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Jak-inhibitor

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https://www.readbyqxmd.com/read/29030706/rare-adar-and-rnaseh2b-variants-and-a-type-i-interferon-signature-in-glioma-and-prostate-carcinoma-risk-and-tumorigenesis
#1
Ulrike Beyer, Frank Brand, Helge Martens, Julia Weder, Arne Christians, Natalie Elyan, Bettina Hentschel, Manfred Westphal, Gabriele Schackert, Torsten Pietsch, Bujung Hong, Joachim K Krauss, Amir Samii, Peter Raab, Anibh Das, Claudia A Dumitru, I Erol Sandalcioglu, Oliver W Hakenberg, Andreas Erbersdobler, Ulrich Lehmann, Guido Reifenberger, Michael Weller, Martin A M Reijns, Matthias Preller, Bettina Wiese, Christian Hartmann, Ruthild G Weber
In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date...
October 13, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29030646/-systemic-treatment-of-vitiligo-balance-and-current-developments
#2
REVIEW
M Meurer, P Ceric-Dehdari
Systemic drug treatment of vitiligo is currently limited to predominantly adjuvant measures for increasing the effectiveness of UV light therapy. We here present new approaches for the systemic treatment of vitiligo currently under clinical investigation. These include the α‑MSH-analogue afamelatonide and oral immunosuppressants such as the Janus kinase (JAK) inhibitors which target interferon-α-dependent autotoxic inflammatory reactions. In 2015 the first publications on the successful systemic use of Janus kinase (JAK) inhibitors in vitiligo appeared...
October 13, 2017: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
https://www.readbyqxmd.com/read/29028981/tofacitinib-in-patients-with-ulcerative-colitis-health-related-quality-of-life-in-phase%C3%A2-3-randomized-controlled-induction-and-maintenance-studies
#3
Julian Panés, Séverine Vermeire, James O Lindsay, Bruce E Sands, Chinyu Su, Gary Friedman, Haiying Zhang, Aaron Yarlas, Martha Bayliss, Stephen Maher, Joseph C Cappelleri, Andrew G Bushmakin, David T Rubin
Background and Aims: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for UC. We evaluated healthrelated quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Methods: Patients ≥18 years old in OCTAVE Induction 1 [N=598] and 2 [N=541] with moderately to severely active UC were randomized [1:4] to placebo or tofacitinib 10mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomized [1:1:1] clinical responders [N=593] from induction studies to placebo, tofacitinib 5 or 10mg BID for 52 weeks...
September 27, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/29025600/a-novel-somatic-jak2-kinase-domain-mutation-in-pediatric-acute-lymphoblastic-leukemia-with-rapid-on-treatment-development-of-loh
#4
Teresa Sadras, Susan L Heatley, Chung H Kok, Barbara J McClure, David Yeung, Timothy P Hughes, Rosemary Sutton, David S Ziegler, Deborah L White
We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/28994166/newer-treatments-of-psoriasis-regarding-il-23-inhibitors-phosphodiesterase-4-inhibitors-and-janus-kinase-inhibitors
#5
REVIEW
Dominika Wcisło-Dziadecka, Martyna Zbiciak-Nylec, Ligia Brzezińska-Wcisło, Katarzyna Bebenek, Agata Kaźmierczak
The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23)...
October 10, 2017: Dermatologic Therapy
https://www.readbyqxmd.com/read/28988984/prevention-of-chronic-renal-allograft-rejection-by-as2553627-a-novel-jak-inhibitor-in-a-rat-transplantation-model
#6
Koji Nakamura, Yuka Kawato, Yoko Kaneko, Kaori Hanaoka, Kaori Kubo, Tomonori Nakanishi, Masashi Maeda, Hidehiko Fukahori, Misato Ito, Takahisa Noto, Masamichi Inami, Jun Hirose, Tatsuaki Morokata
BACKGROUND: Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. METHODS: Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed...
October 5, 2017: Transplant Immunology
https://www.readbyqxmd.com/read/28971213/zytopenien-an%C3%A3-mie-leukopenie-und-thrombopenie
#7
REVIEW
C Kneitz, J Atta, H Burkhardt
Hematological alterations can often be observed during rheumatic diseases. The effects can be clinically severe, ranging from anemia of different grades of severity, through increased risk of hemorrhage due to thrombocytopenia up to severe infections as a result of high-grade leukocytopenia. The clinical sequelae for patients are predominantly determined by the extent of cytopenia. The underlying disease itself can initially be considered as the cause. Examples are anemia as a result of chronic inflammation, antibody-mediated thrombocytopenia as in systemic lupus erythematosus (SLE) or granulocytopenia within the framework of Felty's syndrome...
October 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/28960447/jak1-2-inhibitors-azd1480-and-cyt387-inhibit-canine-b-cell-lymphoma-growth-by-increasing-apoptosis-and-disrupting-cell-proliferation
#8
Z Lu, C C Hong, P C Jark, A L F V Assumpção, N Bollig, G Kong, X Pan
BACKGROUND: Canine diffuse large B-cell lymphoma (DLBCL) is a common and aggressive hematologic malignancy. The lack of conventional therapies with sustainable efficacy warrants further investigation of novel therapeutics. The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways play important roles in the pathogenesis of hematologic malignancies in humans including DLBCLs. AZD1480 and CYT387 are novel JAK1/2 inhibitors that have been used in clinical trials for treating various hematologic cancers in humans...
September 27, 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/28952836/a-molecular-mechanism-for-il-4-suppression-of-loricrin-transcription-in-epidermal-keratinocytes-implication-for-atopic-dermatitis-pathogenesis
#9
Lei Bao, Girish C Mohan, Jaime B Alexander, Caroline Doo, Kui Shen, Jeremy Bao, Lawrence S Chan
Skin barrier defects play an important role in atopic dermatitis (AD) pathogenesis. Loricrin, an important barrier protein suppressed in human AD, is down-regulated by IL-4 in keratinocytes. However, the molecular mechanism is unknown. Since loricrin transcription requires p300/CBP, and Stat6 also recruits this common coactivator for its stimulated factors, we hypothesize that IL-4-activated Stat6 competes for the available endogenous p300/CBP, leading to loricrin transcription inhibition. First, we showed that loricrin is suppressed in the skin of IL-4 transgenic mice, an AD mouse model...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/28941219/lymphoma-in-the-tofacitinib-rheumatoid-arthritis-clinical-development-program
#10
Xavier Mariette, Connie Chen, Pinaki Biswas, Kenneth Kwok, Mary G Boy
BACKGROUND: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We characterized lymphoma events in the tofacitinib RA clinical development program. METHODS: Lymphoma events (to March 2015) were identified from 19 tofacitinib studies (two Phase 1, nine Phase 2, six Phase 3, and two long-term extension) of patients with moderate to severe RA. Patients in these studies received tofacitinib dosed at 1-30 mg twice daily or 20 mg once daily, as monotherapy or with conventional synthetic DMARDs...
September 21, 2017: Arthritis Care & Research
https://www.readbyqxmd.com/read/28939759/il-22-increases-permeability-of-intestinal-epithelial-tight-junctions-by-enhancing-claudin-2-expression
#11
Yaya Wang, John Brian Mumm, Ronald Herbst, Roland Kolbeck, Yue Wang
Dysfunction of the epithelial barrier is a hallmark of inflammatory intestinal diseases. The intestinal epithelial barrier is maintained by expression of tight junctions that connect adjacent epithelial cells and seal the paracellular space. IL-22 is critical for the maintenance of intestinal barrier function through promoting antipathogen responses and regeneration of epithelial tissues in the gut. However, little is known about the effects of IL-22 on the regulation of tight junctions in the intestinal epithelium...
September 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28891341/small-molecule-therapy-for-managing-moderate-to-severe-psoriatic-arthritis
#12
Luisa Costa, Antonio Del Puente, Rosario Peluso, Marco Tasso, Paolo Caso, Maria Sole Chimenti, Vincenzo Sabbatino, Nicolò Girolimetto, Carolina Benigno, Nicoletta Bertolini, Aurora Del Puente, Roberto Perricone, Raffaele Scarpa, Francesco Caso
The majority of psoriatic arthritis (PsA) patients experience a good clinical response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic therapies (bDMARDs). However, treatment failure with these drugs can represent a relevant clinical problem. Moreover, in daily clinical practice, the appropriate identification of patients eligible for these agents can be conditioned by numerous aspects, mainly represented by comorbidities, such as history of malignancies, chronic and recurrent infectious diseases...
October 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28890086/sensory-neurons-co-opt-classical-immune-signaling-pathways-to-mediate-chronic-itch
#13
Landon K Oetjen, Madison R Mack, Jing Feng, Timothy M Whelan, Haixia Niu, Changxiong J Guo, Sisi Chen, Anna M Trier, Amy Z Xu, Shivani V Tripathi, Jialie Luo, Xiaofei Gao, Lihua Yang, Samantha L Hamilton, Peter L Wang, Jonathan R Brestoff, M Laurin Council, Richard Brasington, András Schaffer, Frank Brombacher, Chyi-Song Hsieh, Robert W Gereau, Mark J Miller, Zhou-Feng Chen, Hongzhen Hu, Steve Davidson, Qin Liu, Brian S Kim
Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28887107/efficacy-of-systemic-treatments-of-psoriasis-on-pruritus-a-systemic-literature-review-and-meta-analysis
#14
Chloé Théréné, Emilie Brenaut, Thomas Barnetche, Laurent Misery
In the course of the last 30 years, several studies have clearly documented that pruritus is a very frequent symptom of psoriasis and its impact on the patients' quality of life. The variety of available systemic treatments for psoriasis is increasing rapidly. Our objective was to assess their efficacy on pruritus based on a systematic literature review. A systematic literature search was performed using PubMed and Trip Database (from January 1990 to September 2016) to find published clinical trials for the treatments of psoriasis, then a meta-analysis was performed...
September 5, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28865178/inhibition-of-il-6-jak-stat3-signaling-in-castration-resistant-prostate-cancer-cells-enhances-the-nk-cell-mediated-cytotoxicity-via-alteration-of-pd-l1-nkg2d-ligand-levels
#15
LiJun Xu, XiaoDong Chen, MingJing Shen, Dong-Rong Yang, Laifu Fang, Guobin Weng, Ying Tsai, Peter C Keng, Yuhchyau Chen, Soo Ok Lee
To investigate whether IL-6 signaling affects the susceptibility of castration resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL-6 level) were developed by lentiviral transduction. While observing no secreted IL-6 level in parental C4-2 and CWR22Rv1 cells, we found the IL-6 expression/secretion in these cells was induced after the transduction process and the IL-6 level difference in C4-2siIL-6/sc and CWR22siIL-6/sc cell CRPC cell sets could be detected...
September 2, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28864784/sh003-reverses-drug-resistance-by-blocking-signal-transducer-and-activator-of-transcription-3-stat3-signaling-in-breast-cancer-cells
#16
Hye-Sook Seo, Jin Mo Ku, Hee-Jae Lee, Jong-Kyu Woo, Chunhoo Cheon, Mia Kim, Bo-Hyoung Jang, Yong Cheol Shin, Seong-Gyu Ko
Overcoming drug resistance is an important task for investigators and clinician to achieve successful chemotherapy in cancer patients. Drug resistance is caused by various factors, including the overexpression of P-glycoprotein (P-gp, MDR1). The development of new, useful compounds that overcome drug resistance is urgent. SH003 is extracted from the mixture of three different herbs, and its anti-cancer effect has been revealed in different cancer cell types. In the present study, we investigated whether SH003 is able to reverse drug resistance using paclitaxel-resistant breast cancer cells (MCF-7/PAC)...
September 1, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28845577/the-safety-and-immunogenicity-of-live-zoster-vaccination-in-patients-with-rheumatoid-arthritis-before-starting-tofacitinib-a-randomized-phase-ii-trial
#17
RANDOMIZED CONTROLLED TRIAL
Kevin L Winthrop, Ann G Wouters, Ernest H Choy, Koshika Soma, Jennifer A Hodge, Chudy I Nduaka, Pinaki Biswas, Elie Needle, Sherry Passador, Christopher F Mojcik, William F Rigby
OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). METHODS: In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2-3 weeks postvaccination...
October 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28844088/familial-chilblain-lupus-what-can-we-learn-from-type-i-interferonopathies
#18
REVIEW
Christoph Fiehn
PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described...
August 26, 2017: Current Rheumatology Reports
https://www.readbyqxmd.com/read/28842136/philadelphia-chromosome-like-acute-lymphoblastic-leukemia
#19
REVIEW
Ching-Hon Pui, Kathryn G Roberts, Jun J Yang, Charles G Mullighan
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described B-cell precursor ALL with a gene expression profile and a high frequency of IKZF1 gene alteration similar to that of Ph-positive ALL. Its prevalence is approximately 12% in children, 21% in adolescents (16-20 years of age), and 20% to 24% in adults older than 40 years, with a peak (27%) in young adults 21 to 39 years old. It occurs more often in male individuals and patients with Down syndrome. Ph-like ALL is overrepresented in those with Hispanic ethnicity and is associated with inherited genetic variants in GATA3 (rs3824662)...
August 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28838249/filgotinib-for-the-treatment-of-rheumatoid-arthritis
#20
REVIEW
Peter C Taylor, Maha Abdul Azeez, Serafim Kiriakidis
Biologics were the first targeted therapies for rheumatoid arthritis (RA), having in common high clinical efficacy. Being proteins, they are administered parenterally. The first oral targeted small molecules approved for RA are competitive inhibitors of the Janus kinase (JAK) enzyme family which mediate signalling for a cytokine subset important in RA pathogenesis. Areas covered: Several JAK inhibitors have been developed with differing selectivity for the four JAK enzymes with a view to generating oral, multi-cytokine inhibitors...
October 2017: Expert Opinion on Investigational Drugs
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