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https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#1
Elena Calama, Isabel Ramis, Anna Domènech, Cristina Carreño, Jorge De Alba, Neus Prats, Montserrat Miralpeix
BACKGROUND: and purpose: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor...
January 10, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28053127/potent-emt-and-csc-phenotypes-are-induced-by-oncostatin-m-in-pancreatic-cancer
#2
Jacob M Smigiel, Neetha Parameswaran, Mark W Jackson
: Pancreatic ductal adenocarcinoma (PDAC) is referred to as a silent killer due to the lack of clear symptoms, a lack of early detection methods, and a high frequency of metastasis at diagnosis. In addition, pancreatic cancer is remarkably resistant to chemotherapy, and clinical treatment options remain limited. The tumor microenvironment (TME) and associated factors are important determinants of metastatic capacity and drug resistance. Here, oncostatin M (OSM), an IL-6 cytokine family member, was identified as an important driver of mesenchymal and cancer stem cell (CSC) phenotypes...
January 4, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28043820/kinase-signaling-and-targeted-therapy-for-primary-myelofibrosis
#3
REVIEW
Qiong Yang, John D Crispino, Qiang Jeremy Wen
The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematological malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis (PMF) subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes (MK) in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease...
December 30, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/28039266/malignant-astrocytic-tumor-progression-potentiated-by-jak-mediated-recruitment-of-myeloid-cells
#4
Prajwal Rajappa, William S Cobb, Emma Vartanian, Yujie Huang, Laura Daly, Caitlin Hoffman, Jane Zhang, Beiyi Shen, Rachel Yanowitch, Kunal Garg, Babacar Cisse, Sara Haddock, Jason T Huse, David J Pisapia, Timothy A Chan, David Lyden, Jacqueline Bromberg, Jeffrey P Greenfield
PURPOSE: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of non-resident bone marrow-derived cells (BMDCs) remains to be determined in neurological tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas. EXPERIMENTAL DESIGN: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression...
December 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28031410/nuclear-import-of-jak1-is-mediated-by-a-classical-nls-and-is-required-for-survival-of-diffuse-large-b-cell-lymphoma
#5
Fen Zhu, Byounghoon Hwang, Shigeki Miyamoto, Lixin Rui
: Janus kinases (JAKs) are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating signal transducers and activators of transcription (STATs) in response to cytokine stimulation to modulate gene transcription. In contrast, a non-canonical role of JAK2 has recently been discovered in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3...
December 28, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28028027/emerging-treatments-for-classical-myeloproliferative-neoplasms
#6
Alessandro M Vannucchi, Claire Harrison
There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, following the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug has been later approved also as second line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate to cope with the major unmet patients' needs, that include normalization of life span (MF and some PV patients), reduction of cardiovascular complications (mainly PV and essential thrombocythemia (ET)), prevention of hematological progression and improved quality of life (all MPN)...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28008925/biallelic-jak1-mutations-in-immunodeficient-patient-with-mycobacterial-infection
#7
Davide Eletto, Siobhan O Burns, Ivan Angulo, Vincent Plagnol, Kimberly C Gilmour, Frances Henriquez, James Curtis, Miguel Gaspar, Karolin Nowak, Vanessa Daza-Cajigal, Dinakantha Kumararatne, Rainer Doffinger, Adrian J Thrasher, Sergey Nejentsev
Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production...
December 23, 2016: Nature Communications
https://www.readbyqxmd.com/read/28003146/injectable-hyaluronic-acid-down-regulates-interferon-signaling-molecules-igfbp3-and-ifit3-in-the-bovine-intervertebral-disc
#8
Zepur Kazezian, Zhen Li, Mauro Alini, Sibylle Grad, Abhay Pandit
: Low back pain which is a major cause of disability for people aged between 20 and 50 years imposes a serious socio-economic burden. The current focus of regenerative medicine is on identifying molecular markers to facilitate the design of targeted therapeutics. Previously, we have demonstrated that expression of the anti-proliferative interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and pro-apoptotic insulin-like growth factor-binding protein-3 (IGFBP3), are up-regulated as downstream targets of the inflammatory cytokine interferon α (IFNα) signaling pathway in the human annulus fibrosus (AF)...
December 18, 2016: Acta Biomaterialia
https://www.readbyqxmd.com/read/27998770/microrna-340-inhibits-the-proliferation-and-invasion-of-hepatocellular-carcinoma-cells-by-targeting-jak1
#9
Jianyong Yuan, Hongxiang Ji, Feng Xiao, Zhipeng Lin, Xijun Zhao, Zhouchong Wang, Jun Zhao, Junhua Lu
Increasing evidence indicates that dysregulation of microRNAs (miRNAs) contributes to tumorigenesis. MicroRNA-340 (miR-340) is downregulated in several types of cancer. However, the functional mechanism of miR-340 in hepatocellular carcinoma (HCC) remains unclear. Here, we showed that miR-340 was significantly downregulated in HCC tissues and cell lines. Gain-of-function experiments demonstrated that miR-340 overexpression inhibited HCC cell proliferation, migration, and invasion in vitro, and suppressed tumor growth in vivo...
December 18, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27997540/il-7-receptor-mutations-and-steroid-resistance-in-pediatric-t-cell-acute-lymphoblastic-leukemia-a-genome-sequencing-study
#10
Yunlei Li, Jessica G C A M Buijs-Gladdines, Kirsten Canté-Barrett, Andrew P Stubbs, Eric M Vroegindeweij, Willem K Smits, Ronald van Marion, Winand N M Dinjens, Martin Horstmann, Roland P Kuiper, Rogier C Buijsman, Guido J R Zaman, Peter J van der Spek, Rob Pieters, Jules P P Meijerink
BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/27995146/comparison-of-experimental-diabetic-periodontitis-induced-by-porphyromonas-gingivalis-in-mice
#11
Qi Wang, Peng Zhang, Ray Aprecio, Dongjiao Zhang, Hao Li, Ning Ji, Omaima Mohamed, Wu Zhang, Yiming Li, Yi Ding
Periodontitis is one of the severe complications in diabetic patients and gingival epithelium plays an initial role on the onset and progression of this disease. However the potential mechanism is yet sufficiently understood. Meanwhile, the research on the correlational experimental animal models was also insufficient. Here, we established periodontitis with type 2 diabetes in db/db and Tallyho/JngJ (TH) mice and periodontitis with type 1 diabetes in streptozotocin induced diabetes C57BL/6J (STZ-C57) mice by oral infection of periodontal pathogen Porphyromonas gingivalis W50...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27993829/filgotinib-glpg0634-gs-6034-an-oral-jak1-selective-inhibitor-is-effective-in-combination-with-methotrexate-mtx-in-patients-with-active-rheumatoid-arthritis-and-insufficient-response-to-mtx-results-from-a-randomised-dose-finding-study-darwin-1
#12
R Westhovens, P C Taylor, R Alten, D Pavlova, F Enríquez-Sosa, M Mazur, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset, P Harrison
OBJECTIVES: To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. METHODS: In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily...
December 19, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27993828/filgotinib-glpg0634-gs-6034-an-oral-selective-jak1-inhibitor-is-effective-as-monotherapy-in-patients-with-active-rheumatoid-arthritis-results-from-a-randomised-dose-finding-study-darwin-2
#13
A Kavanaugh, J Kremer, L Ponce, R Cseuz, O V Reshetko, M Stanislavchuk, M Greenwald, A Van der Aa, F Vanhoutte, C Tasset, P Harrison
OBJECTIVES: To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). METHODS: In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12...
December 19, 2016: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/27988142/clinical-remission-in-patients-with-moderate-to-severe-crohn-s-disease-treated-with-filgotinib-the-fitzroy-study-results-from-a-phase-2-double-blind-randomised-placebo-controlled-trial
#14
Séverine Vermeire, Stefan Schreiber, Robert Petryka, Tanja Kuehbacher, Xavier Hebuterne, Xavier Roblin, Maria Klopocka, Adrian Goldis, Maria Wisniewska-Jarosinska, Andrey Baranovsky, Robert Sike, Kremena Stoyanova, Chantal Tasset, Annegret Van der Aa, Pille Harrison
BACKGROUND: Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive...
December 14, 2016: Lancet
https://www.readbyqxmd.com/read/27983914/protease-serine-s1-family-member-8-prss8-inhibits-tumor-growth-in-vitro-and-in-vivo-in-human-non-small-cell-lung-cancer
#15
Chaonan Ma, Wei Ma, Nannan Zhou, Na Chen, Li An, Yijie Zhang
Protease serine S1 family member 8 (PRSS8), a membrane-anchored serine protease, has been reported to be involved in the development of several human cancers. However, the role of PRSS8 in non-small cell lung cancer (NSCLC) pathogenesis remains unclear. The objective of this study was to investigate PRSS8 expression, biological functions and related molecular mechanism in NSCLC. Our results showed that PRSS8 was lowly expressed in NSCLC cell lines. Ectopic expression of PRSS8 inhibited tumor growth in vitro and in vivo...
October 27, 2016: Oncology Research
https://www.readbyqxmd.com/read/27983880/how-ruxolitinib-modified-the-outcome-in-myelofibrosis-focus-on-overall-survival-allele-burden-reduction-and-fibrosis-changes
#16
Fulvio Massaro, Matteo Molica, Massimo Breccia
Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has shown superiority as compared to available conventional chemotherapies, in terms of reduction in splenomegaly and improvement of symptoms and quality of life. Areas covered: Data published about overall survival in the major randomized sponsored trials and in independent series of patients were detailed. Indeed, data regarding action of ruxolitinib on allele burden reduction and potential activity of the drug on pathogenetic mechanisms involved in increased fibrosis has been reviewed...
December 16, 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27974423/vegf165b-modulates-endothelial-vegfr1-stat3-signaling-pathway-and-angiogenesis-in-human-and-experimental-peripheral-arterial-disease
#17
Vijay C Ganta, Min Choi, Anna Kutateladze, Brian H Annex
RATIONALE: Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of pro-angiogenic VEGFxxxa isoforms (VEGF165a, 165 for the 165 amino acid product) and anti-angiogenic VEGFxxxb (VEGF165b) isoforms...
December 14, 2016: Circulation Research
https://www.readbyqxmd.com/read/27965977/lack-of-association-between-genetic-polymorphisms-of-jak-stat-signaling-pathway-genes-and-acute-anterior-uveitis-in-han-chinese
#18
Ling Cheng, Hongsong Yu, Yan Jiang, Juan He, Sisi Pu, Xin Li, Li Zhang
Purpose. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) of JAK-STAT signaling pathway genes and acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS) in the Han Chinese population. Methods. Eleven SNPs of the JAK1, JAK2, STAT1, IRF1, and NOS2 genes were analyzed in 443 AAU patients with AS, 486 AAU patients without AS, and 714 healthy controls. Genotyping was performed by PCR-RFLP assay or TaqMan® probe assay. The Chi-squared (χ(2)) test and multivariate logistic regression analysis were used to compare the distributions of alleles and genotypes between patients and controls...
2016: BioMed Research International
https://www.readbyqxmd.com/read/27941591/m2a-and-m2c-macrophage-subsets-ameliorate-inflammation-and-fibroproliferation-in-acute-lung-injury-through-interleukin-10-pathway
#19
Lunxian Tang, Hua Zhang, Chunmei Wang, Hongqiang Li, Qian Zhang, Jianwen Bai
The role of M2 macrophages in the resolution and fibroproliferation of acute lung injury (ALI) is poorly understood. In this study, we investigated the effects of two M2 macrophage subtypes, M2a induced by interleukin (IL)-4/IL-13 and M2c induced by IL-10/transforming growth factor (TGF)-β, on the pathogenesis of ALI. M2a and M2c were adoptively transferred into LPS-induced ALI mice model. Data showed that Vybrant-labeled macrophages appeared in the lungs of ALI mice. Subsequently, we observed that both subsets significantly reduced lung inflammation and injury including a reduction of neutrophil influx into the lung and an augmentation of apoptosis...
December 9, 2016: Shock
https://www.readbyqxmd.com/read/27939373/molecular-classification-of-hepatocellular-adenoma-associates-with-risk-factors-bleeding-and-malignant-transformation
#20
Jean Charles Nault, Gabrielle Couchy, Charles Balabaud, Guillaume Morcrette, Stefano Caruso, Jean-Frederic Blanc, Yannick Bacq, Julien Calderaro, Valérie Paradis, Jeanne Ramos, Jean-Yves Scoazec, Viviane Gnemmi, Nathalie Sturm, Catherine Guettier, Monique Fabre, Eric Savier, Laurence Chiche, Philippe Labrune, Janick Selves, Dominique Wendum, Camilla Pilati, Alexis Laurent, Anne De Muret, Brigitte Le Bail, Sandra Rebouissou, Sandrine Imbeaud, Paulette Bioulac-Sage, Eric Letouzé, Jessica Zucman-Rossi
BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in HNF1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. METHODS: We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014...
December 7, 2016: Gastroenterology
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