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https://www.readbyqxmd.com/read/29228301/targeted-inhibition-of-janus-kinases-abates-interfon-gamma-induced-invasive-behaviour-of-fibroblast-like-synoviocytes
#1
Thomas Karonitsch, Denise Beckmann, Karolina Dalwigk, Birgit Niederreiter, Paul Studenic, Ruth A Byrne, Johannes Holinka, Florian Sevelda, Adelheid Korb-Pap, Günter Steiner, Josef S Smolen, Thomas Pap, Hans P Kiener
Objectives: The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions...
December 7, 2017: Rheumatology
https://www.readbyqxmd.com/read/29226168/risks-of-ruxolitinib-in-stat1-gain-of-function-associated-severe-fungal-disease
#2
Ofer Zimmerman, Berenice Rösler, Christa S Zerbe, Lindsey B Rosen, Amy P Hsu, Gulbu Uzel, Alexandra F Freeman, Elizabeth P Sampaio, Sergio D Rosenzwieg, Hye Sun Kuehn, Tiffany Kim, Kristina M Brooks, Parag Kumar, Xiaowen Wang, Mihai G Netea, Frank L van de Veerdonk, Steven M Holland
Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29225517/intestinally-restricted-janus-kinase-inhibition-a-potential-approach-to-maximize-the-therapeutic-index-in-inflammatory-bowel-disease-therapy
#3
David T Beattie, M Teresa Pulido-Rios, Fei Shen, Melissa Ho, Eva Situ, Pam R Tsuruda, Patrick Brassil, Melanie Kleinschek, Sharath Hegde
Background: An unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may be safety concerns associated with its use. This preclinical study evaluated whether modulating intestinal inflammation via local JAK inhibition can provide efficacy without systemic immunosuppression...
2017: Journal of Inflammation
https://www.readbyqxmd.com/read/29222297/current-treatment-algorithm-for-the-management-of-patients-with-myelofibrosis-jak-inhibitors-and-beyond
#4
REVIEW
Claire N Harrison, Donal P McLornan
Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an inherent risk of leukemic transformation. The past decade has seen a massive shift in available therapeutic options for our patients and we are learning how and when to use novel agents, either alone or in combination, during the disease course. This has translated into improved management of splenomegaly, significant amelioration in disease-related symptom burden for many, and may lead to improved survival...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29222295/myeloproliferative-neoplasms-from-origins-to-outcomes
#5
REVIEW
Jyoti Nangalia, Anthony R Green
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29212804/myeloproliferative-neoplasms-from-origins-to-outcomes
#6
REVIEW
Jyoti Nangalia, Anthony R Green
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation...
December 7, 2017: Blood
https://www.readbyqxmd.com/read/29205406/systematic-review-and-network-meta-analysis-first-and-second-line-pharmacotherapy-for-moderate-severe-ulcerative-colitis
#7
S Singh, M Fumery, W J Sandborn, M H Murad
BACKGROUND: There are limited data to inform positioning of agents for treating moderate-severe ulcerative colitis (UC). AIM: To assess comparative efficacy and safety of different therapies as first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor(TNF)-α) agents for moderate-severe UC, through a systematic review and network meta-analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach...
December 4, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29203240/il-13-regulates-il-17c-expression-by-suppressing-nf-%C3%AE%C2%BAb-mediated-transcriptional-activation-in-airway-epithelial-cells
#8
Katsumasa Yamanaka, Tomoyuki Fujisawa, Hideki Kusagaya, Kazutaka Mori, Mitsuru Niwa, Kazuki Furuhashi, Masato Kono, Etsuko Hamada, Takafumi Suda, Masato Maekawa
The cytokine interleukin (IL)-17C is highly expressed in epithelial tissues and involved in innate immune responses; however, the regulation of IL-17C expression in the airways remains poorly understood. Here, we show that IL-1β strongly induces both IL-17C mRNA and protein expression in primary normal human bronchial epithelial cells. Conversely, IL-13 significantly reduced the IL-1β-induced IL-17C expression. Attenuation of the nuclear factor (NF)-κB-signaling pathway using an NF-κB-subunit p65-specific small-interfering RNA (siRNA), reduced IL-1β-induced IL-17C expression, demonstrating the importance of NF-κB signaling in IL-17C regulation...
December 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29202299/repression-of-interferon-%C3%AE-regulated-cytokines-by-the-jak1-2-inhibitor-ruxolitinib-in-inflammatory-human-macrophages
#9
Marie Febvre-James, Valérie Lecureur, Yu Augagneur, Abdullah Mayati, Olivier Fardel
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n=84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n=44), 61...
December 1, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29196988/analysis-of-spontaneous-postmarket-case-reports-submitted-to-the-fda-regarding-thromboembolic-adverse-events-and-jak-inhibitors
#10
Abril Verden, Mo Dimbil, Robert Kyle, Brian Overstreet, Keith B Hoffman
INTRODUCTION: The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks...
December 2, 2017: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29182760/expression-patterns-of-tnf%C3%AE-madcam1-and-stat3-in-intestinal-and-skin-manifestations-of-inflammatory-bowel-disease
#11
Stephan R Vavricka, Jose A Galván, Heather Dawson, Alex Soltermann, Luc Biedermann, Michael Scharl, Alain M Schoepfer, Gerhard Rogler, Mareike B Prinz Vavricka, Luigi Terracciano, Alexander Navarini, Inti Zlobec, Alessandro Lugli, Thomas Greuter
Background: Pathogenesis of cutaneous extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics such as anti-integrins or JAK-inhibitors is not yet clear. Methods: We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, Hsp-27/70 on 240 intestinal (55 controls, 185 IBD) and 64 skin biopsies (11 controls, 18 Erythema nodosum (EN), 13 Pyoderma gangenosum (PG), 22 psoriasis)...
November 22, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/29180110/interleukin-6-inhibits-the-differentiation-of-rat-stem-leydig-cells
#12
Yiyan Wang, Lanlan Chen, Lubin Xie, Linchao Li, Xiaoheng Li, Huitao Li, Jianpeng Liu, Xianwu Chen, Baiping Mao, Tiantian Song, Qingquan Lian, Ren-Shan Ge
Inflammation causes male hypogonadism. Several inflammatory cytokines, including interleukin 6 (IL-6), are released into the blood and may suppress Leydig cell development. The objective of the present study was to investigate whether IL-6 affected the proliferation and differentiation of rat stem Leydig cells. Leydig cell-depleted rat testis (in vivo) and seminiferous tubules (in vitro) with ethane dimethane sulfonate (EDS) were used to explore the effects of IL-6 on stem Leydig cell development. Intratesticular injection of IL-6 (10 and 100 ng/testis) from post-EDS day 14 to 28 blocked the regeneration of Leydig cells, as shown by the lower serum testosterone levels (21...
November 24, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29163799/jak2-aberrations-in-childhood-b-cell-precursor-acute-lymphoblastic-leukemia
#13
Elisabeth M P Steeghs, Isabel S Jerchel, Willemieke de Goffau-Nobel, Alex Q Hoogkamer, Judith M Boer, Aurélie Boeree, Cesca van de Ven, Marco J Koudijs, Nicolle J M Besselink, Hester A de Groot-Kruseman, Christian Michel Zwaan, Martin A Horstmann, Rob Pieters, Monique L den Boer
JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions)...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29162613/the-jak1-2-inhibitor-ruxolitinib-reverses-interleukin-6-mediated-suppression-of-drug-detoxifying-proteins-in-cultured-human-hepatocytes
#14
Marie Febvre-James, Arnaud Bruyere, Marc Le Vee, Olivier Fardel
The inflammatory cytokine interleukin (IL)-6, which basically activates the JAK/STAT signaling pathway, is well-known to repress expression of hepatic cytochromes P-450 (CYPs) and transporters. Therapeutic proteins, like mAbs targeting IL-6 or its receptor, have been consequently demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract IL-6 repressing effects towards hepatic detoxifying systems...
November 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29150291/ruxolitinib-conjugated-gold-nanoparticles-for-topical-administration-an-alternative-for-treating-alopecia
#15
Sanda Boca, Cristian Berce, Ancuta Jurj, Bobe Petrushev, Laura Pop, Grigore-Aristide Gafencu, Sonia Selicean, Vlad Moisoiu, Daiana Temian, Wilhelm-Thomas Micu, Simion Astilean, Cornelia Braicu, Ciprian Tomuleasa, Ioana Berindan-Neagoe
Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration...
November 2017: Medical Hypotheses
https://www.readbyqxmd.com/read/29139090/tofacitinib-a-review-in-rheumatoid-arthritis
#16
Sohita Dhillon
Tofacitinib (Xeljanz(®)) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months' duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months)...
November 14, 2017: Drugs
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#17
Martin Griesshammer, Parvis Sadjadian
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythaemia vera (PV) and essential thrombocythaemia (ET). They are characterized by stem cell-derived clonal proliferation, harbour Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukaemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials...
November 14, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29132131/il-6-promotes-fsh-induced-vegf-expression-through-jak-stat3-signaling-pathway-in-bovine-granulosa-cells
#18
Meng Yang, Lei Wang, Xurong Wang, Xuezhi Wang, Zhiqiang Yang, Jianxi Li
BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6) is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles...
November 13, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29127481/expression-of-janus-kinase-1-in-vitiligo-psoriasis-before-and-after-narrow-band-uvb-a-case-control-study
#19
Hanan Rabea Nada, Dina Ahmed El Sharkawy, Maha Fathy Elmasry, Laila Ahmed Rashed, Sally Mamdouh
Janus kinases (JAKs) are non-receptor protein tyrosine kinases that are expressed in many tissues. Once the JAKs are activated, a cascade of further signaling events is triggered involving phosphorylation of selected receptor chain tyrosines, binding of signal transducer and activator of transcription (STAT) proteins and phosphorylation of these STATs. Due to their ability to selectively modulate immune function, targeted JAK inhibitors are promising candidates for some skin diseases such as psoriasis and atopic dermatitis...
November 10, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/29119628/stat3-expression-and-activity-are-up-regulated-in-diffuse-large-b-cell-lymphoma-of-dogs
#20
A L F V Assumpção, P C Jark, C C Hong, Z Lu, H M Ruetten, C M Heaton, M E Pinkerton, X Pan
BACKGROUND: The Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathways play important roles in the pathogenesis of diffuse large B cell lymphoma (DLBCL) in humans, and up-regulated STAT3 expression and activity are associated with worse clinical outcome in humans. No studies have evaluated the JAK-STAT signaling pathway in DLBCL of dogs. HYPOTHESIS: STAT3 pathway is deregulated in DLBCL in dogs. We aim to assess the expression, activation, and cellular localization of STAT3 and mitogen-activated protein kinase ERK1/2 in DLBCL of dogs...
November 9, 2017: Journal of Veterinary Internal Medicine
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