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https://www.readbyqxmd.com/read/29328397/aberrant-expression-of-il-23-il-23r-in-patients-with-breast-cancer-and-its-clinical-significance
#1
Shuhai Sheng, Jinji Zhang, Jianzhong Ai, Xueli Hao, Ruishen Luan
Breast cancer tissues and adjacent tissues were collected from 32 patients who were treated in The Third Hospital of Chengde City. Reverse transcription‑quantitative polymerase chain reaction results demonstrated that, compared with the adjacent tissues, interleukin (IL)‑23/IL‑23 receptor (R) gene expression levels were notably higher in breast cancer tissues. Furthermore, IL‑23 and IL‑23R expression levels were positively correlated with patients' tumor size, TNM stage and metastasis. Recombinant human (rh) IL‑23 (10 ng/ml) was used for the stimulation of the MCF‑7 cell line...
January 12, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29328389/mir-375-inhibits-ifn-%C3%AE-induced-programmed-death-1-ligand%C3%A2-1-surface-expression-in-head-and-neck-squamous-cell-carcinoma-cells-by-blocking-jak2-stat1-signaling
#2
Qingwei Wu, Yingying Zhao, Yiyuan Sun, Xiaojun Yan, Peihua Wang
Upregulation of programmed death 1 ligand 1 (PD-L1) in cancer cells and its ligation to PD-1 on T cells facilitates cancer cell escape from immune surveillance. Therapies with PD-1 or PD-L1 antibodies have resulted in marked clinical responses in various cancer types. Hence, modulators that inhibit PD-L1 expression in cancer cells may serve as a novel strategy by which to enhance host immune responses. In the present study, we investigated the effects of miR-375 on PD-L1 expression in head and neck squamous cell carcinoma (HNSCC) cells by qRT-PCR and western blot analyses...
January 2, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29322424/expression-and-purification-of-jak1-and-socs1-for-structural-and-biochemical-studies
#3
Nicholas P D Liau, Jeffrey J Babon
Interferon gamma (IFNγ) is a potent inflammatory and immune cytokine. IFNγ signals via the interferon gamma receptor (IFNGR), which is constitutively bound to Janus Kinase (JAK) 1 and JAK2 via its intracellular domain. These two JAK proteins then initiate the inflammatory signaling cascade. The most potent inhibitor of IFNγ signaling is Suppressor of Cytokine Signaling 1 (SOCS1). SOCS1 negatively regulates IFNγ signaling pathway (and other pathways) by directly inhibiting JAKs. Here, we describe a protocol for the recombinant production and purification of the JAK1 kinase domain and its inhibitor SOCS1, for structural and biochemical studies...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29317823/european-perspective-on-the-management-of-rheumatoid-arthritis-clinical-utility-of-tofacitinib
#4
REVIEW
Paweł Kawalec, Katarzyna Śladowska, Iwona Malinowska-Lipień, Tomasz Brzostek, Maria Kózka
Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time...
2018: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/29316631/psoriasis-a-stat3-centric-view
#5
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/29314645/tofacitinib-with-conventional-synthetic-disease-modifying-antirheumatic-drugs-in-chinese-patients-with-rheumatoid-arthritis-patient-reported-outcomes-from-a-phase-3-randomized-controlled-trial
#6
Zhanguo Li, Yuan An, Houheng Su, Xiangpei Li, Jianhua Xu, Yi Zheng, Guiye Li, Kenneth Kwok, Lisy Wang, Qizhe Wu
AIM: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We assess the effect of tofacitinib + conventional synthetic disease-modifying anti rheumatic drugs (csDMARDs) on patient-reported outcomes in Chinese patients with RA and inadequate response to DMARDs. METHODS: This analysis of data from the Phase 3 study ORAL Sync included Chinese patients randomized 4 : 4 : 1 : 1 to receive tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, placebo→tofacitinib 5 mg twice daily, or placebo→tofacitinib 10 mg twice daily, with csDMARDs...
January 4, 2018: International Journal of Rheumatic Diseases
https://www.readbyqxmd.com/read/29311136/pharmacokinetics-and-disposition-of-momelotinib-revealed-a-disproportionate-human-metabolite-%C3%A2-resolution-for-clinical-development
#7
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/29309427/distinct-temporal-roles-for-the-promyelocytic-leukaemia-pml-protein-in-the-sequential-regulation-of-intracellular-host-immunity-to-hsv-1-infection
#8
Thamir Alandijany, Ashley P E Roberts, Kristen L Conn, Colin Loney, Steven McFarlane, Anne Orr, Chris Boutell
Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2'-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions...
January 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29307696/role-of-hypothalamic-leptin-leprb-signaling-in-npy-cart-mediated-appetite-suppression-in-amphetamine-treated-rats
#9
Shu-Chen Chu, Pei-Ni Chen, Jeng-Rung Chen, Ching-Han Yu, Yih-Shou Hsieh, Dong-Yih Kuo
Leptin is an adipose tissue hormone which plays an important role in regulating energy homeostasis. Amphetamine (AMPH) is a drug of appetite suppressant, which exerts its effect by decreasing the expression of hypothalamic neuropeptide Y (NPY) and increasing that of cocaine- and amphetamine-regulated transcript (CART). This study investigated whether leptin, the leptin receptor (LepRb) and the signal transducer and activator of transcription-3 (STAT3) were involved in NPY/CART-mediated appetite suppression in AMPH-treated rats...
January 4, 2018: Hormones and Behavior
https://www.readbyqxmd.com/read/29305625/ifn-%C3%AE-induces-a-preferential-long-lasting-expression-of-mhc-class-i-in-human-pancreatic-beta-cells
#10
Alexandra Coomans de Brachène, Reinaldo S Dos Santos, Laura Marroqui, Maikel L Colli, Lorella Marselli, Raghavendra G Mirmira, Piero Marchetti, Decio L Eizirik
AIMS/HYPOTHESIS: IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition. METHODS: IFN-α-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-βH1 cells or human islets exposed to IFN-α with or without the presence of Janus kinase (JAK) inhibitors...
January 5, 2018: Diabetologia
https://www.readbyqxmd.com/read/29304536/defibrotide-stimulates-angiogenesis-and-protects-endothelial-cells-from-calcineurin-inhibitor-induced-apoptosis-via-upregulation-of-akt-bcl-xl
#11
Xiangmin Wang, Bin Pan, Yuko Hashimoto, Hiroshi Ohkawara, Kailin Xu, Lingyu Zeng, Takayuki Ikezoe
Sinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays...
January 2018: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/29304122/comprehensive-analysis-of-three-tyk2-gene-variants-in-the-susceptibility-to-chagas-disease-infection-and-cardiomyopathy
#12
Daniel A Leon Rodriguez, Marialbert Acosta-Herrera, F David Carmona, Nuria Dolade, Sofia Vargas, Luis Eduardo Echeverría, Clara Isabel González, Javier Martin
Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population...
2018: PloS One
https://www.readbyqxmd.com/read/29302720/anti-inflammatory-effect-and-mechanism-of-the-spirocyclopiperazinium-salt-compound-lxm-15-in-rats-and-mice
#13
Xiaoli Gao, Qi Sun, Weiwei Zhang, Yimin Jiang, Runtao Li, Jia Ye
OBJECTIVE: This study aimed to investigate the anti-inflammatory effects of a novel spirocyclopiperazinium salt compound LXM-15, and explore the underlying mechanisms. METHODS: Xylene-induced mouse ear oedema and carrageenan-induced rat paw oedema tests were used to evaluate the anti-inflammatory effects of LXM-15. The protein levels of TNF-α, IL-6, phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were detected by ELISA or Western blot analysis...
January 4, 2018: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/29301607/force-mediated-proinvasive-matrix-remodeling-driven-by-tumor-associated-mesenchymal-stem-like-cells-in-glioblastoma
#14
Eun-Jung Lim, Yongjoon Suh, Seungmo Kim, Seok-Gu Kang, Su-Jae Lee
In carcinoma, cancer-associated fibroblasts participate in force-mediated extracellular matrix (ECM) remodeling, consequently leading to invasion of cancer cells. Likewise, the ECM remodeling actively occurs in glioblastoma (GBM) and the consequent microenvironmental stiffness is strongly linked to migration behavior of GBM cells. However, in GBM the stromal cells responsible for force-mediated ECM remodeling remain unidentified. We show that tumor-associated mesenchymal stem-like cells (tMSLCs) provide a proinvasive matrix condition in GBM by force-mediated ECM remodeling...
January 5, 2018: BMB Reports
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
#15
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/29296821/progenitor-b-1-b-cell-acute-lymphoblastic-leukemia-is-associated-with-collaborative-mutations-in-3-critical-pathways
#16
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/29289756/the-role-of-janus-kinase-signaling-in-graft-versus-host-disease-and-graft-versus-leukemia
#17
REVIEW
Mark A Schroeder, Jaebok Choi, Karl Staser, John F DiPersio
For patients with hematologic malignancies, allogeneic hematopoietic cell transplantation (alloHCT) offers a potential curative treatment option, primarily due to an allogeneic immune response against recipient tumor cells (ie, graft-versus-leukemia [GVL] activity). However, many recipients of alloHCT develop graft-versus-host disease (GVHD), in which allogeneic immune responses lead to the damage of healthy tissue. GVHD is a leading cause of nonrelapse mortality and a key contributor to morbidity among patients undergoing alloHCT...
December 28, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29286140/identification-of-key-genes-implicated-in-the-suppressive-function-of-human-foxp3-cd25-cd4-regulatory-t-cells-through-the-analysis-of-time%C3%A2-series-data
#18
Xiaofeng Bai, Hua Shi, Mingxi Yang, Yuanlin Wang, Zhaolin Sun, Shuxiong Xu
Human forkhead box P3 (FOXP3)+ cluster of differentiation (CD)25+CD4+ regulatory T cells (Tregs) are a type of T cell that express CD4, CD25 and FOXP3, which are critical for maintaining immune homeostasis. The present study aimed to determine the mechanisms underlying Treg function. The GSE11292 dataset was downloaded from the Gene Expression Omnibus, which included data from Treg cells at 19 time points (0‑360 min) with an equal interval of 20 min, and corresponding repeated samples. However, data for Treg cells at time point 120 min were missing...
December 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29285104/carboxymethyl-chitosan-attenuates-inducible-nitric-oxide-synthase-and-promotes-interleukin-10-production-in-rat-chondrocytes
#19
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/29283448/pharmacokinetics-and-safety-of-momelotinib-in-subjects-with-hepatic-or-renal-impairment
#20
Yan Xin, Jun Kawashima, Winnie Weng, Ellen Kwan, Thomas Tarnowski, Jeffrey A Silverman
Momelotinib is a Janus kinase 1/2 inhibitor in clinical development for the treatment of myelofibrosis. Two phase 1 open-label, parallel-group, adaptive studies were conducted to evaluate the pharmacokinetics of a single 200-mg oral dose of momelotinib in subjects with hepatic or renal impairment compared with healthy matched control subjects with normal hepatic or renal function. Plasma pharmacokinetics of momelotinib and its major active metabolite, M21, were evaluated, and geometric least-squares mean ratios (GMRs) and associated 90% confidence intervals (CIs) for impaired versus each control group were calculated for plasma exposures (area under concentration-time curve from time 0 to ∞ [AUC∞ ] and maximum concentration) of momelotinib and M21...
December 28, 2017: Journal of Clinical Pharmacology
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