severe COVID-19 disease, 92 (16.6%) …
Cross-sectional and longitudinal associations between urinary zinc and lung function among urban adults in China
Authors: Min Zhou, Lili Xiao, Shijie Yang, Bin Wang, Tingming Shi, Aijun Tan, Xing Wang, Ge Mu, Weihong Chen
Journal: Thorax (2020)

Background Exposure to zinc was suggested to be associated with pulmonary damage, but whether zinc exposure affects lung function remains unclear. Objectives To quantify the association between urinary zinc and lung function and explore the potential mechanisms. Methods Urinary zinc and lung function were measured in 3917 adults from the Wuhan-Zhuhai cohort and were repeated after 3 years of follow-up. Indicators of systemic inflammation (C reactive protein), lung epithelium integrity (club cell secretory protein-16) and oxidative damage (8-hydroxy-2′-deoxyguanosine and 8-isoprostane) were measured at baseline. Linear mixed models were used to estimate the exposure–response relationship between urinary zinc and lung function. Mediation analyses were conducted to assess mediating roles of inflammation and oxidative damage in above relationships. Results Each 1-unit increase in log-transformed urinary zinc values was associated with a 35.72 mL decrease in forced vital capacity (FVC) and a 24.89 mL decrease in forced expiratory volume in 1 s (FEV1) in the baseline analyses. In the follow-up analyses, there was a negative association between urinary zinc and FVC among participants with persistent high urinary zinc levels, with an estimated change of −93.31 mL (95% CI −178.47 to −8.14). Furthermore, urinary zinc was positively associated with restrictive ventilatory impairment. The mediation analyses suggested that C reactive protein mediated 8.62% and 8.71% of the associations of urinary zinc with FVC and FEV1, respectively. Conclusion Urinary zinc was negatively associated with lung function, and the systemic inflammation may be one of the underlying mechanisms.
Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity
Authors: Ilgen Mender, Anli Zhang, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jiankun Zhu, Aishwarya Vemula, Jerry W. Shay, Yang-Xin Fu
Journal: Cancer Cell (2020)
Calcineurin Aβ–Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy
Authors: Xiaofeng Li, Jinliang Li, Eliana C. Martinez, Alexander Froese, Catherine L. Passariello, Kathryn Henshaw, Francesca Rusconi, Yang Li, Qian Yu, Hrishikesh Thakur, Viacheslav O. Nikolaev, Michael S. Kapiloff
Journal: Circulation (2020)

The Ca2+/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the β isoform of the calcineurin catalytic A-subunit (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. It is unclear how the pleiotropic second messenger Ca2+ drives excitation-contraction coupling while not stimulating hypertrophy by calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectivity in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease.Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Förster resonance energy transfer reporters were used to assay Ca2+ and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus-mediated gene delivery in the mouse were used to study calcineurin signaling after transverse aortic constriction in vivo.CIP4 (Cdc42-interacting protein 4)/TRIP10 (thyroid hormone receptor interactor 10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast 2-hybrid screen. Cardiac myocyte-specific CIP4 gene deletion in mice attenuated pressure overload-induced pathological cardiac remodeling and heart failure. Blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes; disruption of anchoring in vivo using an adeno-associated virus gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell Förster resonance energy transfer biosensor imaging of cultured myocytes revealed that Ca2+ levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca2+ levels and calcineurin activity detected by nonlocalized Förster resonance energy transfer sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca2+ and calcineurin signal transduction.These results support a structural model for Ca2+ and CaNAβ compartmentation in cells based on an isoform-specific mechanism for calcineurin protein-protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further preclinical investigation.
Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection
Authors: Hadi Kuriry, Julia Casey, Lisette Krassenburg, Danie La, Magdalena Kuczynski, Hemant Shah, Harry L.A. Janssen, Bettina E. Hansen, Jordan J. Feld
Journal: Clinical Gastroenterology and Hepatology (2020)