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Jak 2 mutation

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https://www.readbyqxmd.com/read/29645296/effects-of-jak1-2-inhibition-on-bone-marrow-stromal-cells-of-myeloproliferative-neoplasm-mpn-patients-and-healthy-individuals
#1
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
#2
Francesca Musumeci, Chiara Greco, Ilaria Giacchell, 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
#3
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...
March 22, 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
#4
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...
March 20, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29562644/understanding-splenomegaly-in-myelofibrosis-association-with-molecular-pathogenesis
#5
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
#6
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
#7
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
#8
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...
February 16, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29399328/jak-inhibitors-for-the-treatment-of-myeloproliferative-neoplasms-and-other-disorders
#9
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
https://www.readbyqxmd.com/read/29397859/-research-progress-on-effect-of-jak-inhibitors-on-myelofibrosis-review
#10
Jun-Xiu Liu, Wei Chen, Kai-Lin Xu
Myelofibrosis(MF) is a type of myeloprolifirative neoplasms which is difficult to be treated. With the discovery of V617F mutation site in Janus kinase 2 (JAK2), JAK inhibitor provides a new treatment strategy for patients with myelofibrosis. Since 2011 the FDA in USA approved the first generation of JAK inhibitor Ruxolitinib for marketing, a growing number of JAK inhibitors have been entering into the clinical trials and showed a certain clinical efficacy. On the one hand, some JAK inhibitors for single application can effectively relieve the clinical symptoms of patients with myelofibrosis, slow down disease progression, and prolong the survival; on the other hand, JAK inhibitor can also be applied in combination with traditional or other new targeted drugs for MF patients, even during the allogenetic hematopoietic stem cell transplantation, thus providing more choices for targeted therapy on the patients with myelofibrosis...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/29385279/chronic-lymphoproliferative-disorder-of-nk-cells-a-single-institution-review-with-emphasis-on-relative-utility-of-multimodality-diagnostic-tools
#11
Habibe Kurt, Jeffrey L Jorgensen, Hesham M Amin, Keyur P Patel, Sa A Wang, Pei Lin, Rashmi Kanagal-Shamanna, Sanam Loghavi, Beenu Thakral, Haitham A Khogeer, Elias J Jabbour, Shaoying Li, C Cameron Yin, L Jeffrey Medeiros, Joseph D Khoury
BACKGROUND: Chronic lymphoproliferative disorder of NK-cells (CLPD-NK) manifests as a persistent increase (≥2 x 109 /L, for > 6 months) of mature NK-cells in peripheral blood with an indolent clinical course. The disease is rare, and only limited case series have been published. METHODS: We retrospectively studied 11 patients with CLPD-NK diagnosed at our institution between 2005 and 2017. RESULTS: Patients included 7 men and 4 women (median age, 60 years)...
January 31, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29296821/progenitor-b-1-b-cell-acute-lymphoblastic-leukemia-is-associated-with-collaborative-mutations-in-3-critical-pathways
#12
Sheryl M Gough, Liat Goldberg, Marbin Pineda, Robert L Walker, Yuelin J Zhu, Sven Bilke, Yang Jo Chung, Joseph Dufraine, Subhadip Kundu, Elad Jacoby, Terry J Fry, Susanna Fischer, Renate Panzer-Grümayer, Paul S Meltzer, Peter D Aplan
B-1 and B-2 lymphocytes are derived from distinct developmental pathways and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to a majority of murine B-cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98 - PHF23 ( NP23 ) transgenic mice. The immunophenotype (Lin- B220- CD19+ AA4.1+ ) was identical to that of progenitor (pro) B-1 cells, and VH gene usage was skewed toward 3' V regions, similar to murine fetal liver B cells...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29290793/epigenomic-characterization-of-a-p53-regulated-3p22-2-tumor-suppressor-that-inhibits-stat3-phosphorylation-via-protein-docking-and-is-frequently-methylated-in-esophageal-and-other-carcinomas
#13
Lili Li, Juan Xu, Guohua Qiu, Jianming Ying, Zhenfang Du, Tingxiu Xiang, Kai Yau Wong, Gopesh Srivastava, Xiao-Feng Zhu, Tony S Mok, Anthony Tc Chan, Francis Kl Chan, Richard F Ambinder, Qian Tao
Rationale: Oncogenic STAT3 signaling activation and 3p22-21.3 locus alteration are common in multiple tumors, especially carcinomas of the nasopharynx, esophagus and lung. Whether these two events are linked remains unclear. Our CpG methylome analysis identified a 3p22.2 gene, DLEC1, as a methylated target in esophageal squamous cell (ESCC), nasopharyngeal (NPC) and lung carcinomas. Thus, we further characterized its epigenetic abnormalities and functions. Methods: CpG methylomes were established by methylated DNA immunoprecipitation...
2018: Theranostics
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#14
REVIEW
Prithviraj Bose, Jason Gotlib, Claire N Harrison, Srdan Verstovsek
The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29259370/pancreatic-acinar-cell-carcinoma-a-review-on-molecular-profiling-of-patient-tumors
#15
REVIEW
Ahmad Al-Hader, Rami N Al-Rohil, Haiyong Han, Daniel Von Hoff
Pancreatic carcinomas with acinar differentiation are rare, accounting for 1%-2% of adult pancreatic tumors; they include pancreatic acinar cell carcinoma (PACC), pancreatoblastoma, and carcinomas of mixed differentiation. Patients with PACC have a prognosis better than pancreatic ductal adenocarcinomas but worse than pancreatic neuroendocrine tumors. Reports of overall survival range from 18 to 47 mo. A literature review on PACCs included comprehensive genomic profiling and whole exome sequencing on a series of more than 70 patients as well as other diagnostic studies including immunohistochemistry...
December 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29246863/essential-roles-of-stat5-1-stat5b-in-controlling-fish-somatic-growth
#16
Shuting Xiong, Jie Mei, Peipei Huang, Jing Jing, Zhi Li, Jingliang Kang, Jian-Fang Gui
Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of growth hormone (GH) signaling in somatic growth of mammalian. However, the corresponding homologue gene of Stat5b is unknown in fish species. In this study, we generated loss-of-function mutants in stat5.1 and stat5.2, two stat5 homologues existing in zebrafish. In stat5.1-deficient zebrafish, a significant reduction of body length and body weight was detected in the embryos/larvae and adults compared with the wild-type control fish, and sexual size dimorphism in adult zebrafish was also eliminated...
December 20, 2017: Journal of Genetics and Genomics, Yi Chuan Xue Bao
https://www.readbyqxmd.com/read/29226168/risks-of-ruxolitinib-in-stat1-gain-of-function-associated-severe-fungal-disease
#17
Ofer Zimmerman, Berenice Rösler, Christa S Zerbe, Lindsey B Rosen, Amy P Hsu, Gulbu Uzel, Alexandra F Freeman, Elizabeth P Sampaio, Sergio D Rosenzwieg, Hye Sun Kuehn, Tiffany Kim, Kristina M Brooks, Parag Kumar, Xiaowen Wang, Mihai G Netea, Frank L van de Veerdonk, Steven M Holland
Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.
2017: Open Forum Infectious Diseases
https://www.readbyqxmd.com/read/29222281/improved-biological-insight-and-influence-on-management-in-indolent-lymphoma-talk-3-update-on-nodal-and-splenic-marginal-zone-lymphoma
#18
REVIEW
Catherine Thieblemont
Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29202476/stromal-lkb1-deficiency-leads-to-gastrointestinal-tumorigenesis-involving-the-il-11-jak-stat3-pathway
#19
Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris Pl Wong, Sushil Tripathi, Nalle Pentinmikko, Yajing Gao, Yan Yan, Elina H Niemelä, Timothy C Wang, Benoit Viollet, Gustavo Leone, Pekka Katajisto, Kari Vaahtomeri, Tomi P Mäkelä
Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma...
January 2, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29134817/the-bcr-abl1-negative-myeloproliferative-neoplasms-a-review-of-jak-inhibitors-in-the-therapeutic-armamentarium
#20
REVIEW
Martin Griesshammer, Parvis Sadjadian
The classical BCR-ABL1-negative myeloproliferative neoplasms (MPN) include primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). They are characterized by stem cell-derived clonal proliferation, harbor Janus kinase 2 (JAK2), or calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) driver mutations and exert an over activated JAK-signal transducer and activator of transcription (STAT) pathway. Therefore JAK inhibiting strategies have been successfully investigated in MPN clinical trials...
December 2017: Expert Opinion on Pharmacotherapy
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