tbuckley/cabot-search huggingface dataset:
Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice
Authors: Guilin Chen, Shengkai Zuo, Juan Tang, Caojian Zuo, Daile Jia, Qian Liu, Guizhu Liu, Qian Zhu, Yuanyang Wang, Jian Zhang, Yujun Shen, Dongrui Chen, Ping Yuan, Zhiqiang Qin, Chengchao Ruan, Jue Ye, Xiao-Jian Wang, Yuping Zhou, Pingjin Gao, Peng Zhang, Jinming Liu, Zhi-Cheng Jing, Ankang Lu, Ying Yu
Journal: The Journal of Experimental Medicine (2018)

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin–induced PAH in CRTH2−/− mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.
The Epigenomic Landscape of Pituitary Adenomas Reveals Specific Alterations and Differentiates Among Acromegaly, Cushing's Disease and Endocrine-Inactive Subtypes
Authors: Matthew P. Salomon, Xiaowen Wang, Diego M. Marzese, Sandy C. Hsu, Nellie Nelson, Xin Zhang, Chikako Matsuba, Yuki Takasumi, Carmen Ballesteros-Merino, Bernard A. Fox, Garni Barkhoudarian, Daniel F. Kelly, Dave S.B. Hoon
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Pituitary adenomas are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood. Experimental Design: A multiplatform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically resected pituitary adenomas in 48 patients: growth hormone (GH)–secreting (n = 17), adrenocorticotropic hormone (ACTH)–secreting (n = 13, including 3 silent-ACTH adenomas), and endocrine-inactive (n = 18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease-specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation. Results: Recurrent single-nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy-number alterations (SCNA) were identified in all three pituitary adenoma subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene-expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene-expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMC gene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1 among all three adenoma subtypes. Conclusions: Taken together, these data stress the contribution of epigenomic alterations to disease-specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments. This article reveals novel insights into the epigenomics underlying pituitary adenomas and highlights how differences in epigenomic states are related to important transcriptome alterations that define adenoma subtypes. Clin Cancer Res; 24(17); 4126–36. ©2018 AACR.
Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome
Authors: Nicholas W Fischer, Aaron Prodeus, James Tran, David Malkin, Jean Gariépy
Journal: JNCI Journal of the National Cancer Institute (2018)

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.
Utility of GeneXpert in analysis of bronchoalveolar lavage samples from patients with suspected tuberculosis in an intermediate-burden setting
Authors: Kin Wang To, Kai Man Kam, Denise Pui Chung Chan, Wing Ho Yip, Ka Pang Chan, Rachael Lo, Susanna Ng, Jenny Ngai, Shui Shan Lee
Journal: Journal of Infection (2018)
Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study
Authors: Hyun-Kyoung Koo, Dragoş M Vasilescu, Steven Booth, Aileen Hsieh, Orestis L Katsamenis, Nick Fishbane, W Mark Elliott, Miranda Kirby, Peter Lackie, Ian Sinclair, Jane A Warner, Joel D Cooper, Harvey O Coxson, Peter D Paré, James C Hogg, Tillie-Louise Hackett
Journal: The Lancet Respiratory Medicine (2018)
Abstract 16002: A 3D Engineered Model of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes Reveals Functional and Structural Characteristics of β-Myosin Heavy Chain Mutation Mediated Hypertrophic Cardiomyopathy
Authors: Katherine Campbell, Justin Davis, Andre Monteiro da Rocha, Guadalupe Guerrero-Serna, Xiang Li, Lakshmi Mundada, Evan Hoopingarner, Adam Helms, Sharlene Day, Jose Jalife, Jianping Fu, Todd J Herron
Journal: Circulation (2016)

Introduction: Hypertrophic Cardiomyopathy (HCM) affects 1 in 500 people and may result in heart failure, stroke and sudden cardiac death. However, mechanism based research has been limited by the p...
Enhanced Glycolysis Supports Cell Survival in EGFR-Mutant Lung Adenocarcinoma by Inhibiting Autophagy-Mediated EGFR Degradation
Authors: Ji Hye Kim, Boas Nam, Yun Jung Choi, Seon Ye Kim, Jung-Eun Lee, Ki Jung Sung, Woo Sung Kim, Chang-Min Choi, Eun-Ju Chang, Jae Soo Koh, Joon Seon Song, Shinkyo Yoon, Jae Cheol Lee, Jin Kyung Rho, Jaekyoung Son
Journal: Cancer Research (2018)

Abstract Oncogenic EGFR is essential for the development and growth of non–small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs. Significance: Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. Cancer Res; 78(16); 4482–96. ©2018 AACR.
Abstract 3304: The mutation landscape of cancers serves as a record of early malignant transformation
Authors: Paz Polak, Rosa Karlic, Kirsten Kubler, William D. Foulkes, Gad Getz
Journal: Cancer Research (2018)

Abstract How the cell lineage influences a tissue's susceptibility to malignant transformation is a fundamental question in cancer biology, which has been barely addressed in cancer genomics thus far. Cell properties are encoded in the cell type-specific chromatin structure and we previously demonstrated that the cell-of-origin (COO) chromatin organization is a key determinant of the landscape of somatic mutations, which accumulated over lifetime serving as a memory of the historical cell lineage (Polak et al, Nature , 2015). We now show that this principle is generalizable to common tumor types and offers insights into the molecular events of cancer initiation. We extended our work to 2,641 genomes from 30 cancer types and epigenetic modifications from 98 normal tissues. In 25 cancer types, the tumor originated from a cell type that was its direct cellular counterpart or a close proxy; in only two, there was no match or a close proxy; and in the remaining three (esophageal, pancreatic ductal and biliary adenocarcinoma) the best matched cell type suggested metaplasia to stomack mucosa like tissue.The cellular context of breast tumor formation was investigated in more detail, showing that the COO, and not the gene inactivation event, determines the subtype. Basal-like tumors appeared to arise from luminal progenitor cells, while all other subtypes arose from mature luminal cells. Furthermore, irrespective of the inactivation mechanism (pathogenic germline, somatic truncating or epigenetic silencing event), all BRCA1/2- and RAD51C-altered basal-like tumors best matched to luminal progenitors while BRCA1/2- and CHEK2 -mutated luminal A/B subtypes best matched mature luminal cells. Finally, we observed that tumor type-specific driver genes reside in genomic regions that are defined by a highly active chromatin environment in their COOs. This highlights their essential role in cell type differentiation and implies the acquisition of somatic mutations early, when the chromatin architecture still reflected the COO. Taken together, our findings shed light on the crucial role of the COO in shaping the mutational landscape and tumor evolution. Citation Format: Paz Polak, Rosa Karlic, Kirsten Kubler, William D. Foulkes, Gad Getz. The mutation landscape of cancers serves as a record of early malignant transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3304.
Pathology, Chemoprevention, and Preclinical Models for Target Validation in Barrett Esophagus
Authors: Aleksandra M. Urbanska, Selvarangan Ponnazhagan, Masoud Mozafari
Journal: Cancer Research (2018)

Despite esophageal adenocarcinoma (EAC) being the most widespread among gastrointestinal cancers, with an 11-fold increase in the risk of cancer for patients with Barrett esophagus (BE), its prognosis is still poor. There is a critical need to better perceive the biology of cancer progression and identification of specific targets that are the hallmark of BE's progression. This review explores the established animal models of BE, including genetic, surgical and nonsurgical approaches, potential chemoprevention targets, and the reasoning behind their applications to prevent Barrett-related EAC. The key methodological features in the design feasibility of relevant studies are also discussed. Cancer Res; 78(14); 3747-54. ©2018 AACR.
短報: B系列ALL(急性リンパ性白血病)のMRD(微小残存病変)患者を対象とするブリナツモマブの第2相試験における血液学的無再発生存率の長期追跡調査
Authors: S Topp Max, Goekbuget Nicola, Zugmaier Gerhard, Degenhard Evelyn, Goebeler Marie-Elisabeth, Klinger Matthias, A Neumann Svenja, A Horst Heinz, Raff Thorsten, Viardot Andreas, Stelljes Matthias, Schaich Markus, Koehne-Volland Rudolf, Brueggemann Monika, G Ottmann Oliver, Burmeister Thomas, A Baeuerle Patrick, Nagorsen Dirk, Schmidt Margit, Einsele Hermann, Riethmueller Gert, Kneba Michael, Hoelzer Dieter, Kufer Peter, C Bargou Ralf
Journal: Blood (2012)
Association of mast cells with clinical, endoscopic, and histologic findings in adults with eosinophilic esophagitis
Authors: Manaswita Tappata, Swathi Eluri, Irina Perjar, Johnathan Hollyfield, Renee Betancourt, Cara Randall, John T. Woosley, Joshua B. Wechsler, Evan S. Dellon
Journal: Allergy (2018)

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A large epidemiological study of erythema multiforme in France, with emphasis on treatment choices
Authors: E. Kechichian, S. Ingen-Housz-Oro, E. Sbidian, F. Hemery, C. Bernier, C. Fite, J. Delaunay, D. Staumont-Sallé, F. Toukal, N. Dupin, C. Abasq, M. Samimi, C. Picard, V. Hebert, C. Prost, J.-B. Monfort, B. Milpied, P. Wolkenstein, O. Chosidow
Journal: British Journal of Dermatology (2018)
Myocardial Injury and Cardiac Reserve in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Masaru Obokata, Yogesh N.V. Reddy, Vojtech Melenovsky, Garvan C. Kane, Thomas P. Olson, Petr Jarolim, Barry A. Borlaug
Journal: Journal of the American College of Cardiology (2018)
Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden
Authors: Jonas F Ludvigsson, Martin Neovius, Jonas Söderling, Soffia Gudbjörnsdottir, Ann-Marie Svensson, Stefan Franzén, Olof Stephansson, Björn Pasternak
Journal: BMJ (2018)

To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception.Population based historical cohort study using nationwide health registers.Sweden, 2003-15.2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes.Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels.122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33).Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.
Abstract 17949: Recruitment of Pro-Inflammatory Ly6ChighCCR2+ Monocytes to the Myocardium is Critical to the Development of Hypertension Related Myocardial Fibrosis
Authors: Chloe Wong, Alec Falkenham, Tanya Myers, Jean-Francois Legare
Journal: Circulation (2016)

Background: Monocytes/macrophages (Mφ) are key regulators of myocardial inflammation and fibrosis. It is known that Ly6ChighCCR2+ monocytes are the primary infiltrating cell in hypertension-depende...
Disease-specific regulation of gene expression in a comparative analysis of juvenile idiopathic arthritis and inflammatory bowel disease
Authors: Angela Mo, Urko M. Marigorta, Dalia Arafat, Lai Hin Kimi Chan, Lori Ponder, Se Ryeong Jang, Jarod Prince, Subra Kugathasan, Sampath Prahalad, Greg Gibson
Journal: Genome Medicine (2018)

The genetic and immunological factors that contribute to differences in susceptibility and progression between sub-types of inflammatory and autoimmune diseases continue to be elucidated. Inflammatory bowel disease and juvenile idiopathic arthritis are both clinically heterogeneous and known to be due in part to abnormal regulation of gene activity in diverse immune cell types. Comparative genomic analysis of these conditions is expected to reveal differences in underlying genetic mechanisms of disease. We performed RNA-Seq on whole blood samples from 202 patients with oligoarticular, polyarticular, or systemic juvenile idiopathic arthritis, or with Crohn's disease or ulcerative colitis, as well as healthy controls, to characterize differences in gene expression. Gene ontology analysis combined with Blood Transcript Module and Blood Informative Transcript analysis was used to infer immunological differences. Comparative expression quantitative trait locus (eQTL) analysis was used to quantify disease-specific regulation of transcript abundance. A pattern of differentially expressed genes and pathways reveals a gradient of disease spanning from healthy controls to oligoarticular, polyarticular, and systemic juvenile idiopathic arthritis (JIA); Crohn's disease; and ulcerative colitis. Transcriptional risk scores also provide good discrimination of controls, JIA, and IBD. Most eQTL are found to have similar effects across disease sub-types, but we also identify disease-specific eQTL at loci associated with disease by GWAS. JIA and IBD are characterized by divergent peripheral blood transcriptomes, the genetic regulation of which displays limited disease specificity, implying that disease-specific genetic influences are largely independent of, or downstream of, eQTL effects.
Abstract 3584: Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors
Authors: Ekta Patel, Jian Ding, Nikolaus Thorausch, Janani Krishnamurthy, Rashmi Choudhary, Solly Weiler, Bonnie Le, Patrick Tavares, Adam Zieba, Justin Quinn, Yan Wang, Wolfgang Schamel, Irene Scarfo, Marcela Maus, Patrick Baeuerle, Dainel Getts, Robert Hofmeister
Journal: Cancer Research (2018)

Abstract T cells expressing chimeric antigen receptors (CARs) have demonstrated remarkable clinical benefit in certain hematological malignancies albeit with side effect such as cytokine release syndrome, on Target off tumor response and limited efficacy in solid tumors. Here, we present the preclinical evaluation of a novel T cell engineering platform designed to overcome potential hurdles of CARs and other T cell receptor modalities. Specifically, we have generated novel T Cell Receptor Fusion Constructs (TRuC™s) that fuse binder domains to subunits of the T cell receptor. These constructs when introduced using lentiviral technology, integrate into endogenous TCR, reprograming T cells to target tumor antigen in a non-major histocompatibility complex (MHC) restricted fashion and harnessing the full spectrum of TCR signaling. TRuC™ variants were constructed by recombinant fusion of an scFv or sdAb to various TCR subunits via a flexible linker sequence. Likewise, CD28ζ and 41BBζ CARs were generated using the same binders for side-by-side comparison. We demonstrated that TRuC™ variants can effectively reprogram T cells to recognize tumor surface antigens in a non-MHC-restricted fashion. TRuC™s are distinct from CARs in their ability to activate T cells through the entire TCR without additional costimulatory domains. In vitro, TRuC™ T cells were equally potent as CAR T cells in eliminating tumor cells. Compared to CAR-T cells, TRuC-T cells produced lower cytokine levels and proliferated less. Despite these difference, TRuC™ T cells were more efficient in clearing tumors in subcutaneous Raji and MSTO-211H mesothelioma models. Our findings support the development of TRuC-T cells for the treatment of solid tumors. Citation Format: Ekta Patel, Jian Ding, Nikolaus Thorausch, Janani Krishnamurthy, Rashmi Choudhary, Solly Weiler, Bonnie Le, Patrick Tavares, Adam Zieba, Justin Quinn, Yan Wang, Wolfgang Schamel, Irene Scarfo, Marcela Maus, Patrick Baeuerle, Dainel Getts, Robert Hofmeister. Characterization of a novel class of engineered (TCR) fusion constructs (TRuCTMs) aimed to treat solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3584.
Out-of-hours discharge from intensive care, in-hospital mortality and intensive care readmission rates: a systematic review and meta-analysis
Authors: Sarah Vollam, Susan Dutton, Sallie Lamb, Tatjana Petrinic, J. Duncan Young, Peter Watkinson
Journal: Intensive Care Medicine (2018)

Discharge from an intensive care unit (ICU) out of hours is common. We undertook a systematic review and meta-analysis to explore the association between time of discharge and mortality/ICU readmission. We searched Medline, Embase, Web of Knowledge, CINAHL, the Cochrane Library and OpenGrey to June 2017. We included studies reporting in-hospital mortality and/or ICU readmission rates by ICU discharge "out-of-hours" and "in-hours". Inclusion was limited to patients aged ≥ 16 years discharged alive from a non-specialist ICU to a lower level of hospital care. Studies restricted to specific diseases were excluded. We assessed study quality using the Newcastle Ottowa Scale. We extracted published data, summarising using a random-effects meta-analysis. Our searches identified 1961 studies. We included unadjusted data from 1,191,178 patients from 18 cohort studies (presenting data from 1994 to 2014). "Out of hours" had multiple definitions, beginning between 16:00 and 22:00 and ending between 05:59 and 09:00. Patients discharged out of hours had higher in-hospital mortality [relative risk (95% CI) 1.39 (1.24, 1.57) p < 0.0001] and readmission rates [1·30 (1.19, 1.42), p < 0.001] than patients discharged in hours. Heterogeneity was high (I2 90.1% for mortality and 90.2% for readmission), resulting from differences in effect size rather than the presence of an effect. Out-of-hours discharge from an ICU is strongly associated with both in-hospital death and ICU readmission. These effects persisted across all definitions of "out of hours" and across healthcare systems in different geographical locations. Whether these increases in mortality and readmission result from patient differences, differences in care, or a combination remains unclear.