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https://www.readbyqxmd.com/read/28525837/differentially-expressed-jak-stat-signaling-pathway-genes-and-target-micrornas-in-the-spleen-of-necrotic-enteritis-afflicted-chicken-lines
#1
Anh Duc Truong, Deivendran Rengaraj, Yeojin Hong, Cong Thanh Hoang, Yeong Ho Hong, Hyun S Lillehoj
The JAK signal transducer and STAT signaling pathway is an important regulator of cell proliferation, differentiation, survival, motility, apoptosis, immune response, and development. In this study, we used RNA-Sequencing, qRT-PCR, and bioinformatics tools to investigate the differential expression of JAK-STAT pathway genes, their interactions, and regulators in the spleen of two genetically disparate chicken lines (Marek's disease-resistant line 6.3 and MD-susceptible line 7.2) induced necrotic enteritis (NE) disease by co-infection with Eimeria maxima and Clostridium perfringens...
May 13, 2017: Research in Veterinary Science
https://www.readbyqxmd.com/read/28515254/nccn-debuts-new-guidelines-for-myeloproliferative-neoplasms
#2
Ruben A Mesa
For the first time, NCCN has published guidelines specifically geared toward treating myeloproliferative neoplasms (MPNs). The first set of guidelines was developed for myelofibrosis (MF), and was presented at the NCCN 22nd Annual Conference. Future guidelines will be issued for polycythemia vera, essential thrombocytopenia, and atypical MPNs. Patients with MF can have an unpredictable course, one that is largely dependent on the presence of certain molecular alterations. Models are currently emerging that take into account molecular factors...
May 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28503781/assessment-of-effect-of-cyp3a-inhibition-cyp-induction-oatp1b-inhibition-and-high-fat-meal-on-pharmacokinetics-of-the-jak1-inhibitor-upadacitinib
#3
Mohamed-Eslam F Mohamed, Steven Jungerwirth, Armen Asatryan, Ping Jiang, Ahmed A Othman
AIMS: Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor developed for treatment of auto-immune inflammatory disorders. This work evaluated effects of high-fat meal, cytochrome P450 (CYP) 3A inhibition, CYP induction, and organic anion transporting polypeptide (OATP) 1B inhibition on upadacitinib pharmacokinetics. METHODS: Two Phase 1 evaluations were conducted, each in 12 healthy subjects. In Study 1, using a randomized, 2-sequence cross-over design, a 3 mg dose of upadacitinib (immediate-release capsules) was administered alone under fasting conditions, after high-fat meal, or on Day 4 of a 6-day regimen of 400 mg once-daily ketoconazole...
May 14, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28498822/interleukin-4-and-interleukin-13-increase-nadph-oxidase-1-related-proliferation-of-human-colon-cancer-cells
#4
Han Liu, Smitha Antony, Krishnendu Roy, Agnes Juhasz, Yongzhong Wu, Jiamo Lu, Jennifer L Meitzler, Guojian Jiang, Eric Polley, James H Doroshow
Human colon cancers express higher levels of NADPH oxidase 1 [NOX1] than adjacent normal epithelium. It has been suggested that reactive oxygen species [ROS] derived from NOX1 contribute to DNA damage and neoplastic transformation in the colon, particularly during chronic inflammatory stress. However, the mechanism(s) underlying increased NOX1 expression in malignant tumors or chronic inflammatory states involving the intestine are poorly characterized. We examined the effects of two pro-inflammatory cytokines, IL-4 and IL-13, on the regulation of NOX1...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28496202/inhibition-of-jak-stat-signaling-reduces-the-activation-of-pancreatic-stellate-cells-in-vitro-and-limits-caerulein-induced-chronic-pancreatitis-in-vivo
#5
Hannah M Komar, Gregory Serpa, Claire Kerscher, Erin Schwoegl, Thomas A Mace, Ming Jin, Ming-Chen Yang, Ching-Shih Chen, Mark Bloomston, Michael C Ostrowski, Phil A Hart, Darwin L Conwell, Gregory B Lesinski
Chronic pancreatitis (CP) is a fibro-inflammatory disease leading to pain, maldigestion, and pancreatic insufficiency. No therapeutic options exist due to a limited understanding of the biology of CP pathology. Recent findings implicate pancreatic stellate cells (PSC) as prominent mediators of inflammatory and fibrotic processes during CP. Here, we utilized primary and immortalized PSC obtained from mice and patients with CP or pancreatic cancer to examine the effect of Jak/STAT and MAPK pathway inhibition in vitro...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28494922/analysis-of-jak-stat-signaling-pathway-genes-and-their-micrornas-in-the-intestinal-mucosa-of-genetically-disparate-chicken-lines-induced-with-necrotic-enteritis
#6
Anh Duc Truong, Deivendran Rengaraj, Yeojin Hong, Cong Thanh Hoang, Yeong Ho Hong, Hyun S Lillehoj
The JAK-STAT signaling pathway plays a key role in cytokine and growth factor activation and is involved in several cellular functions and diseases. The main objective of this study was to investigate the expression of candidate JAK-STAT pathway genes and their regulators and interactors in the intestinal mucosal layer of two genetically disparate chicken lines [Marek's disease (MD)-resistant line 6.3 and MD-susceptible line 7.2] induced with necrotic enteritis (NE). Through RNA-sequencing, we investigated 116 JAK-STAT signaling pathway-related genes that were significant and differentially expressed between the intestinal mucosa of the two lines compared with respective uninfected controls...
May 2017: Veterinary Immunology and Immunopathology
https://www.readbyqxmd.com/read/28494868/interferon-receptor-signaling-pathways-regulating-pd-l1-and-pd-l2-expression
#7
Angel Garcia-Diaz, Daniel Sanghoon Shin, Blanca Homet Moreno, Justin Saco, Helena Escuin-Ordinas, Gabriel Abril Rodriguez, Jesse M Zaretsky, Lu Sun, Willy Hugo, Xiaoyan Wang, Giulia Parisi, Cristina Puig Saus, Davis Y Torrejon, Thomas G Graeber, Begonya Comin-Anduix, Siwen Hu-Lieskovan, Robert Damoiseaux, Roger S Lo, Antoni Ribas
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter...
May 9, 2017: Cell Reports
https://www.readbyqxmd.com/read/28484267/microrna-146a-reduces-mhc-ii-expression-via-targeting-jak-stat-signaling-in-dendritic-cells-after-stem-cell-transplantation
#8
N Stickel, K Hanke, D Marschner, G Prinz, M Köhler, W Melchinger, D Pfeifer, A Schmitt-Graeff, T Brummer, A Heine, P Brossart, D Wolf, N von Bubnoff, J Finke, J Duyster, J Ferrara, U Salzer, R Zeiser
Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant-recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a(-/-) dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected-DCs ameliorated disease...
May 9, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28484265/jak-stat-pathway-inhibition-overcomes-il7-induced-glucocorticoid-resistance-in-a-subset-of-human-t-cell-acute-lymphoblastic-leukemias
#9
C Delgado-Martin, L K Meyer, B J Huang, K A Shimano, M S Zinter, J V Nguyen, G A Smith, J Taunton, S S Winter, J R Roderick, M A Kelliher, T M Horton, B L Wood, D Teachey, M L Hermiston
While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid (GC) resistance is more common than resistance to other chemotherapies at relapse. Additionally, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor (ETP) T-ALLs as well as in a subset of non-ETP T-ALLs...
May 9, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28472150/both-mapk-and-stat3-signal-transduction-pathways-are-necessary-for-il-6-dependent-hepatic-stellate-cells-activation
#10
Polina Kagan, Maya Sultan, Irina Tachlytski, Michal Safran, Ziv Ben-Ari
BACKGROUND: During liver injury, hepatic stellate cells (HSCs) can undergo activation and transform into alpha-smooth muscle actin (αSMA)-expressing contractile myofibroblast-like cells, leading to deposition of excessive scar matrix. We have recently demonstrated that depletion of adenosine deaminase acting on double-stranded RNA (ADAR1) from mouse hepatocytes leads to HSC activation and induction of inflammation and hepatic fibrosis that is mediated by interleukin 6 (IL-6). Our aim was to identify and characterize the molecular pathways involved in the direct, inflammation-independent activation of HSCs by IL-6...
2017: PloS One
https://www.readbyqxmd.com/read/28469959/treatment-with-the-c-c-chemokine-receptor-type-5-ccr5-inhibitor-maraviroc-suppresses-growth-and-induces-apoptosis-of-acute-lymphoblastic-leukemia-cells
#11
Jie Zi, Shushu Yuan, Jianlin Qiao, Kai Zhao, Linyan Xu, Kunming Qi, Kailin Xu, Lingyu Zeng
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy diagnosed in children and is a malignant disorder that originates from one single hematopoietic precursor committed to B- or T-cell lineage. C-C chemokine receptor type 5 (CCR5) is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. A highly potent competitive antagonist of CCR5, maraviroc, recently has been identified with suppression of cancer cells aggressive in a variety of cancers. However, the effects of maraviroc on ALL cells have not yet been defined...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28466543/mutation-patterns-in-genes-encoding-interferon-signaling-and-antigen-presentation-a-pan-cancer-survey-with-implications-for-the-use-of-immune-checkpoint-inhibitors
#12
Jan Budczies, Michael Bockmayr, Frederick Klauschen, Volker Endris, Stefan Fröhling, Peter Schirmacher, Carsten Denkert, Albrecht Stenzinger
Blockade of immune checkpoints has become a powerful tool in cancer medicine, which is effective across various solid cancer types and hematologic malignancies. While immunohistochemical detection of PD-L1 expression in tumor cells, immune cells, or both has been introduced as predictive biomarker in several clinical trials, shortcomings and limitations of this approach were quickly recognized. As a single biomarker is unlikely to adequately reflect the complex interplay between immune cells and cancer, various genetic determinants of therapy success, including microsatellite instability, mutational burden, and PD-L1 amplification, are being investigated...
May 2, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28461107/tofacitinib-attenuates-arthritis-manifestations-and-reduces-the-pathogenic-cd4-t-cells-in-adjuvant-arthritis-rats
#13
Smadar Gertel, Hussein Mahagna, Gidi Karmon, Abdulla Watad, Howard Amital
Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and leukocyte infiltration in affected joints. Tofacitinib is new agent, a selective inhibitor of Janus kinase (JAK) signaling pathways mediated by JAK1 and JAK3 and inhibits the key transcription factors STAT1 and STAT3. We investigated the action mechanisms of tofacitinib in rats with adjuvant-induced-arthritis (AIA). AIA-rats were treated orally with tofacitinib or with methotrexate. Arthritis severity and serum C-reactive protein (CRP) levels were evaluated, splenic cells were examined by flow cytometry and cytokines were analyzed by real-time PCR...
April 28, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28441920/investigational-janus-kinase-inhibitors-in-development-for-myelofibrosis
#14
Prithviraj Bose, Abdallah Abou Zahr, Srdan Verstovsek
Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail...
May 8, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28438776/the-immunoproteasome-is-induced-by-cytokines-and-regulates-apoptosis-in-human-islets
#15
Morten Lundh, Marco Bugliani, Tina Dahlby, Danny Hung-Chieh Chou, Bridget Wagner, Seyed Mojtaba Ghiasi, Vincenzo De Tata, Zhifei Chen, Marianne Nissen Lund, Michael J Davies, Piero Marchetti, Thomas Mandrup-Poulsen
In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. INS-1, INS-1E and human islets were exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules. Gene expression was assessed by microarray or quantitative PCR. Proteasome activities were analyzed using luminescent assays. Protein oxidation, Western blotting and electron microscopy were used to examine mechanisms underlying cytokine-induced apoptosis...
April 24, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28428136/hesperetin-derivative-14-alleviates-inflammation-by-activating-ppar-%C3%AE-in-mice-with-ccl4-induced-acute-liver-injury-and-lps-treated-raw264-7-cells
#16
Xin Chen, Hai-Wen Ding, Hai-Di Li, Hui-Min Huang, Xiao-Feng Li, Yang Yang, Yi-Long Zhang, Xue-Yin Pan, Cheng Huang, Xiao-Ming Meng, Jun Li
Hesperetin is a flavanone glycoside compound naturally occurring in the fruit peel of Citrusaurantium L. (Rutaceae). Previous studies revealed that hesperetin possesses various pharmacological effects, including anti-inflammation, anti-tumor, anti-oxidant and neuroprotective properties. Hesperetin derivative-14 (HD-14) is a derivative of hesperetin improved in water solubility and bioavailability. In this study, we indicated that HD-14 (2μM) significantly attenuated inflammation in LPS-treated RAW264.7 cells, besides, HD-14 (100mg/kg) exhibited hepato-protective effects and anti-inflammatory effects on C57BL/6J mice with CCl4-induced acute liver injury...
April 18, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28425456/salt-suppresses-ifn%C3%AE-inducible-chemokines-through-the-ifn%C3%AE-jak1-stat1-signaling-pathway-in-proximal-tubular-cells
#17
Yohei Arai, Daiei Takahashi, Kenichi Asano, Masato Tanaka, Mayumi Oda, Shigeru B H Ko, Minoru S H Ko, Shintaro Mandai, Naohiro Nomura, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
The mechanisms of immunoactivation by salt are now becoming clearer. However, those of immunosuppression remain unknown. Since clinical evidence indicates that salt protects proximal tubules from injury, we investigated mechanisms responsible for salt causing immunosuppression in proximal tubules. We focused on cytokine-related gene expression profiles in kidneys of mice fed a high salt diet using microarray analysis and found that both an interferon gamma (IFNγ) inducible chemokine, chemokine (C-X-C motif) ligand 9 (CXCL9), and receptor, CXCR3, were suppressed...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424246/enteropathy-associated-t-cell-lymphoma-subtypes-are-characterized-by-loss-of-function-of-setd2
#18
Andrea B Moffitt, Sarah L Ondrejka, Matthew McKinney, Rachel E Rempel, John R Goodlad, Chun Huat Teh, Sirpa Leppa, Susanna Mannisto, Panu E Kovanen, Eric Tse, Rex K H Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, Javeed Iqbal, Jiayu Yu, Kikkeri Naresh, Diego Villa, Randy D Gascoyne, Jonathan Said, Magdalena B Czader, Amy Chadburn, Kristy L Richards, Deepthi Rajagopalan, Nicholas S Davis, Eileen C Smith, Brooke C Palus, Tiffany J Tzeng, Jane A Healy, Patricia L Lugar, Jyotishka Datta, Cassandra Love, Shawn Levy, David B Dunson, Yuan Zhuang, Eric D Hsi, Sandeep S Dave
Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1 We also identified mutations in KRAS, TP53, and TERT Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis...
May 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28410228/identification-of-a-novel-functional-jak1-s646p-mutation-in-acute-lymphoblastic-leukemia
#19
Qian Li, Botao Li, Liangding Hu, Hongmei Ning, Min Jiang, Danhong Wang, Tingting Liu, Bin Zhang, Hu Chen
The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408464/targetable-kinase-gene-fusions-in-high-risk-b-all-a-study-from-the-children-s-oncology-group
#20
Shalini C Reshmi, Richard C Harvey, Kathryn G Roberts, Eileen Stonerock, Amy Smith, Heather Jenkins, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Ying Shao, John Easton, Debbie Payne-Turner, Zhaohui Gu, Thai Hoa Tran, Jonathan V Nguyen, Meenakshi Devidas, Yunfeng Dai, Nyla A Heerema, Andrew J Carroll, Elizabeth A Raetz, Michael J Borowitz, Brent L Wood, Anne L Angiolillo, Michael J Burke, Wanda L Salzer, Patrick A Zweidler-McKay, Karen R Rabin, William L Carroll, Jinghui Zhang, Mignon L Loh, Charles G Mullighan, Cheryl L Willman, Julie M Gastier-Foster, Stephen P Hunger
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed childhood B-ALL patients with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of which were excluded from additional analysis because of the presence of BCR-ABL1 (n=46) or ETV6-RUNX1 (n=11)...
April 13, 2017: Blood
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