tbuckley/cabot-search huggingface dataset:
A 5-Decade Analysis of Incidence Trends of Ischemic Stroke After Transient Ischemic Attack
Authors: Shima Shahjouei, Alireza Sadighi, Durgesh Chaudhary, Jiang Li, Vida Abedi, Neil Holland, Michael Phipps, Ramin Zand
Journal: JAMA Neurology (2020)

<h3>Importance</h3> Management of transient ischemic attack (TIA) has gained significant attention during the past 25 years after several landmark studies indicated the high incidence of a subsequent stroke. <h3>Objective</h3> To calculate the pooled event rate of subsequent ischemic stroke within 2, 7, 30, and 90 days of a TIA and compare this incidence among the population with TIA recruited before 1999 (group A), from 1999 to 2007 (group B), and after 2007 (group C). <h3>Data Sources</h3> All published studies of TIA outcomes were obtained by searching PubMed from 1996, to the last update on January 31, 2020, irrespective of the study design, document type, or language. <h3>Study Selection</h3> Of 11 516 identified citations, 175 articles were relevant to this review. Both the classic time-based definition of TIA and the new tissue-based definition were accepted. Studies with a combined record of patients with TIA and ischemic stroke, without clinical evaluation for the index TIA, with diagnosis of index TIA event after ischemic stroke occurrence, with low suspicion for TIA, or duplicate reports of the same database were excluded. <h3>Data Extraction and Synthesis</h3> The study was conducted and reported according to the PRISMA, MOOSE, and EQUATOR guidelines. Critical appraisal and methodological quality assessment used the Quality in Prognosis Studies tool. Publication bias was visualized by funnel plots and measured by the Begg-Mazumdar rank correlation Kendall τ<sup>2</sup>statistic and Egger bias test. Data were pooled using double arcsine transformations, DerSimonian-Laird estimator, and random-effects models. <h3>Main Outcomes and Measures</h3> The proportion of the early ischemic stroke after TIA within 4 evaluation intervals (2, 7, 30, and 90 days) was considered as effect size. <h3>Results</h3> Systematic review yielded 68 unique studies with 223 866 unique patients from 1971 to 2019. The meta-analysis included 206 455 patients (58% women) during a span of 4 decades. The overall subsequent ischemic stroke incidence rates were estimated as 2.4% (95% CI, 1.8%-3.2%) within 2 days, 3.8% (95% CI, 2.5%-5.4%) within 7 days, 4.1% (95% CI, 2.4%-6.3%) within 30 days, and 4.7% (95% CI, 3.3%-6.4%) within 90 days. There was a recurrence risk of 3.4% among group A in comparison with 2.1% in group B or 2.1% in group C within 2 days; 5.5% in group A vs 2.9% in group B or 3.2% in group C within 7 days; 6.3% in group A vs 2.9% in group B or 3.4% in group C within 30 days, and 7.4% in group A vs 3.9% in group B or 3.9% in group C within 90 days. <h3>Conclusions and Relevance</h3> These findings suggest that TIA continues to be associated with a high risk of early stroke; however, the rate of post-TIA stroke might have decreased slightly during the past 2 decades.
Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement
Authors: Kimberly Showalter, Robert Spiera, Cynthia Magro, Phaedra Agius, Viktor Martyanov, Jennifer M Franks, Roshan Sharma, Heather Geiger, Tammara A Wood, Yaxia Zhang, Caryn R Hale, Jackie Finik, Michael L Whitfield, Dana E Orange, Jessica K Gordon
Journal: Annals of the Rheumatic Diseases (2020)

Objective We sought to determine histologic and gene expression features of clinical improvement in early diffuse cutaneous systemic sclerosis (dcSSc; scleroderma). Methods Fifty-eight forearm biopsies were evaluated from 26 individuals with dcSSc in two clinical trials. Histologic/immunophenotypic assessments of global severity, alpha-smooth muscle actin (aSMA), CD34, collagen, inflammatory infiltrate, follicles and thickness were compared with gene expression and clinical data. Support vector machine learning was performed using scleroderma gene expression subset (normal-like, fibroproliferative, inflammatory) as classifiers and histology scores as inputs. Comparison of w-vector mean absolute weights was used to identify histologic features most predictive of gene expression subset. We then tested for differential gene expression according to histologic severity and compared those with clinical improvement (according to the Combined Response Index in Systemic Sclerosis). Results aSMA was highest and CD34 lowest in samples with highest local Modified Rodnan Skin Score. CD34 and aSMA changed significantly from baseline to 52 weeks in clinical improvers. CD34 and aSMA were the strongest predictors of gene expression subset, with highest CD34 staining in the normal-like subset (p&lt;0.001) and highest aSMA staining in the inflammatory subset (p=0.016). Analysis of gene expression according to CD34 and aSMA binarised scores identified a 47-gene fibroblast polarisation signature that decreases over time only in improvers (vs non-improvers). Pathway analysis of these genes identified gene expression signatures of inflammatory fibroblasts. Conclusion CD34 and aSMA stains describe distinct fibroblast polarisation states, are associated with gene expression subsets and clinical assessments, and may be useful biomarkers of clinical severity and improvement in dcSSc.
Abstract 466: Vascular Claudin-11 Plays a Protective Role for Human Atherosclerosis Progression
Authors: Eun Hee Kim, Moon Hee Jung, Man Seok Park, Kang Ho Choi, Su Jin Lee, Hyung Seok Kim
Journal: Circulation Research (2020)

Background and Aims: The expression and the role of tight junction protein, Claudin-11 (CLDN11) in vasculat smooth muscle cell (vSMC) is unknown. Methods: To understand the role of CLDN11 in the vSMC, we transfected siRNA-CLDN11 into human coronary vascular smooth muscle cell line (hCSMC). cDNA microarray using Agilent Human mRNA arrays, immunocytochemistry, tube formation assay, FACS, and cell cycle analysis were performed 7 days after CLDN11 knock-down. To know the role of CLDN11 in the human cardiovascular system, we obtained vascular smooth muscle layer from autopsied left anterior descending artery and CLDN11 mRNA expression was evaluated following modified AHA Consensus Classification Based on Morphologic Descriptions (three groups, total n=45). Results: CLDN11 was well expressed in vascular smooth mucscle layer in immunohistochemisty and western blot analysis. We observed the angiogenesis (CXCL8, SOX17, HEY1), cell proliferation (EGR3, ITGB2), and extracellular matrix (BMPER, WNT1) associated gene expression. Following CLDN11-siRNA transfection, the tube formation assay and proliferating cellular phase was markedly increased in siRNA treatment group (p&lt;0.01, respectively). In the human sample, CLDN11 expression was inversely correlated with the progression of coronary atherosclerosis (p=0.0026), and the sudden cardiac death with complicated coronary atherosclerosis (p&lt;0.05). Conclusions: These results indicate that CLDN11 could tightly regulate the vascular smooth muscle physiology. And CLDN11 might play a certain role for atherosclerosis propagation to regulate the vSMCs plasticity and possible new etiology for cardiovascular events.
Incidence Patterns of Patients with Two or More Lymphoid Malignancies in a Patient with a Prior History of Lymphoid Malignancy: A Population-Based Cancer Registry Study in Nagasaki, Japan
Authors: Masako Iwanaga, Daisuke Niino, Thi My Hanh Luong, Shiro Miura, Masahiro Nakashima
Journal: Blood (2017)
ASXL1 mutation confers poor prognosis in primary myelofibrosis patients with low JAK2V617F allele burden but not in those with high allele burden
Authors: Yu-Hung Wang, Chien-Chin Lin, Sze-Hwei Lee, Cheng-Hong Tsai, Shan-Ju Wu, Hsin-An Hou, Tai-Chung Huang, Yuan-Yeh Kuo, Ming Yao, Koping Chang, Chung-Wu Lin, Yun-Chu Lin, Fen-Ming Tien, Wen-Chien Chou, Jih-Luh Tang, Hwei-Fang Tien
Journal: Blood Cancer Journal (2020)

JAK2V617F is the most common driver mutation identified in primary myelofibrosis (PMF), followed by CALR and MPL mutations.In addition to the International Prognostic Scoring System (IPSS), Dynamic IPSS (DIPSS), and DIPSS plus, three widely adopted prognostic systems for PMF patients 1-3 , the prognostic implication of JAK2V617F allele burden on the survival of PMF patients has also been evaluated 4-6 .Tefferi et al. first reported that PMF patients with lower JAK2V617F allele burden had a poorer prognosis compared to those with higher allele burden, and the observation was verified by Guglielmelli et al. 5 .Besides, ASXL1, EZH2, SRSF2, and IDH mutations were reported to contribute to the disease progression and acute leukemia transformation of PMF, and thus classified as high-molecular risk (HMR) mutations 7,8 .Among them, ASXL1 mutation is the most frequently harbored mutation.While the JAK2V617F allele burden predicts the prognosis of PMF patients, its clinical association with ASXL1 mutation remains unexplored.In this study, we found that ASXL1 mutation confers poor prognosis in PMF patients with low JAK2V617F allele burden but not in those with high allele burden, irrespective of DIPSS-plus/DIPSS/IPSS risk classification and other HMR mutations.We retrospectively enrolled 122 adult patients with PMF diagnosed at the National Taiwan University
Understanding and Responding to Health Literacy as a Social Determinant of Health
Authors: Don Nutbeam, Jane E. Lloyd
Journal: Annual Review of Public Health (2020)

Evidence of a social gradient in health literacy has been found in all reported national population surveys. Health literacy is a midstream determinant of health but not a panacea for addressing health inequities created by the maldistribution of opportunity and resources. It is possible to optimize the contribution health literacy makes in mediating the causes and effects of established social determinants of health. Existing interventions demonstrate the feasibility of improving health literacy among higher-risk populations, but research remains underdeveloped and effects on health inequity are largely untested. Future health literacy intervention research should focus on (a) improving the quality of health communication that reaches a diversity of populations, especially by improving frontline professional skills and support; (b) enabling people to develop transferable skills in accessing, understanding, analyzing, and applying health information; and (c) ensuring that priority is proportionate to need by reaching and engaging the population groups who are disproportionately affected by low health literacy.
SIRT1-Mediated Expression of CD24 and Epigenetic Suppression of Novel Tumor Suppressor miR-1185-1 Increases Colorectal Cancer Stemness
Authors: Teh-Wei Wang, Edward Chern, Chao-Wei Hsu, Kuo-Chang Tseng, Hsiao-Mei Chao
Journal: Cancer Research (2020)

NAD-dependent deacetylase sirtuin-1 (SIRT1) is a class III histone deacetylase that positively regulates cancer-related pathways such as proliferation and stress resistance. SIRT1 has been shown to promote progression of colorectal cancer and is associated with cancer stemness, yet the precise mechanism between colorectal cancer stemness and SIRT1 remains to be further clarified. Here we report that SIRT1 signaling regulates colorectal cancer stemness by enhancing expression of CD24, a colorectal cancer stemness promoter. A novel miRNA, miR-1185-1, suppressed the expression of CD24 by targeting its 3'UTR (untranslated region) and could be inhibited by SIRT1 via histone deacetylation. Targeting SIRT1 by RNAi led to elevated H3 lysine 9 acetylation on the promoter region of miR-1185-1, which increased expression of miR-1185-1 and further repressed CD24 translation and colorectal cancer stemness. In a mouse xenograft model, overexpression of miR-1185-1 in colorectal cancer cells substantially reduced tumor growth. In addition, expression of miR-1185-1 was downregulated in human colorectal cancer tissues, whereas expression of CD24 was increased. In conclusion, this study not only demonstrates the essential roles of a SIRT1-miR-1185-1-CD24 axis in both colorectal cancer stemness properties and tumorigenesis but provides a potential therapeutic target for colorectal cancer treatment. SIGNIFICANCE: A novel tumor suppressor miR-1185-1 is involved in molecular regulation of CD24- and SIRT1-related cancer stemness networks, marking it a potential therapeutic target in colorectal cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5257/F1.large.jpg.
Divergence and Remarkable Diversity of the Y Chromosome in Guppies
Authors: Pedro Almeida, Benjamin A Sandkam, Jake Morris, Iulia Darolti, Felix Breden, Judith E Mank
Journal: Molecular Biology and Evolution (2020)

The guppy sex chromosomes show an extraordinary diversity in divergence across populations and closely related species. In order to understand the dynamics of the guppy Y chromosome, we used linked-read sequencing to assess Y chromosome evolution and diversity across upstream and downstream population pairs that vary in predator and food abundance in three replicate watersheds. Based on our population-specific genome assemblies, we first confirmed and extended earlier reports of two strata on the guppy sex chromosomes. Stratum I shows significant accumulation of male-specific sequence, consistent with Y divergence, and predates the colonization of Trinidad. In contrast, Stratum II shows divergence from the X, but no Y-specific sequence, and this divergence is greater in three replicate upstream populations compared with their downstream pair. Despite longstanding assumptions that sex chromosome recombination suppression is achieved through inversions, we find no evidence of inversions associated with either Stratum I or Stratum II. Instead, we observe a remarkable diversity in Y chromosome haplotypes within each population, even in the ancestral Stratum I. This diversity is likely due to gradual mechanisms of recombination suppression, which, unlike an inversion, allow for the maintenance of multiple haplotypes. In addition, we show that this Y diversity is dominated by low-frequency haplotypes segregating in the population, suggesting a link between haplotype diversity and female preference for rare Y-linked color variation. Our results reveal the complex interplay between recombination suppression and Y chromosome divergence at the earliest stages of sex chromosome divergence.
Ragweed plants grown under elevated CO<sub>2</sub> levels produce pollen which elicit stronger allergic lung inflammation
Authors: Denise Rauer, Stefanie Gilles, Maria Wimmer, Ulrike Frank, Constanze Mueller, Stephanie Musiol, Behnam Vafadari, Lorenz Aglas, Fatima Ferreira, Philippe Schmitt‐Kopplin, Jörg Durner, Jana Barbro Winkler, Dieter Ernst, Heidrun Behrendt, Carsten B. Schmidt‐Weber, Claudia Traidl‐Hoffmann, Francesca Alessandrini
Journal: Allergy (2020)

Common ragweed has been spreading as a neophyte in Europe. Elevated CO2 levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated.Ragweed was grown in climate-controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO2 levels. Aqueous pollen extracts (RWE) from control- or CO2 -pollen were administered in vivo in a mouse model for allergic disease (daily for 3-11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte-derived dendritic cells (DCs), and HNEC-DC co-cultures. Additionally, adjuvant factors and metabolites in control- and CO2 -RWE were investigated using ELISA and untargeted metabolomics.In vivo, CO2 -RWE induced stronger allergic lung inflammation compared to control-RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro-inflammatory cytokines (IL-8, IL-1β, and IL-6). In contrast, supernatants from CO2 -RWE-stimulated HNECs, compared to control-RWE-stimulated HNECS, significantly increased TNF and decreased IL-10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control- vs CO2 -RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs.Our results indicate that elevated ambient CO2 levels elicit a stronger RWE-induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites.
Diagnostic utility of CT for suspected immune checkpoint inhibitor enterocolitis
Authors: Sienna M Durbin, Meghan J Mooradian, Florian Johannes Fintelmann, Leyre Zubiri, Donald F Chute, Avinash Kambadakone, Nisanard Pisuchpen, Kerry L Reynolds, Michael Dougan
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background and aims Immune checkpoint inhibitor (ICI) enterocolitis is a common immune-related adverse event and can be fatal, especially when not diagnosed and treated promptly. The current gold standard for diagnosis is endoscopy with biopsy, but CT scan is a possible alternative. The primary objective of this study is to identify the diagnostic performance of CT in the evaluation of ICI enterocolitis. Methods With institutional review board approval, we conducted a retrospective cohort study of patients who received ICI therapy between 2015 and 2019 across a healthcare system. Patients were included if they underwent both abdominal CT and endoscopy with biopsy within 3 days. The radiological and pathological diagnoses, as well as clinical characteristics, were extracted from the electronic medical record. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CT for diagnosing ICI enterocolitis when compared with tissue diagnosis. Results Of the 4474 patients screened, 138 met inclusion criteria. Most common tumor types were melanoma (37%) and lung cancer (19%). Seventy-four per cent were treated with antiprogrammed cell death (PD-1)/PD-L1 therapy. Thirty-nine per cent had signs of enterocolitis on CT scan and 58% had biopsy-proven ICI enterocolitis. Sensitivity and specificity of CT were 50% and 74%, respectively. PPV was 73% and NPV was 52%. Of those with confirmed ICI enterocolitis, 70% had grade 3 or higher symptoms, 91% received steroids and 40% received infliximab. Conclusion The performance of CT scan for diagnosis of ICI enterocolitis is moderate to poor and does not replace endoscopy with biopsy.
Post-peroral endoscopic myotomy dehiscence treated with an esophageal fully covered self-expandable metal stent
Authors: Margarida Flor de Lima, Nuno Nunes, Carolina Chálim Rebelo, Diogo Bernardo Moura, Ana Catarina Rego, Nuno Paz, Maria Antónia Duarte
Journal: Endoscopy (2020)

Peroral endoscopic myotomy (POEM) is an effective and safe technique for treating esophageal achalasia [1] [2]. Adverse events related to POEM, although uncommon, may present a diagnostic and therapeutic challenge [2] [3]. Fully covered self-expandable metal stents (FCSEMSs) have been successfully used in several complications of esophageal procedures, such as perforation, fistula, and leakage [4] [5].
4-1BB (CD137) in anticancer chimeras
Authors: Ignacio Melero, Pedro Berraondo
Journal: The Journal of Experimental Medicine (2020)

4-1BB (CD137, TNFRSF9) mediates costimulatory signals important for activation and persistence of cytotoxic T lymphocytes. In this issue of JEM, Oda et al. (https://doi.org/10.1084/jem.20191166) report on a chimeric construction encompassing extracellular Fas and intracellular 4-1BB to dramatically improve adoptive T cell therapy.
Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study
Authors: Thomas J Hwang, Joseph S Ross, Kerstin N Vokinger, Aaron S Kesselheim
Journal: BMJ (2020)

To characterize the therapeutic value of new drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and the association between these ratings and regulatory approval through expedited programs.Retrospective cohort study.New drugs approved by the FDA and EMA between 2007 and 2017, with follow-up through 1 April 2020.Therapeutic value was measured using ratings of new drugs by five independent organizations (Prescrire and health authorities of Canada, France, Germany, and Italy).Proportion of new drugs rated as having high therapeutic value; association between high therapeutic value rating and expedited status.From 2007 through 2017, the FDA and EMA approved 320 and 268 new drugs, respectively, of which 181 (57%) and 39 (15%) qualified for least one expedited program. Among 267 new drugs with a therapeutic value rating, 84 (31%) were rated as having high therapeutic value by at least one organization. Compared with non-expedited drugs, a greater proportion of expedited drugs were rated as having high therapeutic value among both FDA approvals (45% (69/153) v 13% (15/114); P<0.001) and EMA approvals (67% (18/27) v 27% (65/240); P<0.001). The sensitivity and specificity of expedited program for a drug being independently rated as having high therapeutic value were 82% (95% confidence interval 72% to 90%) and 54% (47% to 62%), respectively, for the FDA, compared with 25.3% (16.4% to 36.0%) and 90.2% (85.0% to 94.1%) for the EMA.Less than a third of new drugs approved by the FDA and EMA over the past decade were rated as having high therapeutic value by at least one of five independent organizations. Although expedited drugs were more likely than non-expedited drugs to be highly rated, most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.
MRI of the joint and evaluation of the granulocyte–macrophage colony-stimulating factor–CCL17 axis in patients with rheumatoid arthritis receiving otilimab: a phase 2a randomised mechanistic study
Authors: Mark C Genovese, Mario Berkowitz, Philip G Conaghan, Charles Peterfy, Katherine Davy, Elena Fisheleva, Anubha Gupta, David Inman, Robert Janiczek, Mark Layton, Nina Mitchell, Jatin Patel, Alexandra Roberts, Didier Saurigny, Julia E Smith, Russell Williamson, Paul P Tak
Journal: The Lancet Rheumatology (2020)