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Q N Yu, Y B Guo, X Li, C L Li, W P Tan, X L Fan, Z L Qin, D Chen, W P Wen, S G Zheng, Q L Fu
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) were closely associated with asthma. However, there were no perspective studies about the effects of glucocorticoid on ILC2s in asthma patients. Our objective was to perform a perspective study and evaluate the ILC2 activity after glucocorticoid therapy in asthma patients. METHODS: The asthma and asthma with allergic rhinitis patients were treated with glucocorticoid for 3 months. The circulating ILC2 levels were evaluated...
March 15, 2018: Allergy
Yrina Rochman, Krista Dienger-Stambaugh, Phoebe K Richgels, Ian P Lewkowich, Andrey V Kartashov, Artem Barski, Gurjit K Khurana Hershey, Warren J Leonard, Harinder Singh
Pathogenic T helper 2 (TH 2) cells, which produce increased amounts of the cytokines interleukin-5 (IL-5) and IL-13, promote allergic disorders, including asthma. Thymic stromal lymphopoietin (TSLP), a cytokine secreted by epithelial and innate immune cells, stimulates such pathogenic TH 2 cell responses. We found that TSLP signaling in mouse CD4+ T cells initiated transcriptional changes associated with TH 2 cell programming. IL-4 signaling amplified and stabilized the genomic response of T cells to TSLP, which increased the frequency of T cells producing IL-4, IL-5, and IL-13...
March 13, 2018: Science Signaling
Seungyeop Lee, Si-On Lee, Gyu-Lee Kim, Dong-Kwon Rhee
AIMS: Streptococcus pneumoniae infection in acute bacterial meningitis can lead to widespread brain damage and mortality. Inflammatory responses by immune cells in the brain are thought to determine the degree of brain injury. Yet, the mechanisms underlying host responses to pneumococcal meningitis are largely unknown. To explore host responses as a potential therapeutic target for preventing brain injury after pneumococcal meningitis. METHODS: We evaluated signaling mechanisms that minimize neuronal damage caused by pneumococcal infection; specifically, we assessed pathways related to neuronal survival after enhancing estrogen receptor-β (ER-β) expression using a natural therapeutic substance known as ginsenoside Rb1 and Rg3 enhanced ginseng...
March 9, 2018: CNS Neuroscience & Therapeutics
Xian-Tao Zeng, Xiao-Ping Liu, Tong-Zu Liu, Xing-Huan Wang
The present study was aimed to investigate the relationship between the expression of collagen type V alpha 2 chain (COL5A2) and clinical outcomes of patients with bladder cancer.Chi-square test and log-rank-based survival analysis were performed to assess the correlation of COL5A2 expression with clinical characteristics and survivals of patients with bladder cancer using GSE13507. Gene set enrichment analysis was conducted to study the relevant mechanisms.Bladder cancer patients in COL5A2 low expression group were associated with better invasiveness (P < ...
March 2018: Medicine (Baltimore)
Dorina Ujvari, Noemi Nagy, Harsha S Madapura, Tomasz Kallas, Marijke C L Kröhnke, Leif Stenke, Eva Klein, Daniel Salamon
B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that can repress more than 1200 potential target genes. It exerts oncogenic effects through the inhibition of differentiation, DNA damage sensing and apoptosis in several human hematopoietic malignancies, including multiple myeloma (MM). The multifunctional cytokine interferon γ (IFNγ) exerts pro-apoptotic and anti-proliferative effects on MM cells in vitro, at least partially through the inhibition of the effects of interleukin 6 (IL6), one of the most important growth factor of MM and a strong inducer of BCL6 expression...
March 3, 2018: Biochemical and Biophysical Research Communications
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
Charles E de Bock, Sofie Demeyer, Sandrine Degryse, Delphine Verbeke, Bram Sweron, Olga Gielen, Roel Vandepoel, Carmen Vicente, Marlies Vanden Bempt, Antonis Dagklis, Ellen Geerdens, Simon Bornschein, Rik Gijsbers, Jean Soulier, Jules P Meijerink, Merja Heinäniemi, Susanna Teppo, Maria Bouvy-Liivrand, Olli Lohi, Enrico Radaelli, Jan Cools
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared to JAK3 or HOXA9 alone...
March 1, 2018: Cancer Discovery
Farhad Dehkhoda, Christine M M Lee, Johan Medina, Andrew J Brooks
The growth hormone receptor (GHR), although most well known for regulating growth, has many other important biological functions including regulating metabolism and controlling physiological processes related to the hepatobiliary, cardiovascular, renal, gastrointestinal, and reproductive systems. In addition, growth hormone signaling is an important regulator of aging and plays a significant role in cancer development. Growth hormone activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor...
2018: Frontiers in Endocrinology
Devayani Machiraju, Iris Moll, Christoffer Gebhardt, Antje Sucker, Kristina Buder-Bakhaya, Dirk Schadendorf, Jessica C Hassel
Interferons (IFN) have a direct growth-inhibiting effect on tumor cells through Janus kinase-dependent activation of the transcription factor signal transducer and activator of transcription (STAT1). In vitro, signaling through STAT5 has been demonstrated to counteract this effect and lead to IFN resistance of melanoma cell lines. In 32 patients treated with IFN-α in an adjuvant setting, we investigated paraffin-embedded tumor tissue from primary melanomas and melanoma metastases for expression of STAT3 and STAT5, by immunohistochemistry, and for expression of phosphorylated signaling transduction activating transcription factor (pSTAT)3 and pSTAT5, by immunofluorescence...
February 26, 2018: Melanoma Research
Francesca Pagano, Federico Comoglio, Jacob Grinfeld, Juan Li, Anna Godfrey, Joanna Baxter, Yvonne Silber, Anthony R Green
No abstract text is available yet for this article.
February 27, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Cristina Maranto, Vindhya Udhane, David T Hoang, Lei Gu, Vitali Alexeev, Kareem M Malas, Karmel Cardenas, Jonathan R Brody, Ulrich Rodeck, Carmen Bergom, Kenneth A Iczkowski, Kenneth Jacobsohn, William A See, Sara M Schmitt, Marja T Nevalainen
PURPOSE: The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double strand DNA break repair in PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. EXPERIMENTAL DESIGN: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair...
February 26, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jiabi Zhang, Juan Shan, Xuelu Chen, Shengfu Li, Dan Long, Youping Li
A T helper 17 (Th17) cell/regulatory T (Treg) cell imbalance is involved in many immune disorders and diseases. Celastrol, a Chinese herbal compound that has anti-inflammatory and immunosuppressive properties, has been indicated to suppress T cell proliferation and Th17 cell induction, while facilitating Forkhead box P3 (Foxp3) expression and Treg cell generation. In this study, we explored the impact and mechanism of celastrol on Th17 cell/induced Treg (iTreg) cell induction. CD4+ CD25- T cells were purified, stimulated with anti-CD3 and anti-CD28 antibodies, and polarized in vitro to generate Th17 or iTreg cells in the presence or absence of celastrol...
February 21, 2018: Biochemical and Biophysical Research Communications
Bettina Wingelhofer, Barbara Maurer, Elizabeth C Heyes, Abbarna A Cumaraswamy, Angelika Berger-Becvar, Elvin D de Araujo, Anna Orlova, Patricia Freund, Frank Ruge, Jisung Park, Gary Tin, Siawash Ahmar, Charles-Hugues Lardeau, Irina Sadovnik, Dávid Bajusz, György Miklós Keserű, Florian Grebien, Stefan Kubicek, Peter Valent, Patrick T Gunning, Richard Moriggl
The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4-130, which can efficiently block pathological levels of STAT5 activity in AML...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
João Agostinho Machado-Neto, Bruna Alves Fenerich, Renata Scopim-Ribeiro, Christopher A Eide, Juan Luiz Coelho-Silva, Carlos Roberto Porto Dechandt, Jaqueline Cristina Fernandes, Ana Paula Nunes Rodrigues Alves, Priscila Santos Scheucher, Belinda Pinto Simões, Luciane Carla Alberici, Lorena Lôbo de Figueiredo Pontes, Cristina E Tognon, Brian J Druker, Eduardo Magalhães Rego, Fabiola Traina
The recurrent gain-of-function JAK2V617F mutation confers growth factor-independent proliferation for hematopoietic cells and is a major contributor to the pathogenesis of myeloproliferative neoplasms (MPN). The lack of complete response in most patients treated with the JAK1/2 inhibitor ruxolitinib indicates the need for identifying novel therapeutic strategies. Metformin is a biguanide that exerts selective antineoplastic activity in hematological malignancies. In the present study, we investigate and compare effects of metformin and ruxolitinib alone and in combination on cell signaling and cellular functions in JAK2V617F -positive cells...
February 22, 2018: Cell Death & Disease
Alessandro Prestipino, Alica J Emhardt, Konrad Aumann, David O'Sullivan, Sivahari P Gorantla, Sandra Duquesne, Wolfgang Melchinger, Lukas Braun, Slavica Vuckovic, Melanie Boerries, Hauke Busch, Sebastian Halbach, Sandra Pennisi, Teresa Poggio, Petya Apostolova, Pia Veratti, Michael Hettich, Gabriele Niedermann, Mark Bartholomä, Khalid Shoumariyeh, Jonas S Jutzi, Julius Wehrle, Christine Dierks, Heiko Becker, Annette Schmitt-Graeff, Marie Follo, Dietmar Pfeifer, Jan Rohr, Sebastian Fuchs, Stephan Ehl, Frederike A Hartl, Susana Minguet, Cornelius Miething, Florian H Heidel, Nicolaus Kröger, Ioanna Triviai, Tilman Brummer, Jürgen Finke, Anna L Illert, Eliana Ruggiero, Chiara Bonini, Justus Duyster, Heike L Pahl, Steven W Lane, Geoffrey R Hill, Bruce R Blazar, Nikolas von Bubnoff, Erika L Pearce, Robert Zeiser
Recent evidence has revealed that oncogenic mutations may confer immune escape. A better understanding of how an oncogenic mutation affects immunosuppressive programmed death ligand 1 (PD-L1) expression may help in developing new therapeutic strategies. We show that oncogenic JAK2 (Janus kinase 2) activity caused STAT3 (signal transducer and activator of transcription 3) and STAT5 phosphorylation, which enhanced PD-L1 promoter activity and PD-L1 protein expression in JAK2V617F -mutant cells, whereas blockade of JAK2 reduced PD-L1 expression in myeloid JAK2V617F -mutant cells...
February 21, 2018: Science Translational Medicine
Valérie Bernard, Chiara Villa, Aurélie Auguste, Sophie Lamothe, Anne Guillou, Agnès Martin, Sandrine Caburet, Jacques Young, Reiner A Veitia, Nadine Binart
Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr -/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr -/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development...
January 19, 2018: Oncotarget
Yang Zhao, Xiaofei Shen, Ning Na, Zhulang Chu, Huiting Su, Shanshan Chao, Lu Shi, Yanan Xu, Lianfeng Zhang, Bingyi Shi, Yong Zhao
Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris and wound healing. mTOR inhibitor, rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Herein we found that mTOR intrinsically controls monocyte/macrophage development as evidenced by the decreased percentages and cell numbers of CD11b+F4/80+ cells caused by mTOR inhibition in SCID mice, mTOR-deficient mice, mixed chimera mice and the in vitro colony formation and monocyte/macrophage induction assays...
February 20, 2018: Blood
R-F Li, G-F Wang
OBJECTIVE: The aim of this study was to explore the role of JAK/STAT signaling pathway inhibitor Ruxolitinib in neutrophilic airway inflammation and its possible immunological mechanism. MATERIALS AND METHODS: A total of 60 female C57BL/6 mice were randomly divided into neutrophilic asthma (NA) group, Ruxolitinib-treated (Ruxo) group and control (Con) group. Mice in NA and Ruxo groups were sensitized with ovalbumin (OVA) and excited to establish mice models of asthma...
February 2018: European Review for Medical and Pharmacological Sciences
Isadora C Furigo, Helen M Melo, Natalia M Lyra E Silva, Angela M Ramos-Lobo, Pryscila D S Teixeira, Daniella C Buonfiglio, Frederick Wasinski, Eliana R Lima, Eliza Higuti, Cibele N Peroni, Paolo Bartolini, Carlos R J Soares, Martin Metzger, Fernanda G de Felice, Jose Donato
The signal transducer and activator of transcription 5 (STAT5) is a transcription factor recruited by numerous cytokines. STAT5 is important for several physiological functions, including body and tissue growth, mammary gland development, immune system and lipid metabolism. However, the role of STAT5 signaling for brain functions is still poorly investigated, especially regarding cognitive aspects. Therefore, the objective of the present study was to investigate whether brain STAT5 signaling modulates learning and memory formation...
February 19, 2018: Brain Structure & Function
Haiying Zhang, Daniela Freitas, Han Sang Kim, Kristina Fabijanic, Zhong Li, Haiyan Chen, Milica Tesic Mark, Henrik Molina, Alberto Benito Martin, Linda Bojmar, Justin Fang, Sham Rampersaud, Ayuko Hoshino, Irina Matei, Candia M Kenific, Miho Nakajima, Anders Peter Mutvei, Pasquale Sansone, Weston Buehring, Huajuan Wang, Juan Pablo Jimenez, Leona Cohen-Gould, Navid Paknejad, Matthew Brendel, Katia Manova-Todorova, Ana Magalhães, José Alexandre Ferreira, Hugo Osório, André M Silva, Ashish Massey, Juan R Cubillos-Ruiz, Giuseppe Galletti, Paraskevi Giannakakou, Ana Maria Cuervo, John Blenis, Robert Schwartz, Mary Sue Brady, Héctor Peinado, Jacqueline Bromberg, Hiroshi Matsui, Celso A Reis, David Lyden
The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90-120 nm; small exosome vesicles, Exo-S, 60-80 nm) and discovered an abundant population of non-membranous nanoparticles termed 'exomeres' (~35 nm). Exomere proteomic profiling revealed an enrichment in metabolic enzymes and hypoxia, microtubule and coagulation proteins as well as specific pathways, such as glycolysis and mTOR signalling...
March 2018: Nature Cell Biology
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