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https://www.readbyqxmd.com/read/29321238/an-open-label-trial-of-jak-1-2-blockade-in-progressive-ifih1-associated-neuroinflammation
#1
Kavitha Kothur, Sushil Bandodkar, Stephanie Chu, Louise Wienholt, Alexandra Johnson, Peter Barclay, Paul A Brogan, Gillian I Rice, Yanick J Crow, Russell C Dale
No abstract text is available yet for this article.
January 10, 2018: Neurology
https://www.readbyqxmd.com/read/29320511/application-of-a-phenotypic-drug-discovery-strategy-to-identify-biological-and-chemical-starting-points-for-inhibition-of-tslp-production-in-lung-epithelial-cells
#2
Adelina Orellana, Vicente García-González, Rosa López, Sonia Pascual-Guiral, Estrella Lozoya, Julia Díaz, Daniel Casals, Antolín Barrena, Stephane Paris, Miriam Andrés, Victor Segarra, Dolors Vilella, Rajneesh Malhotra, Paul Eastwood, Anna Planagumà, Montserrat Miralpeix, Arsenio Nueda
Thymic stromal lymphopoietin (TSLP) is a cytokine released by human lung epithelium in response to external insult. Considered as a master switch in T helper 2 lymphocyte (Th2) mediated responses, TSLP is believed to play a key role in allergic diseases including asthma. The aim of this study was to use a phenotypic approach to identify new biological and chemical starting points for inhibition of TSLP production in human bronchial epithelial cells (NHBE), with the objective of reducing Th2-mediated airway inflammation...
2018: PloS One
https://www.readbyqxmd.com/read/29316631/psoriasis-a-stat3-centric-view
#3
REVIEW
Enzo Calautti, Lidia Avalle, Valeria Poli
Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options...
January 6, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29314205/cdc42-is-essential-for-both-articular-cartilage-degeneration-and-subchondral-bone-deterioration-in-experimental-osteoarthritis
#4
Xinhua Hu, Xing Ji, Mengting Yang, Shihao Fan, Jirong Wang, Meiping Lu, Wei Shi, Liu Mei, Chengyun Xu, Xueying Fan, Musaddique Hussain, Jingyu Du, Junsong Wu, Ximei Wu
Cdc42, a member of Rho family small GTPases, is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilisation of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages...
January 3, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29312576/matrine-inhibits-bcr-abl-mediated-erk-mapk-pathway-in-human-leukemia-cells
#5
Lingdi Ma, Zhenyu Xu, Jian Wang, Zhichao Zhu, Guibin Lin, Lijia Jiang, Xuzhang Lu, Chang Zou
The BCR/ABL fusion gene and its downstream signaling pathways such as Ras/Raf/MAPK, JAK/STAT3, and PI3K/AKT pathways play important roles in malignant transformation of leukemia, especially chronic myelogenous leukemia (CML). Our previous study showed that matrine, an alkaloid extracted from a Chinese herb radix sophorae, significantly inhibited the proliferation of human CML K562cells, induced cell cycle arrest in G0/G1, and promoted cell apoptosis. In the present study, we investigated the molecular mechanism of matrine in the growth inhibition of leukemia cells using K562 and HL-60 cell lines...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311136/pharmacokinetics-and-disposition-of-momelotinib-revealed-a-disproportionate-human-metabolite-%C3%A2-resolution-for-clinical-development
#6
Jim Zheng, Yan Xin, Jingyu Zhang, Raju Subramanian, Bernard P Murray, J Andrew Whitney, Matthew R Warr, John Ling, Lisa Moorehead, Ellen Kwan, Jeffrey Hemenway, Bill J Smith, Jeffrey A Silverman
Momelotinib (MMB) is a small molecule inhibitor of Janus kinase (JAK)1/2 and of activin A receptor type 1 (ACVR1), in clinical development for the treatment of myeloproliferative neoplasms. The pharmacokinetics and disposition of [14C]MMB were characterized in a single-dose, human mass balance study. Metabolism and the pharmacologic activity of key metabolites were elucidated in multiple in vitro and in vivo experiments. MMB was rapidly absorbed following oral dosing with approximately 97% of the radioactivity recovered, primarily in feces with urine as a secondary route...
January 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29305165/differential-expression-of-mirna-in-carassius-auratus-gibelio-in-response-to-cyprinid-herpesvirus-2-infection
#7
Jianfei Lu, Dan Xu, Zhaoyuan Shen, Liqun Lu
miRNAs (microRNAs), a small endogenous non-coding RNAs, play crucial roles in post-transcriptional regulator of genes expression in various biological processes. Cyprinid Herpesvirus-2 (CyHV-2) is a highly pathogenic member of the alloherpesviridae that causes acute mass mortalities in populations of Carassius auratus gibelio and Carassius auratus auratus. However, the molecular mechanisms underlying the pathogenicity of CyHV-2 have not been fully determined. Here, miRNA expression profiles were identified via high-throughput sequencing in the kidney of Carassius auratus gibelio infected or uninfected with CyHV-2...
January 2, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29299358/pacritinib-to-inhibit-jak-stat-signaling-in-refractory-metastatic-colon-and-rectal-cancer
#8
Thomas Regenbogen, Ling Chen, Kathryn Trinkaus, Andrea Wang-Gillam, Benjamin R Tan, Manik Amin, Katrina S Pedersen, Haeseong Park, Rama Suresh, Kian-Huat Lim, Emily Ratchford, Amberly Brown, A Craig Lockhart
Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma. Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment...
December 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/29298069/identification-of-n-cis-3-methyl-7h-pyrrolo-2-3-d-pyrimidin-4-yl-amino-cyclobutyl-propane-1-sulfonamide-pf-04965842-a-selective-jak1-clinical-candidate-for-the-treatment-of-autoimmune-diseases
#9
Michael L Vazquez, Neelu Kaila, Joseph W Strohbach, John D Trzupek, Matthew F Brown, Mark E Flanagan, Mark J MItton-Fry, Timothy A Johnson, Ruth E TenBrink, Eric P Arnold, Arindrajit Basak, Steven E Heasley, Soojin Kwon, Jonathan Langille, Mihir D Parikh, Sarah H Griffin, Jeffrey M Casavant, Brian A Duclos, Ashley E Fenwick, Thomas M Harris, Seungil Han, Nicole L Caspers, Martin E Dowty, Xin Yang, Mary Ellen Banker, Martin Hegen, Peter T Symanowicz, Li Li, Lu Wang, Tsung H Lin, Jason Jussif, James D Clark, Jean-Baptiste Telliez, Ralph P Robinson, Ray Unwalla
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation and hematopoiesis. As JAK1 pairs with JAK2, JAK3 and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function, while avoiding inhibition of the JAK2 homodimer regulating EPO and TPO signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis (RA)...
January 3, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29297981/primary-biliary-cholangitis-in-british-columbia-first-nations-clinical-features-and-discovery-of-novel-genetic-susceptibility-loci
#10
Sirisha Asuri, Sarah McIntosh, Valerie Taylor, Andrew Rokeby, James Kelly, Karey Shumansky, L Leigh Field, Eric M Yoshida, Laura Arbour
BACKGROUND AND AIMS: Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by destruction of intrahepatic bile ducts, portal inflammation, and cirrhosis. Although rare in most populations, it is prevalent and often familial in British Columbia First Nations. We hypothesized that major genetic factors increased the risk in First Nations. METHODS: 44 individuals with PBC and 61 unaffected relatives from 32 First Nations families participated...
January 3, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29296821/progenitor-b-1-b-cell-acute-lymphoblastic-leukemia-is-associated-with-collaborative-mutations-in-3-critical-pathways
#11
Sheryl M Gough, Liat Goldberg, Marbin Pineda, Robert L Walker, Yuelin J Zhu, Sven Bilke, Yang Jo Chung, Joseph Dufraine, Subhadip Kundu, Elad Jacoby, Terry J Fry, Susanna Fischer, Renate Panzer-Grümayer, Paul S Meltzer, Peter D Aplan
B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice. The immunophenotype (Lin- B220- CD19+ AA4.1+) was identical to that of progenitor (pro) B-1 cells, and VH gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290793/epigenomic-characterization-of-a-p53-regulated-3p22-2-tumor-suppressor-that-inhibits-stat3-phosphorylation-via-protein-docking-and-is-frequently-methylated-in-esophageal-and-other-carcinomas
#12
Lili Li, Juan Xu, Guohua Qiu, Jianming Ying, Zhenfang Du, Tingxiu Xiang, Kai Yau Wong, Gopesh Srivastava, Xiao-Feng Zhu, Tony S Mok, Anthony Tc Chan, Francis Kl Chan, Richard F Ambinder, Qian Tao
Rationale: Oncogenic STAT3 signaling activation and 3p22-21.3 locus alteration are common in multiple tumors, especially carcinomas of the nasopharynx, esophagus and lung. Whether these two events are linked remains unclear. Our CpG methylome analysis identified a 3p22.2 gene, DLEC1, as a methylated target in esophageal squamous cell (ESCC), nasopharyngeal (NPC) and lung carcinomas. Thus, we further characterized its epigenetic abnormalities and functions. Methods: CpG methylomes were established by methylated DNA immunoprecipitation...
2018: Theranostics
https://www.readbyqxmd.com/read/29287200/gramine-attenuates-egfr-mediated-inflammation-and-cell-proliferation-in-oral-carcinogenesis-via-regulation-of-nf-%C3%AE%C2%BAb-and-stat3-signaling
#13
Arunkumar Ramu, Suresh Kathiresan, Hemavardhini Ramadoss, Anandhi Nallu, Ramachandran Kaliyan, Theerthu Azamuthu
Gramine, a natural indole alkaloid found in Hordeum vulgare has been possesses anti-mutagenic properties. The aim of the present study was to evaluate the effect of gramine on inflammation and proliferation in 7,12-dimethylbenz[a]anthracene(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation trigged PI3K/Akt/mTOR and JAK signaling that activates NF-κB and STAT3. In contrast, gramine suppressed EGFR tyrosine kinase phosphorylation and simultaneously inhibiting PI3K/Akt/mTOR and JAK phosphorylation, thereby blockage NF-κB and STAT3 nuclear translocation...
December 26, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29285303/insulin-receptor-substrate-4-interacts-with-ubiquitin-specific-protease-18-to-activate-the-jak-stat-signaling-pathway
#14
Baihai Jiao, Xuezhen Shi, Yanzhao Chen, Haiyan Ye, Min Yao, Wenxu Hong, Shilin Li, Xiaoqiong Duan, Yujia Li, Yancui Wang, Limin Chen
Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co-precipitation assays revealed that two regions (amino acids 335-400 and 1094-1257) of IRS4 were related to bind to the C- terminal region of USP18...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29285104/carboxymethyl-chitosan-attenuates-inducible-nitric-oxide-synthase-and-promotes-interleukin-10-production-in-rat-chondrocytes
#15
Ying Kong, Yuanmin Zhang, Xiaowei Zhao, Guodong Wang, Qingkuan Liu
Osteoarthritis (OA) is a common age-related degenerative joint disease, which is caused by the breakdown of joint cartilage and the underlying bone. Carboxymethyl (CM)-chitosan is a soluble derivative of chitosan that has similar physicochemical properties to the extracellular proteoglycans identified in hyaline cartilage. Previous studies have demonstrated that CM-chitosan serves a protective role in a rabbit OA model. The aim of the present study was to investigate the effect of CM-chitosan on NO production and inflammation through its upregulation of interleukin (IL)-10, and the activation of the janus kinase (JAK)/signal transducer and activator of transcription (STAT)/suppressor of cytokine signaling (SOCS) signaling pathway...
December 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29284516/lack-of-socs3-increases-lps-induced-murine-acute-lung-injury-through-modulation-of-ly6c-macrophages
#16
Zhilong Jiang, Zhihong Chen, Liyang Li, Wenjun Zhou, Lei Zhu
BACKGROUND: SOCS3 (suppressor of cytokine signaling 3) is a negative regulator of JAK/STAT3 signaling pathway and participates in the regulation of lung inflammation in a mouse model with acute lung injury (ALI). However, it is not well understood how SOCS3 regulates lung inflammation in the ALI mouse model. METHOD: In the present study, we investigated the effects of SOCS3 on modulation of Ly6C(+) monocyte phenotypes in a mouse model with lipopolysaccharide (LPS)-induced ALI...
December 29, 2017: Respiratory Research
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#17
REVIEW
Prithviraj Bose, Jason Gotlib, Claire N Harrison, Srdan Verstovsek
The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29275119/momelotinib-versus-best-available-therapy-in-patients-with-myelofibrosis-previously-treated-with-ruxolitinib-simplify-2-a-randomised-open-label-phase-3-trial
#18
Claire N Harrison, Alessandro M Vannucchi, Uwe Platzbecker, Francisco Cervantes, Vikas Gupta, David Lavie, Francesco Passamonti, Elliott F Winton, Hua Dong, Jun Kawashima, Julia D Maltzman, Jean-Jacques Kiladjian, Srdan Verstovsek
BACKGROUND: The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib. METHODS: In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA...
December 20, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/29259370/pancreatic-acinar-cell-carcinoma-a-review-on-molecular-profiling-of-patient-tumors
#19
REVIEW
Ahmad Al-Hader, Rami N Al-Rohil, Haiyong Han, Daniel Von Hoff
Pancreatic carcinomas with acinar differentiation are rare, accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma (PACC), pancreatoblastoma, and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry...
December 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29247327/il-21-enhances-the-degradation-of-cartilage-through-the-jak-stat-signaling-pathway-during-osteonecrosis-of-femoral-head-cartilage
#20
Bin Chen, Yi Liu, Lei Cheng
This study aims to investigate the role of interleukin-21 (IL-21) in the mechanism of osteonecrosis of the femoral head. The serum content of IL-21 in patients with osteonecrosis of the femoral head (ONFH) and with femoral neck fracture (FNF) was examined by an enzyme-linked immunosorbent assay (ELISA). The cartilage specimens were stained with safranin-O. The expression of IL-21, tumor necrosis factor-α (TNF-α), cyclooxygenase (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), matrix metalloproteinase-13(MMP-13), and aggrecan in the cartilage was detected, by immunohistochemistry and western blot analysis...
December 15, 2017: Inflammation
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