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Jak2 inhibitor

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https://www.readbyqxmd.com/read/28087469/tofacitinib-ameliorates-inflammation-in-a-rat-model-of-airway-neutrophilia-induced-by-inhaled-lps
#1
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
#2
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
#3
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
https://www.readbyqxmd.com/read/28054986/d-l-sulforaphane-induces-ros-dependent-apoptosis-in-human-gliomablastoma-cells-by-inactivating-stat3-signaling-pathway
#4
Ziwei Miao, Fei Yu, Yahao Ren, Jun Yang
d,l-Sulforaphane (SFN), a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM) cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2...
January 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28042144/novel-bet-protein-proteolysis-targeting-chimera-bet-protac-exerts-superior-lethal-activity-than-bromodomain-inhibitor-beti-against-post-myeloproliferative-neoplasm-mpn-secondary-s-aml-cells
#5
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28038379/high-density-lipoprotein-hdl-associated-sphingosine-1-phosphate-s1p-inhibits-macrophage-apoptosis-by-stimulating-stat3-activity-and-survivin-expression
#6
Renata Feuerborn, Susen Becker, Francesco Potì, Petra Nagel, Martin Brodde, Harmut Schmidt, Christina Christoffersen, Uta Ceglarek, Ralph Burkhardt, Jerzy-Roch Nofer
BACKGROUND AND AIMS: Macrophage apoptosis is critically involved in atherosclerosis. We here examined the effect of anti-atherogenic high density lipoprotein (HDL) and its component sphingosine-1-phosphate (S1P) on apoptosis in RAW264.7 murine macrophages. METHODS: Mitochondrial or endoplasmic reticulum-dependent apoptosis was induced by exposure of macrophages to etoposide or thapsigargin/fukoidan, respectively. RESULTS: Cell death induced by these compounds was inhibited by S1P as inferred from reduced annexin V binding, TUNEL staining, and caspase 3, 9 and 12 activities...
December 9, 2016: Atherosclerosis
https://www.readbyqxmd.com/read/28035365/matrine-induces-the-apoptosis-of-fibroblast-like-synoviocytes-derived-from-rats-with-collagen-induced-arthritis-by-suppressing-the-activation-of-the-jak-stat-signaling-pathway
#7
Yongsheng Yang, Qiumei Dong, Rongheng Li
The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA)...
December 29, 2016: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28028030/myeloid-neoplasms-with-eosinophilia
#8
Andreas Reiter, Jason Gotlib
Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, 'Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2' In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed phenotype acute leukemias/lymphomas...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28028027/emerging-treatments-for-classical-myeloproliferative-neoplasms
#9
Alessandro M Vannucchi, Claire Harrison
There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, following the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug has been later approved also as second line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate to cope with the major unmet patients' needs, that include normalization of life span (MF and some PV patients), reduction of cardiovascular complications (mainly PV and essential thrombocythemia (ET)), prevention of hematological progression and improved quality of life (all MPN)...
December 27, 2016: Blood
https://www.readbyqxmd.com/read/28027695/inhibitory-mechanism-of-the-outer-membrane-growth-of-chronic-subdural-hematomas
#10
Koji Osuka, Yasuo Watanabe, Nobuteru Usuda, Masahiro Aoyama, Kenichiro Iwami, Mikinobu Takeuchi, Takeya Watabe, Masakazu Takayasu
We previously demonstrated that the inflammatory cytokine interleukin-6 (IL-6) activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway in fibroblasts within the outer membranes of chronic subdural hematomas (CSDHs), and the activation of this pathway may induce CSDH outer membrane growth. The inhibitory system for this signal transduction pathway is unknown. CSDH fluids were obtained from ten patients during trepanation surgery as the case group, and CSF samples were obtained from seven patients suffering from subarachnoid hemorrhage (SAH) on day 1 as the control group...
December 27, 2016: Journal of Neurotrauma
https://www.readbyqxmd.com/read/28011890/idiopathic-myelofibrosis-with-disseminated-hepatosplenic-mesenteric-renal-and-pulmonary-extramedullary-haematopoeisis-portal-hypertension-and-tuberculosis-initial-presentation-and-2%C3%A2-years-follow-up
#11
Ananya Panda, Sheragaru Hanumanthappa Chandrashekhara, Aruna Nambirajan, Pravas Mishra
A 35-year-old man with a 12-year history of idiopathic myelofibrosis (IMF) presented in 2014 with fatigue and abdominal distension. CT scan revealed massive hepatosplenomegaly with focal splenic lesions, soft tissue around renal pelvis, mesenteric masses compressing bowel loops and perilymphatic nodules in lungs. There was portal hypertension, ascites, pleural effusion, bilateral psoas abscesses and necrotic retroperitoneal lymphadenopathy. MRI additionally revealed hypointense periportal infiltrative lesions in liver, not seen on CT scan...
December 23, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/28007500/novel-sulfoglycolipid-ig20-causes-neuroprotection-by-activating-the-phase-ii-antioxidant-response-in-rat-hippocampal-slices
#12
Eva Punzón, Fernanda García-Alvarado, Marcos Maroto, Cristina Fernández-Mendívil, Patrycja Michalska, Isabel García-Álvarez, Juan Alberto Arranz-Tagarro, Izaskun Buendia, Manuela G López, Rafael León, Luis Gandía, Alfonso Fernández-Mayoralas, Antonio G García
Compound IG20 is a newly synthesised sulphated glycolipid that promotes neuritic outgrowth and myelinisation, at the time it causes the inhibition of glial proliferation and facilitates exocytosis in chromaffin cells. Here we have shown that IG20 at 0.3-10 μM afforded neuroprotection in rat hippocampal slices stressed with veratridine, glutamate or with oxygen plus glucose deprivation followed by reoxygenation (OGD/reox). Excess production of reactive oxygen species (ROS) elicited by glutamate or ODG/reox was prevented by IG20 that also restored the depressed tissue levels of GSH and ATP in hippocampal slices subjected to OGD/reox...
December 20, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27998796/propofol-postconditioning-attenuates-hippocampus-ischemia-reperfusion-injury-via-modulating-jak2-stat3-pathway-in-rats-after-autogenous-orthotropic-liver-transplantation
#13
Jia Lili, Wang Fei, Gu Xiangqian, Weng Yiqi, Sheng Mingwei, Wang Gang, Li Shipeng, Du Hongyin, Yu Wenli
Liver transplantation has been a routine treatment for the end stage liver diseases. Severe changes in circulation system and internal environment may accur during transplant surgery and cause injury to many organs including brain. Specific mechanisms of brain injury associated with liver transplantation are not yet elucidated. Previous studies have shown that the JAK/STAT signal transduction pathways are involved in the development of the central nervous system, such as nerve cell proliferation, survival, differentiation, and it also have a role in the disease processes, including brain tumor, brain ischemia and other diseases of the central nervous system...
December 17, 2016: Brain Research
https://www.readbyqxmd.com/read/27991718/polycythemia-vera-and-essential-thrombocythemia-2017-update-on-diagnosis-risk-stratification-and-management
#14
Ayalew Tefferi, Tiziano Barbui
DISEASE OVERVIEW: Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely...
January 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/27983880/how-ruxolitinib-modified-the-outcome-in-myelofibrosis-focus-on-overall-survival-allele-burden-reduction-and-fibrosis-changes
#15
Fulvio Massaro, Matteo Molica, Massimo Breccia
Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has shown superiority as compared to available conventional chemotherapies, in terms of reduction in splenomegaly and improvement of symptoms and quality of life. Areas covered: Data published about overall survival in the major randomized sponsored trials and in independent series of patients were detailed. Indeed, data regarding action of ruxolitinib on allele burden reduction and potential activity of the drug on pathogenetic mechanisms involved in increased fibrosis has been reviewed...
December 16, 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27977878/effects-of-potentially-functional-polymorphisms-in-suppressor-of-cytokine-signaling-3-socs3-on-the-risk-of-head-and-neck-squamous-cancer
#16
Dong Hang, Yin Yin, Lihua Wang, Hua Yuan, Jiangbo Du, Meng Zhu, Juncheng Dai, Ning Chen, Zhibin Hu, Hongbing Shen, Hongxia Ma
BACKGROUND: Suppressor of cytokine signaling 3 (SOCS3) has been identified as an inhibitor of JAK/STAT pathway that plays a significant role in carcinogenesis. SOCS3 and JAK2 polymorphisms may influence the gene expression or function, contributing to the disease susceptibility; however, such effect has not been evaluated in head and neck squamous cell carcinoma (HNSCC). METHODS: A case-control study was performed to test the associations of SOCS3 and JAK2 polymorphisms with risk of HNSCC in 576 cases and 1552 cancer-free controls from China...
December 15, 2016: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/27976373/tumor-associated-macrophage-mediated-survival-of-myeloma-cells-through-stat3-activation
#17
Nathan De Beule, Kim De Veirman, Ken Maes, Elke De Bruyne, Eline Menu, Karine Breckpot, Hendrik De Raeve, Rian Van Rampelbergh, Jo A Van Ginderachter, Rik Schots, Els Van Valckenborgh, Karin Vanderkerken
Overcoming drug resistance is one of the greatest challenges in the treatment of multiple myeloma (MM). The interaction of myeloma cells with the bone marrow (BM) micro-environment is a major contributing factor to drug resistance. Tumor-associated macrophages or TAMs with different polarization states are an important component of this micro-environment. Previous studies revealed a role of TAMs in MM survival and drug resistance; however, the impact of macrophage polarization (anti-tumoral "M1" versus pro-tumoral "M2"-like phenotype) in this process is not yet described...
December 15, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27957861/codelivery-of-ponatinib-and-sar302503-by-active-bone-targeted-polymeric-micelles-for-the-treatment-of-therapy-resistant-chronic-myeloid-leukemia
#18
Chao-Feng Mu, Yang Xiong, Xue Bai, Yun-Jie Sheng, Jiajun Cui
Point mutations in the BCR-ABL1 domain and primitive chronic myelogenous leukemia (CML) cells existing in the bone marrow environment insensitive to tyrosine kinase inhibitors (TKIs) have become two major challenges in the CML therapy. In this study, combined TKI ponatinib and JAK2 inhibitor SAR302503 short-term treatment effectively suppressed growth and promoted apoptosis of BaF3/T315I cells in cytokine-containing medium in vitro. SAR302503 prevented cytokine-dependent resistance to ponatinib via inhibition of JAK2/STAT5 phosphorylation...
January 3, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/27956543/drug-development-pipeline-for-myeloproliferative-neoplasms-potential-future-impact-on-guidelines-and-management
#19
REVIEW
Prithviraj Bose, Srdan Verstovsek
The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia...
December 2016: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/27942391/metastatic-basal-cell-carcinoma-with-amplification-of-pd-l1-exceptional-response-to-anti-pd1-therapy
#20
Sadakatsu Ikeda, Aaron M Goodman, Philip R Cohen, Taylor J Jensen, Christopher K Ellison, Garrett Frampton, Vincent Miller, Sandip P Patel, Razelle Kurzrock
Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA)...
2016: NPJ Genomic Medicine
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