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Jaeseon Lee, Jennifer Lee, Seung-Ki Kwok, SeungYe Baek, Se Gwang Jang, Seung-Min Hong, Jae-Woong Min, Sun Shim Choi, Juhyun Lee, Mi-La Cho, Sung-Hwan Park
OBJECTIVE: To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGEC) and disease parameters in a Sjögren's syndrome animal model. METHODS: Common differentially expressed genes (DEGs) were analyzed among peripheral blood mononuclear cells from patients with primary Sjögren's syndrome (pSS) and other datasets, using blood and salivary gland (SG) tissue. Validation of expression in SG was analyzed by focus score...
June 21, 2018: Arthritis & Rheumatology
Qiao Yang, Yumo Zhao, Chen Li, Yaping Luo, Weixin Hao, Wen Zhang
INTRODUCTION: Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is an autoinflammatory disorder without standardized treatment. Janus kinase (JAK) inhibitors can block a range of cytokines and might possess significant anti-inflammatory activity. Here, we report the first case of efficacious treatment of refractory SAPHO syndrome with the JAK inhibitor tofacitinib. CASE PRESENTATION: A 44-year-old woman presented with arthralgia in the right wrist and complained of having difficulty in doing housework...
June 2018: Medicine (Baltimore)
Bruce E Sands, William J Sandborn, Brian G Feagan, Gary R Lichtenstein, Hongyan Zhang, Richard Strauss, Philippe Szapary, Jewel Johanns, Julian Panes, Severine Vermeire, Christopher D O'Brien, Zijiang Yang, Kirk Bertelsen, Colleen Marano
Background and Aims: Janus kinase (JAK) inhibitors have shown efficacy in ulcerative colitis (UC). We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. Methods: In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25mg once daily (qd), 75mg qd, 150mg qd, and 75mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8 with response assessed using Mayo score change from baseline...
June 15, 2018: Journal of Crohn's & Colitis
Guro L Goll, Tore K Kvien
No abstract text is available yet for this article.
June 12, 2018: Lancet
Aisha S Shariq, Elisa Brietzke, Joshua D Rosenblat, Zihang Pan, Carola Rong, Renee-Marie Ragguett, Caroline Park, Roger S McIntyre
Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders...
June 14, 2018: Reviews in the Neurosciences
Satoshi Nakagawa, Satoshi Serada, Reisa Kakubari, Kosuke Hiramatsu, Takahito Sugase, Shinya Matsuzaki, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Tomoharu Ohkawara, Minoru Fujimoto, Tadamitsu Kishimoto, Tadashi Kimura, Tetsuji Naka
Ovarian cancer (OvCa) is the leading cause of gynecological cancer-related deaths and novel therapeutic strategies are required. Programmed cell death 1 and programmed cell death ligand 1 (PD-L1), which are key mediators of host immune tolerance, are associated with OvCa progression. Recent evidence indicates the importance of IFN-γ-induced PD-L1 for immune tolerance in OvCa. This study aimed to reveal the therapeutic potential of suppressor of cytokine signaling 1 (SOCS-1), an endogenous inhibitor of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, for the treatment of OvCa...
June 11, 2018: Molecular Cancer Therapeutics
Hal M Hoffman, Lori Broderick
Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects...
June 11, 2018: Journal of Clinical Investigation
Mai Takamura-Ishii, Takaaki Nakaya, Katsuro Hagiwara
Newcastle disease virus (NDV) is an oncolytic virus. As immunogenicity of tumor cells is enhanced by NDV infection, recombinant NDV-infected tumor vaccines (rNDV-TV) are effective methods for inducing specific immunity. However, several tumor cells resist NDV infection, and tumor specific immunity is not sufficiently induced by rNDV-TV. Therefore, we clarified the factor contributing to the suppression of NDV infection and attempted to improve rNDV-TV. Initially we investigated the correlation between the NDV infection rate and interferon-related gene expression in six murine tumor cell lines...
June 6, 2018: Cancers
Jared S Kahn, Sandhya Chowdary Deverapalli, David M Rosmarin
BACKGROUND: Discoid lupus erythematosus (DLE) and dermatomyositis (DM) are inflammatory autoimmune diseases that manifest primarily in the skin but can be linked to systemic complications. Although there is an in-depth understanding of the clinical presentation of these two diseases, much less is known regarding the pathophysiology. This has limited the effective treatment options for patients. OBJECTIVE: An understanding of the pathogenesis of each disease in greater detail will lead to newer targeted medications with less morbidity...
June 5, 2018: International Journal of Dermatology
Animesh Pardanani, Ayalew Tefferi
The introduction of JAK inhibitors, leading to regulatory approval of ruxolitinib, represents a major therapeutic advance in myelofibrosis. Most patients experience reduction in splenomegaly and improved quality of life from symptom improvement. It is a paradox however that, despite inhibition of signaling downstream of disease-related driver mutations, JAK inhibitor treatment is not associated with consistent molecular or pathologic responses in myelofibrosis. Furthermore, there are important limitations to JAK inhibitor therapy including development of dose-limiting cytopenias and/or non-hematological toxicities such as neuropathy or opportunistic infections...
June 4, 2018: Blood
Przemyslaw J Kotyla
The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response...
2018: BioMed Research International
Yasuaki Ishii, Wataru Shibata, Makoto Sugimori, Yoshihiro Kaneta, Masatomo Kanno, Takeshi Sato, Soichiro Sue, Eri Kameta, Hiroaki Kaneko, Kuniyasu Irie, Tomohiko Sasaki, Masaaki Kondo, Shin Maeda
Background/Aim: Although IL-6-mediated activation of the signal transduction and activator of transcription 3 (STAT3) axis is involved in inflammation and cancer, the role of STAT3 in Helicobacter -associated gastric inflammation and carcinogenesis is unclear. This study investigated the role of STAT3 in gastric inflammation and carcinogenesis and examined the molecular mechanism of Helicobacter -induced gastric phenotypes. Methods: To evaluate the contribution of STAT3 to gastric inflammation and carcinogenesis, we used wild-type (WT) and gastric epithelial conditional Stat3 -knockout ( Stat3Δgec ) mice...
2018: Gastroenterology Research and Practice
Eun Ha Kang, Katherine P Liao, Seoyoung C Kim
PURPOSE OF REVIEW: Increased cardiovascular (CV) risk and associated mortality in rheumatoid arthritis (RA) are not fully explained by traditional CV risk factors. This review discusses the epidemiology and mechanisms of increased CV risk in RA and treatment effects on CV risk focusing on biologic disease-modifying anti-rheumatic drugs (DMARDs) and JAK inhibitors. RECENT FINDINGS: Intermediary metabolic changes by inflammatory cytokines are observed in body composition, lipid profile, and insulin sensitivity of RA patients, leading to accelerated atherosclerosis and increased CV risk...
May 30, 2018: Current Rheumatology Reports
Linna Xie, Yanhua Zeng, Zichan Dai, Wensheng He, Huozhao Ke, Qiaofa Lin, Yan Chen, Jingjing Bu, Dexin Lin, Min Zheng
Hepatocellular carcinoma (HCC) has become the second leading cause of cancer related death, with an increasing death rate in recent years. For advanced HCC, sorafenib is the first-line FDA approved drug, with no more than 3 months' overall survival advantage. Recently, a novel strategy has been proposed to improve sorafenib efficacy through enhancing the ability of sorafenib to induce cell death. STAT3 plays a key role in cancer development and recurrence by promoting cell proliferation, survival and immune evasion through its well-established function as a transcription factor in cancer...
2018: International Journal of Biological Sciences
Jolanda Sarno, Angela M Savino, Chiara Buracchi, Chiara Palmi, Stefania Pinto, Cristina Bugarin, Astraea Jager, Silvia Bresolin, Ruth C Barber, Daniela Silvestri, Shai Israeli, Martin J S Dyer, Giovanni Cazzaniga, Garry P Nolan, Andrea Biondi, Kara L Davis, Giuseppe Gaipa
Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the CRLF2 gene ( hiCRLF2 ) have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in hiCRLF2 cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples...
May 1, 2018: Oncotarget
Cheyne Kurokawa, Ianko D Iankov, S Keith Anderson, Ileana Aderca, Alexey A Leontovich, Matthew J Maurer, Ann L Oberg, Mark A Schroeder, Caterina Giannini, Suzanne M Greiner, Marc A Becker, E Aubrey Thompson, Paul Haluska, Mark E Jentoft, Ian F Parney, S John Weroha, Jin Jen, Jann N Sarkaria, Evanthia Galanis
Background: Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however. Methods: We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX)...
May 16, 2018: Journal of the National Cancer Institute
Jean-Frédéric Colombel
Increased risk of herpes zoster (HZ) has been observed in patients with immune-mediated diseases, including rheumatoid arthritis (RA), psoriasis (PsO), and inflammatory bowel disease; this risk can be further increased by the use of immunosuppressive therapy. One advancing modality of therapy for these diseases is Janus kinase (JAK) inhibition. Tofacitinib is an oral JAK inhibitor for the treatment of RA and psoriatic arthritis, which is currently under investigation for the treatment of ulcerative colitis (UC) and was previously investigated for psoriasis...
May 17, 2018: Inflammatory Bowel Diseases
Kikid Rucira Qurania, Koji Ikeda, Donytra Arby Wardhana, Agian Jeffilano Barinda, Dhite Bayu Nugroho, Yuko Kuribayashi, Elda Putri Rahardini, Pranindya Rinastiti, Gusty Rizky Teguh Ryanto, Keiko Yagi, Ken-Ichi Hirata, Noriaki Emoto
Browning of white adipose tissue is a promising strategy to tackle obesity. Recently, Janus kinase (JAK) inhibition was shown to induce white-to-brown metabolic conversion of adipocytes in vitro; however effects of JAK inhibition on browning and systemic metabolic health in vivo remain to be elucidated. Here, we report that systemic administration of JAK inhibitor (JAKi) ameliorated obesity-related metabolic disorders. Administration of JAKi in mice fed a high-fat diet increased UCP-1 and PRDM16 expression in white adipose tissue, indicating the browning of white adipocyte...
July 7, 2018: Biochemical and Biophysical Research Communications
Yuval Ramot, Abraham Zlotogorski
While most alopecia areata (AA) cases resolve spontaneously, the more severe types of AA, alopecia totalis (AT) and alopecia universalis (AU), can be highly resistant to therapy. We report on a 33-year-old ultraorthodox Jewish man with an 11-year history of AA that resulted in complete loss of the scalp and body hair 7 years ago. Previous treatments with intralesional and systemic corticosteroids had only partial and temporary effects. The patient was treated with ruxolitinib, 20 mg twice daily, resulting in complete growth of the beard after 4 months of treatment...
April 2018: Skin Appendage Disorders
Leandro Ladislau, Xavier Suárez-Calvet, Ségolène Toquet, Océane Landon-Cardinal, Damien Amelin, Marine Depp, Mathieu P Rodero, Denisa Hathazi, Darragh Duffy, Vincent Bondet, Corinna Preusse, Boris Bienvenu, Flore Rozenberg, Andreas Roos, Claudia F Benjamim, Eduard Gallardo, Isabel Illa, Vincent Mouly, Werner Stenzel, Gillian Butler-Browne, Olivier Benveniste, Yves Allenbach
Dermatomyositis is an acquired auto-immune disease characterized by skin lesions and muscle-specific pathological features such as perifascicular muscle fibre atrophy and vasculopathy. Dermatomyositis patients display an upregulation of type I interferon-inducible genes in muscle fibres, endothelial cells, skin and peripheral blood. However, the effect of type I interferon on muscle tissue has not yet been determined. Our aim was to study the pathogenicity of type I interferon in vitro and to evaluate the efficacy of the type I interferon pathway blockade for therapeutic purposes...
May 8, 2018: Brain: a Journal of Neurology
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