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Yasuhiro Kishi, Takaaki Kondo, Sheng Xiao, Nir Yosef, Jellert Gaublomme, Chuan Wu, Chao Wang, Norio Chihara, Aviv Regev, Nicole Joller, Vijay K Kuchroo
Th17 cells are key players in defense against pathogens and maintaining tissue homeostasis, but also act as critical drivers of autoimmune diseases. Based on single-cell RNA-seq profiling of pathogenic versus nonpathogenic Th17 cells, we identified protein C receptor (PROCR) as a cell surface molecule expressed in covariance with the regulatory module of Th17 cells. Although PROCR expression in T cells was controlled by the cooperative action of the Th17 lineage-specific transcription factors RORγt, IRF4, and STAT3, PROCR negatively regulated Th17 differentiation...
September 26, 2016: Journal of Experimental Medicine
O Brew, M H F Sullivan, A Woodman
Pre-eclampsia (PE) is a serious multi-factorial disorder of human pregnancy. It is associated with changes in the expression of placental genes. Recent transcription profiling of placental genes with microarray analyses have offered better opportunities to define the molecular pathology of this disorder. However, the extent to which placental gene expression changes in PE is not fully understood. We conducted a systematic review of published PE and normal pregnancy (NP) control placental RNA microarrays to describe the similarities and differences between NP and PE placental gene expression, and examined how these differences could contribute to the molecular pathology of the disease...
2016: PloS One
Shiri Gur-Cohen, Tsvee Lapidot
Generation and growth of the blood vasculature network is a highly synchronized process, requiring coordinated efforts of endothelial cells and pericytes to maintain blood vessel integrity and regeneration. In a recent paper published in Cell Research, Yu et al. identified and characterized bipotent Procr-expressing vascular endothelial stem cells, which give rise to both endothelial cells and pericytes.
October 2016: Cell Research
Pierre Suchon, Fadi Al Frouh, Manal Ibrahim, Gabrielle Sarlon, Geoffroy Venton, Marie-Christine Alessi, David-Alexandre Trégouët, Pierre-Emmanuel Morange
Identifying women at risk of venous thrombosis (VT) under combined oral contraceptives (COC) is a major public health issue. The aim of the present study was to investigate in COC users the impact on disease of genetic polymorphisms recently identified to associate with VT risk in the general population. Nine polymorphisms located on KNG1, F11, F5,F2,PROCR,FGG, TSPAN15andSLC44A2geneswere genotyped in a sample of 766 patients and 464 controls part of the PILGRIM (Pill Genetic Risk Monitoring) study. Cases were women who experienced an episode of documented VT during COC use while controls were women with no history of VT using COC at the time of inclusion...
July 14, 2016: Clinical Genetics
Qing Cissy Yu, Wenqian Song, Daisong Wang, Yi Arial Zeng
Vascular growth and remodeling are dependent on the generation of new endothelial cells from stem cells and the involvement of perivascular cells to maintain vessel integrity and function. The existence and cellular identity of vascular endothelial stem cells (VESCs) remain unclear. The perivascular pericytes in adult tissues are thought to arise from the recruitment and differentiation of mesenchymal progenitors during early development. In this study, we identified Protein C receptor-expressing (Procr(+)) endothelial cells as VESCs in multiple tissues...
July 1, 2016: Cell Research
Wei-Ching Chen, Chih-Yang Wang, Yu-Hsuan Hung, Tzu-Yang Weng, Meng-Chi Yen, Ming-Derg Lai
Dysregulated lipid metabolism contributes to cancer progression. Our previous study indicates that long-chain fatty acyl-Co A synthetase (ACSL) 3 is essential for lipid upregulation induced by endoplasmic reticulum stress. In this report, we aimed to identify the role of ACSL family in cancer with systematic analysis and in vitro experiment. We explored the ACSL expression using Oncomine database to determine the gene alteration during carcinogenesis and identified the association between ACSL expression and the survival of cancer patient using PrognoScan database...
2016: PloS One
Stefano Giuliani, Yew-Wei Tan, Dongling Zheng, Evmorfia Petropoulou, Ali Sohail, Sarah Bradley, Justin Richards, Nigel Kennea, Yalda Jamshidi
OBJECTIVES: Coagulopathy and mesenteric thrombosis are common in premature neonates with necrotizing enterocolitis (NEC). This pilot study aimed to investigate the hypothesis that there are changes in the gene expression related to the coagulation and anticoagulation systems in NEC. METHODS: Consecutive neonates (n = 11) with NEC (Bell's stages 2-3) were recruited. Two comparison groups, matched for birth weight and corrected gestational age, were selected based on: the absence of inflammation and coagulopathy (healthy control, n = 10); or the presence of a confirmed blood infection (sepsis control, n = 12)...
March 31, 2016: Journal of Pediatric Gastroenterology and Nutrition
Elizabeth A Staiger, Chia T Tseng, Donald Miller, Jennifer M Cassano, Lubna Nasir, Dorian Garrick, Samantha A Brooks, Douglas F Antczak
The common equine skin tumors known as sarcoids have been causally associated with infection by bovine papillomavirus (BPV). Additionally, there is evidence for host genetic susceptibility to sarcoids. We investigated the genetic basis of susceptibility to sarcoid tumors on a cohort of 82 affected horses and 270 controls genotyped on a genome-wide platform and two custom panels. A Genome Wide Association Study (GWAS) identified candidate regions on six chromosomes. Bayesian probability analysis of the same dataset verified only the regions on equine chromosomes (ECA) 20 and 22...
August 15, 2016: International Journal of Cancer. Journal International du Cancer
David A Hinds, Alfonso Buil, Daniel Ziemek, Angel Martinez-Perez, Rainer Malik, Lasse Folkersen, Marine Germain, Anders Mälarstig, Andrew Brown, Jose Manuel Soria, Martin Dichgans, Nan Bing, Anders Franco-Cereceda, Juan Carlos Souto, Emmanouil T Dermitzakis, Anders Hamsten, Bradford B Worrall, Joyce Y Tung, Maria Sabater-Lleal
Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk...
May 1, 2016: Human Molecular Genetics
Sarah K C Cheung, Po-Kai Chuang, Han-Wen Huang, Wendy W Hwang-Verslues, Candy Hsin-Hua Cho, Wen-Bin Yang, Chia-Ning Shen, Michael Hsiao, Tsui-Ling Hsu, Chuan-Fa Chang, Chi-Huey Wong
The discovery of cancer stem cells (CSCs), which are responsible for self-renewal and tumor growth in heterogeneous cancer tissues, has stimulated interests in developing new cancer therapies and early diagnosis. However, the markers currently used for isolation of CSCs are often not selective enough to enrich CSCs for the study of this special cell population. Here we show that the breast CSCs isolated with CD44(+)CD24(-/lo)SSEA-3(+) or ESA(hi)PROCR(hi)SSEA-3(+) markers had higher tumorigenicity than those with conventional markers in vitro and in vivo...
January 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Helle Holm Hansson, Louise Turner, Line Møller, Christian William Wang, Daniel T R Minja, Samwel Gesase, Bruno Mmbando, Ib Christian Bygbjerg, Thor G Theander, John P A Lusingu, Michael Alifrangis, Thomas Lavstsen
BACKGROUND: Endothelial protein C receptor (EPCR) was recently identified as a key receptor for Plasmodium falciparum erythrocyte membrane protein 1 mediating sequestration of P. falciparum-infected erythrocytes in patients suffering from severe malaria. Soluble EPCR (sEPCR) inhibits binding of P. falciparum to EPCR in vitro and increased levels of sEPCR have been associated with the H3 haplotype of the EPCR encoding PROCR gene. It has been hypothesized that elevated sEPCR levels, possibly linked to the PROCR H3 genetic variant, may confer protection against severe forms of malaria...
2015: Malaria Journal
R Saigusa, Y Asano, T Yamashita, T Taniguchi, T Takahashi, Y Ichimura, T Toyama, A Yoshizaki, T Miyagaki, M Sugaya, S Sato
BACKGROUND: Endothelial protein C receptor (EPCR), expressed predominantly on endothelial cells, plays a critical role in the regulation of the coagulation system and also mediates various cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc). OBJECTIVES: To investigate the potential contribution of EPCR to the development of SSc. METHODS: EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting and/or quantitative reverse-transcription polymerase chain reaction...
February 2016: British Journal of Dermatology
Pierre-Emmanuel Morange, Pierre Suchon, David-Alexandre Trégouët
Venous thrombosis (VT) is a common multifactorial disease with a genetic component that was first suspected nearly 60 years ago. In this review, we document the genetic determinants of the disease, and update recent findings delivered by the application of high-throughput genotyping and sequencing technologies. To date, 17 genes have been robustly demonstrated to harbour genetic variations associated with VT risk: ABO, F2, F5, F9, F11, FGG, GP6, KNG1, PROC, PROCR, PROS1, SERPINC1, SLC44A2, STXBP5, THBD, TSPAN15 and VWF...
November 2015: Thrombosis and Haemostasis
Harikrishna Nakshatri, Manjushree Anjanappa, Poornima Bhat-Nakshatri
Recent reports of widespread genetic variation affecting regulation of gene expression raise the possibility of significant inter-individual differences in stem-progenitor-mature cell hierarchy in adult organs. This has not been explored because of paucity of methods to quantitatively assess subpopulation of normal epithelial cells on individual basis. We report the remarkable inter-individual differences in differentiation capabilities as documented by phenotypic heterogeneity in stem-progenitor-mature cell hierarchy of the normal breast...
2015: Scientific Reports
Marine Germain, Daniel I Chasman, Hugoline de Haan, Weihong Tang, Sara Lindström, Lu-Chen Weng, Mariza de Andrade, Marieke C H de Visser, Kerri L Wiggins, Pierre Suchon, Noémie Saut, David M Smadja, Grégoire Le Gal, Astrid van Hylckama Vlieg, Antonio Di Narzo, Ke Hao, Christopher P Nelson, Ares Rocanin-Arjo, Lasse Folkersen, Ramin Monajemi, Lynda M Rose, Jennifer A Brody, Eline Slagboom, Dylan Aïssi, France Gagnon, Jean-Francois Deleuze, Panos Deloukas, Christophe Tzourio, Jean-Francois Dartigues, Claudine Berr, Kent D Taylor, Mete Civelek, Per Eriksson, Bruce M Psaty, Jeanine Houwing-Duitermaat, Alison H Goodall, François Cambien, Peter Kraft, Philippe Amouyel, Nilesh J Samani, Saonli Basu, Paul M Ridker, Frits R Rosendaal, Christopher Kabrhel, Aaron R Folsom, John Heit, Pieter H Reitsma, David-Alexandre Trégouët, Nicholas L Smith, Pierre-Emmanuel Morange
Venous thromboembolism (VTE), the third leading cause of cardiovascular mortality, is a complex thrombotic disorder with environmental and genetic determinants. Although several genetic variants have been found associated with VTE, they explain a minor proportion of VTE risk in cases. We undertook a meta-analysis of genome-wide association studies (GWASs) to identify additional VTE susceptibility genes. Twelve GWASs totaling 7,507 VTE case subjects and 52,632 control subjects formed our discovery stage where 6,751,884 SNPs were tested for association with VTE...
April 2, 2015: American Journal of Human Genetics
Hai Po H Liang, Edward J Kerschen, Irene Hernandez, Sreemanti Basu, Mark Zogg, Fady Botros, Shuang Jia, Martin J Hessner, John H Griffin, Wolfram Ruf, Hartmut Weiler
Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow-derived myeloid cells and in monocytic RAW264...
April 30, 2015: Blood
E Kerschen, I Hernandez, M Zogg, M Maas, H Weiler
BACKGROUND: The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (FV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes and of mouse models of infection with various pathogens remained inconclusive...
June 2015: Journal of Thrombosis and Haemostasis: JTH
Angela Burleigh, Steven McKinney, Jazmine Brimhall, Damian Yap, Peter Eirew, Steven Poon, Viola Ng, Adrian Wan, Leah Prentice, Lois Annab, J Carl Barrett, Carlos Caldas, Connie Eaves, Samuel Aparicio
INTRODUCTION: The extracellular signals regulating mammary epithelial cell growth are of relevance to understanding the pathophysiology of mammary epithelia, yet they remain poorly characterized. In this study, we applied an unbiased approach to understanding the functional role of signalling molecules in several models of normal physiological growth and translated these results to the biological understanding of breast cancer subtypes. METHODS: We developed and utilized a cytogenetically normal clonal line of hTERT immortalized human mammary epithelial cells in a fibroblast-enhanced co-culture assay to conduct a genome-wide small interfering RNA (siRNA) screen for evaluation of the functional effect of silencing each gene...
2015: Breast Cancer Research: BCR
Kathrin Schuldt, Christa Ehmen, Jennifer Evans, Juergen May, Daniel Ansong, Juergen Sievertsen, Birgit Muntau, Gerd Ruge, Tsiri Agbenyega, Rolf D Horstmann
BACKGROUND: Two recent reports have identified the Endothelial Protein C Receptor (EPCR) as a key molecule implicated in severe malaria pathology. First, it was shown that EPCR in the human microvasculature mediates sequestration of Plasmodium falciparum-infected erythrocytes. Second, microvascular thrombosis, one of the major processes causing cerebral malaria, was linked to a reduction in EPCR expression in cerebral endothelial layers. It was speculated that genetic variation affecting EPCR functionality could influence susceptibility to severe malaria phenotypes, rendering PROCR, the gene encoding EPCR, a promising candidate for an association study...
2014: PloS One
Teresa Fidalgo, Patrícia Martinho, Ramon Salvado, Licínio Manco, Ana C Oliveira, Catarina S Pinto, Elsa Gonçalves, Dalila Marques, Teresa Sevivas, Natália Martins, Maria Letícia Ribeiro
INTRODUCTION: Inherited protein C (PC) deficiency is a well-known risk factor for venous thrombosis (VT). Plasma PC levels are reliable in moderate to severe deficiencies; however, in mildly deficient individuals, the levels may overlap with those considered normal. Genetic studies of PROC, which encodes PC, could help identify carriers; genome-wide association studies (GWAS) have shown that approximately 50% of phenotypic variation in PC deficiency is caused by the cumulative effects of mutations in several other loci, namely in the PROCR...
October 2015: European Journal of Haematology
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