tbuckley/cabot-search huggingface dataset:
Long Noncoding RNA TYKRIL Plays a Role in Pulmonary Hypertension via the p53-mediated Regulation of PDGFRβ
Authors: Christoph M. Zehendner, Chanil Valasarajan, Astrid Werner, Jes-Niels Boeckel, Florian C. Bischoff, David John, Tyler Weirick, Simone F. Glaser, Oliver Rossbach, Nicolas Jaé, Shemsi Demolli, Fatemeh Khassafi, Ke Yuan, Vinicio A. de Jesus Perez, Katharina M. Michalik, Wei Chen, Werner Seeger, Andreas Guenther, Roxana M. Wasnick, Shizuka Uchida, Andreas M. Zeiher, Stefanie Dimmeler, Soni S. Pullamsetti
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Long noncoding RNAs (lncRNAs) are emerging as important regulators of diverse biological functions. Their role in pulmonary arterial hypertension (PAH) remains to be explored.Objectives: To elucidate the role of TYKRIL (tyrosine kinase receptor–inducing lncRNA) as a regulator of p53/ PDGFRβ (platelet-derived growth factor receptor β) signaling pathway and to investigate its role in PAH.Methods: Pericytes and pulmonary arterial smooth muscle cells exposed to hypoxia and derived from patients with idiopathic PAH were analyzed with RNA sequencing. TYKRIL knockdown was performed in above-mentioned human primary cells and in precision-cut lung slices derived from patients with PAH.Measurements and Main Results: Using RNA sequencing data, TYKRIL was identified to be consistently upregulated in pericytes and pulmonary arterial smooth muscles cells exposed to hypoxia and derived from patients with idiopathic PAH. TYKRIL knockdown reversed the proproliferative (n = 3) and antiapoptotic (n = 3) phenotype induced under hypoxic and idiopathic PAH conditions. Owing to the poor species conservation of TYKRIL, ex vivo studies were performed in precision-cut lung slices from patients with PAH. Knockdown of TYKRIL in precision-cut lung slices decreased the vascular remodeling (n = 5). The number of proliferating cell nuclear antigen–positive cells in the vessels was decreased and the number of terminal deoxynucleotide transferase–mediated dUTP nick end label–positive cells in the vessels was increased in the LNA (locked nucleic acid)-treated group compared with control. Expression of PDGFRβ, a key player in PAH, was found to strongly correlate with TYKRIL expression in the patient samples (n = 12), and TYKRIL knockdown decreased PDGFRβ expression (n = 3). From the transcription factor–screening array, it was observed that TYKRIL knockdown increased the p53 activity, a known repressor of PDGFRβ. RNA immunoprecipitation using various p53 mutants demonstrated that TYKRIL binds to the N-terminal of p53 (an important region for p300 interaction with p53). The proximity ligation assay revealed that TYKRIL interferes with the p53–p300 interaction (n = 3) and regulates p53 nuclear translocation.Conclusions: TYKRIL plays an important role in PAH by regulating the p53/PDGFRβ axis.
Modern approaches in gene therapy of motor neuron diseases
Authors: Maria Zakharova
Journal: Medicinal Research Reviews (2020)

Abstract Motor neuron disorders are a group of neurodegenerative diseases characterized by muscle weakness, loss of ambulation, respiratory insufficiency, leading to an early death. Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis are the most common and fatal motor neuron diseases. The last 3 years became very successful for novel gene therapy approaches in SMA in infants. Two innovative drugs—nusinersen (Spinraza) and onasemnogene abeparvovec (Zolgensma) have been approved by health authorities. The numerous molecular and genetic overlaps between different neurodegenerative diseases are of great importance in the development of innovative therapeutic strategies, including viral vector therapy and RNA modulating approaches.
Effects of Lixisenatide Versus Liraglutide (Short- and Long-Acting GLP-1 Receptor Agonists) on Esophageal and Gastric Function in Patients With Type 2 Diabetes
Authors: Daniel R. Quast, Nina Schenker, Björn A. Menge, Michael A. Nauck, Christoph Kapitza, Juris J. Meier
Journal: Diabetes Care (2020)

OBJECTIVE Short-acting glucagon-like peptide 1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short-acting (lixisenatide) and long-acting (liraglutide) GLP-1 RAs. RESEARCH DESIGN AND METHODS A total of 57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-h pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying (13C-sodium octanoate acid breath test), and gastric acid secretion (13C-calcium carbonate breath test) were analyzed. RESULTS Gastric emptying half-time was delayed by 52 min (Δ 95% CI 16, 88) with lixisenatide (P = 0.0065) and by 25 min (3, 46) with liraglutide (P = 0.025). There was no difference in the number of reflux episodes (mean ± SEM 33.7 ± 4.1 vs. 40.1 ± 5.3 for lixisenatide and liraglutide, respectively, P = 0.17) or the extent of gastroesophageal reflux (DeMeester score) (35.1 ± 6.7 vs. 39.7 ± 7.5, P = 0.61), with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by −20.7% (−40.6, −0.8) (P = 0.042) with the GLP-1 RAs. CONCLUSIONS Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs.
P-115 PEMREC: A phase II study to evaluate safety and efficacy of neo-adjuvant pembrolizumab and radiotherapy in localized microsatellite stable rectal cancer
Authors: T. Kössler, N. Buchs, V. Dutoit, G. Puppa, P. Tsantoulis, J. Frossard, P. Bichard, T. McKee, M. Di Marco, P. Dietrich, A. Roth, T. Zilli, F. Ris
Journal: Annals of Oncology (2020)
Coffee & herbal tea consumption is protective of liver stiffness in the general population : The Rotterdam Study
Authors: L.J. Alferink, J. Fittipaldi, J.C. Kiefte-de Jong, J. Schoufour, P. Taimr, Ikram, H.J. Metselaar, H.L. Janssen, O.H.F. Duran, S.D. Murad
Journal: Hepatology (2016)
Stimulation of endoplasmic reticulum (ER) stress by tunicamycin senstizes human non-small cell lung cancer (NSCLC) cells to the EGFR tyrosine kinase inhibitor erlotinib
Authors: Yi-He Ling, Tianhong Li, Roman Perez-Soler
Journal: Cancer Research (2006)

3787  Tunicamycin, a naturally occurring antibiotic, has been shown to induce endoplasmic reticulum (ER) stress by inhibiting protein glycosylation. Erlotinib (Tarceva, OSI-774) is an orally active EGFR tyrosine kinase inhibitor approved as second/third line treatment for patients with NSCLC. In this study, we used two erlotinib-sensitive (H322 and H358) and two erlotinib-resistant NSCLC cell lines (H1650 and A549) as models to determine whether ER stress induced by tunicamycin enhances erlotinib-induced cell death in NSCLC cell lines. Cytotoxicity was assessed using the colorimetric tetrazolium-based (MTT). In the presence of 1 μM tunicamycin, the antiproliferative effect of erlotinib was increased by about 2-fold in the erlotinib-sensitive cells and about 10-fold in the erlotinib resistant cells: the erlotinib IC50 values in erlotinib-resistant H1650 and A549 cells were 8.5 and 12.3 μM vs 0.63 and 1.8 μM, respectively, in the presence of 1 μM tunicamycin. We used the H1650 cell line as a model to explore the cellular and biochemical mechanisms of the synergism observed. A remarkable enhancement of the apoptotic response as assessed by activation of caspase-12 and caspase-3, induction of PARP and Bak proteins cleavage, and down-regulation of the expression of anti-apoptotic proteins Bcl-XL and survivin was observed with the combination. Tunicamycin by itself was found to inhibit EGFR glycosylation, to generate the truncated EGFR (130 kDa), and to induce a survival response with AKT/PKB activation. Interestingly, the combination was also more effective in causing inhibition of EGFR phosphorylation, as well as of AKT/PKB when compared with erlotinib alone. Overall, our results demonstrate that tunicamycin sensitizes erlotinib-resistant cells to erlotinib and that such sensitization effect may be related to enhanced interruption of EGFR-related survival pathways. This work was supported in part by NIH CA91784, CA84119 and OSI Pharmaceuticals.
Population Genetics of SARS-CoV-2: Disentangling Effects of Sampling Bias and Infection Clusters
Authors: Qi Liu, Shilei Zhao, Cheng-Min Shi, Shuhui Song, Sihui Zhu, Yankai Su, Wenming Zhao, Mingkun Li, Yiming Bao, Yongbiao Xue, Hua Chen
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract A novel RNA virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the ongoing outbreak of coronavirus disease 2019 (COVID-19). Population genetic analysis could be useful for investigating the origin and evolutionary dynamics of COVID-19. However, due to extensive sampling bias and existence of infection clusters during the epidemic spread, direct applications of existing approaches can lead to biased parameter estimations and data misinterpretation. In this study, we first present robust estimator for the time to the most recent common ancestor (TMRCA) and the mutation rate, and then apply the approach to analyze 12,909 genomic sequences of SARS-CoV-2. The mutation rate is inferred to be 8.69 × 10−4 per site per year with a 95% confidence interval (CI) of [8.61 × 10−4, 8.77 × 10−4], and the TMRCA of the samples inferred to be Nov 28, 2019 with a 95% CI of [Oct 20, 2019, Dec 9, 2019]. The results indicate that COVID-19 might originate earlier than and outside of Wuhan Seafood Market. We further demonstrate that genetic polymorphism patterns, including the enrichment of specific haplotypes and the temporal allele frequency trajectories generated from infection clusters, are similar to those caused by evolutionary forces such as natural selection. Our results show that population genetic methods need to be developed to efficiently detangle the effects of sampling bias and infection clusters to gain insights into the evolutionary mechanism of SARS-CoV-2. Software for implementing VirusMuT can be downloaded at https://bigd.big.ac.cn/biocode/tools/BT007081.
Covid-19: Symptoms are common after acute phase of disease, Italian study shows
Authors: Jacqui Wise
Journal: BMJ (2020)

Covid-19: Symptoms are common after acute phase of disease, Italian study shows Jacqui WiseAlmost nine out of 10 patients discharged from a Rome hospital after recovery from covid-19 were still experiencing at least one symptom two months later, a study shows.Fatigue and shortness of breath were the most common symptoms reported in the study of 143 patients. 1More than half of patients were still experiencing three or more symptoms.The research, published as a letter in JAMA, is further evidence of a "long tail" of covid-19 related illness.On 5 July health and social care secretary Matt Hancock announced the launch of a study into the long term health effects of covid-19 on hospitalised patients in the UK.The post-hospitalisation covid-19 study aims to recruit 10 000 patients who have been hospitalised with covid-19 and will track them over a year. 2 In the waning phase of the pandemic in Italy, beginning on 21 April, the Fondazione Policlinico Universitario Agostino Gemelli hospital established a post-acute outpatient service for patients discharged from the hospital after recovering from covid-19.The mean age of the patients was 56.5 years and 63% were men.They had been in hospital for an average of 13.5 days and 72% had evidence of interstitial pneumonia.Some 15% of patients had received non-invasive ventilation and 5% had received invasive ventilation.The patients were only included in the study if they had a negative transcriptase polymerase chain reaction test for SARS-CoV-2, indicating they were not in the acute phase of the illness.When patients were assessed a mean of 60 days after onset of the first covid-19 symptoms, only 18 (12.6%)were completely free of any covid-19 related symptom, while 32% had one or two symptoms, and 55% had three or more.None of the patients had fever or any signs or symptoms of acute illness.Worsened quality of life was reported by 44% of patients.A high proportion of patients still reported fatigue (53%), dyspnea (43%), joint pain (27%), and chest pain (22%).The study has limitations as it is based on a single centre with a relatively small number of patients and without a control group of patients discharged for other reasons.There is also a lack of information on symptom history before acute covid-19 illness and no information on symptom severity.Furthermore, the study authors point out that patients with community acquired pneumonia can also have persistent symptoms.
Expression of <i>Nras</i> <i>Q61R</i> and <i>MYC</i> transgene in germinal center B cells induces a highly malignant multiple myeloma in mice
Authors: Zhi Wen, Adhithi Rajagopalan, Evan D. Flietner, Grant Yun, Marta Chesi, Quinlan Furumo, Robert T. Burns, Athanasios Papadas, Erik A. Ranheim, Adam C. Pagenkopf, Zachary T. Morrow, Remington Finn, Yun Zhou, Shuyi Li, Xiaona You, Jeffrey Jensen, Mei Yu, Alexander Cicala, James Menting, Constantine S. Mitsiades, Natalie S. Callander, P. Leif Bergsagel, Demin Wang, Fotis Asimakopoulos, Jing Zhang
Journal: Blood (2020)
Dengue virus induces PCSK9 expression to alter antiviral responses and disease outcomes
Authors: Esther Shuyi Gan, Hwee Cheng Tan, Duyen Huynh Thi Le, Trieu Trung Huynh, Bridget Wills, Nabil G. Seidah, Eng Eong Ooi, Sophie Yacoub
Journal: Journal of Clinical Investigation (2020)

Dengue virus (DENV) infection requires cholesterol as a proviral factor, although statin treatment did not show antiviral efficacy in patients with dengue. Here, we show that DENV infection manipulated cholesterol metabolism in cells residing in low-oxygen microenvironments (hypoxia) such as in the liver, spleen, and lymph nodes. DENV infection induced expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces low-density lipoprotein receptor (LDLR) recycling and hence cholesterol uptake. We found that, whereas LDLR uptake would have distributed cholesterol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the endoplasmic reticulum (ER). With cholesterol enrichment in the ER, ER-resident STING and type I IFN (IFN) activation was repressed during DENV infection. Our in vitro findings were further supported by the detection of elevated plasma PCSK9 levels in patients with dengue with high viremia and increased severity of plasma leakage. Our findings therefore suggest that PCSK9 plays a hitherto unrecognized role in dengue pathogenesis and that PCSK9 inhibitors could be a suitable host-directed treatment for patients with dengue.
The Effect of Immune Checkpoint Inhibitors in Patients with Concomitant Advanced Melanoma and Chronic Lymphocytic Leukaemia
Authors: Joshua W.D. Tobin, Jane Royle, Robert Mason, Millward Michael, Warburton Lydia, Shahneen Sandhu, Andrew Haydon, Georgina Long, Matteo Carlino, Jessica L Smith, Helen Dearden, Peter Mollee, Devinder Gill, Sally Mapp, Victoria Atkinson, Colm Keane
Journal: Blood (2017)
Covid-19: Data show 5000 fewer hospital admissions for acute coronary syndrome during pandemic
Authors: Shaun Griffin
Journal: BMJ (2020)

Data show 5000 fewer hospital admissions for acute coronary syndrome during pandemic Shaun GriffinAround 5000 fewer people were admitted to hospitals in England for acute coronary syndrome than expected from January to the end of May this year, an analysis has shown.The results, published in the Lancet, indicate that many patients have missed out on lifesaving treatments during the covid-19 outbreak. 11
セフタジジム-アビバクタム: 新規セファロスポリン/β-ラクタマーゼ阻害剤の併用 | 文献情報 | J-GLOBAL 科学技術総合リンクセンター
Authors: G Zhanel George, D Lawson Christopher, Adam Heather, Schweizer Frank, Zelenitsky Sheryl, R S Lagace-Wiens Philippe, Denisuik Andrew, Rubinstein Ethan, S Gin Alfred, J Hoban Daryl, Lynch Joseph P. rd, A Karlowsky James
Journal: Drugs (2013)
Contrasting views on human population growth
Authors: A J McMichael, J Guillebaud, Maurice King
Journal: BMJ (1999)

World population reaches 6 billion on 12 October, according to the best guess of demographers. It has tripled in a single lifetime, is projected to increase by half as much again next century, and, if current declines in fertility falter, could yet double. We have heard such statistics before, to the point of population crisis fatigue Yet we are living through a spectacular phenomenon in demographic history. Three quarters of the 1000-fold increase in human numbers since agriculture emerged 10 000 years ago has occurred during this past century—75% of the absolute increase in 1% of the time.

The size of the human population is an important determinant of its condition. It is increasingly the combination of human numbers with levels of consumption and types of technology that determines the impact on the environment—and whether that impact exceeds the local or global carrying capacity. Humanity's response to this population surge is one crucial test of its wisdom. Put simply, there are two “wisdoms.”

The first wisdom denies that population increase is a cause for alarm. This view is common on the neoliberal right: complacent, consumerist, and laissez faire. Although population has been increasing a …
Computer‐aided Drug Design: Additive Manufacturing of a Point‐of‐Care “Polypill:” Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease (Adv. Healthcare Mater. 13/2020)
Authors: Beatriz C. Pereira, Abdullah Isreb, Mohammad Isreb, Robert T. Forbes, Enoche F. Oga, Mohamed A. Alhnan
Journal: Advanced Healthcare Materials (2020)
Abstract 12261: Inflammatory Properties of Diet Mediate the Relationship Between Depressive Symptoms and Cardiovascular Disease Risk in Men and Women
Authors: Junghee Kang, Debra K Moser, Martha Biddle, Terry A Lennie, Susan Smyth, Olga Vsevolozhskaya
Journal: Circulation (2019)

Introduction: Depression and inflammation are associated with cardiovascular disease (CVD). Inflammation can be moderated by diet. However, the role that the inflammatory properties of diet play in...
Covid-19: clinicians need continuing professional development in ethics
Authors: Desmond J O’Neill
Journal: BMJ (2020)

The call for an ethical road map is timely given the explosion of ethical statements of variable quality, overt and occult bias, and obscure provenance during the covid-19 pandemic.1 A missing element is ongoing continuous professional development (CPD) in ethics for clinicians. Deficits in ethical fluency and articulacy have been notable in many settings—for example, editorial oversight of an article in the New England Journal of Medicine that …
Interferon-γ release assays or tuberculin skin test for detection and management of latent tuberculosis infection: a systematic review and meta-analysis
Authors: Guozhong Zhou, Qingyi Luo, Shiqi Luo, Zhaowei Teng, Zhenhua Ji, Jiaru Yang, Feng Wang, Shiyuan Wen, Zhe Ding, Lianbao Li, Taigui Chen, Manzama-Esso Abi, Miaomiao Jian, Lisha Luo, Aihua Liu, Fukai Bao
Journal: The Lancet Infectious Diseases (2020)
The Genetic Control of Stoichiometry Underlying Autism
Authors: Robert B. Darnell
Journal: Annual Review of Neuroscience (2020)

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes—stoichiometry—plays a critical role in defining the clinical features of autism.
Targeted and immunotherapies in <i>BRAF</i> mutant melanoma: where we stand and what to expect
Authors: X. Bai, K.T. Flaherty
Journal: British Journal of Dermatology (2020)

The therapeutic landscape for melanoma has evolved drastically in the past decade. Currently, immune checkpoint inhibitors and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway are the two mainstay therapies for BRAFV600 mutant advanced melanoma. Although MAPK dependence has been variably demonstrated in melanomas lacking BRAFV600 mutations, definitive evidence of benefit with MAPK inhibitors has not been demonstrated. Thus, in the BRAFV600 'wild-type' setting, immune checkpoint inhibitors are the standalone option(s). In the BRAFV600 mutant setting, there is no definitive evidence prioritizing one therapeutic modality over another. Herein, we review the updated data of the pivotal phase III randomized controlled trials that established the standard-of-care first-line treatment for advanced melanoma, as it provides insights into long-term benefit, which is a major factor in therapy selection. We discuss the clinical considerations for choosing between these therapies in the front-line setting and beyond, specifically for patients with BRAFV600 mutant melanoma based on currently available evidence. We have previously proposed a time-dependent resistance paradigm in which future therapeutic development strategies can be rooted. We also discuss how these Food and Drug Administration (FDA)-approved therapeutic modalities are being pursued earlier in the course of disease management, namely in adjuvant and neoadjuvant settings. FDA-approved interlesional oncolytic virotherapy in the modern era is also briefly discussed.
Letter by Ma et al Regarding Article, “Ischemic Postconditioning During Primary Percutaneous Coronary Intervention: The Effects of Postconditioning on Myocardial Reperfusion in Patients With ST-Segment Elevation Myocardial Infarction (POST) Randomized Trial”
Authors: Lei-Lei Ma, Fei-Juan Kong, Ren-Hua Sun
Journal: Circulation (2014)
Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19
Authors: Jennifer A. Juno, Hyon-Xhi Tan, Wen Shi Lee, Arnold Reynaldi, Hannah G. Kelly, Kathleen Wragg, Robyn Esterbauer, Helen E. Kent, C. Jane Batten, Francesca L. Mordant, Nicholas A. Gherardin, Phillip Pymm, Melanie H. Dietrich, Nichollas E. Scott, Wai-Hong Tham, Dale I. Godfrey, Kanta Subbarao, Miles P. Davenport, Stephen J. Kent, Adam K. Wheatley
Journal: Nature Medicine (2020)