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Jak 2 mutation

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https://www.readbyqxmd.com/read/29925658/the-mtase-like-domain-of-chikungunya-virus-nsp2-inhibits-the-interferon-response-by-promoting-the-nuclear-export-of-stat1
#1
Giel P Göertz, Kristin L McNally, Shelly J Robertson, Sonja M Best, Gorben P Pijlman, Jelke J Fros
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has evolved effective mechanisms to counteract the type I interferon (IFN) response. Upon viral recognition, cells secrete IFNs which signal through transmembrane receptors (IFNAR) to phosphorylate STAT proteins (pSTAT). pSTAT dimers are transported into the nucleus by importin-α5 and activate the transcription of IFN stimulated genes (ISGs) increasing cellular resistance to infection. Subsequently, STAT proteins are shuttled back into the cytoplasm by exportin CRM1...
June 20, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29907875/a-novel-homozygous-missense-mutation-in-the-sh3-binding-motif-of-stambp-causing-microcephaly-capillary-malformation-syndrome
#2
Ikumi Hori, Fuyuki Miya, Yutaka Negishi, Ayako Hattori, Naoki Ando, Keith A Boroevich, Nobuhiko Okamoto, Mitsuhiro Kato, Tatsuhiko Tsunoda, Mami Yamasaki, Yonehiro Kanemura, Kenjiro Kosaki, Shinji Saitoh
Microcephaly-capillary malformation syndrome is a congenital and neurodevelopmental disorder caused by biallelic mutations in the STAMBP gene. Here we identify the novel homozygous mutation located in the SH3 binding motif of STAMBP (NM_006463.4) (c.707C>T: p.Ser236Phe) through whole-exome sequencing. The case patient was a 2-year-old boy showing severe global developmental delay, progressive microcephaly, refractory seizures, dysmorphic facial features, and multiple capillary malformations. Immunoblot analysis of patient-derived lymphoblastoid cell lines (LCLs) revealed a severe reduction in STAMBP expression, indicating that Ser236Phe induces protein instability...
June 15, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29907599/aggressive-b-cell-lymphomas-in-patients-with-myelofibrosis-receiving-jak1-2-inhibitor-therapy
#3
Edit Porpaczy, Sabrina Tripolt, Andrea Hoelbl-Kovacic, Bettina Gisslinger, Zsuzsanna Bago-Horvath, Emilio Casanova-Hevia, Emmanuelle Clappier, Thomas Decker, Sabine Fajmann, Daniela A Fux, Georg Greiner, Sinan Gueltekin, Gerwin Heller, Harald Herkner, Gregor Hoermann, Jean-Jacques Kiladjian, Thomas Kolbe, Christoph Kornauth, Maria-Theresa Krauth, Robert Kralovics, Leonhard Muellauer, Mathias Mueller, Michaela Prchal-Murphy, Eva Maria Putz, Emmanuel Raffoux, Ana-Iris Schiefer, Klaus Schmetterer, Christine Schneckenleithner, Ingrid Simonitsch-Klupp, Cathrin Skrabs, Wolfgang R Sperr, Philipp Bernhard Staber, Birgit Strobl, Peter Valent, Ulrich Jaeger, Heinz Gisslinger, Veronika Sexl
Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 MPN patients including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4/69 patients (5.8%) upon JAK1/2 inhibition compared to 2/557 (0.36%) with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 MPN patients...
June 14, 2018: Blood
https://www.readbyqxmd.com/read/29879498/precision-medicine-approaches-may-be-the-future-for-crlf2-rearranged-down-syndrome-acute-lymphoblastic-leukaemia-patients
#4
Elyse C Page, Susan L Heatley, David T Yeung, Paul Q Thomas, Deborah L White
Breakthrough studies over the past decade have uncovered unique gene fusions implicated in acute lymphoblastic leukaemia (ALL). The critical gene, cytokine receptor-like factor 2 (CRLF2), is rearranged in 5-16% of B-ALL, comprising 50% of Philadelphia-like ALL and cooperates with genomic lesions in the Jak, Mapk and Ras signalling pathways. Children with Down Syndrome (DS) have a predisposition to developing CRLF2 rearranged-ALL which is observed in 60% of DS-ALL patients. These patients experience a poor survival outcome...
June 4, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29800615/peritransplant-ruxolitinib-prevents-acute-gvhd-in-myelofibrosis-patients-undergoing-allogenic-stem-cell-transplantation
#5
Nicolaus Kröger, Sharifah Shahnaz Syed Abd Kadir, Tatjana Zabelina, Anita Badbaran, Maximilian Christopeit, Francis Ayuk, Christine Wolschke
JAK inhibition by Ruxolitinib is approved for treatment of myelofibrosis and showed efficacy in steroid resistant acute and chronic graft-versus-host disease (GVHD) In twelve patients with a median age of 63 years (range 43-71) and myelofibrosis who were treated with ruxolitinib and underwent allogeneic stem cell transplantation (ASCT) ruxolitinib was continued (2 x 5mg) daily until stable engraftment. No graft failure was observed and leukocyte engraftment was achieved after a median of 12 days (range 11 - 18) One patient developed fever of unknown origin after discontinuation of ruxolitinib, otherwise no case of withdrawal syndrome was observed...
May 22, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29785143/pilot-study-of-the-antifibrotic-effects-of-the-multikinase-inhibitor-pacritinib-in-a-mouse-model-of-liver-fibrosis
#6
Suliman Al-Fayoumi, Taishi Hashiguchi, Yuka Shirakata, John Mascarenhas, Jack W Singer
Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK-STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients...
2018: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/29741263/the-2017-who-update-on-mature-t-and-natural-killer-nk-cell-neoplasms
#7
REVIEW
E Matutes
Over the last decade, there has been a significant body of information regarding the biology of the lymphoid neoplasms. This clearly supports the need for updating the 2008 WHO (World Health Organization) classification of haematopoietic and lymphoid tumours. The 2017 WHO classification is not a new edition but an update and revision of the 4th edition. New provisional entities but not new definitive entities are included, and novel molecular data in most of the entities and changes in the nomenclature in few of them have been incorporated...
May 2018: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/29732039/jak-2-mutation-frequency-in-patients-with-thrombocytosis
#8
Osman Yokus, Habip Gedik
Background: We aimed to investigate the etiologic causes and the existence of Janus kinase 2 mutation (JAK2) in cases with thrombocytosis. Methods: In this retrospective study, patients who were admitted to hematology clinic with thrombocytosis between 2013 and 2015 were investigated in terms of the etiological causes of thrombocytosis and the existence of JAK2 mutation. Results: We retrospectively evaluated 136 cases that underwent JAK2 mutation analysis due to ET preliminary diagnosis in our hematology clinic...
2018: Caspian Journal of Internal Medicine
https://www.readbyqxmd.com/read/29728434/focal-segmental-glomerulosclerosis-in-a-patient-with-prefibrotic-primary-myelofibrosis
#9
Gopal Krishana Bohra, Durga Shankar Meena, Nitin Bajpai, Abhishek Purohit
We report a case of 56-year-old man presented to us with chief complaints of frothy urine and leg swelling. A urinalysis revealed nephrotic-range proteinuria. Haematological investigations revealed thrombocytosis, leucocytosis and peripheral blood smear showed a leucoerythroblastic picture. JAK 2 mutation was positive. To confirm the diagnosis of myeloproliferative neoplasm, bone marrow biopsy was done, which was suggestive of primary myelofibrosis. The patient underwent kidney biopsy due to rapidly declining renal function and persistent proteinuria, which was suggestive of focal segmental glomerulosclerosis...
May 4, 2018: BMJ Case Reports
https://www.readbyqxmd.com/read/29725364/asxl1-mutations-in-chinese-patients-with-essential-thrombocythemia
#10
Yan-Bo Nie, Meng Sun, Colin K He, Man-Kai Ju, Fu-Ling Zhou, San-Yun Wu, Yi Zhou, Li Liu, Hui Shen, Ting-Ting Huang, Pan Liu, Ying Xu, Liang Shao, Xue-Lan Zuo
Essential thrombocythemia (ET) is characterized by thrombotic and hemorrhagic events. The association of clinical characteristics of Chinese ET patients and additional sex combs like 1 (ASXL1) mutations in these patients has remained to be elucidated. In the present study, 72 newly diagnosed Chinese ET patients were enrolled to determine ASXL1 mutations. Mutations in ASXL1, Janus kinase (JAK)2, calreticulin (CALR) and myeloproliferative leukemia (MPL) genes were detected using Sanger sequencing, and data were statistically analyzed...
May 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29682185/stat5-inhibition-induces-trail-dr4-dependent-apoptosis-in-peripheral-t-cell-lymphoma
#11
Haley M Simpson, Aki Furusawa, Kavitha Sadashivaiah, Curt I Civin, Arnob Banerjee
Peripheral T-cell lymphoma (PTCL) is a rare, aggressive, heterogeneous, Non-Hodgkin's lymphoma with poor prognosis and inadequate response to current therapies. Recent sequencing studies indicate a prevalence of activating mutations in the JAK/STAT signaling pathway. Oncogenic mutations in STAT5B, observed in approximately one third of cases of multiple different PTCL subtypes, correlate with inferior patient outcomes. Therefore, interest in the development of therapeutic strategies for targeting STAT5 in PTCL is warranted...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29645296/effects-of-jak1-2-inhibition-on-bone-marrow-stromal-cells-of-myeloproliferative-neoplasm-mpn-patients-and-healthy-individuals
#12
Dimitra Zacharaki, Roshanak Ghazanfari, Hongzhe Li, Hooi Ching Lim, Stefan Scheding
OBJECTIVE: Philadelphia-negative myeloproliferative neoplasms (MPNs) commonly share hyperactive JAK-STAT signaling affecting hematopoietic stem cells (HSC) and their progeny. The JAK1/2 inhibitor Ruxolitinib has remarkable clinical efficacy, including spleen reduction, improvement of constitutional symptoms, and bone marrow (BM) fibrosis reversal. Whether this is due to inhibition of JAK2-mutated HSC only, or whether Ruxolitinib also affects BM stroma is not known. METHODS: This study investigated potential effects of Ruxolitinib on BM mesenchymal stromal cells (MSC), which are not only major regulators of hematopoiesis but also contribute to fibrosis, from 10 healthy donors and 7 JAK2V617F -positive MPN patients...
April 12, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29589523/an-update-on-jak-inhibitors
#13
Francesca Musumeci, Chiara Greco, Ilaria Giacchello, Anna Lucia Fallacara, Munjed M Ibrahim, Giancarlo Grossi, Chiara Brullo, Silvia Schenone
Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors...
March 26, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29587261/high-frequency-of-copy-neutral-loss-of-heterozygosity-in-patients-with-myelofibrosis
#14
COMPARATIVE STUDY
Milton Rego de Paula Junior, Alexandre Nonino, Juliana Minuncio Nascimento, Raphael S Bonadio, Aline Pic-Taylor, Silviene F de Oliveira, Rinaldo Wellerson Pereira, Cintia do Couto Mascarenhas, Juliana Forte Mazzeu
Myelofibrosis is the rarest and most severe type of Philadelphia-negative classical myeloproliferative neoplasms. Although mutually exclusive driver mutations in JAK2, MPL, or CALR that activate JAK-STAT pathway have been related to the pathogenesis of the disease, chromosome abnormalities have also been associated with the phenotype and prognosis of the disease. Here, we report the use of a chromosomal microarray platform consisting of both oligo and SNP probes to improve the detection of chromosome abnormalities in patients with myelofibrosis...
2018: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29568923/atm%C3%A2-jak%C3%A2-pd%C3%A2-l1-signaling-pathway-inhibition-decreases-emt-and-metastasis-of-androgen%C3%A2-independent-prostate-cancer
#15
Lan Zhang, Li-Jun Xu, Jin Zhu, Jian Li, Bo-Xin Xue, Jie Gao, Chuan-Yang Sun, Ya-Chen Zang, Yi-Bin Zhou, Dong-Rong Yang, Yu-Xi Shan
Castration-resistant prostate cancer (CRPC), also known as androgen-independent prostate cancer, frequently develops local and distant metastases, the underlying mechanisms of which remain undetermined. In the present study, surgical specimens obtained from patients with clinical prostate cancer were investigated, and it was revealed that the expression levels of ataxia telangiectasia mutated kinase (ATM) were significantly enhanced in prostate cancer tissues isolated from patients with CRPC compared with from patients with hormone‑dependent prostate cancer...
May 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29562644/understanding-splenomegaly-in-myelofibrosis-association-with-molecular-pathogenesis
#16
REVIEW
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen...
March 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29492207/evaluation-of-vascular-events-in-patients-with-myeloproliferative-syndromes-and-mutations-of-either-the-januskinase-2-or-calreticulin-gene-at-the-university-hospital-krems-from-2008-to-2015
#17
Sarah Hintermair, Elisabeth Zwickl-Traxler, Martin Pecherstorfer, Josef Singer
Myeloproliferative neoplasms (MPN), classified as polycythemia vera (PV), essential thrombocytosis (ET) and myelofibrosis (MF) are stem-cell derived disorders. Mutations in either the januskinase-2 (JAK-2) or the calreticulin (CALR) gene are characteristic for MPN and may result in enhanced proliferation of red blood cells, white blood cells and platelets, and thus increase the risk for vascular events. This study is a retrospective and descriptive analysis of records of patients, who underwent treatment for myeloproliferative syndromes at the Department of Hemato-Oncology of the University hospital Krems from 2008 to the end of 2015...
February 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29487712/inhibition-of-mtorc1-c2-signaling-improves-anti-leukemia-efficacy-of-jak-stat-blockade-in-crlf2-rearranged-and-or-jak-driven-philadelphia-chromosome-like-acute-b-cell-lymphoblastic-leukemia
#18
Qi Zhang, Ce Shi, Lina Han, Nitin Jain, Kathryn G Roberts, Helen Ma, Tianyu Cai, Antonio Cavazos, Yoko Tabe, Rodrigo O Jacamo, Hong Mu, Yang Zhao, Jing Wang, Shuo-Chieh Wu, Fenglin Cao, Zhihong Zeng, Jin Zhou, Yingchang Mi, Elias J Jabbour, Ross Levine, Sarah K Tasian, Charles G Mullighan, David M Weinstock, David A Fruman, Marina Konopleva
Patients with cytokine receptor-like factor 2 rearranged ( CRLF2 -re) subgroup Philadelphia chromosome-like B-cell acute lymphoblastic leukemia (Ph-like B-ALL) have a high relapse rate and poor clinical outcomes. CRFL2 -re Ph-like B-ALL is characterized by heightened activation of multiple signaling pathways, including the JAK/STAT and PI3K/AKT/mTOR pathways. We hypothesized that the combined inhibition by JAK2 and mTOR inhibitors would induce an additive antileukemia effect in CRLF2 -re Ph-like B-ALL. In this study, we tested the antileukemia efficacy of the type I JAK inhibitor ruxolitinib and type II JAK inhibitor NVP-BBT594 (hereafter abbreviated BBT594) [1] alone and combined with allosteric mTOR inhibitor rapamycin and a second generation ATP-competitive mTOR kinase inhibitor AZD2014...
January 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29453195/mutation-of-ifnlr1-an-interferon-lambda-receptor-1-is-associated-with-autosomal-dominant-non-syndromic-hearing-loss
#19
Xue Gao, Yong-Yi Yuan, Qiong-Fen Lin, Jin-Cao Xu, Wei-Qian Wang, Yue-Hua Qiao, Dong-Yang Kang, Dan Bai, Feng Xin, Sha-Sha Huang, Shi-Wei Qiu, Li-Ping Guan, Yu Su, Guo-Jian Wang, Ming-Yu Han, Yi Jiang, Han-Kui Liu, Pu Dai
Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism...
May 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29399328/jak-inhibitors-for-the-treatment-of-myeloproliferative-neoplasms-and-other-disorders
#20
REVIEW
William Vainchenker, Emilie Leroy, Laure Gilles, Caroline Marty, Isabelle Plo, Stefan N Constantinescu
JAK inhibitors have been developed following the discovery of the JAK2 V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL ) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity...
2018: F1000Research
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