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https://www.readbyqxmd.com/read/28742206/bioinformatics-analysis-of-rna-seq-data-revealed-critical-genes-in-colon-adenocarcinoma
#1
W-D Xi, Y-J Liu, X-B Sun, J Shan, L Yi, T-T Zhang
OBJECTIVE: RNA-seq data of colon adenocarcinoma (COAD) were analyzed with bioinformatics tools to discover critical genes in the disease. Relevant small molecule drugs, transcription factors (TFs) and microRNAs (miRNAs) were also investigated. MATERIALS AND METHODS: RNA-seq data of COAD were downloaded from The Cancer Genome Atlas (TCGA). Differential analysis was performed with package edgeR. False positive discovery (FDR) < 0.05 and |log2 (fold change)|>1 were set as the cut-offs to screen out differentially expressed genes (DEGs)...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28738836/metabolism-associated-danger-signal-induced-immune-response-and-reverse-immune-checkpoint-activated-cd40-monocyte-differentiation
#2
REVIEW
Jin Dai, Pu Fang, Jason Saredy, Hang Xi, Cueto Ramon, William Yang, Eric T Choi, Yong Ji, Wei Mao, Xiaofeng Yang, Hong Wang
Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response...
July 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28735186/development-of-a-robust-reporter-gene-assay-to-measure-the-bioactivity-of-anti-pd-1-anti-pd-l1-therapeutic-antibodies
#3
Lan Wang, Chuanfei Yu, Yalan Yang, Kai Gao, Junzhi Wang
Being regarded as the 'cancer panacea', the anti-PD-1/anti-PD-L1 monoclonal antibodies (mAbs) have become the R&D focus of biopharmaceutical industries. Several marketed such mAbs have been proved particularly effective in treating various cancers. However, the cell-based bioassay to measure the biological activities of the anti-PD-1/anti-PD-L1 mAbs as the lot release or stability test has been a great challenge to quality control laboratories due to the immunomodulating nature of the mAbs. Here, we describe the development and validation of a reporter gene assay consisting of two-cell systems to measure the bioactivity of the anti-PD-1/anti-PD-L1 mAbs...
May 8, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28729555/inhibition-of-phosphodiesterase-5-suppresses-calcineurin-nfat-mediated-trpc6-expression-in-pulmonary-artery-smooth-muscle-cells
#4
Shaojun Li, Yilin Pan, Rui Ke, Xinming Xie, Cui Zhai, Wenhua Shi, Jian Wang, Xin Yan, Limin Chai, Qingting Wang, Qianqian Zhang, Xiaofan Su, Lan Yang, Li Gao, Manxiang Li
The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724617/human-venous-valve-disease-caused-by-mutations-in-foxc2-and-gjc2
#5
Oliver Lyons, Prakash Saha, Christopher Seet, Adam Kuchta, Andrew Arnold, Steven Grover, Victoria Rashbrook, Amélie Sabine, Gema Vizcay-Barrena, Ash Patel, Francesca Ludwinski, Soundrie Padayachee, Tsutomu Kume, Brenda R Kwak, Glen Brice, Sahar Mansour, Pia Ostergaard, Peter Mortimer, Steve Jeffery, Nigel Brown, Taija Makinen, Tatiana V Petrova, Bijan Modarai, Alberto Smith
Venous valves (VVs) prevent venous hypertension and ulceration. We report that FOXC2 and GJC2 mutations are associated with reduced VV number and length. In mice, early VV formation is marked by elongation and reorientation ("organization") of Prox1(hi) endothelial cells by postnatal day 0. The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. Foxc2 and Nfatc1 were coexpressed at P0, and combined Foxc2 deletion with calcineurin-Nfat inhibition disrupted early Prox1(hi) endothelial organization, suggesting cooperative Foxc2-Nfatc1 patterning of these events...
July 19, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28720890/iron-overload-exacerbates-age-associated-cardiac-hypertrophy-in-a-mouse-model-of-hemochromatosis
#6
Abitha Sukumaran, JuOae Chang, Murui Han, Shrutika Mintri, Ban-An Khaw, Jonghan Kim
Cardiac damage associated with iron overload is the most common cause of morbidity and mortality in patients with hereditary hemochromatosis, but the precise mechanisms leading to disease progression are largely unexplored. Here we investigated the effects of iron overload and age on cardiac hypertrophy using 1-, 5- and 12-month old Hfe-deficient mice, an animal model of hemochromatosis in humans. Cardiac iron levels increased progressively with age, which was exacerbated in Hfe-deficient mice. The heart/body weight ratios were greater in Hfe-deficient mice at 5- and 12-month old, compared with their age-matched wild-type controls...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28717008/the-cardiac-z-disc-protein-cefip-regulates-cardiomyocyte-hypertrophy-by-modulating-calcineurin-signaling
#7
Franziska Dierck, Christian Kuhn, Claudia Rohr, Susanne Hille, Julia Braune, Samuel Sossalla, Sibylle Molt, Peter F M van der Ven, Dieter O Fürst, Norbert Frey
The z-disc is a structural component at the lateral borders of the sarcomere and is important for mechanical stability and contractility of both cardiac and skeletal muscles. Of note, the sarcomeric z-disc also represents a nodal point in cardiomyocyte function and signaling. Mutations of numerous z-disc proteins are associated with cardiomyopathies and muscle diseases. To identify additional z-disc proteins that might contribute to cardiac disease, we employed an in silico screen for cardiac-enriched cDNAs...
July 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28716943/visualizing-context-dependent-calcium-signaling-in-encephalitogenic-t-cells-in-vivo-by-two-photon-microscopy
#8
Nikolaos I Kyratsous, Isabel J Bauer, Guokun Zhang, Marija Pesic, Ingo Bartholomäus, Marsilius Mues, Ping Fang, Miriam Wörner, Stephanie Everts, Joachim W Ellwart, Joanna M Watt, Barry V L Potter, Reinhard Hohlfeld, Hartmut Wekerle, Naoto Kawakami
In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT...
July 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28710230/the-tissue-reconstructing-ability-of-colon-cscs-is-enhanced-by-fk506-and-suppressed-by-gsk3-inhibition
#9
Ryo Ishida, Michiyo Koyanagi-Aoi, Nobu Oshima, Yoshihiro Kakeji, Takashi Aoi
Cancer stem cells (CSCs) are capable of reconstructing cancer tissues, are involved in both recurrence and metastasis, and contribute to therapeutic resistance. Therefore, elucidating the molecular mechanism in CSCs is important to successfully treat unresectable cancers. Previously we observed that colon cancer stem-like cells can be induced from human colon cancer cell lines by retrovirally introducing OCT3/4, SOX2 and KLF4, and we have designated such cells as induced cancer stem cells (iCSCs). In the current study, we used iCSCs to evaluate the molecular mechanism of colon CSCs and developed new methods to control them...
July 14, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28708287/regulation-of-rankl-induced-osteoclastogenesis-by-ring-finger-protein-rnf114
#10
Boren Lin, Qi Ke, Douglas W Leaman, Vijay Goel, Anand Agarwal
Normal bone remodeling is a continuous process orchestrated by bone-resorbing osteoclasts and bone-forming osteoblasts, which an imbalance in bone remodeling results in metabolic bone diseases. RANKL, a member of the TNF cytokine family, functions as a key stimulator for osteoclast differentiation and maturation. Here, we report that RNF114, previously identified as a psoriasis susceptibility gene, plays a regulatory role in the RANKL/RANK/TRAF6 signaling pathway that mediates osteoclastogenesis. Our results demonstrated that RNF114 expression was significantly down-regulated in mouse osteoclast precursor cells undergoing RANKL-induced osteoclast differentiation...
July 14, 2017: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
https://www.readbyqxmd.com/read/28706520/hypothermia-promotes-interleukin-22-expression-and-fine-tunes-its-biological-activity
#11
Evgeny Chichelnitskiy, Britta Himmelseher, Malte Bachmann, Josef Pfeilschifter, Heiko Mühl
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5-h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0° and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor-α and IL-17A were not increased...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28704638/regulator-of-calcineurin-3-ameliorates-autoimmune-arthritis-by-suppressing-th17-cell-differentiation
#12
Jin-Sil Park, Jeong-Hee Jeong, Jae-Kyeong Byun, Mi-Ae Lim, Eun-Kyung Kim, Sung-Min Kim, Si-Young Choi, Sung-Hwan Park, Jun-Ki Min, Mi-La Cho
Regulator of calcineurin 3 (RCAN3), an endogenous regulator of the calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway, inhibits the phosphatase activity of calcineurin, the nuclear translocation of NFAT, and the NFAT downstream pathway. To investigate the effects of RCAN3 on T-cell regulatory function and the development and progression of inflammatory arthritis, we studied the effects of RCAN3 transfection on regulation of Th17 cell differentiation in a murine T-lymphoma cell line and primary splenic CD4(+) T cells...
July 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28688805/low-level-of-ochratoxin-a-affects-genome-wide-expression-in-kidney-of-pig
#13
Daniela Eliza Marin, Cornelia Braicu, Mihai Alexandru Gras, Gina Cecilia Pistol, Roxana Cojocneanu Petric, Ioana Berindan Neagoe, Mihai Palade, Ionelia Taranu
Ochratoxin A (OTA) is a mycotoxin produced by fungus belonging to Aspergillus and Penicillium genra. The aim of the present paper was to investigate if a low concentration OTA has toxic effect in pigs. Twelve piglets were fed with a control or an OTA (0.05 mg/kg feed) contaminated diet. After 30 days, animals were slaughtered and samples of blood and kidney were used for further analyses. The mycotoxin analyses showed a significant higher (6.25 times) concentration of OTA in the kidney of OTA intoxicated piglets than in control ones...
July 6, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28686294/nfat-regulated-cytokine-gene-expression-during-tacrolimus-therapy-early-after-renal-transplantation
#14
Sara Bremer, Nils T Vethe, Morten Skauby, Margrete Kasbo, Elisabet D Johansson, Karsten Midtvedt, Stein Bergan
AIMS: Despite pharmacokinetic monitoring of calcineurin inhibitors, the long-term outcome after transplantation (Tx) is still hampered by the side effects of these drugs. The aim of this study was to characterize the nuclear factor of activated T cells (NFAT)-regulated gene expression as a potential pharmacodynamic biomarker for further individualization of tacrolimus (Tac) therapy. METHODS: In 29 renal allograft recipients samples were drawn once pre-Tx, and before and 1...
July 7, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28684310/selective-inhibition-of-plasma-membrane-calcium-atpase-4-improves-angiogenesis-and-vascular-reperfusion
#15
Sathishkumar Kurusamy, Dolores López-Maderuelo, Robert Little, David Cadagan, Aaron M Savage, Jude C Ihugba, Rhiannon R Baggott, Farjana B Rowther, Sara Martínez-Martínez, Pablo Gómez-Del Arco, Clare Murcott, Weiguang Wang, J Francisco Nistal, Delvac Oceandy, Ludwig Neyses, Robert N Wilkinson, Elizabeth J Cartwright, Juan Miguel Redondo, Angel Luis Armesilla
AIMS: Ischaemic cardiovascular disease is a major cause of morbidity and mortality worldwide. Despite promising results from pre-clinical animal models, VEGF-based strategies for therapeutic angiogenesis have yet to achieve successful reperfusion of ischaemic tissues in patients. Failure to restore efficient VEGF activity in the ischaemic organ remains a major problem in current pro-angiogenic therapeutic approaches. Plasma membrane calcium ATPase 4 (PMCA4) negatively regulates VEGF-activated angiogenesis via inhibition of the calcineurin/NFAT signalling pathway...
July 3, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28680569/ppar%C3%AE-attenuates-hypoxia-induced-hypertrophic-transcriptional-pathways-in-the-heart
#16
Abubakr Chaudhry, Kristal A Carthan, Bum-Yong Kang, John Calvert, Roy L Sutliff, C Michael Hart
Chronic hypoxia-induced pulmonary hypertension (PH) is characterized by increased pressure and resistance in the pulmonary vasculature and hypertrophy of the right ventricle (RV). The transcription factors, nuclear factor activated T-cells (NFAT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB/p65) contribute to RV hypertrophy (RVH). Because peroxisome proliferator-activated receptor gamma (PPARγ) activation attenuates hypoxia-induced PH and RVH, we hypothesized that PPARγ inhibits activation of RV hypertrophic transcriptional signaling mechanisms...
March 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28674297/characterization-of-therapeutic-monoclonal-antibodies-by-using-fc%C3%AE-r-expressing-reporter-cell-lines
#17
Minoru Tada, Akiko Ishii-Watabe
 Fcγ receptors (FcγRs), which bind to the Fc regions of antibodies, play an important role in antibody effector functions. In humans, there are four types of activating FcγRs: FcγRI, FcγRIIa, FcγRIIIa, and FcγRIIIb. These are expressed on various effector cells such as natural killer (NK) cells, neutrophils and macrophages. FcγRIIIa expressed on NK cells is known to play a pivotal role in antibody-dependent cellular cytotoxicity (ADCC) by therapeutic monoclonal antibodies (mAbs). To assess the ADCC activity of mAbs, the killing of target cells is often measured using human peripheral mononuclear blood cells (hPBMCs) or isolated primary NK cells as effector cells...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28630062/the-transcription-factor-nfat1-participates-in-the-induction-of-cd4-t-cell-functional-exhaustion-during-plasmodium-yoelii-infection
#18
Rachel Y Ames, Li-Min Ting, Inessa Gendlina, Kami Kim, Fernando Macian
Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and up-regulate cell-surface inhibitory molecules such as PD-1 and LAG-3...
June 19, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28617945/microrna-cluster-106a-363-is-involved-in-t-helper-17-th17-cell-differentiation
#19
Marc Kaestle, Sabine Bartel, Kerstin Geillinger-Kästle, Martin Irmler, Johannes Beckers, Bernhard Ryffel, Oliver Eickelberg, Susanne Krauss-Etschmann
T-helper cell 17 (Th17) mediated inflammation is associated with various diseases including autoimmune encephalitis, inflammatory bowel disease and lung diseases such as chronic obstructive pulmonary disease and asthma. Differentiation into distinct Th subtypes needs to be tightly regulated to ensure an immunological balance. As microRNAs (miRNAs) are critical regulators of signaling pathways, we aimed to identify specific miRNAs implicated in controlling Th17 differentiation. We were able to create a regulatory network model of murine Th cell differentiation by combining Affymetrix mRNA and miRNA arrays and in-silico analysis...
June 15, 2017: Immunology
https://www.readbyqxmd.com/read/28615692/wnt5a-is-associated-with-right-ventricular-dysfunction-and-adverse-outcome-in-dilated-cardiomyopathy
#20
Aurelija Abraityte, Ida G Lunde, Erik T Askevold, Annika E Michelsen, Geir Christensen, Pål Aukrust, Arne Yndestad, Arnt Fiane, Arne Andreassen, Svend Aakhus, Christen P Dahl, Lars Gullestad, Kaspar Broch, Thor Ueland
The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients...
June 14, 2017: Scientific Reports
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