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https://www.readbyqxmd.com/read/28344884/the-differentiation-and-plasticity-of-tc17-cells-are-regulated-by-ctla-4-mediated-effects-on-stats
#1
Aditya Arra, Holger Lingel, Benno Kuropka, Jonas Pick, Tina Schnoeder, Thomas Fischer, Christian Freund, Mandy Pierau, Monika C Brunner-Weinzierl
As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8(+) T cells to evoke effective cytotoxic antitumor responses. Using in vitro and in vivo models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8(+) T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORγt...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28344041/stat5-signaling-in-kisspeptin-cells-regulates-the-timing-of-puberty
#2
Marina Augusto Silveira, Isadora C Furigo, Thais T Zampieri, Tabata M Bohlen, Daniella G de Paula, Celso Rodrigues Franci, Jose Donato, Renata Frazao
Previous studies have shown that kisspeptin neurons are important mediators of prolactin's effects on reproduction. However, the cellular mechanisms recruited by prolactin to affect kisspeptin neurons remain unknown. Using whole-cell patch-clamp recordings of brain slices from kisspeptin reporter mice, we observed that 20% of kisspeptin neurons in the anteroventral periventricular nucleus was indirectly depolarized by prolactin via an unknown population of prolactin responsive neurons. This effect required the phosphatidylinositol 3-kinase signaling pathway...
March 23, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28332288/tetrandrine-an-agonist-of-aryl-hydrocarbon-receptor-reciprocally-modulates-the-activities-of-stat3-and-stat5-to-suppress-th17-cell-differentiation
#3
Xusheng Yuan, Yannong Dou, Xin Wu, Zhifeng Wei, Yue Dai
Tetrandrine, a bisbenzylisoquinoline alkaloid constituent of the root of Stephania tetrandra S. Moore, was previously shown to suppress the differentiation of T helper 17 (Th17) cells and consequently ameliorate the collagen-induced arthritis (CIA) in mice by activating the aryl hydrocarbon receptor (AhR), but its underlying mechanism is incompletely understood. Here, we investigated how tetrandrine suppressed Th17 cell differentiation through the AhR pathway. The naïve CD4(+) T cells were stimulated with anti-CD3/CD28 for 72 hrs in the presence or absence of tetrandrine under the Th17-polarizing condition...
March 22, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28331226/the-histone-deacetylase-inhibitor-givinostat-itf2357-exhibits-potent-anti-tumor-activity-against-crlf2-rearranged-bcp-all
#4
A M Savino, J Sarno, L Trentin, M Vieri, G Fazio, M Bardini, C Bugarin, G Fossati, K Davis, G Gaipa, S Izraeli, L H Meyer, G P Nolan, A Biondi, G Te Kronnie, C Palmi, G Cazzaniga
Leukemias bearing CRLF2 and JAK2 gene alterations are characterized by aberrant JAK/STAT signaling and poor prognosis. The HDAC inhibitor givinostat/ITF2357 has been shown to exert antineoplastic activity against both systemic juvenile idiopathic arthritis and myeloproliferative neoplasms through inhibition of the JAK/STAT pathway. These findings led us to hypothesize that givinostat might also act against CRLF2-rearranged BCP-ALL, which lack effective therapies. Here, we found that givinostat inhibited proliferation and induced apoptosis of BCP-ALL CRLF2-rearranged cell lines, positive for exon 16 JAK2 mutations...
March 23, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28329851/short-tslp-attenuates-toluene-diisocyanate-tdi-induced-airway-inflammation-and-inhibits-hmgb1-rage-and-long-tslp-expression
#5
Yanhong Wang, Yanqing Le, Wenqu Zhao, Yun Lin, Yue Wu, Changhui Yu, Jing Xiong, Fei Zou, Hangming Dong, Shaoxi Cai, Haijin Zhao
Short thymic stromal lymphopoietin (short TSLP), one of TSLP variants, exerts anti-inflammatory activities in endotoxin shock and colitis mouse models. Our latest work reported that short TSLP prevented house dust mite (HDM)-induced epithelial barrier disruption. Yet the role of short TSLP in toluene diisocyanate (TDI)-induced asthma is unknown. Male BALB/c mice were sensitized and challenged with TDI to generate a chemical-induced asthma model. Synthetic short TSLP peptides were given intranasally (i.n.) or intraperitoneally (i...
February 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28329231/cardiac-protective-effects-of-remote-ischaemic-preconditioning-in-children-undergoing-tetralogy-of-fallot-repair-surgery-a-randomized-controlled-trial
#6
Qingping Wu, Tingting Wang, Shiqiang Chen, Quanjun Zhou, Haobo Li, Na Hu, Yinglu Feng, Nianguo Dong, Shanglong Yao, Zhengyuan Xia
Aims: Remote ischaemic preconditioning (RIPC) by inducing brief ischaemia in distant tissues protects the heart against myocardial ischaemia-reperfusion injury (IRI) in children undergoing open-heart surgery, although its effectiveness in adults with comorbidities is controversial. The effectiveness and mechanism of RIPC with respect to myocardial IRI in children with tetralogy of Fallot (ToF), a severe cyanotic congenital cardiac disease, undergoing open heart surgery are unclear. We hypothesized that RIPC can confer cardioprotection in children undergoing ToF repair surgery...
February 18, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28327619/il-36%C3%AE-signaling-controls-the-induced-regulatory-t-cell-th9-cell-balance-via-nf%C3%AE%C2%BAb-activation-and-stat-transcription-factors
#7
A Harusato, H Abo, V L Ngo, S W Yi, K Mitsutake, S Osuka, J E Kohlmeier, J D Li, A T Gewirtz, A Nusrat, T L Denning
Regulatory and effector T helper (Th) cells are abundant at mucosal surfaces, especially in the intestine, where they control the critical balance between tolerance and inflammation. However, the key factors that reciprocally dictate differentiation along these specific lineages remain incompletely understood. Here we report that the interleukin-1 (IL-1) family member IL-36γ signals through IL-36 receptor, myeloid differentiation primary response gene 88, and nuclear factor-κBp50 in CD4(+) T cells to potently inhibit Foxp3-expressing induced regulatory T cell (Treg) development, while concomitantly promoting the differentiation of Th9 cells via a IL-2-STAT5- (signal transducer and activator of transcription factor 5) and IL-4-STAT6-dependent pathway...
March 22, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28323953/activation-of-male-liver-chromatin-accessibility-and-stat5-dependent-gene-transcription-by-plasma-growth-hormone-pulses
#8
Jeannette Connerney, Dana Lau-Corona, Andy Rampersaud, David J Waxman
Sex-differences in pituitary growth hormone (GH) secretion (pulsatile in males vs near continuous/persistent in females) impart sex-dependent expression to hundreds of genes in adult mouse liver. STAT5, a GH-activated transcription factor that is essential for liver sexual dimorphism, is dynamically activated in direct response to each male plasma GH pulse. However, the impact of GH-induced STAT5 pulses on liver chromatin accessibility and downstream transcriptional events is unknown. Here, we investigate the impact of a single pulse of GH given to hypophysectomized mice on local liver chromatin accessibility [DNase hypersensitive site analysis], transcription rates [hnRNA analysis], and gene expression [quantitative PCR and RNA-Seq] determined 30, 90 or 240 min later...
February 17, 2017: Endocrinology
https://www.readbyqxmd.com/read/28321124/combined-inhibition-of-%C3%AE-catenin-and-bcr-abl-synergistically-targets-tyrosine-kinase-inhibitor-resistant-blast-crisis-chronic-myeloid-leukemia-blasts-and-progenitors-in-vitro-and-in-vivo
#9
H Zhou, P Y Mak, H Mu, D H Mak, Z Zeng, J Cortes, Q Liu, M Andreeff, B Z Carter
Tyrosine kinase inhibitor (TKI) resistance and progression to blast crisis (BC), both related to persistent β-catenin activation remain formidable challenges for chronic myeloid leukemia (CML). We observed overexpression of β-catenin in BC-CML stem/progenitor cells, particularly in GMP progenitors, and highest among a novel CD34(+)CD38(+)CD123(hi)Tim-3(hi) subset as determined by CyTOF analysis. Co-culture with mesenchymal stromal cells (MSCs) induced the expression of β-catenin and its target CD44 in CML cells...
March 21, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28318095/clinicopathologic-and-molecular-characterization-of-myeloid-neoplasms-with-isolated-t-6-9-p23-q34
#10
V Visconte, S Shetty, B Przychodzen, C Hirsch, J Bodo, J P Maciejewski, E D Hsi, H J Rogers
INTRODUCTION: The t(6;9)(p23;q34);DEK-NUP214 [t(6;9)] abnormality is found in 0.7-1.8% of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). FLT3-ITD mutations are detected in t(6;9) patients. The t(6;9) abnormality is associated with poor outcomes. We studied the clinicopathologic and molecular profiles of patients with AML/MDS carrying t(6;9). METHODS: We collected clinical data of nine patients with AML/MDS with isolated t(6;9) (median age = 41 years; male/female = 4/5) and genotyped DNAs using whole exome, Sanger, and targeted sequencing...
March 20, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28302567/alpha2-adrenoceptor-agonists-trigger-prolactin-signaling-in-breast-cancer-cells
#11
Lilian Fedra Castillo, Ezequiel M Rivero, Vincent Goffin, Isabel Alicia Lüthy
Breast cancer is the most frequent malignancy among women worldwide. We have described the expression of α2-adrenoceptors in breast cancer cell lines, associated with increased cell proliferation and tumor growth. A mitogenic autocrine/paracrine loop of prolactin (Prl) has been described in breast cancer cells. We hypothesized that the α2-adrenergic enhancement of proliferation could be mediated, at least in part, by this Prl loop. In both T47D and MCF-7 cell lines, the incubation with the α2-adrenergic agonist dexmedetomidine significantly increased Prl release into the culture medium (measured by the Nb2 bioassay), this effect being reversed by the α2-adrenergic antagonist rauwolscine...
March 14, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28300289/dehydrocostus-lactone-suppresses-proliferation-of-human-chronic-myeloid-leukemia-cells-through-bcr-abl-jak-stat-signaling-pathways
#12
Hong Cai, Xiaosong Qin, Chunhui Yang
This study evaluates the anticancer effects of dehydrocostus lactone, a plant-derived sesquiterpene lactone, on human chronic myeloid leukemia cells. Dehydrocostus lactone significantly inhibits cell proliferation by inducing cells to undergo cell cycle arrest, apoptosis and differentiation. Dehydrocostus lactone suppresses the expression of cyclin B1, cyclin A, cyclin E, cyclin-dependent kinase 2 (CDK2), and cyclin-dependent kinase 1 (CDK2) and increases p21 expression, resulting in S-G2/M phase arrest in K562 cells...
March 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28298334/erythropoietin-facilitates-definitive-endodermal-differentiation-of-mouse-embryonic-stem-cells-via-activation-of-erk-signaling
#13
Taku Kaitsuka, Kohei Kobayashi, Wakako Otsuka, Takuya Kubo, Farzana Hakim, Fan-Yan Wei, Nobuaki Shiraki, Shoen Kume, Kazuhito Tomizawa
Artificially generated pancreatic β-cells from pluripotent stem cells are expected for cell replacement therapy for type 1 diabetes. Several strategies are adopted to direct pluripotent stem cells toward pancreatic differentiation. However, a standard differentiation method for clinical application has not been established. It is important to develop more effective and safer methods for generating pancreatic β-cells without toxic or mutagenic chemicals. In the present study, we screened several endogenous factors involved in organ development to identify the factor, which induced the efficiency of pancreatic differentiation and found that treatment with erythropoietin (EPO) facilitated the differentiation of mouse embryonic stem cells (ESCs) into definitive endoderm...
March 15, 2017: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/28293439/proteomic-analysis-of-hdac3-selective-inhibitor-in-the-regulation-of-inflammatory-response-of-primary-microglia
#14
Mingxu Xia, Qiuchen Zhao, He Zhang, Yanting Chen, Zengqiang Yuan, Yun Xu, Meijuan Zhang
HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28287479/stat5-interacting-proteins-a-synopsis-of-proteins-that-regulate-stat5-activity
#15
REVIEW
Ashley A Able, Jasmine A Burrell, Jacqueline M Stephens
Signal Transducers and Activators of Transcription (STATs) are key components of the JAK/STAT pathway. Of the seven STATs, STAT5A and STAT5B are of particular interest for their critical roles in cellular differentiation, adipogenesis, oncogenesis, and immune function. The interactions of STAT5A and STAT5B with cytokine/hormone receptors, nuclear receptors, transcriptional regulators, proto-oncogenes, kinases, and phosphatases all contribute to modulating STAT5 activity. Among these STAT5 interacting proteins, some serve as coactivators or corepressors to regulate STAT5 transcriptional activity and some proteins can interact with STAT5 to enhance or repress STAT5 signaling...
March 11, 2017: Biology
https://www.readbyqxmd.com/read/28283061/functional-selectivity-in-cytokine-signaling-revealed-through-a-pathogenic-epo-mutation
#16
Ah Ram Kim, Jacob C Ulirsch, Stephan Wilmes, Ekrem Unal, Ignacio Moraga, Musa Karakukcu, Daniel Yuan, Shideh Kazerounian, Nour J Abdulhay, David S King, Namrata Gupta, Stacey B Gabriel, Eric S Lander, Turkan Patiroglu, Alper Ozcan, Mehmet Akif Ozdemir, K Christopher Garcia, Jacob Piehler, Hanna T Gazda, Daryl E Klein, Vijay G Sankaran
Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28278176/cuzd1-is-a-critical-mediator-of-the-jak-stat5-signaling-pathway-that-controls-mammary-gland-development-during-pregnancy
#17
Janelle Mapes, Quanxi Li, Athilakshmi Kannan, Lavanya Anandan, Mary Laws, John P Lydon, Indrani C Bagchi, Milan K Bagchi
In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28276286/arsenic-trioxide-and-all-trans-retinoic-acid-selectively-exert-synergistic-cytotoxicity-against-flt3-itd-aml-cells-via-co-inhibition-of-flt3-signaling-pathways
#18
Li-Na Wang, Yan-Lai Tang, Yin-Chuan Zhang, Zu-Han Zhang, Xiao-Jian Liu, Zhi-Yong Ke, Yu Li, Hui-Zhen Tan, Li-Bin Huang, Xue-Qun Luo
FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML...
March 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28260027/pstat5-and-erk-exhibit-different-expression-in-myeloproliferative-neoplasms
#19
Ewa Wiśniewska-Chudy, Łukasz Szylberg, Grzegorz Dworacki, Ewa Mizera-Nyczak, Andrzej Marszałek
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic progenitor cell disorders characterized by the proliferation of one or more hematopoietic lineages. The classical MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) entities. These disorders are characterized by bone marrow morphology typical for each disease, and by the presence of JAK2V617F mutation in the marrow and blood. However, JAK2V617F cannot account for the phenotypic heterogeneity of MPNs because approximately half of all cases of ET and PMF show no evidence of this molecular marker...
February 24, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28257089/blockade-of-y177-and-nuclear-translocation-of-bcr-abl-inhibits-proliferation-and-promotes-apoptosis-in-chronic-myeloid-leukemia-cells
#20
Qianyin Li, Zhenglan Huang, Miao Gao, Weixi Cao, Qin Xiao, Hongwei Luo, Wenli Feng
The gradual emerging of resistance to imatinib urgently calls for the development of new therapy for chronic myeloid leukemia (CML). The fusion protein Bcr-Abl, which promotes the malignant transformation of CML cells, is mainly located in the cytoplasm, while the c-Abl protein which is expressed in the nucleus can induce apoptosis. Based on the hetero-dimerization of FKBP (the 12-kDa FK506- and rapamycin-binding protein) and FRB (the FKBP-rapamycin binding domain of the protein kinase, mTOR) mediated by AP21967, we constructed a nuclear transport system to induce cytoplasmic Bcr-Abl into nuclear...
March 2, 2017: International Journal of Molecular Sciences
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