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https://www.readbyqxmd.com/read/29681195/biologics-for-treating-axial-spondyloarthritis
#1
Alexis Jones, Coziana Ciurtin, Mediola Ismajli, Maria Leandro, Raj Sengupta, Pedro M Machado
Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis...
April 21, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29665062/phase-1-studies-to-assess-the-safety-tolerability-and-pharmacokinetics-of-jte-052-a-novel-janus-kinase-inhibitor-ointment-in-japanese-healthy-volunteers-and-patients-with-atopic-dermatitis
#2
Hidemi Nakagawa, Osamu Nemoto, Hiroyuki Yamada, Takeshi Nagata, Noriko Ninomiya
The purpose of the present two phase 1 studies was to assess the safety, tolerability and pharmacokinetics for topical application of a novel Janus kinase (JAK) inhibitor, JTE-052, in Japanese healthy adult male volunteers and Japanese adult patients with atopic dermatitis (AD). Additionally, exploratory investigation was performed on the efficacy for disease severity and pruritus score in AD patients. In the QBX1-1 study, the cutaneous safety of JTE-052 ointment by a patch test and a photo patch test was assessed in an intra-individual comparative study using placebo ointment, white petrolatum and non-application as comparators...
April 17, 2018: Journal of Dermatology
https://www.readbyqxmd.com/read/29649002/jak1-2-inhibition-with-baricitinib-in-the-treatment-of-autoinflammatory-interferonopathies
#3
Gina A Montealegre Sanchez, Adam Reinhardt, Suzanne Ramsey, Helmut Wittkowski, Philip J Hashkes, Yackov Berkun, Susanne Schalm, Sara Murias, Jason A Dare, Diane Brown, Deborah L Stone, Ling Gao, Thomas Klausmeier, Dirk Foell, Adriana A de Jesus, Dawn C Chapelle, Hanna Kim, Samantha Dill, Robert Colbert, Laura Failla, Bahar Kost, Michelle O'Brien, James C Reynolds, Les R Folio, Katherine R Calvo, Scott M Paul, Nargues Weir, Alessandra Brofferio, Ariane Soldatos, Angélique Biancotto, Edward W Cowen, John G Digiovanna, Massimo Gadina, Andrew J Lipton, Colleen Hadigan, Steven M Holland, Joseph Fontana, Ahmad S Alawad, Rebecca J Brown, Kristina I Rother, Theo Heller, Kristina M Brooks, Parag Kumar, Stephen R Brooks, Meryl Waldman, Harsharan K Singh, Volker Nickeleit, Maria Silk, Apurva Prakash, Jonathan M Janes, Seza Ozen, Paul G Wakim, Paul A Brogan, William L Macias, Raphaela Goldbach-Mansky
BACKGROUND: Monogenic Interferon (IFN)-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN-response-gene-signature (IRS), inflammatory organ damage and high mortality. We used the janus kinase (JAK) inhibitor baricitinib with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 with SAVI (Stimulator of IFN genes (STING)-associated vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an Expanded Access Program...
April 12, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29648682/elderly-onset-varicella-pneumonia-in-a-patient-with-rheumatoid-arthritis-taking-tofacitinib
#4
Nobuya Abe, Takashi Kudo, Satoshi Jodo
A 68-year-old woman with rheumatoid arthritis, who was treated with tofacitinib, a type of Janus kinase (JAK) inhibitor, was admitted for dyspnea and generalized purpuric vesicular rash, following 3 days of fever and malaise. She developed hypoxia from respiratory insufficiency. On physical examination, the systemic eruptions had an erythematous base and were present in various stages, from maculopapular to vesicular and pustular, with crusting (left). Chest radiograph demonstrated diffuse infiltrates with reticular and nodular lesions in the bilateral lung fields (right)...
April 12, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29622655/repurposing-tofacitinib-as-an-anti-myeloma-therapeutic-to-reverse-growth-promoting-effects-of-the-bone-marrow-microenvironment
#5
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
https://www.readbyqxmd.com/read/29620234/crocin-prevents-platelet%C3%A2-derived-growth-factor-bb%C3%A2-induced-vascular-smooth-muscle-cells-proliferation-and-phenotypic-switch
#6
Lijian Tong, Guoxian Qi
The phenotypic switch of vascular smooth muscle cells (VSMCs) is a major initiating factor for atherosclerotic cardiovascular diseases. Platelet‑derived growth factor‑BB (PDGF‑BB) initiates a number of biological processes that contribute to VSMC proliferation and phenotypic switch. Crocin, a component of saffron, has been reported to inhibit atheromatous plaque formation. However, the effects of crocin on PDGF‑BB‑induced VSMC proliferation and phenotypic switch remain unclear. The aim of the present study was to investigate the role of crocin on PDGF‑BB‑induced VSMCs proliferation and phenotypic switch and its underlying mechanisms...
April 5, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29618084/the-rationale-for-janus-kinase-inhibitors-for-the-treatment-of-spondyloarthritis
#7
Douglas J Veale, Dennis McGonagle, Iain B McInnes, James G Krueger, Christopher T Ritchlin, Dirk Elewaut, Keith S Kanik, Thijs Hendrikx, Gabriel Berstein, Jennifer Hodge, Jean-Baptiste Telliez
The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations...
April 3, 2018: Rheumatology
https://www.readbyqxmd.com/read/29589523/an-update-on-jak-inhibitors
#8
Francesca Musumeci, Chiara Greco, Ilaria Giacchell, Anna Lucia Fallacara, Munjed M Ibrahim, Giancarlo Grossi, Chiara Brullo, Silvia Schenone
Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors...
March 26, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29588491/identification-of-inhibitors-regulating-cell-proliferation-and-fus-ddit3-expression-in-myxoid-liposarcoma-using-combined-dna-mrna-and-protein-analyses
#9
David Svec, Soheila Dolatabadi, Christer Thomsen, Nicole Cordes, Mark Shannon, Paul Fitzpatrick, Göran Landberg, Pierre Åman, Anders Ståhlberg
FUS-DDIT3 belongs to the FET (FUS, EWSR1, and TAF15) family of fusion oncogenes, which collectively are considered to be key players in tumor development. Even though over 90% of all myxoid liposarcomas (MLS) have a FUS-DDIT3 gene fusion, there is limited understanding of the signaling pathways that regulate its expression. In order to study cell proliferation and FUS-DDIT3 regulation at mRNA and protein levels, we first developed a direct cell lysis approach that allows DNA, mRNA, and protein to be analyzed in the same sample using quantitative PCR, reverse transcription quantitative qPCR and proximity ligation assay, respectively...
March 27, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29587202/stattic-inhibits-rankl-mediated-osteoclastogenesis-by-suppressing-activation-of-stat3-and-nf-%C3%AE%C2%BAb-pathways
#10
Chang-Hong Li, Lin-Lin Xu, Lei-Lei Jian, Ruo-Han Yu, Jin-Xia Zhao, Lin Sun, Guo-Hong Du, Xiang-Yuan Liu
Tofacitinib, a small molecule JAK inhibitor, has been widely used to reduce inflammation and inhibit progression of bone destruction in rheumatoid arthritis. STAT3, a downstream signaling molecule of JAK, plays a key role in the activation of signaling in response to inflammatory cytokines. Thus, targeting STAT3 may be an inspiring strategy for treating osteoclast-related diseases such as rheumatoid arthritis. In this study, we first investigated the effects of Stattic, a STAT3 inhibitor, on receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis...
March 24, 2018: International Immunopharmacology
https://www.readbyqxmd.com/read/29574002/treatment-with-jak-inhibitors-in-myelofibrosis-patients-nullifies-the-prognostic-impact-of-unfavorable-cytogenetics
#11
Vincent T Ma, Philip S Boonstra, Kamal Menghrajani, Cecelia Perkins, Krisstina L Gowin, Ruben A Mesa, Jason R Gotlib, Moshe Talpaz
INTRODUCTION: In the era before Janus kinase (JAK) inhibitors, cytogenetic information was used to predict survival in myelofibrosis patients. However, the prognostic value of cytogenetics in the setting of JAK inhibitor therapy remains unknown. PATIENTS AND METHODS: We performed a retrospective analysis of 180 patients with bone marrow biopsy-proven myelofibrosis from 3 US academic medical centers. We fit Cox proportional hazards models for overall survival and transformation-free survival on the bases of 3 factors: JAK inhibitor therapy as a time-dependent covariate, dichotomized cytogenetic status (favorable vs...
March 2, 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29568923/atm%C3%A2-jak%C3%A2-pd%C3%A2-l1-signaling-pathway-inhibition-decreases-emt-and-metastasis-of-androgen%C3%A2-independent-prostate-cancer
#12
Lan Zhang, Li-Jun Xu, Jin Zhu, Jian Li, Bo-Xin Xue, Jie Gao, Chuan-Yang Sun, Ya-Chen Zang, Yi-Bin Zhou, Dong-Rong Yang, Yu-Xi Shan
Castration-resistant prostate cancer (CRPC), also known as androgen-independent prostate cancer, frequently develops local and distant metastases, the underlying mechanisms of which remain undetermined. In the present study, surgical specimens obtained from patients with clinical prostate cancer were investigated, and it was revealed that the expression levels of ataxia telangiectasia mutated kinase (ATM) were significantly enhanced in prostate cancer tissues isolated from patients with CRPC compared with from patients with hormone‑dependent prostate cancer...
March 20, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29562644/understanding-splenomegaly-in-myelofibrosis-association-with-molecular-pathogenesis
#13
REVIEW
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen...
March 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29559168/the-respiratory-syncytial-virus-fusion-protein-formulated-with-a-polymer-based-adjuvant-induces-multiple-signaling-pathways-in-macrophages
#14
Indranil Sarkar, Ravendra Garg, Sylvia van Drunen Littel-van den Hurk
Respiratory syncytial virus (RSV) causes acute respiratory tract infections in infants, the elderly and immunocompromised individuals. No licensed vaccine is available against RSV. We previously reported that intranasal immunization of rodents and lambs with a RSV vaccine candidate (ΔF/TriAdj) induces protective immunity with a good safety profile. ΔF/TriAdj promoted innate immune responses in respiratory mucosal tissues in vivo, by local chemokine and cytokine production, as well as infiltration and activation of immune cells including macrophages...
March 17, 2018: Vaccine
https://www.readbyqxmd.com/read/29556726/new-treatment-options-for-inflammatory-bowel-diseases
#15
REVIEW
Bram Verstockt, Marc Ferrante, Séverine Vermeire, Gert Van Assche
The advent of anti-TNF agents has dramatically changed the treatment algorithms for IBD in the last 15 years, but primarily and more importantly secondary loss of response is often observed. Fortunately , new treatment options have been actively explored and some have already entered our clinical practice. In the class of anti-cytokine agents, the anti-IL12/IL23 monoclonal antibodies (mAbs) have entered clinical practice with the anti-p40 mAb ustekinumab in Crohn's disease (CD). Also, more selective anti-IL23 agents (anti-p19) have shown efficacy and are being further developed, in contrast to agents inhibiting IL-17 downstream which have failed in clinical trials despite their clear efficacy in psoriasis (Verstockt et al...
March 19, 2018: Journal of Gastroenterology
https://www.readbyqxmd.com/read/29518827/-stimulator-of-interferon-genes-associated-vasculopathy-with-onset-in-infancy-first-case-report-in-china
#16
Z X Yu, L Q Zhong, H M Song, C Y Wang, W Wang, J Li, M S Ma
Objective: To summarize the clinical characteristics and treatment efficacy of the first reported case of a Chinese boy with stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI). Methods: Sanger sequencing of the gene TMEM173 was performed based on systemic evaluation and clinical analysis of a highly suspected SAVI child admitted to Peking Union Medical College Hospital. A literature search (search terms included 'STING''SAVI''autoinflammatory diseases' and 'interferonopathy') was conducted using Chinese literature database, EMBASE and PubMed to include recently published SAVI studies (searched from January 2010 to December 2017)...
March 2, 2018: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29500799/thromboembolism-with-janus-kinase-jak-inhibitors-for-rheumatoid-arthritis-how-real-is-the-risk
#17
Ian C Scott, Samantha L Hider, David L Scott
Two different Janus kinase (JAK) inhibitors-baricitinib and tofacitinib-are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs)...
March 2, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29487712/inhibition-of-mtorc1-c2-signaling-improves-anti-leukemia-efficacy-of-jak-stat-blockade-in-crlf2-rearranged-and-or-jak-driven-philadelphia-chromosome-like-acute-b-cell-lymphoblastic-leukemia
#18
Qi Zhang, Ce Shi, Lina Han, Nitin Jain, Kathryn G Roberts, Helen Ma, Tianyu Cai, Antonio Cavazos, Yoko Tabe, Rodrigo O Jacamo, Hong Mu, Yang Zhao, Jing Wang, Shuo-Chieh Wu, Fenglin Cao, Zhihong Zeng, Jin Zhou, Yingchang Mi, Elias J Jabbour, Ross Levine, Sarah K Tasian, Charles G Mullighan, David M Weinstock, David A Fruman, Marina Konopleva
Patients with cytokine receptor-like factor 2 rearranged ( CRLF2 -re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2 -re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2 -re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP-BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014...
January 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29480036/-emerging-drugs-for-the-treatment-of-myelofibrosis
#19
Aditya Shreenivas, John Mascarenhas
INTRODUCTION: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN). It can be sub-categorized into primary myelofibrosis, post polycythemia vera myelofibrosis and post essential thrombocythemia myelofibrosis. MF is a life-threatening hematologic malignancy characterized by dysregulation of the Janus associated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling network and a heightened inflammatory state. AREAS COVERED: We cover the pathogenesis, clinical features, new prognostic models, current treatment of MF and discuss agents in development...
February 26, 2018: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29471605/-emerging-therapies-what-are-promising-in-the-near-future
#20
REVIEW
Geom Seog Seo, Sung Hee Lee
The treatment of inflammatory bowel disease has evolved with the development of anti-TNF agents. In spite of long-term effectiveness, many patients do not respond or no longer responds to these drugs. Therefore, the development of new drugs that act on different inflammatory pathways has become necessary. Vedolizumab, a gut-specific biological agent, inhibits interaction α4β7 integrin with mucosal addressin cell adhesion molecule-1 without inhibiting systemic immune responses. Long-term vedolizumab therapy in patients with Crohn's disease and ulcerative colitis was safe and effective...
February 25, 2018: Korean Journal of Gastroenterology, Taehan Sohwagi Hakhoe Chi
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