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https://www.readbyqxmd.com/read/28432872/human-effector-memory-t-helper-cells-engage-with-mouse-macrophages-and-cause-graft-versus-host-like-pathology-in-skin-of-humanized-mice-used-in-a-nonclinical-immunization-study
#1
Bala S Sundarasetty, Valery Volk, Sebastian J Theobald, Susanne Rittinghausen, Dirk Schaudien, Vanessa Neuhaus, Constanca Figueiredo, Andreas Schneider, Laura Gerasch, Adele Mucci, Thomas Moritz, Constantin von Kaisenberg, Loukia M Spineli, Katherina Sewald, Armin Braun, Henning Weigt, Arnold Ganser, Renata Stripecke
Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4(+) T cells in peripheral blood and lymph nodes...
April 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28423649/stellettin-b-induces-apoptosis-in-human-chronic-myeloid-leukemia-cells-via-targeting-pi3k-and-stat5
#2
Yali Chen, Qianxiang Zhou, Lei Zhang, Yuxu Zhong, Guanwei Fan, Zhe Zhang, Ran Wang, Meihua Jin, Yuling Qiu, Dexin Kong
Novel agents are still urgently expected for therapy of chronic myeloid leukemia (CML). The in vitro anti-leukemia activity of Stellettin B (Stel B), a triterpenoid we isolated from marine sponge Jaspis stellifera, on human CML K562 and KU812 cells was recently investigated. Stel B inhibited K562 and KU812 cell proliferation with IC50 as 0.035 μM and 0.95 μM respectively. While no obvious cell cycle arrest was observed, apoptosis was induced in K562 cells after Stel B treatment. The Stel B-induced apoptosis might be in mitochondrial pathway, with increase of Bad and Bax, decrease of Bcl-2 and activation of caspase-9...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422740/involvement-of-mir-106b-in-tumorigenic-actions-of-both-prolactin-and-estradiol
#3
Kuan-Hui Ethan Chen, Karissa Bustamante, Vi Nguyen, Ameae M Walker
Prolactin promotes a variety of cancers by an array of different mechanisms. Here, we have investigated prolactin's inhibitory effect on expression of the cell cycle-regulating protein, p21. Using a miRNA array, we identified a number of miRNAs upregulated by prolactin treatment, but one in particular that was strongly induced by prolactin and predicted to bind to the 3'UTR of p21 mRNA, miR-106b. By creating a p21 mRNA 3'UTR-luciferase mRNA construct, we demonstrated degradation of the construct in response to prolactin in human breast, prostate and ovarian cancer cell lines...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422713/sel120-34a-is-a-novel-cdk8-inhibitor-active-in-aml-cells-with-high-levels-of-serine-phosphorylation-of-stat1-and-stat5-transactivation-domains
#4
Tomasz Rzymski, Michał Mikula, Eliza Żyłkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Gołas, Katarzyna Wójcik, Magdalena Masiejczyk, Anna Wróbel, Izabela Dolata, Agata Kitlińska, Małgorzata Statkiewicz, Urszula Kuklinska, Krzysztof Goryca, Łukasz Sapała, Aleksandra Grochowska, Aleksandra Cabaj, Małgorzata Szajewska-Skuta, Ewelina Gabor-Worwa, Katarzyna Kucwaj, Arkadiusz Białas, Adam Radzimierski, Michał Combik, Jakub Woyciechowski, Maciej Mikulski, Renata Windak, Jerzy Ostrowski, Krzysztof Brzózka
Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416389/shp1-positively-regulates-egfr-signaling-by-controlling-egfr-protein-expression-in-mammary-epithelial-cells
#5
Taichang Yuan, Hua Ma, Zhuanyun Du, Xusheng Xiong, Hongwei Gao, Zenghui Fang, Licai He, Hongzhi Li, Haihua Gu
SH2-domain containing protein tyrosine phosphatase 1 (Shp1/PTPN6) is mainly expressed in hematopoietic cells and acts a negative signaling regulator. Although Shp1 is also expressed in epithelial cells, the function of shp1 in normal epithelial is still less well understood, especially in regulating the growth of epithelial cells. In this study, different shRNAs and siRNAs against Shp1were used to knockdown Shp1 expression in MCF10A, an immortalized mammary epithelial cell line. Shp1 knockdown resulted in inhibited cell growth in part due to lower percentage of MCF10A cells entering into S phase and reduced cyclin D1 expression...
April 14, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28415816/targeting-the-pim-protein-kinases-for-the-treatment-of-a-t-cell-acute-lymphoblastic-leukemia-subset
#6
Sathish K R Padi, Libia A Luevano, Ningfei An, Ritu Pandey, Neha Singh, Jin H Song, Jon C Aster, Xue-Zhong Yu, Shikhar Mehrotra, Andrew S Kraft
New approaches are needed for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission with chemotherapy. Analysis of the effects of pan-PIM protein kinase inhibitors on human T-ALL cell lines demonstrated that the sensitive cell lines expressed higher PIM1 protein kinase levels, whereas T-ALL cell lines with NOTCH mutations tended to have lower levels of PIM1 kinase and were insensitive to these inhibitors. NOTCH-mutant cells selected for resistance to gamma secretase inhibitors developed elevated PIM1 kinase levels and increased sensitivity to PIM inhibitors...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410970/insulin-and-insulin-like-growth-factor-1-modulate-the-lipolytic-action-of-growth-hormone-by-altering-signal-pathway-linkages
#7
Heather E Bergan-Roller, Alicia T Ickstadt, Jeffrey D Kittilson, Mark A Sheridan
Growth hormone (GH) has many actions in vertebrates, including the regulation of two disparate metabolic processes: growth promotion (anabolic) and th e mobilization of stored lipids (catabolic). Our previous studies showed that GH stimulated IGF-1 production in hepatocytes from fed rainbow trout, but in cells from fasted fish GH stimulated lipolysis. In this study, we used rainbow trout (Oncorhynchus mykiss) to elucidate regulation of the mechanisms that enable cells to alter their lipolytic responsiveness to GH...
April 11, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28410882/epo-reprograms-the-epigenome-of-erythroid-cells
#8
Andrea A Perreault, Mary Lauren Benton, Mark J Koury, Stephen J Brandt, Bryan J Venters
The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly in regards to chromatin dynamics. To investigate how Epo modulates the erythroid epigenome, we performed epigenetic profiling using an ex vivo murine cell system that undergoes synchronous erythroid maturation in response to Epo stimulation. Our findings define the repertoire of Epo-modulated enhancers, illuminating a new facet of Epo signaling. First, a large number of enhancers rapidly responded to Epo stimulation, revealing a cis-regulatory network of Epo-responsive enhancers...
April 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28404633/il-7r%C3%AE-expression-regulates-murine-dendritic-cell-sensitivity-to-thymic-stromal-lymphopoietin
#9
Laura Kummola, Zsuzsanna Ortutay, Xi Chen, Stephane Caucheteux, Sanna Hämäläinen, Saara Aittomäki, Ryoji Yagi, Jinfang Zhu, Marko Pesu, William E Paul, Ilkka S Junttila
Thymic stromal lymphopoietin (TSLP) and IL-7 are related cytokines that mediate growth and differentiation events in the immune system. They signal through IL-7Rα-containing receptors. Target cells of TSLP in Th2 responses include CD4 T cells and dendritic cells (DCs). Although it has been reported that expression of TSLP receptor (TSLPR) on CD4 T cells is required for OVA-induced lung inflammation, DCs have also been shown to be target cells of TSLP. In this study, we show that murine ex vivo splenic DCs are unresponsive to TSLP, as they fail to phosphorylate STAT5, but in vitro overnight culture, especially in presence of IL-4, renders DCs responsive to both TSLP and IL-7...
April 12, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28403213/m-copa-suppresses-endolysosomal-kit-akt-oncogenic-signalling-through-inhibiting-the-secretory-pathway-in-neoplastic-mast-cells
#10
Yasushi Hara, Yuuki Obata, Keita Horikawa, Yasutaka Tasaki, Kyohei Suzuki, Takatsugu Murata, Isamu Shiina, Ryo Abe
Gain-of-function mutations in Kit receptor tyrosine kinase result in the development of a variety of cancers, such as mast cell tumours, gastrointestinal stromal tumours (GISTs), acute myeloid leukemia, and melanomas. The drug imatinib, a selective inhibitor of Kit, is used for treatment of mutant Kit-positive cancers. However, mutations in the Kit kinase domain, which are frequently found in neoplastic mast cells, confer an imatinib resistance, and cancers expressing the mutants can proliferate in the presence of imatinib...
2017: PloS One
https://www.readbyqxmd.com/read/28400581/rational-development-of-stafib-2-a-selective-nanomolar-inhibitor-of-the-transcription-factor-stat5b
#11
Nagarajan Elumalai, Angela Berg, Stefan Rubner, Linda Blechschmidt, Chen Song, Kalaiselvi Natarajan, Jörg Matysik, Thorsten Berg
The transcription factor STAT5b is a target for tumour therapy. We recently reported catechol bisphosphate and derivatives such as Stafib-1 as the first selective inhibitors of the STAT5b SH2 domain. Here, we demonstrate STAT5b binding of catechol bisphosphate by solid-state nuclear magnetic resonance, and report on rational optimization of Stafib-1 (Ki = 44 nM) to Stafib-2 (Ki = 9 nM). The binding site of Stafib-2 was validated using combined isothermal titration calorimetry (ITC) and protein point mutant analysis, representing the first time that functional comparison of wild-type versus mutant protein by ITC has been used to characterize the binding site of a small-molecule ligand of a STAT protein with amino acid resolution...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28397975/the-jak2-stat5-signaling-pathway-as-a-potential-therapeutic-target-in-canine-mastocytoma
#12
Alexandra Keller, Bettina Wingelhofer, Barbara Peter, Karin Bauer, Daniela Berger, Susanne Gamperl, Martin Reifinger, Sabine Cerny-Reiterer, Richard Moriggl, Michael Willmann, Peter Valent, Emir Hadzijusufovic
BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1...
April 11, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28390952/hypothyroidism-decreases-jak-stat-signaling-pathway-in-lactating-rat-mammary-gland
#13
Fiorella Campo Verde Arboccó, Fabio Andres Persia, María Belén Hapon, Graciela A Jahn
Thyroid pathologies have deleterious effects on lactation. Especially hypothyroidism (HypoT) induces premature mammary involution at the end of lactation and decreases milk production and quality in mid lactation. Milk synthesis is controlled by JAK2/STAT5 signaling pathway and prolactin (PRL), which activates the pathway. In this work we analyzed the effect of chronic 6-propyl-2- thiouracil (PTU)-induced HypoT on PRL signaling pathway on mammary glands from rats on lactation (L) days 2, 7 and 14. HypoT decreased prolactin receptor expression, and expression and activation of Stat5a/b protein...
April 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28390197/hdac8-overexpression-in-mesenchymal-stromal-cells-from-jak2-myeloproliferative-neoplasms-a-new-therapeutic-target
#14
Teresa L Ramos, Luis Ignacio Sánchez-Abarca, Alba Redondo, Ángel Hernández-Hernández, Antonio M Almeida, Noemí Puig, Concepción Rodríguez, Rebeca Ortega, Silvia Preciado, Ana Rico, Sandra Muntión, José Ramón González Porras, Consuelo Del Cañizo, Fermín Sánchez-Guijo
Histone deacetylases (HDACs) are involved in epigenetic modulation and their aberrant expression has been demonstrated in myeloproliferative neoplasms (MPN). HDAC8 inhibition has been shown to inhibit JAK2/STAT5 signaling in hematopoietic cells from MPN. Nevertheless, the role of HDAC8 expression in bone marrow-mesenchymal stromal cells (BM-MSC) has not been assessed. In the current work we describe that HDAC8 is significantly over-expressed in MSC from in JAK-2 positive MPN compared to those from healthy-donors (HD-MSC)...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28390194/stat5-deficiency-decreases-transcriptional-heterogeneity-and-supports-emergence-of-hematopoietic-sub-populations
#15
Zhengqi Wang, Kevin D Bunting
Aging is associated with significant changes in hematopoiesis, including clonal dominance, anemia, myeloid malignancies, and reduced activation of signal transducer and activator of transcription 5 (Stat5). In previous studies, Stat5 deletion surprisingly amplified FLT3/ITD+ myeloid expansion or Myc-driven lymphoid expansion. Here we show that Stat5 deficiency has a strong impact upon transcriptional heterogeneity in single sorted c-Kit+Lin-Sca-1+ (KLS) cells or CD150+CD48- KLS long-term repopulating hematopoietic stem cells (LT-HSC)...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28387753/imatinib-mesylate-inhibits-stat5-phosphorylation-in-response-to-il-7-and-promotes-t-cell-lymphopenia-in-chronic-myelogenous-leukemia-patients
#16
S Thiant, M M Moutuou, P Laflamme, R Sidi Boumedine, D M Leboeuf, L Busque, J Roy, M Guimond
Imatinib mesylate (IM) therapy has been shown to induce lower T cell counts in chronic myelogenous leukemia (CML) patients and an interference of IM with T cell receptor (TCR) signaling has been invoked to explain this observation. However, IL-7 and TCR signaling are both essential for lymphocyte survival. This study was undertaken to determine whether IM interferes with IL-7 or TCR signaling to explain lower T cell counts in patients. At diagnosis, CML patients have typically lower CD4(+) counts in their blood, yet CD8(+) counts are normal or even increased in some...
April 7, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28383049/suppressor-of-cytokine-signaling-2-negatively-regulates-nk-cell-differentiation-by-inhibiting-jak2-activity
#17
Won Sam Kim, Mi Jeong Kim, Dong Oh Kim, Jae-Eun Byun, Hangsak Huy, Hae Young Song, Young-Jun Park, Tae-Don Kim, Suk Ran Yoon, Eun-Ji Choi, Haiyoung Jung, Inpyo Choi
Suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine responses. Although recent reports have shown regulatory roles for SOCS proteins in innate and adaptive immunity, their roles in natural killer (NK) cell development are largely unknown. Here, we show that SOCS2 is involved in NK cell development. SOCS2(-/-) mice showed a high frequency of NK cells in the bone marrow and spleen. Knockdown of SOCS2 was associated with enhanced differentiation of NK cells in vitro, and the transplantation of hematopoietic stem cells (HSCs) into congenic mice resulted in enhanced differentiation in SOCS2(-/-) HSCs...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28371169/a-rapid-method-for-quantifying-cytoplasmic-versus-nuclear-localization-in-endogenous-peripheral-blood-leukocytes-by-conventional-flow-cytometry
#18
George C Brittain, Sergei Gulnik
A biochemical system and method have been developed to enable the quantitative measurement of cytoplasmic versus nuclear localization within cells in whole blood. Compared with the analyses of nuclear localization by western blot or fluorescence microscopy, this system saves a lot of time and resources by eliminating the necessity of purification and culturing steps, and generates data that are free from the errors and artifacts associated with using tumor cell lines or calculating nuclear signals from 2D images...
April 2017: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/28369050/antagonism-of-b-cell-enhancer-networks-by-stat5-drives-leukemia-and-poor-patient-survival
#19
Casey D S Katerndahl, Lynn M Heltemes-Harris, Mark J L Willette, Christine M Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B Ramsey, Gregory Hubbard, Andrew D Wells, Roland P Kuiper, Blanca Scheijen, Frank N van Leeuwen, Markus Müschen, Steven M Kornblau, Michael A Farrar
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU...
April 3, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28366783/intestinal-immune-responses-of-jian-carp-against-aeromonas-hydrophila-depressed-by-choline-deficiency-varied-change-patterns-of-mrna-levels-of-cytokines-tight-junction-proteins-and-related-signaling-molecules-among-three-intestinal-segments
#20
Pei Wu, Yang Liu, Wei-Dan Jiang, Jun Jiang, Yong-An Zhang, Xiao-Qiu Zhou, Lin Feng
This study aimed to investigate the effects of choline deficiency on intestinal inflammation of fish after Aeromonas hydrophila infection and the potential molecular mechanisms. Juvenile Jian carp (Cyprinus carpio var. Jian) were fed two diets containing choline at 165 (deficient group) and 607 mg/kg diet respectively for 65 days. Choline deficiency decreased intestinal lysozyme activity, C3 and IgM contents, increased acid phosphatase activity, downregulated mRNA levels of antimicrobial peptides [liver-expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin and defensin], cytokines [interleukin (IL) 6a, tumor necrosis factor α (TNF-α), interferon γ2b (IFN-γ2b), IL-6b and transforming growth factor β2 (TGF-β2) only in proximal intestine, IL-10 in mid and distal intestine], immune-related signaling molecules [Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), nuclear factor kappa B (NF-κB), inhibitor of NF-κB (IκB), Janus kinase 3 (JAK3), and signal transducers and activators of transcription 5 (STAT5)], tight junction proteins (claudin 3b, claudin 3c, claudin 11 and occludin), and mitogen-activated protein kinases p38 (p38(MAPK)) in proximal and distal intestine of juvenile Jian carp after A...
March 30, 2017: Fish & Shellfish Immunology
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