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Jak2 inhibitor

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https://www.readbyqxmd.com/read/28318222/selective-downregulation-of-jak2-and-jak3-by-an-atp-competitive-pan-jak-inhibitor
#1
S Denise Field, Jacob Arkin, Jing Li, Lyn H Jones
PF-956980 has been used previously as a JAK3-selective chemical probe in numerous cell-based experiments. Here, we report that not only is PF-956980 a pan-JAK ATP-competitive inhibitor, but it also causes selective reduction of endogenous JAK2 and JAK3 protein levels in human primary immune cells (in a time-dependent manner), leaving the other JAK family members (JAK1 and TYK2) unchanged. We found that PF-956980 selectively downregulated JAK2 and JAK3 mRNA, corresponding to changes observed at the protein level...
March 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28314843/quantitative-proteome-heterogeneity-in-myeloproliferative-neoplasm-subtypes-and-association-with-jak2-mutation-status
#2
Nuria Socoro-Yuste, Cokic Vladan P, Julie Mondet, Isabelle Plo, Pascal Mossuz
Apart from well-known genetic abnormalities, several studies have reported variations in protein expression in Philadelphia negative (Ph-) Myeloproliferative Neoplasm (MPN) patients that could contribute towards their clinical phenotype. In this context, a quantitative mass spectrometry proteomics protocol was used to identify differences in the granulocyte proteome with the goal to characterize the pathogenic role of aberrant protein expression in MPNs. LC MS/MS (LTQ Orbitrap) coupled to iTRAQ labeling showed significant and quantitative differences in protein content among various MPN subtypes [polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)], and according to the genetic status of JAK2 (JAK2V617F presence and JAK2V617F allele burden)...
March 17, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28303311/-immunotherapy-of-cancer-with-checkpoint-inhibitors-not-only-in-malignant-melanoma
#3
A Neubauer
The newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research. The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic. Ipilimumab was the first monoclonal antibody developed against a target present on T cells after becoming activated, CTLA-4. In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide...
March 16, 2017: Der Internist
https://www.readbyqxmd.com/read/28302714/ruxolitinib-a-potent-jak1-jak2-inhibitor-induces-temporary-reductions-in-the-allelic-burden-of-concurrent-csf3r-mutations-in-chronic-neutrophilic-leukemia
#4
Arief S Gunawan, Donal P McLornan, Bridget Wilkins, Katherine Waghorn, Yvette Hoade, Nick C P Cross, Claire N Harrison
No abstract text is available yet for this article.
March 16, 2017: Haematologica
https://www.readbyqxmd.com/read/28298334/erythropoietin-facilitates-definitive-endodermal-differentiation-of-mouse-embryonic-stem-cells-via-activation-of-erk-signaling
#5
Taku Kaitsuka, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan-Yan Wei, Nobuaki Shiraki, Shoen Kume, Kazuhito Tomizawa
Artificially generated pancreatic β-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic β-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm...
March 15, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28295507/crocin-suppresses-constitutively-active-stat3-through-induction-of-protein-tyrosine-phosphatase-shp-1
#6
Buyun Kim, Ki Yong Lee, Byoungduck Park
The aim of the present study is to investigate the effect of a natural compound crocin, one of the active components of saffron, on human multiple myeloma cells. Crocin effectively suppressed constitutive STAT3 activation, translocation of STAT3 to the nucleus, and its target gene expression. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases JAK1, JAK2 and c-Src. We found that crocin induced the expression of SHP-1, a tyrosine protein phosphatase, and pervanadate treatment reversed the crocin-induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase...
March 10, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28292965/repurposed-jak1-jak2-inhibitor-reverses-established-autoimmune-insulitis-in-non-obese-diabetic-mice
#7
Prerak M Trivedi, Kate L Graham, Nicholas A Scott, Misty R Jenkins, Suktilang Majaw, Robyn M Sutherland, Stacey Fynch, Andrew M Lew, Christopher J Burns, Balasubramanian Krishnamurthy, Thomas C Brodnicki, Stuart I Mannering, Thomas W Kay, Helen E Thomas
Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics from other diseases to type 1 diabetes, especially when there is evidence for overlapping mechanisms. JAK1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and STAT1 pathway in human type 1 diabetes and in mouse models, especially in beta cells...
March 14, 2017: Diabetes
https://www.readbyqxmd.com/read/28279039/-regulation-of-ruxolitinib-on-matrix-metalloproteinase-in-jak2v617f-positive-myeloroliferative-neoplasms-cells
#8
G M Liu, L J Zhang, J Z Fu, W T Liang, Z Y Cheng, P Bai, Y S Bian, J S Wan
Objective: To investigate the regulation of JAK2 tyrosine kinase inhibitor ruxolitinib on extracellular matrix metalloproteinase (MMP in JAK2V617F positive myeloproliferative neoplasms (MPN) cells. Methods: ①Forty cases of newly diagnosed JAK2V617F positive MPN patients and 15 healthy volunteers as control in Baoding No.1 Hospital between January 2012 and December 2015 were enrolled in this study. JAK2V617F/JAK2 ratio was detected by real-time-PCR; the expression levels of phosphorylation protein tyrosine kinase 2 (p-JAK2) , MMP-2 and MMP-9 in pathological tissues of bone marrow were detected by immunohistochemistry...
February 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28278513/il-6-enhances-osteocyte-mediated-osteoclastogenesis-by-promoting-jak2-and-rankl-activity-in-vitro
#9
Qing Wu, Xiaokang Zhou, Danqing Huang, Yingchen Ji, Feiwu Kang
BACKGROUND/AIMS: Evidence suggests that IL-6 affects bone mass by modulating osteocyte communication towards osteoclasts. However, the mechanism by which IL-6 enhances osteocyte-mediated osteoclastogenesis is unclear. We aimed to investigate the inflammatory factors in serum after orthodontic surgery and their relationship between osteocytes and osteoclasts. METHODS: Serum was obtained from 10 orthognathic surgery patients, and inflammatory factors were detected by ELISA...
March 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28277287/the-promise-of-janus-kinase-inhibitors-in-the-treatment-of-hematological-malignancies
#10
REVIEW
Emilee Senkevitch, Scott Durum
The Janus kinases (JAK) are a family of kinases that play an essential role in cytokine signaling and are implicated in the pathogenesis of autoimmune diseases and hematological malignancies. As a result, the JAKs have become attractive therapeutic targets. The discovery of a JAK2 point mutation (JAK2 V617F) as the main cause of polycythemia vera lead to the development and FDA approval of a JAK1/2 inhibitor, ruxolitinib, in 2011. This review focuses on the various JAK and associated components aberrations implicated in myeloproliferative neoplasms, leukemias, and lymphomas...
October 27, 2016: Cytokine
https://www.readbyqxmd.com/read/28273188/-treatment-options-and-limitations-in-the-management-of-myelofibrosis
#11
Gábor Körösmezey, Gabriella Gyõri, Gábor Rudas, Hanna Eid, Zsolt Nagy, Judit Demeter
Primary myelofibrosis has the worst outcome among classical chronic myeloproliferative neoplasms. The past decade has brought numerous discoveries elucidating the role of proliferative mutations in disease pathogenesis. Mutations of the genes JAK2, MPL and CALR are present in about 90 percent of all primary myelofibrosis cases. The prognosis of myelofibrosis is considered heterogeneous, the expected survival of patients may range from one year to more than a decade based on several prognostic factors. Estimated survival can be assessed based on clinical prognostic scores...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28262948/swelling-induced-chloride-current-in-glioblastoma-proliferation-migration-and-invasion
#12
Raymond Wong, Wenliang Chen, Xiao Zhong, James T Rutka, Zhong-Ping Feng, Hong-Shuo Sun
Glioblastoma (GBM) remains as the most common and aggressive brain tumor. The survival of GBM has been linked to the aberrant activation of swelling-induced chloride current ICl,swell . In this study, we investigated the effects of ICl,swell on cell viability, proliferation and migration in the human GBM cell lines, U251 and U87, using a combination of patch clamp electrophysiology, MTT, colony formation, wound healing assays and Western immunoblotting. First, we showed that the specific inhibitor of ICl,swell , DCPIB, potently reduced the ICl,swell in U87 cells...
March 6, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28260800/a-novel-stat3-inhibitor-negatively-modulates-platelet-activation-and-aggregation
#13
Zhuan Xu, Yu-Jia Xu, Ya-Nan Hao, Li-Jie Ren, Zu-Bin Zhang, Xin Xu, Bi-Yin Cao, Ke-Sheng Dai, Li Zhu, Qi Fang, Yan Kong, Xin-Liang Mao
The signal transducer and activator of transcription 3 (STAT3) plays a critical role in platelet functions. This study sought to understand the effects of the STAT3 inhibitor SC99 on platelet activation and aggregation. Immunoblotting assays were applied to measure the effects of SC99 on the STAT3 signaling pathway. A ChronoLog aggregometer was used to evaluate platelet aggregation. A flow cytometer was used to evaluate P-selectin expression in the presence of SC99. AlamarBlue and Annexin-V staining were used to evaluate platelet viability and apoptosis, respectively...
March 6, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28260257/a-case-based-discussion-of-clinical-problems-in-the-management-of-patients-treated-with-ruxolitinib-for-myelofibrosis
#14
P Joy Ho, Ashish Bajel, Kate Burbury, Lindsay Dunlop, Simon Durrant, Cecily Forsyth, Andrew C Perkins, David M Ross
Ruxolitinib is a dual janus kinase 1 (JAK1)/JAK2 inhibitor used to treat splenomegaly and symptoms associated with myelofibrosis (MF). Current therapeutic options for symptomatic MF include supportive care, myelosuppressive therapy (such as hydroxycarbamide) and janus kinase (JAK) inhibitors (in particular ruxolitinib). Allogeneic stem cell transplantation remains the only potentially curative treatment for MF, and younger transplant-eligible patients should still be considered for allogeneic stem cell transplantation; however, this is applicable only to a small proportion of patients...
March 2017: Internal Medicine Journal
https://www.readbyqxmd.com/read/28239766/up-regulation-of-gbp2-is-associated-with-neuronal-apoptosis-in-rat-brain-cortex-following-traumatic-brain-injury
#15
Qi Miao, Meihong Ge, Lili Huang
Guanylate binding protein 2 (GBP2) is one member of GBP family. Recently, GBP2 has been proposed to be a novel target of anti-cancer drugs. However, the role of GBP2 in the traumatic brain injury (TBI) is very limited. In this study, we sought to define GBP2's role in brain injury. GBP2 protein levels were significantly increased in the brain 3 days after injury, suggesting a functional role for GBP2 in TBI. Neuronal cells overexpressing GBP2 exhibited up-regulation of co-location of GBP2 and NeuN following TBI, suggesting that GBP2 potentiates the neuron apoptosis...
February 27, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28228106/long-term-treatment-with-ruxolitinib-for-patients-with-myelofibrosis-5-year-update-from-the-randomized-double-blind-placebo-controlled-phase-3-comfort-i-trial
#16
Srdan Verstovsek, Ruben A Mesa, Jason Gotlib, Vikas Gupta, John F DiPersio, John V Catalano, Michael W N Deininger, Carole B Miller, Richard T Silver, Moshe Talpaz, Elliott F Winton, Jimmie H Harvey, Murat O Arcasoy, Elizabeth O Hexner, Roger M Lyons, Ronald Paquette, Azra Raza, Mark Jones, Deanna Kornacki, Kang Sun, Hagop Kantarjian
BACKGROUND: The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. METHODS: Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo...
February 22, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28214951/inhibition-of-jak-stat-pathway-restrains-tslp-activated-dendritic-cells-mediated-inflammatory-t-helper-type-2-cell-response-in-allergic-rhinitis
#17
Zhaohui Shi, Weihong Jiang, Min Wang, Xiaocheng Wang, Xiaoyuan Li, Xiaodong Chen, Li Qiao
Thymic stromal lymphopoietin (TSLP) has recently been implicated as a key molecule for initiating allergic rhinitis (AR) at the cell-dendritic cell (DC) interface. Previous studies demonstrated that TSLP activated DCs to express more OX40 ligand (OX40L), which is associated with the initiation of T helper type 2 (Th2) cell responses. STAT phosphorylation has been reported to be promoted by TSLP. Thus, we investigated if the JAK/STAT pathway inhibitor CYT387 could affect TSLP-DC-mediated Th2 cell response in naive T cell and AR mice model...
February 18, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28208828/ginkgolic-acid-c-17-1-derived-from-ginkgo-biloba-leaves-suppresses-constitutive-and-inducible-stat3-activation-through-induction-of-pten-and-shp-1-tyrosine-phosphatase
#18
Seung Ho Baek, Jong Hyun Lee, Chulwon Kim, Jeong-Hyeon Ko, Seung-Hee Ryu, Seok-Geun Lee, Woong Mo Yang, Jae-Young Um, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Gautam Sethi, Kwang Seok Ahn
Ginkgolic acid C 17:1 (GAC 17:1) extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s) through modulation of several molecular targets in tumor cells, however the detailed mechanism(s) of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy...
February 13, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28199814/baricitinib-versus-placebo-or-adalimumab-in-rheumatoid-arthritis
#19
RANDOMIZED CONTROLLED TRIAL
Peter C Taylor, Edward C Keystone, Désirée van der Heijde, Michael E Weinblatt, Liliana Del Carmen Morales, Jaime Reyes Gonzaga, Sergey Yakushin, Taeko Ishii, Kahaku Emoto, Scott Beattie, Vipin Arora, Carol Gaich, Terence Rooney, Douglas Schlichting, William L Macias, Stephanie de Bono, Yoshiya Tanaka
Background Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. Methods We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week...
February 16, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28193568/markers-of-iron-deficiency-in-patients-with-polycythemia-vera-receiving-ruxolitinib-or-best-available-therapy
#20
Srdan Verstovsek, Claire N Harrison, Jean-Jacques Kiladjian, Carole Miller, Ahmad B Naim, Dilan C Paranagama, Dany Habr, Alessandro M Vannucchi
Polycythemia vera (PV) is characterized by erythropoiesis and JAK2-activating mutations, with increased risks of morbidity and mortality. Most patients with PV are iron deficient, and treatment often includes hematocrit control with phlebotomy, which may exacerbate iron deficiency-associated complications. The phase 3 RESPONSE trial evaluated the JAK1/JAK2 inhibitor ruxolitinib (n=110) versus best available therapy (BAT; n=112) in patients with PV who were hydroxyurea-resistant/intolerant. Ruxolitinib was superior to BAT for hematocrit control, reduction in splenomegaly, and blood count normalization...
January 31, 2017: Leukemia Research
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