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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
#1
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
#2
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
#3
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
#4
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...
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
#5
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
https://www.readbyqxmd.com/read/28188131/momelotinib-inhibits-acvr1-alk2-decreases-hepcidin-production-and-ameliorates-anemia-of-chronic-disease-in-rodents
#6
Malte Asshoff, Verena Petzer, Matthew R Warr, David Haschka, Piotr Tymoszuk, Egon Demetz, Markus Seifert, Wilfried Posch, Manfred Nairz, Pat Maciejewski, Peter Fowles, Christopher J Burns, Gregg Smith, Kay-Uwe Wagner, Guenter Weiss, J Andrew Whitney, Igor Theurl
Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Results from a phase 2 study for the treatment of MF with the Janus kinase1/2 (JAK1/2) inhibitor momelotinib (MMB) demonstrated that MMB treatment ameliorated anemia, unexpected for a JAK1/2 inhibitor, as erythropoietin-mediated JAK2 signaling is essential for erythropoiesis. Using a rat model of anemia of chronic disease (ACD), we now demonstrate that MMB treatment can normalize hemoglobin and red blood cell numbers...
February 10, 2017: Blood
https://www.readbyqxmd.com/read/28187727/cryptotanshinone-enhances-the-effect-of-arsenic-trioxide-in-treating-liver-cancer-cell-by-inducing-apoptosis-through-downregulating-phosphorylated-stat3-in-vitro-and-in-vivo
#7
Li Shen, Guangshun Zhang, Zhaohuan Lou, Guanhua Xu, Guangji Zhang
BACKGROUND: Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo. METHODS: Cell viability of ATO combined with CT was assessed by (1)MTT assay...
February 10, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28186964/il-6-secreted-by-cancer-associated-fibroblasts-promotes-epithelial-mesenchymal-transition-and-metastasis-of-gastric-cancer-via-jak2-stat3-signaling-pathway
#8
Xiongyan Wu, Pan Tao, Quan Zhou, Jie Li, Zhenjia Yu, Xiaofeng Wang, Jiaanfang Li, Chen Li, Min Yan, Zhenggang Zhu, Bingya Liu, Liping Su
Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs...
February 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28185846/corticoids-synergize-with-il-1-in-the-induction-of-lcn2
#9
J Conde, V Lazzaro, M Scotece, V Abella, R Villar, V López, M Á Gonzalez-Gay, J Pino, R Gómez, A Mera, O Gualillo
OBJECTIVE: Lipocalin-2 (LCN2) is an adipokine that was first identified in neutrophil granules. In the last years it was recognized as a factor that could impair chondrocyte phenotype, cartilage homeostasis as well as growth plate development. Both pro-inflammatory cytokines and glucocorticoids (GCs) modulate LCN2 expression. Actually, GCs were found to be LCN2 inducers, suggesting that part of the negative actions exerted by these anti-inflammatory drugs at cartilage level could be mediated by this adipokine...
February 6, 2017: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28159736/myeloproliferative-neoplasm-stem-cells
#10
Adam J Mead, Ann Mullally
Myeloproliferative neoplasms (MPN) arise in the hematopoietic stem cell (HSC) compartment as a result of the acquisition of somatic mutations in a single HSC that provide a selective advantage to mutant HSC over normal HSC and promote myeloid differentiation to engender a myeloproliferative phenotype. This population of somatically mutated HSC, which initiate and sustain MPN, are termed MPN stem cells. In greater than 95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in one of three genes: JAK2, CALR or MPL The thrombopoietin receptor, MPL is the key cytokine receptor in MPN development and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells...
February 3, 2017: Blood
https://www.readbyqxmd.com/read/28119526/rethinking-jak2-inhibition-towards-novel-strategies-of-more-specific-and-versatile-janus-kinase-inhibition
#11
REVIEW
E Leroy, S N Constantinescu
Janus kinases (JAKs) are required for cytokine receptor signaling. Since the discovery of the highly prevalent JAK2 V617F mutation in myeloproliferative neoplasms (MPNs), JAK2 became a prime target for inhibition. Only one approved JAK2 inhibitor exists, with positive, but not curative effects in MPNs, and promising effects in autoimmune diseases and cancer. Based on recent advances in the structural features regulating both normal and mutant JAKs, as well as in small-molecule targeting, we review the current state of JAK2 inhibitor development and present novel avenues of selecting JAK2 inhibitors, with broad and narrow specificities and extend these approaches to other JAKs...
January 25, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28112370/the-jak-stat-pathway-is-involved-in-the-upregulation-of-pd-l1-expression-in-pancreatic-cancer-cell-lines
#12
Toshifumi Doi, Takeshi Ishikawa, Tetsuya Okayama, Kaname Oka, Katsura Mizushima, Tomoyo Yasuda, Naoyuki Sakamoto, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Tomohisa Takagi, Yuji Naito, Yoshito Itoh
Although improvements in the chemotherapy modalities for pancreatic cancer have been realized, pancreatic cancer remains one of the most lethal malignancies. New-generation cancer immunotherapy methods, such as blocking of the PD-1/PD-L1 pathway, are consistently being investigated to improve the survival of pancreatic cancer patients. In the present study, we evaluated the influence of anticancer agents 5-fluorouracil, gemcitabine and paclitaxel on PD-L1 expression in human pancreatic cancer cell lines MIA PaCa-2 and AsPC-1 and in murine pancreatic cancer cell line Pan02...
January 23, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28109944/synthesis-biological-evaluation-and-molecular-dynamics-md-simulation-studies-of-three-novel-f-18-labeled-and-focal-adhesion-kinase-fak-targeted-5-bromo-pyrimidines-as-radiotracers-for-tumor
#13
Yu Fang, Dawei Wang, Xingyu Xu, Jianping Liu, Aiqin Wu, Xiang Li, Qianqian Xue, Huan Wang, Hang Wang, Huabei Zhang
Focal adhesion kinase (FAK) is considered as an attractive target for oncology. A series of F-18 labeled 5-bromo-N(2)-(4-(2-fluoro-pegylated (FPEG))-3,5-dimethoxyphenyl)-N(4)-(4-methoxyphenyl)pyrimidine-2,4-diamine derivatives were prepared and evaluated as the FAK targeted radiotracers for the early diagnoses of tumor. For the study of the FAK targeted drug molecules, this was the first attempt to develop the tumor diagnostic imaging agents on the radiopharmaceutical level. They inhibited the activity of FAK with IC50 in the range of 91...
January 11, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28109147/-co-culture-with-umbilical-cord-mesenchymal-stem-cells-promotes-the-synthesis-and-mechnism-of-milk-protein-in-bovine-mammary-epithelial-cells
#14
Yankun Zhao, Wei Shao, Chenglong Luo, Kaile Wu, Xiong Yu
Objective To explore the possible mechanism of umbilical cord mesenchymal stem cells (UCMSCs) regulating milk protein synthesis in bovine mammary gland epithelial cells (BMECs). Methods UCMSCs and BMECs were co-cultured by double-chamber Transwell(TM), and other BMECs were cultured alone as a control group. Insulin like growth factor 1 receptor (IGF-1R) inhibitor AG1024 was used to treat cells. IGF-1, β casein (CSN2) and κ casein (CSN3) content in the supernatants were determined by ELISA; the relative expression abundance of Janus kinase and signal transducer and activator of transcription factor (JAK/STAT) signaling pathway-related genes were detected by quantitative real-time PCR (qRT-PCR); and after the cells were treated with JAK2 signal blocker AG490, qRT-PCR was performed to test the relative expression abundance of CSN2 and CSN3 mRNAs...
February 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/28094778/adipocyte-fatty-acid-binding-protein-potentiates-toxic-lipids-induced-endoplasmic-reticulum-stress-in-macrophages-via-inhibition-of-janus-kinase-2-dependent-autophagy
#15
Ruby L C Hoo, Lingling Shu, Kenneth K Y Cheng, Xiaoping Wu, Boya Liao, Donghai Wu, Zhiguang Zhou, Aimin Xu
Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation. Endoplasmic reticulum (ER) stress and adipocyte fatty acid binding protein (A-FABP) play key roles in obesity and mediate inflammatory activity through similar signaling pathways. However, little is known about their interplay in lipid-induced inflammatory responses. Here, we showed that prolonged treatment of palmitic acid (PA) increased ER stress and expression of A-FABP, which was accompanied by reduced autophagic flux in macrophages...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28094236/deficiency-of-ptp1b-attenuates-hypothalamic-inflammation-via-activation-of-the-jak2-stat3-pathway-in-microglia
#16
Taku Tsunekawa, Ryoichi Banno, Akira Mizoguchi, Mariko Sugiyama, Takashi Tominaga, Takeshi Onoue, Daisuke Hagiwara, Yoshihiro Ito, Shintaro Iwama, Motomitsu Goto, Hidetaka Suga, Yoshihisa Sugimura, Hiroshi Arima
Protein tyrosine phosphatase 1B (PTP1B) regulates leptin signaling in hypothalamic neurons via the JAK2-STAT3 pathway. PTP1B has also been implicated in the regulation of inflammation in the periphery. However, the role of PTP1B in hypothalamic inflammation, which is induced by a high-fat diet (HFD), remains to be elucidated. Here, we showed that STAT3 phosphorylation (p-STAT3) was increased in microglia in the hypothalamic arcuate nucleus of PTP1B knock-out mice (KO) on a HFD, accompanied by decreased Tnf and increased Il10 mRNA expression in the hypothalamus compared to wild-type mice (WT)...
January 9, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28089238/ruxolitinib-for-symptom-control-in-patients-with-chronic-lymphocytic-leukaemia-a-single-group-phase-2-trial
#17
Preetesh Jain, Michael Keating, Sarah Renner, Charles Cleeland, Huang Xuelin, Graciela Nogueras Gonzalez, David Harris, Ping Li, Zhiming Liu, Ivo Veletic, Uri Rozovski, Nitin Jain, Phillip Thompson, Prithviraj Bose, Courtney DiNardo, Alessandra Ferrajoli, Susan O'Brien, Jan Burger, William Wierda, Srdan Verstovsek, Hagop Kantarjian, Zeev Estrov
BACKGROUND: Disease-related symptoms impair the quality of life of patients with chronic lymphocytic leukaemia (CLL) who do not require systemic therapy. Available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms in patients with myelofibrosis, we postulated that ruxolitinib would improve disease-related symptoms in patients with CLL. We did a phase 2 trial of ruxolitinib to test this hypothesis...
February 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#18
Elena Calama, Isabel Ramis, Anna Domènech, Cristina Carreño, Jorge De Alba, Neus Prats, Montserrat Miralpeix
BACKGROUND AND PURPOSE: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor...
January 10, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28068330/loss-of-p53-induces-leukemic-transformation-in-a-murine-model-of-jak2-v617f-driven-polycythemia-vera
#19
T Tsuruta-Kishino, J Koya, K Kataoka, K Narukawa, Y Sumitomo, H Kobayashi, T Sato, M Kurokawa
As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28057739/aberrant-let7a-hmga2-signaling-activity-with-unique-clinical-phenotype-in-jak2-mutated-myeloproliferative-neoplasms
#20
Chih-Cheng Chen, Jie-Yu You, Jrhau Lung, Cih-En Huang, Yi-Yang Chen, Yu-Wei Leu, Hsing-Ying Ho, Chian-Pei Li, Chang-Hsien Lu, Kuan-Der Lee, Chia-Chen Hsu, Jyh-Pyng Gau
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA through binding to its 3-untranslated region (3-UTR). Transgenic mice expressing HMGA2 with a truncation of its 3-UTR has been shown to exhibit a myeloproliferative phenotype. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed up-regulation of HMGA2 with concurrent let-7a repression...
January 5, 2017: Haematologica
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