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https://www.readbyqxmd.com/read/28193636/evaluation-of-jak3-biology-in-autoimmune-disease-using-a-highly-selective-irreversible-jak3-inhibitor
#1
Fiona Elwood, David Witter, Jennifer Piesvaux, Brian Kraybill, Nathan Bays, Carla Alpert, Peter Goldenblatt, Yujie Qu, Irena Ivanovska, Hyun-Hee Lee, Chi-Sung Chiu, Hao Tang, Mark E Scott, Sujal Deshmukh, Mark Zielstorff, Alan Byford, Kalyan Chakravarty, Lauren Dorosh, Alexy Rivkin, Joel Klappenbach, Bo-Sheng Pan, Ilona Kariv, Christopher Dinsmore, Deborah Slipetz, Peter Dandliker
Reversible Janus kinase (JAK) inhibitors such as Tofacitinib(Changelian, et al., 2003;Flanagan, et al., 2010) and Decernotinib(Farmer, et al., 2015;Mahajan, et al., 2015) block cytokine signaling and are efficacious in treating autoimmune diseases (Kremer, et al., 2009;Fleischmann, et al., 2015;Fleischmann, et al., 2015;Krueger, et al., 2016;Sandborn, et al., 2012). However therapeutic doses are limited due to inhibition of other JAK/STAT pathways associated with hematopoiesis, lipid biogenesis, infection and immune responses(Kahn C, 2012)...
February 13, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28172803/dop076-a-phase-2b-multicenter-randomized-placebo-controlled-dose-ranging-trial-of-peficitinab-an-oral-jak-inhibitor-in-patients-with-moderately-to-severely-active-ulcerative-colitis
#2
B Sands, W Sandborn, B G Feagan, G Lichtenstein, H Zhang, P Szapary, J Panes, S Vermeire, C O'Brien, J Dewey, Z Yang, J Johanns, R Strauss, C Marano
No abstract text is available yet for this article.
February 1, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28169015/janus-kinase-inhibitors-in-dermatology-a-systematic-review
#3
REVIEW
Rony Shreberk-Hassidim, Yuval Ramot, Abraham Zlotogorski
BACKGROUND: Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions. OBJECTIVE: Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases. METHODS: This is a systematic review of PubMed and ClinicalTrials.gov. RESULTS: One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events...
February 3, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28164724/jak-inhibition-in-inflammatory-bowel-disease
#4
Pablo Olivera, Silvio Danese, Laurent Peyrin-Biroulet
Current available treatments for inflammatory bowel disease (IBD) have some limitations and new options are needed. Several new molecules are being tested for the treatment of IBD and other immune-mediated inflammatory diseases. Among them, Janus kinase (JAK) inhibitors seem to have the lead, since tofacitinib has received regulatory approval in 2012 for the treatment of rheumatoid arthritis, and also it has shown a favorable risk-benefit ratio in phase 3 studies for ulcerative colitis, both in anti-TNF naïve and anti-TNF experienced patients...
February 4, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28147353/anti-cytokine-strategies-beyond-anti-tumour-necrosis-factor-%C3%AE-therapy-pathophysiology-and-clinical-implications
#5
REVIEW
Gerhard Rogler, Luc Biedermann, Michael Scharl
Cytokines are small proteins produced by a broad range of cells important in cell signaling. They include interleukins, but also chemokines, interferons, and tumor necrosis factors (TNF). They play an important role for communication between cells of the innate and adaptive immune system. The cytokine network is complex and, therefore, therapeutic interventions are difficult. The first anti-cytokine strategy successfully introduced into IBD therapy was the neutralization of TNF by antibodies. Beyond targeting this cytokine anti-IL-23 strategies were demonstrated to be of therapeutic benefit in IBD...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28144028/current-and-emerging-therapeutic-targets-for-ibd
#6
REVIEW
Markus F Neurath
Various therapeutic advances have led to a paradigm shift in the clinical management of patients with IBD. The introduction of immunosuppressive (such as azathioprine) and biologic agents (such as TNF blockers) has markedly reduced the need to use corticosteroids for therapy. Furthermore, the α4β7 integrin blocker vedolizumab has been introduced for clinical IBD therapy. Moreover, various new inhibitors of cytokines (for example, IL-6-IL-6R and IL-12-IL-23 blockers or apremilast), modulators of cytokine signalling events (for example, JAK inhibitors or SMAD7 blocker), inhibitors of transcription factors (for example, GATA3 or RORγt) and new anti-adhesion and anti-T-cell-activation and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors and MAdCAM1 inhibitors, regulatory T-cell therapy and stem cells) are currently being evaluated in controlled clinical trials...
February 1, 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28139263/jak-inhibitors-in-dermatology-the-promise-of-a-new-drug-class
#7
REVIEW
William Damsky, Brett A King
New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo...
January 28, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28131799/janus-kinase-inhibitors-display-broad-anti-itch-properties-a-possible-link-via-the-trpv1-receptor
#8
Tomoki Fukuyama, Joy Rachel Ganchingco, Santosh K Mishra, Thierry Olivry, Ignacy Rzagalinski, Dietrich A Volmer, Wolfgang Bäumer
The antipruritic effect of JAK inhibitors is fast and sustained in dogs with atopic dermatitis and in human patients with psoriasis. The inhibitory profiles of these molecules might be more related to their direct inhibition of TRPV1 rather than that of JAKs.
January 25, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28131742/jak-stat-disruption-induces-immune-deficiency-rationale-for-the-development-of-jak-inhibitors-as-immunosuppressive-drugs
#9
Isabelle Cornez, Sowmya Parampalli Yajnanarayana, Anna Maria Wolf, Dominik Wolf
Cytokines are mediating immune cells responses through the activation of the JAK/STAT signaling pathway. Being critical for immune cells, a defective JAK/STAT signaling leads to various immune disorders, such as immunodeficiency. In contrast, hyperactivation of JAK/STAT signaling is linked to autoimmunity and cancer. Targeting the JAK/STAT proteins by small protein inhibitors impedes immune cell function by uncoupling cells from cytokine effects and by interfering with functional immune cell hallmarks, such as cell migration...
January 25, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28123480/correlative-study-on-the-jak-stat-psm%C3%AE-3-signal-transduction-pathway-in-asthenozoospermia
#10
Junguo Li, Li Zhang, Bing Li
The aim of the present study was to investigate the possible mechanism of Janus kinase (JAK)-signal transduction and activator of transcription (STAT)/PSMβ3 signaling in the occurrence of asthenozoospermia. We examined seminal fluid samples from 30 cases of asthenozoospermia and 30 healthy controls. Sperm was collected using the Percoll density gradient centrifugation method. The expression of JAK, STAT and PSMβ3 mRNA was assessed by reverse-transcription quantitative PCR and the protein levels of p-JAK, p-STAT and PSMβ3 were measured by western blot analysis...
January 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28118538/peficitinib-a-jak-inhibitor-in-combination-with-limited-conventional-synthetic-dmards-in-the-treatment-of-moderate-to-severe-rheumatoid-arthritis
#11
Mark C Genovese, Maria Greenwald, Christine Codding, Anna Zubrzycka-Sienkiewicz, Alan J Kivitz, Annie Wang, Kathyjo Shay, Xuegong Wang, Jay P Garg, Mario H Cardiel
OBJECTIVE: To evaluate the efficacy and safety of orally administered once-daily peficitinib in patients with moderate-to-severe rheumatoid arthritis (RA) in combination with limited conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). METHODS: In this double-blind, randomized, phase IIb trial, patients with RA (N=289) were treated with peficitinib 25 mg, 50 mg, 100 mg, 150 mg, or matching placebo once daily for 12 weeks. Primary endpoint was the percentage of patients achieving an American College of Rheumatology (ACR) 20% response at Week 12...
January 24, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28117214/a-novel-jak-inhibitor-peficitinib-demonstrates-potent-efficacy-in-a-rat-adjuvant-induced-arthritis-model
#12
Misato Ito, Shunji Yamazaki, Kaoru Yamagami, Masako Kuno, Yoshiaki Morita, Kenji Okuma, Koji Nakamura, Noboru Chida, Masamichi Inami, Takayuki Inoue, Shohei Shirakami, Yasuyuki Higashi
The Janus kinase (JAK) family of tyrosine kinases is associated with various cytokine receptors. JAK1 and JAK3 play particularly important roles in the immune response, and their inhibition is expected to provide targeted immune modulation. Several oral JAK inhibitors have recently been developed for treating autoimmune diseases, including rheumatoid arthritis (RA). Here, we investigated the pharmacological effects of peficitinib (formerly known as ASP015K), a novel, chemically synthesized JAK inhibitor. We found that peficitinib inhibited JAK1 and JAK3 with 50% inhibitory concentrations of 3...
December 23, 2016: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#13
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/28072602/-jak-ing-up-the-treatment-of-primary-myelofibrosis-building-better-combination-strategies
#14
Rita Assi, Srdan Verstovsek, Naval Daver
PURPOSE OF REVIEW: The article discusses the promising agents that are approved or currently under investigation for the treatment of myelofibrosis and reviews the ongoing Janus kinase (JAK) inhibitors-based combinatorial strategies in this setting. RECENT FINDINGS: Myelofibrosis is a Philadelphia-negative myeloproliferative neoplasm with constitutive JAK/STAT activation. The JAK-inhibitor ruxolitinib is the only approved drug for this disease in the United States and Europe based on two randomized phase III studies that demonstrated clinically meaningful reduction in spleen size, improvement in symptoms, quality of life, and an overall survival advantage with prolonged follow-up...
March 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28068330/loss-of-p53-induces-leukemic-transformation-in-a-murine-model-of-jak2-v617f-driven-polycythemia-vera
#15
T Tsuruta-Kishino, J Koya, K Kataoka, K Narukawa, Y Sumitomo, H Kobayashi, T Sato, M Kurokawa
As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28057739/aberrant-let7a-hmga2-signaling-activity-with-unique-clinical-phenotype-in-jak2-mutated-myeloproliferative-neoplasms
#16
Chih-Cheng Chen, Jie-Yu You, Jrhau Lung, Cih-En Huang, Yi-Yang Chen, Yu-Wei Leu, Hsing-Ying Ho, Chian-Pei Li, Chang-Hsien Lu, Kuan-Der Lee, Chia-Chen Hsu, Jyh-Pyng Gau
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA through binding to its 3-untranslated region (3-UTR). Transgenic mice expressing HMGA2 with a truncation of its 3-UTR has been shown to exhibit a myeloproliferative phenotype. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed up-regulation of HMGA2 with concurrent let-7a repression...
January 5, 2017: Haematologica
https://www.readbyqxmd.com/read/28042144/novel-bet-protein-proteolysis-targeting-chimera-bet-protac-exerts-superior-lethal-activity-than-bromodomain-inhibitor-beti-against-post-myeloproliferative-neoplasm-mpn-secondary-s-aml-cells
#17
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28035720/wp1066-suppresses-macrophage-cell-death-induced-by-inflammasome-agonists-independently-of-its-inhibitory-effect-on-stat3
#18
Shino Honda, Daichi Sadatomi, Yasuo Yamamura, Kazutaka Nakashioya, Susumu Tanimura, Kohsuke Takeda
The compound WP1066 was originally synthesized by modifying the structure of AG490, which inhibits the activation of signal transducer and activator of transcription 3 (STAT3) by directly targeting Janus kinases (JAKs). WP1066 exhibits stronger anti-cancer activity than AG490 against malignant glioma and other cancer cells and is regarded as a promising therapeutic agent. By screening a small library of target-known compounds, we identified WP1066 as an inhibitor of macrophage cell death induced by agonists of the NLRP3 inflammasome, an intracellular protein complex required for the processing of the proinflammatory cytokine interleukin (IL)-1β...
December 30, 2016: Cancer Science
https://www.readbyqxmd.com/read/28024126/janus-kinase-jak-inhibitors-for-the-treatment-of-skin-and-hair-disorders-a-review-of-literature
#19
Aniseh Samadi, Saman Ahmad Nasrollahi, Ashkan Hashemi, Mansour Nassiri-Kashani, Alireza Firooz
Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are U.S. FDA approved drugs in this family approved for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. We overview the JAK/STAT signaling pathway and its involvement in skin diseases...
December 26, 2016: Journal of Dermatological Treatment
https://www.readbyqxmd.com/read/27998802/janus-kinase-inhibition-for-immunosuppression-in-solid-organ-transplantation-is-there-a-role-in-complex-immunologic-challenges
#20
REVIEW
Cody A Moore, Carlo J Iasella, Raman Venkataramanan, Fadi G Lakkis, Randall B Smith, John F McDyer, Adriana Zeevi, Christopher R Ensor
Inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway for immunosuppression in solid organ transplantation is appealing due to its specificity for immune cell function, particularly for JAK3. This is due to its unique association with only the common gamma chain (γc). The γc is an appealing immunosuppression target in transplantation because of the critically important lymphokines that act at it, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Tofacitinib was initially purported to selectively inhibit solely JAK3, but subsequent analyses have also demonstrated its activity at the other members of the JAK family...
December 18, 2016: Human Immunology
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