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Jak 2 mutation

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https://www.readbyqxmd.com/read/29038115/the-common-cytokine-receptor-%C3%AE-chain-family-of-cytokines
#1
Jian-Xin Lin, Warren J Leonard
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain (γc), which was originally discovered as the third receptor component of the IL-2 receptor, IL-2Rγ. The IL2RG gene is located on the X chromosome and is mutated in humans with X-linked severe combined immunodeficiency (XSCID). The breadth of the defects in XSCID could not be explained solely by defects in IL-2 signaling, and it is now clear that γc is a shared receptor component of the six cytokines noted above, making XSCID a disease of defective cytokine signaling...
October 16, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/29029457/prognostic-relevance-of-protein-expression-clinical-factors-and-myd88-mutation-in-primary-bone-lymphoma
#2
Yong Xu, Jian Li, Jian Ouyang, Juan Li, Jingyan Xu, Qiguo Zhang, Yonggong Yang, Min Zhou, Jing Wang, Cuiling Zhang, Yueyi Xu, Ping Li, Rongfu Zhou, Bing Chen
Primary bone lymphomas (PBLs) are composed of malignant lymphoid cells presenting in osseous sites, without supra-regional lymph node or extranodal involvement. We systematically characterized the immunophenotype and the myeloid differentiation factor 88 (MYD88)-L265P gene mutation status in PBL. Clinical data from 19 patients with PBL treated at Nanjing Drum Tower Hospital between 2009 and 2015 were analyzed retrospectively. Protein expression patterns were identified immunohistochemically, and MYD88 mutation was assessed using polymerase chain reaction and direct DNA sequencing...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29025600/a-novel-somatic-jak2-kinase-domain-mutation-in-pediatric-acute-lymphoblastic-leukemia-with-rapid-on-treatment-development-of-loh
#3
Teresa Sadras, Susan L Heatley, Chung H Kok, Barbara J McClure, David Yeung, Timothy P Hughes, Rosemary Sutton, David S Ziegler, Deborah L White
We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation...
October 2017: Cancer Genetics
https://www.readbyqxmd.com/read/29022213/high-prevalence-of-heparin-induced-thrombocytopenia-with-thrombosis-among-patients-with-essential-thrombocytemia-carrying-v617f-mutation
#4
Roberto Castelli, Paolo Gallipoli, Riccardo Schiavon, Thomas Teatini, Giorgio Lambertenghi Deliliers, Luigi Bergamaschini
Arterial and venous complications are major causes of morbidity and mortality in myeloproliferative neoplasms (MPNs). MPNs patients, frequently receive heparin. Heparin-induced thrombocytopenia (HIT) is a rare but potentially life-threatening complication resulting in a severe acquired thrombophilic condition. We carried out a retrospective analysis to evaluate occurrence of new thrombotic events during heparin therapy in essential thrombocythemia (ET) patients. We studied 108 ET patients on heparin for treatment of previous thrombotic events or in thromboprophilaxis...
October 11, 2017: Journal of Thrombosis and Thrombolysis
https://www.readbyqxmd.com/read/28862766/genomic-profiles-of-lung-cancer-associated-with-idiopathic-pulmonary-fibrosis
#5
Ji An Hwang, Deokhoon Kim, Sung-Min Chun, SooHyun Bae, Joon Seon Song, Mi Young Kim, Hyun Jung Koo, Jin Woo Song, Woo Sung Kim, Jae Cheol Lee, Hyeong Ryul Kim, Chang-Min Choi, Se Jin Jang
Little is known on the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC using targeted exome sequencing (OncoPanel version 2) in 35 matched tumor/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed using GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively...
September 1, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28855209/therapeutic-targeting-of-oncogenic-tyrosine-phosphatases
#6
Rochelle Frankson, Zhi-Hong Yu, Yunpeng Bai, Qinglin Li, Ruo-Yu Zhang, Zhong-Yin Zhang
Protein tyrosine phosphatases (PTPs) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTKs) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions...
August 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/28804910/t-cell-protein-tyrosine-phosphatase-prevents-stat1-induction-of-claudin-2-expression-in-intestinal-epithelial-cells
#7
Moorthy Krishnan, Declan F McCole
T cell protein tyrosine phosphatase (TCPTP) dephosphorylates a number of substrates, including JAK-STAT (signal transducer and activator of transcription) signaling proteins, which are activated by interferon (IFN)-γ, a major proinflammatory cytokine involved in conditions such as inflammatory bowel disease. A critical function of the intestinal epithelium is formation of a selective barrier to luminal contents. The structural units of the epithelium that regulate barrier function are the tight junctions (TJs), and the protein composition of the TJ determines the tightness of the barrier...
October 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28712096/myeloproliferative-neoplasms-translating-new-discoveries-into-better-outcomes-better-quality-of-life
#8
REVIEW
Leslie Padrnos, Ruben A Mesa
Despite the identification of JAK mutations and the development of targeted inhibitors, there remain significant unmet needs for patients with myeloproliferative neoplasms. Identification of the myeloproliferative neoplasm populations not currently benefiting from JAK inhibitor therapy highlights the therapeutic deficits still present in this heterogeneous stem cell malignancy. While JAK inhibition has provided significant benefits for patients with intermediate-2 or high-risk myelofibrosis and in patients with polycythemia vera in the second-line setting, JAK inhibitor monotherapy is not approved and not appropriate for all patients with myeloproliferative neoplasms...
July 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/28710306/ruxolitinib-treatment-in-an-infant-with-jak2-polycythaemia-vera-associated-budd-chiari-syndrome
#9
Mehmet Enes Coskun, Sue Height, Anil Dhawan, Nedim Hadzic
Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction commonly seen with myeloproliferative neoplasms (MPNs). Polycythaemia vera (PV) is a very rare MPN in childhood. This is the youngest reported patient diagnosed with PV and BCS secondary to JAK V617F mutation.A 26-month-old girl was admitted with a 5-month history of abdominal distension, hepatosplenomegaly and ascites. Imaging studies revealed occlusion of the right hepatic vein and marked attenuation of the middle and left hepatic veins...
July 14, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/28674362/the-amelioration-of-myelofibrosis-with-thrombocytopenia-by-a-jak1-2-inhibitor-ruxolitinib-in-a-post-polycythemia-vera-myelofibrosis-patient-with-a-jak2-exon-12-mutation
#10
Kazuhiko Ikeda, Koki Ueda, Takahiro Sano, Kazuei Ogawa, Takayuki Ikezoe, Yuko Hashimoto, Soji Morishita, Norio Komatsu, Hitoshi Ohto, Yasuchika Takeishi
Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L)...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28673391/the-development-and-use-of-janus-kinase-2-inhibitors-for-the-treatment-of-myeloproliferative-neoplasms
#11
REVIEW
Gabriela S Hobbs, Sarah Rozelle, Ann Mullally
Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera...
August 2017: Hematology/oncology Clinics of North America
https://www.readbyqxmd.com/read/28668884/loss-of-tyrosine-kinase-2-does-not-affect-the-severity-of-jak2v617f-induced-murine-myeloproliferative-neoplasm
#12
Takumi Yamaji, Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Tomonori Hidaka, Yoko Kubuki, Haruko Shimoda, Hiroo Abe, Tadashi Miike, Hisayoshi Iwakiri, Yoshihiro Tahara, Mitsue Sueta, Shojiro Yamamoto, Satoru Hasuike, Kenji Nagata, Kazuya Shimoda
BACKGROUND/AIM: In myeloproliferative neoplasms (MPN), Janus kinase 2 (JAK2) is activated by mutations including JAK2V617F (JAK2VF). It is unclear whether JAK kinases [i.e. JAK1, JAK2, JAK3, or tyrosine kinase 2 (TYK2)] other than JAK2 have cooperative actions such as enhancement or suppression of JAK2. If other kinases enhance activation, therapies that co-target them could have a therapeutic efficacy. We examined the role of TYK2 in Jak2VF-induced murine MPN. MATERIALS AND METHODS: We crossed Jak2VF transgenic mice and Tyk2-knockout (Tyk2KO) mice to generate Jak2VF/Tyk2KO mice...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28656237/matrine-increases-the-inhibitory-effects-of-afatinib-on-h1975-cells-via-the-il%C3%A2-6-jak1-stat3-signaling-pathway
#13
Shui-Fang Chen, Ze-Ying Zhang, Jian-Li Zhang
Resistance to epidermal growth factor receptor (EGFR) inhibitors is of primary concern in the treatment of non‑small‑cell lung cancer (NSCLC) with EGFR mutations. To investigate the effects of matrine on H1975 cells and to examine a novel, potential treatment option for NSCLC, the present study measured cell viability, apoptotic rate, interleukin 6 (IL‑6) expression and activation of the janus kinase (JAK) 1/signal transducer and activator of transcription (STAT)3 signaling pathway in cells treated with or without matrine, in the presence or absence of afatinib...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28611190/cbl-family-e3-ubiquitin-ligases-control-jak2-ubiquitination-and-stability-in-hematopoietic-stem-cells-and-myeloid-malignancies
#14
Kaosheng Lv, Jing Jiang, Ryan Donaghy, Christopher R Riling, Ying Cheng, Vemika Chandra, Krasimira Rozenova, Wei An, Bhopal C Mohapatra, Benjamin T Goetz, Vinodh Pillai, Xu Han, Emily A Todd, Grace R Jeschke, Wallace Y Langdon, Suresh Kumar, Elizabeth O Hexner, Hamid Band, Wei Tong
Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs...
May 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28601384/polycystin-and-calcium-signaling-in-cell-death-and-survival
#15
REVIEW
Fernanda O Lemos, Barbara E Ehrlich
Mutations in polycystin-1 (PC1) and polycystin-2 (PC2) result in a commonly occurring genetic disorder, called Autosomal Dominant Polycystic Kidney Disease (ADPKD), that is characterized by the formation and development of kidney cysts. Epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation and apoptosis and reduced autophagy. PC1 is a large multifunctional transmembrane protein that serves as a sensor that is usually found in complex with PC2, a calcium (Ca(2+))-permeable cation channel...
May 24, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28596648/the-impact-of-mean-platelet-volume-mpv-and-jak-2-mutation-on-thrombosis-in-chronic-myeloproliferative-diseases
#16
Mesut Ayer, İlhan Menken, Mehmet Yamak, Fatma Aylin Ayer, Onur Kırkızlar, M Burak Aktuğlu
Thrombosis and bleeding are the main complications of chronic myeloproliferative diseases. Mean platelet volume (MPV) is an important indicator of the platelet activation. The aim of the present study was to assess the interrelationships between MPV, JAK-2 gene mutation and thromboembolic events in patients with ET and PV. Patients with ET (n = 60) and PV (n = 46) were compared to the secondary erythrocytosis group (n = 19); and a control group of age and sex matched healthy volunteers (n = 52). Besides demographic, clinical and laboratory data; thrombotic and hemorrhagic events were recorded for each patient...
June 2017: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/28548121/ebv-negative-aggressive-nk-cell-leukemia-lymphoma-a-clinical-and-pathological-study-from-a-single-institution
#17
Juehua Gao, Amir Behdad, Peng Ji, Kristy L Wolniak, Olga Frankfurt, Yi-Hua Chen
Aggressive natural killer (NK)-cell leukemia/lymphoma is a systemic NK-cell neoplasm that preferentially affects Asians with a fulminant clinical course and is almost always associated with Epstein-Barr virus (EBV). The data on EBV-negative aggressive NK-cell leukemia/lymphoma are limited. Here we report a series of three patients (two Caucasians, one African-American) with EBV-negative aggressive NK-cell leukemia/lymphoma from a single institution, including a case diagnosed on post-mortem examination. Similar to EBV-positive aggressive NK-cell leukemia/lymphoma, our patients presented with constitutional symptoms and hepatosplenomegaly, and followed a highly aggressive clinical course...
August 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28518222/the-effect-of-initial-molecular-profile-on-response-to-recombinant-interferon-%C3%AE-rifn%C3%AE-treatment-in-early-myelofibrosis
#18
Richard T Silver, Ariella C Barel, Elena Lascu, Ellen K Ritchie, Gail J Roboz, Paul J Christos, Attilio Orazi, Duane C Hassane, Wayne Tam, Nicholas C P Cross
BACKGROUND: Although recombinant interferon-α (rIFNα) effectively treats patients with early myelofibrosis, the effect of driver and high molecular risk (HMR) mutations has not been considered. In this phase 2 study, for the first time, the authors correlate response to rIFNα treatment with driver and HMR mutations. METHODS: Patients were diagnosed using World Health Organization or International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria...
July 15, 2017: Cancer
https://www.readbyqxmd.com/read/28505169/molecular-basis-of-targeted-therapy-in-t-nk-cell-lymphoma-leukemia-a-comprehensive-genomic-and-immunohistochemical-analysis-of-a-panel-of-33-cell-lines
#19
Rufino Mondejar, Cristina Pérez, Arantza Onaindia, Nerea Martinez, Julia González-Rincón, Helena Pisonero, Jose Pedro Vaqué, Laura Cereceda, Miguel Santibañez, Margarita Sánchez-Beato, Miguel Angel Piris
T and NK-cell lymphoma is a collection of aggressive disorders with unfavorable outcome, in which targeted treatments are still at a preliminary phase. To gain deeper insights into the deregulated mechanisms promoting this disease, we searched a panel of 31 representative T-cell and 2 NK-cell lymphoma/leukemia cell lines for predictive markers of response to targeted therapy. To this end, targeted sequencing was performed alongside the expression of specific biomarkers corresponding to potentially activated survival pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#20
REVIEW
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been 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, in which survival is short...
July 13, 2017: Blood
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