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Jak2 inhibitor

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https://www.readbyqxmd.com/read/29239838/mediator-kinase-phosphorylation-of-stat1-s727-promotes-growth-of-neoplasms-with-jak-stat-activation
#1
Ioana I Nitulescu, Sara C Meyer, Qiang Jeremy Wen, John D Crispino, Madeleine E Lemieux, Ross L Levine, Henry E Pelish, Matthew D Shair
Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727...
November 21, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29235894/pacritinib-and-its-use-in-the-treatment-of-patients-with-myelofibrosis-who-have-thrombocytopenia
#2
Adolfo Enrique Diaz, Ruben A Mesa
The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity...
December 13, 2017: Future Oncology
https://www.readbyqxmd.com/read/29229632/activation-of-the-aryl-hydrocarbon-receptor-leads-to-resistance-to-egfr-tkis-in-non-small-cell-lung-cancer-by-activating-src-mediated-bypass-signaling
#3
Mingxiang Ye, Yong Zhang, Hongjun Gao, Yan Xu, Pengyu Jing, Jianxiong Wu, Xinxin Zhang, Jie Xiong, Chenfang Dong, Libo Yao, Jian Zhang, Jian Zhang
PURPOSE: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. EXPERIMENTAL DESIGN: AhR expression in non-small-cell lung cancer (NSCLC) was determined by Western blotting and IHC staining...
December 11, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29228628/drug-sensitivity-profiling-identifies-potential-therapies-for-lymphoproliferative-disorders-with-overactive-jak-stat3-signaling
#4
Heikki Kuusanmäki, Olli Dufva, Elina Parri, Arjan J van Adrichem, Hanna Rajala, Muntasir M Majumder, Bhagwan Yadav, Alun Parsons, Wing C Chan, Krister Wennerberg, Satu Mustjoki, Caroline A Heckman
Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228585/role-of-the-jak2-stat3-signaling-pathway-in-the-pathogenesis-of-type-2-diabetes-mellitus-with-macrovascular-complications
#5
Mengxue Yang, Mei Tian, Xuan Zhang, Jie Xu, Bo Yang, Jie Yu, Fengping Li, Ya Li, Sicheng Li, Xianwen Li
This study investigated the role of the JAK2/STAT3/SOCS pathway in type 2 diabetes mellitus (T2DM) and macrovascular complications (DV) (T2DM+DV) conditions. Human umbilical vein endothelial cells (HUVECs) were co-cultured with human monocytes (THP-1) and exposed to peripheral blood sera from 30 T2DM patients, 30 patients with T2DM+DV and 30 healthy controls; the groups were divided into the control, T2DM, DV, T2DM+AG490 and DV+AG490 groups. Chemotaxis of treated HUVECs toward THP-1 cells was assessed using Transwell migration...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228564/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#6
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228427/mir-155-regulates-lymphoma-cell-proliferation-and-apoptosis-through-targeting-socs3-jak-stat3-signaling-pathway
#7
X-D Li, X-M Li, J-W Gu, X-C Sun
OBJECTIVE: Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling pathway participates in regulating cell proliferation, differentiation, and apoptosis, and related to lymphoma. Suppressors of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK-STAT signaling pathway. SOCS3 reduction and miR-155 up-regulation are associated with lymphoma pathogenesis. Bioinformatics analysis showed the complementary binding site between miR-155 and SOCS3. This study aimed to investigate the role of miR-155 in regulating SOCS3/JAK-STAT signaling pathway and affecting diffuse large B cell lymphoma (DLBCL) cell proliferation and apoptosis...
November 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29228301/targeted-inhibition-of-janus-kinases-abates-interfon-gamma-induced-invasive-behaviour-of-fibroblast-like-synoviocytes
#8
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/29224367/effect-of-ruxolitinib-therapy-on-the-quality-of-life-of-japanese-patients-with-myelofibrosis
#9
Kenji Oritani, Kohshi Ohishi, Shinichiro Okamoto, Keita Kirito, Norio Komatsu, Tetsuzo Tauchi, Hiroshi Handa, Shigeki Saito, Katsuto Takenaka, Kazuya Shimoda, Hikaru Okada, Taro Amagasaki, Shiho Wakase, Kojiro Shimozuma, Koichi Akashi
OBJECTIVES: Myelofibrosis (MF) is associated with a significant symptom burden that severely impacts patient quality of life (QOL). Ruxolitinib, a potent Janus kinase 1 (JAK1)/JAK2 inhibitor, led to substantial improvements in splenomegaly, MF-associated symptoms, and QOL in the phase 3 COMFORT studies, proving superior to placebo and best available therapy. We evaluated the effect of ruxolitinib on symptoms and QOL in Japanese patients with MF. METHODS: We conducted a pooled analysis of studies A2202 (NCT01392443) and AJP01 (NCT02087059) of ruxolitinib in Japanese patients with MF (N = 81)...
December 9, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/29222296/what-are-the-current-treatment-approaches-for-patients-with-polycythemia-vera-and-essential-thrombocythemia
#10
REVIEW
Alessandro M Vannucchi, Paola Guglielmelli
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the "state of the art" in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies...
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
#11
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/29222267/new-therapeutic-targets-in-transfusion-dependent-and-independent-thalassemia
#12
REVIEW
M Domenica Cappellini, Irene Motta
β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin-heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29215754/inhibition-of-jak2-stat3-reduces-tumor-induced-angiogenesis-and-myeloid-derived-suppressor-cells-in-head-and-neck-cancer
#13
Jian-Feng Liu, Wei-Wei Deng, Lei Chen, Yi-Cun Li, Lei Wu, Si-Rui Ma, Wen-Feng Zhang, Lin-Lin Bu, Zhi-Jun Sun
Angiogenesis is an essential event in tumor growth and metastasis, and immune system also contributes to the tumor evasion. Emerging evidences have suggested the bidirectional link between angiogenesis and immunosuppression. Myeloid-derived suppressor cell (MDSC) is a kind of immunosuppressive cells and plays an important role in this process. However, the actual regulatory mechanisms of angiogenesis and MDSCs in head and neck squamous cell carcinoma (HNSCC) were unclear. In this study, through analyzing the immunohistochemistry staining of human HNSCC tissue microarray, we found that the microvascular density (MVD) was significantly increased in HNSCC patients...
December 7, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29214759/clinical-implications-of-quantitative-jak2-v617f-analysis-using-droplet-digital-pcr-in-myeloproliferative-neoplasms
#14
Eunyoung Lee, Kyoung Joo Lee, Hyein Park, Jin Young Chung, Mi Na Lee, Myung Hee Chang, Jongha Yoo, Hyewon Lee, Sun Young Kong, Hyeon Seok Eom
BACKGROUND: JAK2 V617F is the most common mutation in myeloproliferative neoplasms (MPNs) and is a major diagnostic criterion. Mutation quantification is useful for classifying patients with MPN into subgroups and for prognostic prediction. Droplet digital PCR (ddPCR) can provide accurate and reproducible quantitative analysis of DNA. This study was designed to verify the correlation of ddPCR with pyrosequencing results in the diagnosis of MPN and to investigate clinical implications of the mutational burden...
March 2018: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/29212804/myeloproliferative-neoplasms-from-origins-to-outcomes
#15
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/29210652/inhibition-of-jak2-signaling-alleviates-hyperlipidemia-intensified-caerulin-induced-acute-pancreatitis-in-vivo
#16
F Zhu, Y Guan, R Zhang
RATIONALE: Studies have implied the positive association of JAK2/STAT3 signaling with the onset and severity of acute pancreatitis (AP). However, definitive functional study of JAK2/STAT3 signaling in the pathogenesis of acute pancreatitis in vivo is missing and its potential as a therapeutic target and the underlying mechanisms remain to be determined. OBJECTIVES: The aim of this study was to explore the role of JAK2/STAT3 signaling in the pathogenesis of hyperlipidemia-intensified caerulin-induced AP and its potential as a therapeutic target...
December 5, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/29204732/peripheral-leptin-signaling-mediates-formalin-induced-nociception
#17
Zhi-Jing Hu, Wei Han, Chang-Qing Cao, Qi-Liang Mao-Ying, Wen-Li Mi, Yan-Qing Wang
Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a high-fat diet, we found that: (1) the acute thermal pain sensory threshold did not change in obese mice; (2) the model obese mice had fewer nociceptive responses in formalin-induced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation; (3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice, indicating the dysmodulation of topical leptin-leptin receptor signaling in these mice; and (4) leptin-leptin receptor signaling-deficient mice (ob/ob and db/db) or leptin-leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wild-type mice reduced their nociceptive responses in formalin tests...
December 5, 2017: Neuroscience Bulletin
https://www.readbyqxmd.com/read/29203403/carcinogenicity-assessment-of-baricitinib-in-tg-rash2-mice-and-sprague-dawley-crl-cd-rats
#18
Mark Carfagna, Ellen Cannady, Thomas Ryan, Jay Herman, Lew Truex, Kanchan Narwani, John Sullivan
Baricitinib is a potent and selective Janus kinase (JAK)1 and JAK2 inhibitor, and is approved for the treatment of moderately to severely active RA in adults in Europe, Japan, and other countries. This study evaluated the carcinogenic potential of baricitinib in Tg. rasH2 mice and Sprague-Dawley (Crl:CD) rats. Baricitinib was administered daily by oral gavage to Crl:CD rats for up to 94 weeks (dose levels of 0, 1, 3, or 8 mg/kg for males and 0, 3, 8, or 25 mg/kg for females) and to Tg. rasH2 mice for 26 weeks (dose levels of 0, 15, 40, or 300 mg/kg for males and 0, 10, 30, or 150 mg/kg for females)...
December 1, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29199511/clonogenic-versus-morphogenic-mutations-in-myeloid-neoplasms-chronologic-observations-in-a-u2af1-tet2-csf3r-and-jak2-co-mutated-myeloproliferative-neoplasm-suggest-a-hierarchical-order-of-mutations-and-potential-predictive-value-for-kinase-inhibitor-treatment
#19
Magdalena M Gerlach, Pontus Lundberg, Joerg Halter, Christian Arranto, Friedel Wenzel, Stefan Dirnhofer, Alexandar Tzankov
No abstract text is available yet for this article.
December 3, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29197940/thymoquinone-augments-cisplatin-induced-apoptosis-on-esophageal-carcinoma-through-mitigating-the-activation-of-jak2-stat3-pathway
#20
Xue Hu, Jingjing Ma, Vikash Vikash, Jiao Li, Dandan Wu, Ya Liu, Jixiang Zhang, Weiguo Dong
BACKGROUND: Thymoquinone (TQ) is the major constituent of Nigella sativa seed and has shown biological activity in various human carcinomas. However, few studies have reported its effect on esophageal carcinoma (EC). AIMS: To explore the chemosensitive effect and mechanism of TQ in augmentation of cisplatin (DDP)-induced apoptosis of EC, both in vitro and in vivo. METHODS: The viability and apoptosis of esophageal carcinoma cells were detected by the Cell Counting Kit-8 assay, flow cytometry, and Hoechst 33258 staining...
December 2, 2017: Digestive Diseases and Sciences
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