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https://www.readbyqxmd.com/read/27913528/mutations-in-mpns-prognostic-implications-window-to-biology-and-impact-on-treatment-decisions
#1
Jamile M Shammo, Brady L Stein
The last decade has witnessed tremendous scientific advances, ushered in by the JAK2 V617F discovery, contributing to enhanced diagnostic capability and understanding of the biology of myeloproliferative neoplasms (MPNs). Discovery of the calreticulin mutations filled a diagnostic gap; more recent work sheds light on its contribution to disease pathogenesis, and prognosis. Recent studies have also identified novel JAK2 and MPL mutations in patients with essential thrombocythemia and myelofibrosis (MF). Especially in MF, the driver mutational profile has prognostic implications, with additive contributions from the acquisition of additional somatic mutations...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913526/update-from-the-latest-who-classification-of-mpns-a-user-s-manual
#2
Francesco Passamonti, Margherita Maffioli
The 2016 multiparameter World Health Organization (WHO) classification for Philadelphia-negative myeloproliferative neoplasms (MPNs) integrates clinical features, morphology, and genetic data to diagnose polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The main novelties are: (1) the reduction of the hemoglobin (Hb) level threshold to diagnose PV, now established at 16.5 g/dL for men and 16 g/dL for women (based on the identification of MPN patients with PV-consistent bone marrow [BM] features and a Hb level lower than that established in the 2008 WHO classification for PV); (2) the recognition of prefibrotic/early PMF, distinguishable from ET on the basis of BM morphology, an entity having a higher tendency to develop overt myelofibrosis or acute leukemia, and characterized by inferior survival; (3) the central role of BM morphology in the diagnosis of ET, prefibrotic/early PMF, PMF, and PV with borderline Hb values; megakaryocyte number and morphology (typical in ET, atypical in both PMF forms) accompanied by a new distinction of reticulin fibrosis grade in PMF (grade 1 in prefibrotic/early PMF and grade 2-3 in PMF) constitute diagnostic criteria; and (4) the inclusion of all mutually exclusive MPN driver mutations (JAK2, CALR, and MPL) as major diagnostic criteria in ET and PMF; 10% to 15% of these patients are triple negative, and in these cases the search for an additional clonal marker (eg, mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, and SF3B1) is warranted...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27913189/construction-and-analysis-of-a-human-testis-sperm-enriched-interaction-network-unraveling-the-ppp1cc2-interactome
#3
Joana Vieira Silva, Sooyeon Yoon, Pieter-Jan De Bock, Alexander V Goltsev, Kris Gevaert, José Fernando F Mendes, Margarida Fardilha
BACKGROUND: Phosphoprotein phosphatase 1 catalytic subunit gamma 2 (PPP1CC2), a PPP1CC tissue-specific alternative splice restricted to testicular germ cells and spermatozoa, is essential for spermatogenesis and spermatozoa motility. The key to understand PPP1CC2 regulation lies on the characterization of its interacting partners. METHODS: We construct a testis/sperm-enriched protein interaction network and analyzed the topological properties and biological context of the network...
November 29, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27910962/baricitinib-jak-inhibition-for-rheumatoid-arthritis
#4
J Gras
Rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease characterized by inflammation and joint destruction, is associated with pain, progressive disability, systemic comorbidities and early death. Conventional disease-modifying antirheumatic drugs (DMARDs) and biological DMARDs (bDMARDs) have been able to achieve remission or a very low disease activity status for RA. Nevertheless, since many patients do not reach a sufficient response with DMARDs or present with unacceptable side effects, new therapies are needed...
October 2016: Drugs of Today
https://www.readbyqxmd.com/read/27905037/involvement-of-jak1-jak2-and-jak3-in-stimulation-of-functional-activity-of-mesenchymal-progenitor-cells-by-fibroblast-growth-factor
#5
G N Zyuz'kov, V V Zhdanov, E V Udut, L A Miroshnichenko, E V Simanina, T Yu Polyakova, L A Stavrova, V V Udut, M Yu Minakova, A M Dygai
We studied the involvement of individual JAK kinases in the realization of the growth potential of mesenchymal precursors under the effect of fibroblast growth factor. The important role of JAK2 and JAK3 in determining the initial level of mitotic activity of progenitor cells and participation of JAK1 in this process under conditions of cytokine stimulation of progenitor cells were demonstrated. Specific inhibitors of these kinases reduced the yield of fibroblast CFU and the rate of their division. Moreover, blockade of JAK1, JAK2, and JAK3 under the effect of fibroblast growth factor was accompanied by an increase in the intensity of progenitor cell differentiation...
December 1, 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27900363/integration-of-genomics-and-histology-revises-diagnosis-and-enables-effective-therapy-of-refractory-cancer-of-unknown-primary-with-pdl1-amplification
#6
Stefan Gröschel, Martin Bommer, Barbara Hutter, Jan Budczies, David Bonekamp, Christoph Heining, Peter Horak, Martina Fröhlich, Sebastian Uhrig, Daniel Hübschmann, Christina Geörg, Daniela Richter, Nicole Pfarr, Katrin Pfütze, Stephan Wolf, Peter Schirmacher, Dirk Jäger, Christof von Kalle, Benedikt Brors, Hanno Glimm, Wilko Weichert, Albrecht Stenzinger, Stefan Fröhling
Identification of the tissue of origin in cancer of unknown primary (CUP) poses a diagnostic challenge and is critical for directing site-specific therapy. Currently, clinical decision-making in patients with CUP primarily relies on histopathology and clinical features. Comprehensive molecular profiling has the potential to contribute to diagnostic categorization and, most importantly, guide CUP therapy through identification of actionable lesions. We here report the case of an advanced-stage malignancy initially mimicking poorly differentiated soft-tissue sarcoma that did not respond to multiagent chemotherapy...
November 2016: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/27895800/a-novel-curcumin-analogue-is-a-potent-chemotherapy-candidate-for-human-hepatocellular-carcinoma
#7
Ji-An Zhao, Mei-Xiang Sang, Cui-Zhi Geng, Shi-Jie Wang, Bao-En Shan
Curcumin (CUR) has been demonstrated to protect against carcinogenesis and to prevent tumor development in cancer; however, the clinical application of CUR is limited by its instability and poor metabolic properties. The present study offers an strategy for a novel CUR analogue, (1E,4E)-1,5-bis(2-bromophenyl)penta-1,4-dien-3-one (GL63), to be used as a potential therapeutic agent for hepatocellular carcinoma (HCC) in vitro and in vivo. The current study demonstrated that GL63 exhibited more potent inhibition of proliferation of HCC cells than CUR...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895777/cryptotanshinone-inhibits-lung-tumor-growth-by-increasing-cd4-t-cell-cytotoxicity-through-activation-of-the-jak2-stat4-pathway
#8
Yonghong Man, Le Yang, Dongxian Zhang, Yongyi Bi
Cryptotanshinone is one of the fat-soluble phenanthrene quinone components. In vitro studies have shown that tanshinone compounds can inhibit the proliferation of various tumor cells and affect cell cycle distribution. The aim of the present study was to better understand the effect of cryptotanshinone on the inhibition of small cell lung cancer by cytotoxic cluster of differentiation (CD)4(+) T cells through activation of the Janus kinase 2/signal transducer and activator of transcription 4 (JAK2/STAT4) pathway...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27895669/myeloproliferative-disease-an-unusual-cause-of-raynaud-s-phenomenon-and-digital-ischaemia
#9
Celia Beynon, Gwenan Huws, Tom Lawson
We describe a 59-year-old female who presented with ischaemic digits, preceded by a 6-month history of Raynaud's phenomenon affecting her fingers and toes. There were no clinical or laboratory features of primary vasculitis or connective tissue disease, Doppler imaging was normal, and bloods were unremarkable aside from a platelet count of 786 × 109/L (150-400) and white cells of 16 × 109/L (4-11). In view of the thrombocytosis a JAK2 mutation assay was requested which confirmed a JAK2 V617F mutation, suggesting essential thrombocytosis (ET) as the cause...
2016: Case Reports in Medicine
https://www.readbyqxmd.com/read/27894077/tyrosine-kinase-fusion-genes-in-pediatric-bcr-abl1-like-acute-lymphoblastic-leukemia
#10
Judith M Boer, Elisabeth M P Steeghs, João R M Marchante, Aurélie Boeree, James J Beaudoin, H Berna Beverloo, Roland P Kuiper, Gabriele Escherich, Vincent H J van der Velden, C Ellen van der Schoot, Hester A de Groot-Kruseman, Rob Pieters, Monique L den Boer
Approximately 15% of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by gene expression similar to that of BCR-ABL1-positive disease and unfavorable prognosis. This BCR-ABL1-like subtype shows a high frequency of B-cell development gene aberrations and tyrosine kinase-activating lesions. To evaluate the clinical significance of tyrosine kinase gene fusions in children with BCP-ALL, we studied the frequency of recently identified tyrosine kinase fusions, associated genetic features, and prognosis in a representative Dutch/German cohort...
November 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27892678/characterization-and-prognosis-significance-of-jak2-v617f-mpl-and-calr-mutations-in-philadelphia-negative-myeloproliferative-neoplasms
#11
Roongrudee Singdong, Teerapong Siriboonpiputtana, Takol Chareonsirisuthigul, Adcharee Kongruang, Nittaya Limsuwanachot, Tanasan Sirirat, Suporn Chuncharunee, Budsaba Rerkamnuaychoke
Background: The discovery of somatic acquired mutations of JAK2 (V617F) in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) has not only improved rational disease classification and prognostication but also brings new understanding insight into the pathogenesis of diseases. Dosage effects of the JAK2 (V617F) allelic burden in Ph-negative MPNs may partially influence clinical presentation, disease progression, and treatment outcome...
January 10, 2016: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/27892610/beside-to-bench-jak-inhibitor-ruxolitinib-inhibits-the-expression-of-cytokines-characteristic-of-cutaneous-lupus-erythematosus
#12
Anna Sophie Klaeschen, Dominik Wolf, Peter Brossart, Thomas Bieber, Joerg Wenzel
This study was stimulated by the clinical observation of a rapid response of a chilblain lupus patient to treatment with JAK1/2-kinase inhibitor ruxolitinib. We investigated the in-vivo expression of phospho-JAK2 in CLE skin samples as well as the immunomodulatory in-vitro effect of ruxolitinib in cultured immortalized keratinocytes and in a 3D human epidermis model (epiCS). Our results demonstrate that ruxolitinib significantly decreases the production of CLE-typical cytokines (CXCL10, CXCL9, MxA) and might be a promising drug for future clinical studies in patients with CLE and related autoimmune skin diseases...
November 28, 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27889820/ruxolitinib-in-clinical-practice-for-primary-and-secondary-myelofibrosis-an-analysis-of-safety-and-efficacy-of-gruppo-laziale-of-ph-negative-mpn
#13
Massimo Breccia, Alessandro Andriani, Marco Montanaro, Elisabetta Abruzzese, Francesco Buccisano, Michele Cedrone, Antonietta Centra, Nicoletta Villivà, Francesca Celesti, Malgorzata Monica Trawinska, Fulvio Massaro, Ambra Di Veroli, Barbara Anaclerico, Gioia Colafigli, Matteo Molica, Antonio Spadea, Luca Petriccione, Giuseppe Cimino, Roberto Latagliata
Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis (MF). Aim of our study is to report safety and efficacy of ruxolitinib in 98 patients affected by MF treated outside clinical trials and collected and treated consecutively by the Lazio Cooperative Group for Ph negative myeloproliferative diseases.There were 45 males and 53 females; median age was 61.8 years (range 35.3-88). Forty-five patients were diagnosed as primary MF and 53 as secondary MF...
November 26, 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27889763/inhibition-of-the-jak2-stat3-sosc1-signaling-pathway-improves-secretion-function-of-vascular-endothelial-cells-in-a-rat-model-of-pregnancy-induced-hypertension
#14
Jian-Ying Luo, Dan Fu, Ya-Qin Wu, Ying Gao
BACKGROUND/AIMS: The present study aimed to investigate the effects of the JAK2/STAT3/SOSC1 signaling pathway on the secretion function of vascular endothelial cells (VECs) in a rat model of pregnancy-induced hypertension (PIH). METHODS: A PIH rat model was established. Forty-eight pregnant Sprague-Dawley female rats were selected and assigned into four groups: the normal group (normal non-pregnant rats), the non-PIH group (pregnant rats without PIH), the PIH group (pregnant rats with PIH) and the AG490 group (pregnant rats with PIH treated with AG490)...
November 25, 2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27884974/from-leeches-to-personalized-medicine-evolving-concepts-in-the-management-of-polycythemia-vera
#15
Alessandro Maria Vannucchi
Polycythemia vera (PV), a clonal disorders of hematopoietic stem/progenitor cells that manifests with prevalent expansion of red cell mass, is the most frequent among chronic myeloproliferative neoplasms (MPN). It is characterized by a V617F point mutation in JAK2 exon 14 , or less common mutations in exon 12, in virtually all cases. The landmark discovery of autonomously activated JAK/STAT signaling pathway paved the way for the clinical development of the first target drug, the JAK1 and JAK2 inhibitor ruxolitinib, that is now approved for patients with resistance or intolerance to hydroxyurea...
November 24, 2016: Haematologica
https://www.readbyqxmd.com/read/27884555/after-10years-of-jak2v617f-disease-biology-and-current-management-strategies-in-polycythaemia-vera
#16
REVIEW
Jacob Grinfeld, Anna L Godfrey
The JAK2V617F mutation accounts for the vast majority of patients with polycythaemia vera (PV) and around half of those with other Philadelphia-negative myeloproliferative neoplasms. Since its discovery in 2005, numerous insights have been gained into the pathways by which JAK2V617F causes myeloproliferation, including activation of JAK-STAT signalling but also through other canonical and non-canonical pathways. A variety of mechanisms explain how this one mutation can be associated with distinct clinical disorders, demonstrating how constitutional and acquired factors may interact in the presence of a single mutation to determine disease phenotype...
November 15, 2016: Blood Reviews
https://www.readbyqxmd.com/read/27882812/should-we-be-treating-lower-risk-myelofibrosis-patients-with-a-jak2-inhibitor
#17
Guido Lancman, John Mascarenhas
Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm that is associated with debilitating constitutional symptoms, progressive splenomegaly, and cytopenias. Ruxolitinib, a JAK1/2 inhibitor, is currently the only drug approved for the treatment of patients with intermediate or high risk MF. There is rationale and even limited clinical data supporting the use of ruxolitinib in lower risk patients, although this has not yet been validated in a randomized controlled trial. Areas Covered: We examine rationale for using ruxolitinib in lower risk MF patients, including survival data from COMFORT-I and COMFORT-II, specific patient populations that may derive clinical benefit, and the future impact of molecular analysis on risk stratification and treatment...
November 24, 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27875935/jak2-mpl-and-calr-mutations-in-chinese-han-patients-with-essential-thrombocythemia
#18
Jing Wang, Biao Zhang, Bing Chen, Rong-Fu Zhou, Qi-Guo Zhang, Juan Li, Yong-Gong Yang, Min Zhou, Xiao-Yan Shao, Yong Xu, Xi-Hui Xu, Jian Ouyang, Jingyan Xu, Qing Ye
BACKGROUND: Mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL), and CALR are highly relevant to Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. METHODS: Assessing the prevalence of molecular mutations in Chinese Han patients with essential thrombocythemia (ET), and correlating their mutational profile with disease characteristics/phenotype. RESULTS: Of the 110 subjects studied, 62 carried the JAK2 V617F mutation, 21 had CALR mutations, one carried an MPL (W515) mutation, and 28 had non-mutated JAK2, CALR, and MPL (so-called triple-negative ET)...
November 22, 2016: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/27874086/combined-administration-of-anisodamine-and-neostigmine-rescued-acute-lethal-crush-syndrome-through-%C3%AE-7nachr-dependent-jak2-stat3-signaling
#19
Zhe-Qi Xu, Bo-Zong Shao, Ping Ke, Jian-Guo Liu, Guo-Ku Liu, Xiong-Wen Chen, Ding-Feng Su, Chong Liu
Previously we showed that Ani (anisodamine)/Neo (neostigmine) combination produced anti-shock effect via activating α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we aim to investigate the therapeutic effect and underlying mechanisms of Ani/Neo combination in acute lethal crush syndrome (CS). In rat and rabbit CS models, Ani/Neo combination increased the 24 h survival rates, improved hemodynamics and decreased the levels of creatine kinase, MB isoenzyme of creatine kinase, blood urea nitrogen, creatinine, K(+) in serum...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27871289/inhibition-of-stat3-and-mapk-dependent-pge2-synthesis-ameliorates-phagocytosis-of-fibrillar-%C3%AE-amyloid-peptide-1-42-via-ep2-receptor-in-emf-stimulated-n9-microglial-cells
#20
Gen-Lin He, Zhen Luo, Ting-Ting Shen, Ping Li, Ju Yang, Xue Luo, Chun-Hai Chen, Peng Gao, Xue-Sen Yang
BACKGROUND: Prostaglandin E2 (PGE2)-involved neuroinflammatory processes are prevalent in several neurological conditions and diseases. Amyloid burden is correlated with the activation of E-prostanoid (EP) 2 receptors by PGE2 in Alzheimer's disease. We previously demonstrated that electromagnetic field (EMF) exposure can induce pro-inflammatory responses and the depression of phagocytosis in microglial cells, but the signaling pathways involved in phagocytosis of fibrillar β-amyloid (fAβ) in microglial cells exposed to EMF are poorly understood...
November 21, 2016: Journal of Neuroinflammation
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