tbuckley/cabot-search huggingface dataset:
Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels
Authors: Chenfei Zhou, Wenfei Wei, Jing Ma, Yang Yang, Luojiao Liang, Yanmei Zhang, Zici Wang, Xiaojing Chen, Lei Huang, Wei Wang, Sha Wu
Journal: Molecular Therapy (2021)

Cancer-associated lymphatic endothelial cells (LECs) are an active barrier to the effector arm of the anti-tumor immune response; however, it remains unclear how LECs become immunosuppressive in the tumor microenvironment (TME). Exosomal microRNAs (miRNAs) have recently been implicated in intercellular crosstalk within the TME. Here, we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated microRNA (miR)-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Subsequently, exosomal miR-1468-5p epigenetically activates the JAK2/STAT3 pathway in LECs by directly targeting homeobox containing 1 (HMBOX1) in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to escape anti-cancer immunity. Furthermore, clinical data reveal that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer (CCa) patients. Taken together, our results suggest that cancer-secreted exosomal miR-1468-5p instructs LECs to form an integrated immunosuppressive TME component and may be a prognostic biomarker and therapeutic target for CCa. Cancer-associated lymphatic endothelial cells (LECs) are an active barrier to the effector arm of the anti-tumor immune response; however, it remains unclear how LECs become immunosuppressive in the tumor microenvironment (TME). Exosomal microRNAs (miRNAs) have recently been implicated in intercellular crosstalk within the TME. Here, we report a mechanistic model via which cervical cancer-secreted, exosome-encapsulated microRNA (miR)-1468-5p promotes lymphatic PD-L1 upregulation and lymphangiogenesis to impair T cell immunity. Subsequently, exosomal miR-1468-5p epigenetically activates the JAK2/STAT3 pathway in LECs by directly targeting homeobox containing 1 (HMBOX1) in the SOCS1 promoter, activating an immunosuppressive program that allows cancer cells to escape anti-cancer immunity. Furthermore, clinical data reveal that high serum exosomal miR-1468-5p levels correlate with TME immunosuppressive status and poor prognosis in cervical cancer (CCa) patients. Taken together, our results suggest that cancer-secreted exosomal miR-1468-5p instructs LECs to form an integrated immunosuppressive TME component and may be a prognostic biomarker and therapeutic target for CCa.
YAP plays a crucial role in the development of cardiomyopathy in lysosomal storage diseases
Authors: Shohei Ikeda, Jihoon Nah, Akihiro Shirakabe, Peiyong Zhai, Shin-ichi Oka, Sebastiano Sciarretta, Kun-Liang Guan, Hiroaki Shimokawa, Junichi Sadoshima
Journal: Journal of Clinical Investigation (2020)

Lysosomal dysfunction caused by mutations in lysosomal genes results in lysosomal storage disorder (LSD), characterized by accumulation of damaged proteins and organelles in cells and functional abnormalities in major organs, including the heart, skeletal muscle, and liver. In LSD, autophagy is inhibited at the lysosomal degradation step and accumulation of autophagosomes is observed. Enlargement of the left ventricle (LV) and contractile dysfunction were observed in RagA/B cardiac-specific KO (cKO) mice, a mouse model of LSD in which lysosomal acidification is impaired irreversibly. YAP, a downstream effector of the Hippo pathway, was accumulated in RagA/B cKO mouse hearts. Inhibition of YAP ameliorated cardiac hypertrophy and contractile dysfunction and attenuated accumulation of autophagosomes without affecting lysosomal function, suggesting that YAP plays an important role in mediating cardiomyopathy in RagA/B cKO mice. Cardiomyopathy was also alleviated by downregulation of Atg7, an intervention to inhibit autophagy, whereas it was exacerbated by stimulation of autophagy. YAP physically interacted with transcription factor EB (TFEB), a master transcription factor that controls autophagic and lysosomal gene expression, thereby facilitating accumulation of autophagosomes without degradation. These results indicate that accumulation of YAP in the presence of LSD promotes cardiomyopathy by stimulating accumulation of autophagosomes through activation of TFEB.
Human marginal zone B cell development from early T2 progenitors
Authors: Thomas J. Tull, Michael J. Pitcher, William Guesdon, Jacqueline H.Y. Siu, Cristina Lebrero-Fernández, Yuan Zhao, Nedyalko Petrov, Susanne Heck, Richard Ellis, Pawan Dhami, Ulrich D. Kadolsky, Michelle Kleeman, Yogesh Kamra, David J. Fear, Susan John, Wayel Jassem, Richard W. Groves, Jeremy D. Sanderson, Michael G. Robson, David P. D’Cruz, Mats Bemark, Jo Spencer
Journal: The Journal of Experimental Medicine (2021)

B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.
Innate Inhibiting Proteins Enhance Expression and Immunogenicity of Self-Amplifying RNA
Authors: Anna K. Blakney, Paul F. McKay, Clément R. Bouton, Kai Hu, Karnyart Samnuan, Robin J. Shattock
Journal: Molecular Therapy (2020)

Self-amplifying RNA (saRNA) is a cutting-edge platform for both nucleic acid vaccines and therapeutics. saRNA is self-adjuvanting, as it activates types I and III interferon (IFN), which enhances the immunogenicity of RNA vaccines but can also lead to inhibition of translation. In this study, we screened a library of saRNA constructs with cis-encoded innate inhibiting proteins (IIPs) and determined the effect on protein expression and immunogenicity. We observed that the PIV-5 V and Middle East respiratory syndrome coronavirus (MERS-CoV) ORF4a proteins enhance protein expression 100- to 500-fold in vitro in IFN-competent HeLa and MRC5 cells. We found that the MERS-CoV ORF4a protein partially abates dose nonlinearity in vivo, and that ruxolitinib, a potent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) inhibitor, but not the IIPs, enhances protein expression of saRNA in vivo. Both the PIV-5 V and MERS-CoV ORF4a proteins were found to enhance the percentage of resident cells in human skin explants expressing saRNA and completely rescued dose nonlinearity of saRNA. Finally, we observed that the MERS-CoV ORF4a increased the rabies virus (RABV)-specific immunoglobulin G (IgG) titer and neutralization half-maximal inhibitory concentration (IC50) by ∼10-fold in rabbits, but not in mice or rats. These experiments provide a proof of concept that IIPs can be directly encoded into saRNA vectors and effectively abate the nonlinear dose dependency and enhance immunogenicity.
Trends in Chronic Obstructive Pulmonary Disease Prevalence, Incidence, and Health Services Use in Younger Adults in Ontario, Canada, 2006–2016
Authors: Andrea S. Gershon, Rachel E. McGihon, Jin Luo, Alina J. Blazer, Tetyana Kendzerska, Teresa To, Shawn D. Aaron
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Genome Reduction Is Associated with Bacterial Pathogenicity across Different Scales of Temporal and Ecological Divergence
Authors: Gemma G R Murray, Jane Charlesworth, Eric L Miller, Michael J Casey, Catrin T Lloyd, Marcelo Gottschalk, Alexander W (Dan) Tucker, John J Welch, Lucy A Weinert
Journal: Molecular Biology and Evolution (2020)

Abstract Emerging bacterial pathogens threaten global health and food security, and so it is important to ask whether these transitions to pathogenicity have any common features. We present a systematic study of the claim that pathogenicity is associated with genome reduction and gene loss. We compare broad-scale patterns across all bacteria, with detailed analyses of Streptococcus suis, an emerging zoonotic pathogen of pigs, which has undergone multiple transitions between disease and carriage forms. We find that pathogenicity is consistently associated with reduced genome size across three scales of divergence (between species within genera, and between and within genetic clusters of S. suis). Although genome reduction is also found in mutualist and commensal bacterial endosymbionts, genome reduction in pathogens cannot be solely attributed to the features of their ecology that they share with these species, that is, host restriction or intracellularity. Moreover, other typical correlates of genome reduction in endosymbionts (reduced metabolic capacity, reduced GC content, and the transient expansion of nonfunctional elements) are not consistently observed in pathogens. Together, our results indicate that genome reduction is a consistent correlate of pathogenicity in bacteria.
Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma
Authors: Jens Bedke, Laurence Albiges, Umberto Capitanio, Rachel H. Giles, Milan Hora, Thomas B. Lam, Börje Ljungberg, Lorenzo Marconi, Tobias Klatte, Alessandro Volpe, Yasmin Abu-Ghanem, Saeed Dabestani, Sergio Fernández-Pello, Fabian Hofmann, Teele Kuusk, Rana Tahbaz, Thomas Powles, Axel Bex
Journal: European Urology (2020)
Abstract 321: Pediatric Transfusion Score Predicts Transfusion Requirements for Children With Trauma
Authors: Akira Komori, Toshikazu Abe, Gautam A Deshpande, Makoto Aoki, Toshio Naito
Journal: Circulation (2019)

Introduction: Trauma is a leading cause of death in young populations. Transfusion is often a key life-saving element in cases of children with trauma. Nonetheless, clinicians may hesitate to use transfusion in children given the risks of complications. Hypothesis: A pediatric transfusion score can accurately predict 24-hour transfusion requirement in pediatric trauma patients. Methods: This is a retrospective cohort study using a nationwide registry of trauma patients (Japan Trauma Data Bank). All patients under 16 years of age with blunt or penetrating trauma between 2004 and 2015 were included. A pediatric transfusion score was developed based on previous literature and clinical relevance. One point was given for each of the following criteria: systolic blood pressure ≤ 90 mmHg; heart rate ≥ 120/min; Glasgow Coma Scale (GCS) &lt; 15; and positive result on focused assessment with sonography for trauma (FAST) scan. For sensitivity analysis, age-adjusted pediatric transfusion score was also developed using cut off points for different age categories (infant, toddler, preschool age, school age, and adolescent). Results: Of the eligible 5,976 pediatric trauma patients, 550 patients had transfusion within 24 hours after trauma. In-hospital mortality rate was 2.6% (146/5,647). Transfusion increased from 7.7% (113/315) to 35.9% (437/5,661) in those with systolic blood pressure ≤ 90 mmHg (1 point); from 6.2% (280/4,526) to 18.6% (270/1,450) for heart rate ≥ 120/min (1 point); from 4.1% (113/3,220) to 15.1% (417/2,756) for altered mental status with GCS &lt; 15 (1 point); and from 7.5% (403/5,404) to 25.7% (147/572) for FAST positivity (1 point). Pediatric transfusion scores of 0, 1, 2, 3, and 4 points were associated with transfusion rates of 2.2% (48/2,223), 7.5% (199/2,638), 20.3% (187/919), 53.9% (90/167), and 89.7% (26/29), respectively. The area under the curve (AUC) was 0.77 (95% CI, 0.75-0.79). For those without isolate head injury, it was 0.77 (95% CI, 0.75-0.80). After age adjustment, AUC was 0.76 (95% CI, 0.74-0.78). Conclusions: The pediatric transfusion score using vital signs and FAST may be helpful in predicting transfusion requirements within 24 hours for children with trauma.
Clinical Characteristics, Management, and Outcomes in COVID-19-Positive Dialysis Patients from Three London Renal Centres, United Kingdom
Authors: Dalvir Kular, Irina Chis Ster, Dandisonba B. Braide-Azikiwe, Alexander Sarnowski, Eirini Lioudaki, Martin L. Ford, David Makanjuola, Alexandra C. Rankin, Hugh Cairns, Joyce Popoola, Nicholas I. Cole, Mysore K. Phanish, Richard Hull, Pauline A. Swift, Debasish Banerjee
Journal: Journal of the American Society of Nephrology (2020)

Background: Dialysis patients, with frequent co-morbidities, advanced age and frailty, visiting treatment facilities frequently are perhaps more prone to SARS-Cov-2 infection and related death - the risk-factors and dynamics of which are unknown  The aim of this study was to investigate the hospital outcomes in SARS-CoV-2 infected dialysis patients  Methods: This prospective, observational, multi-centre study collected data on SARS-CoV-2 infected HD patients between 29/02/2020 and 15/05/2020  Data was collected on demographics, comorbidities, WHO performance status, clinical symptoms, laboratory parameters, hospital management and outcomes  Treatment was predominantly supportive, unless patients were part of an approved clinical trial  The study was approved by NHS Research Ethics Committee 20/SW/0077 and Heath Research Authority IRAS 283130  Results: Of 1737 HD patients at the 3 renal centres, 224 (13%) were COVID-19 positive over the study period  The characteristics of the COVID-19 HD patients were: mean age 65 8;59% male;38% Caucasian;81% hypertension;54% diabetes;25% chronic lung disease;29% ischaemic heart disease and 22% cerebrovascular disease  The most common symptoms at presentation were fever (62%) and cough (53%)  About 143 (64%) patients were managed as an inpatient and 81 (36%) as an outpatient  Of 9 patients that required mechanical ventilation: 6 died, 1 patient was discharged and 2 are still under clinical care  Overall 51 patients died (23%), 154 (69%) were discharged alive and 19 (8%) were still under clinical care as of 15/05/2020  Preliminary analyses suggested that those that died were significantly older (p=0 0028), more likely to have ischaemic heart disease (p=0 003), cerebrovascular disease (p=0 019), smoking history (p=0 006), WHO performance status 3-4 (p=0 004), higher neutrophil: lymphocyte ratio at presentation (p=0 0001) and higher CRP at presentation (p=0 0021)  Conclusions: This large cohort of COVID-19 positive haemodialysis demonstrates a high case fatality ratio, which increased significantly with age, cardiovascular disease, smoking history, frailty and markers of inflammation
연구논문 : 위정맥류의 자연경과와 출혈의 위험인자
Authors: 이충현 ( Choong Hyeon Lee ), 이준혁 ( Joon Hyoek Lee ), 최용성 ( Yong Sung Choi ), 백승운 ( Seung Woon Paik ), 신동현 ( Dong Hyun Sinn ), 이춘영 ( Choon Young Lee ), 고광철 ( Kwang Cheol Koh ), 곽금연 ( Geum Youn Gwak ), 최문석 ( Moon Seok Choi ), 유병철 ( Byung Chul Yoo )
Journal: Clinical and Molecular Hepatology (2008)
Systematic Nasogastric Tube Decompression Following Pancreaticoduodenectomy—Is it Safe?—Reply
Authors: Damien Bergeat, Laurent Sulpice
Journal: JAMA Surgery (2020)

In Reply We thank Baroutjian et al for their interest about our article reporting the results from the IPOD (Impact of the Absence of Nasogastric Decompression After Pancreaticoduodenectomy) study.1 All points raised in their Letter are addressed one by one in the following response.
A potential therapeutic strategy for prostatic disease by targeting the oral microbiome
Authors: Cheng Fang, Lan Wu, Cong Zhu, Wen‐Zhong Xie, Hailiang Hu, Xian‐Tao Zeng
Journal: Medicinal Research Reviews (2020)

Abstract Nowadays, human microbiome research is rapidly growing and emerging evidence has witnessed the critical role that oral microbiome plays in the process of human health and disease. Oral microbial dysbiosis has been confirmed as a contributory cause for diseases in multiple body systems, ranging from the oral cavity to the gastrointestinal, endocrine, immune, cardiovascular, and even nervous system. As research progressing, oral microbiome‐based diagnosis and therapy are proposed and applied, which may represent potential drug targets in systemic diseases. Recent studies have uncovered the possible association between periodontal disease and prostatic disease, suggesting new prevention and therapeutic treatment for the disease by targeting periodontal pathogens. Thus, we performed this review to first explore the association between the oral microbiome and prostatic disease, according to current knowledge based on published articles, and then mainly focus on the underlying molecular and cellular mechanisms and the potential prevention and treatment derived from these mechanistic studies.
Association of Antiplatelet and Anticoagulation Therapy with Dialysis-Requiring AKI in Critically Ill Patients with COVID-19
Authors: Andrew A. Moses, Amer Assal, Paul Asadourian, Anson G. Bautista, Rebekah Boyd, Lyle Dershowitz, Aaron Gans, Catherine Ha, Hannah L. Mcmullen, Mary Nattakom, Olivia D. Perez, Connor Stonesifer, William S. Stringer, Yuqing Xiong, Shayan Shirazian
Journal: Journal of the American Society of Nephrology (2020)

Moses, Andrew A.; Assal, Amer; Asadourian, Paul; Bautista, Anson G.; Boyd, Rebekah; Dershowitz, Lyle; Gans, Aaron; Ha, Catherine; Mcmullen, Hannah L.; Nattakom, Mary; Perez, Olivia D.; Stonesifer, Connor; Stringer, William S.; Xiong, Yuqing; Shirazian, Shayan Author Information
Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells
Authors: Erin R Bonner, Sebastian M Waszak, Michael A Grotzer, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2020)

Abstract ONC201 is the first member of the imipridone family of anticancer drugs to enter the clinic for the treatment of diverse solid and hematologic cancers. A subset of pediatric and adult patients with highly aggressive brain tumors has shown remarkable clinical responses to ONC201, and recently, the more potent derivative ONC206 entered clinical trials as a single agent for the treatment of central nervous system (CNS) cancers. Despite the emerging clinical interest in the utility of imipridones, their exact molecular mechanisms are not fully described. In fact, the existing literature points to multiple pathways (e.g. tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) signaling, dopamine receptor antagonism, and mitochondrial metabolism) as putative drug targets. We have performed a comprehensive literature review and highlighted mitochondrial metabolism as the major target of imipridones. In support of this, we performed a meta-analysis of an ONC201 screen across 539 human cancer cell lines and showed that the mitochondrial caseinolytic protease proteolytic subunit (ClpP) is the most significant predictive biomarker of response to treatment. Herein, we summarize the main findings on the anticancer mechanisms of this potent class of drugs, provide clarity on their role, and identify clinically relevant predictive biomarkers of response.
Exposure-Response of the Bruton Tyrosine Kinase Inhibitor, Acalabrutinib, in the Treatment of Hematologic Malignancies
Authors: Feng Jin, Ming Yin, Vinay Mandava, Helena Edlund, Marilee Andrew, Priti Patel, Eric Masson, Nidal Al-Huniti, Xiaolin Wang, J. Greg Slatter
Journal: Blood (2017)
Cardiovascular Disease in Former Pediatric Recipients of Growth Hormone
Authors: Adda Grimberg
Journal: JAMA Pediatrics (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 Pediatrics 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 Pediatrics journal
译后评论：如何全面、正确地评价药物
Authors: 乌正赉
Journal: BMJ (2005)

本期刊登了一篇“药物治疗的获益与损害：观察性研究与随机试验应相互补充”的论述性文章(见本期第5页)。《英国医学杂志》(BMJ)曾刊登过几篇关于不同药物治疗利弊的类似文章。实际上提出一个cc如何全面、正确地评价药物”的问题。药物治疗的目的是为了减少病人的痛苦、提高人群的健康水平、造福社会。
Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF
Authors: Silvio E. Inzucchi, Kieran F. Docherty, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Piotr Ponikowski, Marc S. Sabatine, Scott D. Solomon, Subodh Verma, Jan Bělohlávek, Michael Böhm, Chern-En Chiang, Rudolf A. de Boer, Mirta Diez, Andre Dukát, Charlotta E.A. Ljungman, Olof Bengtsson, Anna Maria Langkilde, Mikaela Sjöstrand, Pardeep S. Jhund, John J.V. McMurray
Journal: Diabetes Care (2020)

OBJECTIVE The sodium–glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial. RESEARCH DESIGN AND METHODS The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of &amp;lt;6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. RESULTS At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of −0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50–0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7–6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. CONCLUSIONS In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.
Acute coronary syndromes, plaque vulnerability,and carotid artery disease: The changing role ofatherosclerosis imaging**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: E.Murat Tuzcu, Paul Schoenhagen
Journal: Journal of the American College of Cardiology (2003)