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Jak2 inhibitor

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https://www.readbyqxmd.com/read/28533538/proteomic-analysis-of-jak2v617f-induced-changes-identifies-potential-new-combinatorial-therapeutic-approaches
#1
S Pearson, A J K Williamson, R Blance, T C P Somervaille, S Taylor, N Azadbakht, A D Whetton, A Pierce
In excess of 90% of patients with polycythemia vera express a mutated form of JAK2, JAK2V617F. Such aberrant proteins offer great potential for the treatment of these diseases however inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. To understand the effects of this oncogene in hematopoietic cells with the aim of improving treatment strategies we undertook a systematic evaluation of the effects of JAK2V617F expression using proteomics. The effects of JAK2V617F on over 5000 proteins and 2000 nuclear phosphopeptides sites were relatively quantified using either SILAC or eight channel iTRAQ mass spectrometry...
May 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28522550/suppression-of-microrna-135b-5pprotects-againstmyocardial-ischemia-reperfusion-injury-by-activatingjak2-stat3-signaling-pathway-in-mice-duringsevofluraneanesthesia
#2
Xiao-Juan Xie, Dong-Mei Fan, Kai Xi, Ya-Wei Chen, Peng-Wei Qi, Qian-Hui Li, Liang Fang, Li-Gang Ma
The study aims to explore the effects of miR-135b-5p on myocardial ischemia/reperfusion (I/R) injuries by regulating JAK2/STAT signaling pathway by mediating inhalation anesthesia with sevoflurane. A sum of 120 healthy Wistar male mice was assigned into six groups. Left ventricular ejection fraction (LVEF) and left ventricular shortening fraction (LVSF) were detected. Cardiomyocyte apoptosis was determined by TUNEL assay. MiR-135b-5p expression, mRNA and protein expression of p-STAT3, p-JAK2, STAT3, JAK2, Bcl2 and Bax were detected by qRT-PCR and Western blotting...
May 18, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#3
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28491265/experience-with-ruxolitinib-in-the-treatment-of-polycythaemia-vera
#4
REVIEW
Samah Alimam, Claire Harrison
Polycythaemia vera (PV) is a myeloproliferative neoplasm classically characterized by an erythrocytosis and is associated with a high risk of thromboembolic events, constitutional symptoms burden and risk of transformation to myelofibrosis and acute myeloid leukaemia. Therapy is directed at the haematocrit (HCT) to reduce the risk of thrombotic events and usually comprises low-dose aspirin and phlebotomy to maintain HCT at >45%. Frequently in addition, cytoreductive therapy is indicated in high-risk patients for normalizing haematological parameters to mitigate the occurrence of thromboembolic events...
April 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28490530/il-6-promotes-epithelial-to-mesenchymal-transition-of-human-peritoneal-mesothelial-cells-possibly-through-jak2-stat3-signaling-pathway
#5
Jing Xiao, Yanan Gong, Ying Chen, Dahai Yu, Xiaoyang Wang, Xiaoxue Zhang, Yanna Dou, Dong Liu, Genyang Cheng, Shan Lu, Wenming Yuan, Yansheng Li, Zhanzheng Zhao
Long-term peritoneal dialysis (PD) therapy results in functional and structural alteration of the peritoneal membrane, including epithelial-to-mesenchymal transition (EMT). Interleukin 6 (IL-6) is a local pleiotropic cytokine, hypothesized to play an important role in EMT. This study was designed to investigate the role of IL-6 in EMT and peritoneal membrane dysfunction in long-term PD patients by assessing the level of IL-6 in dialysate and exploring the relationship between IL-6, the related signaling pathway JAK2/STAT3, and EMT, using in vitro cellular and molecular techniques...
May 10, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28482851/checkpoint-inhibitors-in-hematological-malignancies
#6
REVIEW
Chi Young Ok, Ken H Young
Inhibitory molecules such as PD-1, CTLA-4, LAG-3, or TIM-3 play a role to keep a balance in immune function. However, many cancers exploit such molecules to escape immune surveillance. Accumulating data support that their functions are dysregulated in lymphoid neoplasms, including plasma cell myeloma, myelodysplastic syndrome, and acute myeloid leukemia. In lymphoid neoplasms, aberrations in 9p24.1 (PD-L1, PD-L2, and JAK2 locus), latent Epstein-Barr virus infection, PD-L1 3'-untranslated region disruption, and constitutive JAK-STAT pathway are known mechanisms to induce PD-L1 expression in lymphoma cells...
May 8, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28480959/research-on-the-epigenetic-regulation-mechanism-of-the-ptpn6-gene-in-advanced-chronic-myeloid-leukaemia
#7
Xiaokun Zhang, Lin Yang, Xiaojun Liu, Ziyuan Nie, Xingzhe Wang, Yuxia Pan, Jianmin Luo
PTPN6, a tyrosine phosphatase protein, plays a negative role in cell signal transduction and is negatively correlated with tumour formation and growth. However, epigenetic regulation mechanism of the PTPN6 gene in advanced chronic myeloid leukaemia (CML) remains unclear. This study investigated bone marrow or blood samples from 44 CML patients and 10 healthy volunteers. KCL22 and K562 cells were cultured and treated with demethylation drugs and histone deacetylase inhibitors. Real time quantitative polymerase chain reaction (qPCR), methylation-specific PCR, bisulfite sequencing PCR, Western blotting, co-immunoprecipitation and chromatin immunoprecipitation (ChIP) was performed...
May 8, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28475004/knockdown-of-long-non-coding-rna-hoxd-as1-inhibits-gastric-cancer-cell-growth-via-inactivating-the-jak2-stat3-pathway
#8
Li Zheng, Jiangtao Chen, Zhongyong Zhou, Zhikuan He
Long non-coding RNA HOXD-AS1 (HOXD cluster antisense RNA 1) has been demonstrated to be closely associated with the progression of several tumors. However, the biological function of HOXD-AS1 and the underlying molecular mechanism in gastric cancer are still unclear. The expression of HOXD-AS1 in gastric cancer cell lines was evaluated by quantitative real-time polymerase chain reaction. The association of HOXD-AS1 expression and clinical parameters was statistically analyzed by chi-square test. Cell viability, colony formation capacity, and phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 3 in treated SGC-7901 and BGC-823 cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and western blot analysis, respectively...
May 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28469959/treatment-with-the-c-c-chemokine-receptor-type-5-ccr5-inhibitor-maraviroc-suppresses-growth-and-induces-apoptosis-of-acute-lymphoblastic-leukemia-cells
#9
Jie Zi, Shushu Yuan, Jianlin Qiao, Kai Zhao, Linyan Xu, Kunming Qi, Kailin Xu, Lingyu Zeng
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy diagnosed in children and is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. C-C chemokine receptor type 5 (CCR5) is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. A highly potent competitive antagonist of CCR5, maraviroc, recently has been identified with suppression of cancer cells aggressive in a variety of cancers. However, the effects of maraviroc on ALL cells have not yet been defined...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28468880/selective-activation-of-interferon-%C3%AE-signaling-by-zika-virus-ns5-protein
#10
Vidyanath Chaudhary, Kit-San Yuen, Jasper Fuk-Woo Chan, Ching-Ping Chan, Pei-Hui Wang, Jian-Piao Cai, Shuo Zhang, Mifang Liang, Kin-Hang Kok, Chi-Ping Chan, Kwok-Yung Yuen, Dong-Yan Jin
Severe complications of Zika virus (ZIKV) infection might be caused by inflammation. How ZIKV induces pro-inflammatory cytokines is not understood. In this study, we show opposite regulatory effect of ZIKV NS5 protein on interferon (IFN) signaling. Whereas ZIKV and its NS5 protein were potent suppressors of type I and type III IFN signaling, they were found to activate IFN-γ signaling. Inversely, IFN-γ augmented ZIKV replication. NS5 interacted with STAT2 and targeted it for ubiquitination and degradation, but had no influence on STAT1 stability or nuclear translocation...
May 3, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28466543/mutation-patterns-in-genes-encoding-interferon-signaling-and-antigen-presentation-a-pan-cancer-survey-with-implications-for-the-use-of-immune-checkpoint-inhibitors
#11
Jan Budczies, Michael Bockmayr, Frederick Klauschen, Volker Endris, Stefan Fröhling, Peter Schirmacher, Carsten Denkert, Albrecht Stenzinger
Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated...
May 2, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28465704/huang-gan-formula-eliminates-the-oxidative-stress-effects-of-advanced-oxidation-protein-products-on-the-divergent-regulation-of-the-expression-of-ages-receptors-via-the-jak2-stat3-pathway
#12
Quanwen Deng, Can Bu, Liqian Mo, Bin Lv, Shaolian Song, Xiaoyan Xiao, Guo Dan, Xixiao Yang
Chronic kidney disease (CKD) has a high prevalence and low cure rate and represents a significant health issue. Oxidative stress is common in CKD due to metabolic disorders, inflammation, and impaired renal function changing normal proteins into advanced oxidation protein products (AOPPs). Huang Gan formula (HGF) is a new type of traditional Chinese herbal medicine. Although we previously investigated the protective effects of HGF against oxidative stress, the mechanism of HGF in CKD is still not fully understood...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28461505/suppressors-and-activators-of-jak-stat-signaling-at-diagnosis-and-relapse-of-acute-lymphoblastic-leukemia-in-down-syndrome
#13
Omer Schwartzman, Angela Maria Savino, Michael Gombert, Chiara Palmi, Gunnar Cario, Martin Schrappe, Cornelia Eckert, Arend von Stackelberg, Jin-Yan Huang, Michal Hameiri-Grossman, Smadar Avigad, Geertruy Te Kronnie, Ifat Geron, Yehudit Birger, Avigail Rein, Giulia Zarfati, Ute Fischer, Zohar Mukamel, Martin Stanulla, Andrea Biondi, Giovanni Cazzaniga, Amedeo Vetere, Bridget K Wagner, Zhu Chen, Sai-Juan Chen, Amos Tanay, Arndt Borkhardt, Shai Izraeli
Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DS-ALLs...
May 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28456851/ruxolitinib-reduces-jak2-p-v617f-allele-burden-in-patients-with-polycythemia-vera-enrolled-in-the-response-study
#14
Alessandro Maria Vannucchi, Srdan Verstovsek, Paola Guglielmelli, Martin Griesshammer, Timothy C Burn, Ahmad Naim, Dilan Paranagama, Mahtab Marker, Brian Gadbaw, Jean-Jacques Kiladjian
In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p...
April 30, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28453463/the-igf-i-jak2-stat3-mir-21-signaling-pathway-may-be-associated-with-human-renal-cell-carcinoma-cell-growth
#15
Ying Su, An Zhao, Guoping Cheng, Jingjing Xu, Enming Ji, Wenyong Sun
BACKGROUND: Renal cell carcinoma (RCC) is the highest mortality rate of the genitourinary cancers, and the treatment options are very limited. Thus, identification of molecular mechanisms underlying RCC tumorigenesis, is critical for identifying biomarkers for RCC diagnosis and prognosis. OBJECTIVE: To validate whether the IGF-I/JAK2-STAT3/miR-21 signaling pathway is associated with human RCC cell growth. METHODS: qRT-PCR and Western blotting were used to detect the mRNA and protein expression levels, respectively...
April 21, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28441920/investigational-janus-kinase-inhibitors-in-development-for-myelofibrosis
#16
Prithviraj Bose, Abdallah Abou Zahr, Srdan Verstovsek
Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail...
May 8, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28439875/epigenetic-repression-of-mir-375-is-the-dominant-mechanism-for-constitutive-activation-of-the-pdpk1-rps6ka3-signalling-axis-in-multiple-myeloma
#17
Shotaro Tatekawa, Yoshiaki Chinen, Masaki Ri, Tomoko Narita, Yuji Shimura, Yayoi Matsumura-Kimoto, Taku Tsukamoto, Tsutomu Kobayashi, Eri Kawata, Nobuhiko Uoshima, Tomohiko Taki, Masafumi Taniwaki, Hiroshi Handa, Shinsuke Iida, Junya Kuroda
Cytogenetic/molecular heterogeneity is the hallmark of multiple myeloma (MM). However, we recently showed that the serine/threonine kinase PDPK1 and its substrate RPS6KA3 (also termed RSK2) are universally active in MM, and play pivotal roles in myeloma pathophysiology. In this study, we assessed involvement of aberrant miR-375 repression in PDPK1 overexpression in MM. An analysis of plasma cells from 30 pre-malignant monoclonal gammopathies of undetermined significance and 73 MM patients showed a significant decrease in miR-375 expression in patient-derived plasma cells regardless of the clinical stage, compared to normal plasma cells...
April 25, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28423567/cxcr1-2-pathways-in-paclitaxel-induced-neuropathic-pain
#18
Laura Brandolini, Elisabetta Benedetti, Pier Adelchi Ruffini, Roberto Russo, Loredana Cristiano, Andrea Antonosante, Michele d'Angelo, Vanessa Castelli, Antonio Giordano, Marcello Allegretti, Annamaria Cimini
Chemotherapy-induced peripheral neuropathy (CIPN) is a type of neuropathic pain that represents a frequent and serious consequence of chemotherapy agents. Over the last years, significant progress has been achieved in elucidating the underlying pathogenesis of CIPN. The interference of taxanes with microtubule has been proposed as a mechanism that leads to altered axonal transport and to permanent neurological damages. The inflammatory process activated by chemotherapeutic agents has been considered as a potential trigger of nociceptive process in CIPN...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422740/involvement-of-mir-106b-in-tumorigenic-actions-of-both-prolactin-and-estradiol
#19
Kuan-Hui Ethan Chen, Karissa Bustamante, Vi Nguyen, Ameae M Walker
Prolactin promotes a variety of cancers by an array of different mechanisms. Here, we have investigated prolactin's inhibitory effect on expression of the cell cycle-regulating protein, p21. Using a miRNA array, we identified a number of miRNAs upregulated by prolactin treatment, but one in particular that was strongly induced by prolactin and predicted to bind to the 3'UTR of p21 mRNA, miR-106b. By creating a p21 mRNA 3'UTR-luciferase mRNA construct, we demonstrated degradation of the construct in response to prolactin in human breast, prostate and ovarian cancer cell lines...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28411440/tweak-fn14-promotes-pro-inflammatory-cytokine-secretion-in-hepatic-stellate-cells-via-nf-%C3%AE%C2%BAb-stat3-pathways
#20
Aixiu Wang, Feng Zhang, Hui Xu, Mingcui Xu, Yu Cao, Chen Wang, Yuanyuan Xu, Min Su, Ming Zhang, Yuzheng Zhuge
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) have been associated with liver disease. Hepatic stellate cells (HSCs) play a critical role in the hepatic wound-healing response after liver injury, but there is little information available on the role of the TWEAK/Fn14 pathway in human HSCs. In this study, we explored the role of TWEAK/Fn14 in activated human HSCs. The LX-2 cells were treated with TWEAK, and the expression of pro-inflammatory cytokines was assayed by enzyme-linked immunosorbent assay (ELISA) and real-time PCR (RT-PCR)...
April 12, 2017: Molecular Immunology
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