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Yun Bai, Jia Wang, Jing Han, Xiao-Li Xie, Cheng-Guang Ji, Jie Yin, Lei Chen, Cun-Kai Wang, Xiao-Yu Jiang, Wei Qi, Hui-Qing Jiang
BACKGROUND AND AIMS: BCL2L10 is an apoptosis-related member of the BCL-2 protein family. The role of BCL2L10 in the pathogenesis of hepatocellular carcinoma (HCC) is poorly understood. This study was aimed to investigate the function and underlying mechanisms of BCL2L10 in HCC. METHODS: BCL2L10 expression in human HCC and corresponding adjacent normal tissues was investigated by quantitative real-time PCR and western blot. The biological functions of BCL2L10 in HCC cell lines were determined by cell viability, colony formation, cell apoptosis, cell cycle and cell metastasis assays, and in vivo by tumorigenicity and lung metastasis assays in nude mice...
October 22, 2016: Molecular Carcinogenesis
Izabela Jatczak-Pawlik, Michal Gorzkiewicz, Maciej Studzian, Dietmar Appelhans, Brigitte Voit, Lukasz Pulaski, Barbara Klajnert-Maculewicz
PURPOSE: Fourth-generation poly(propylene imine) dendrimers fully surface-modified by maltose (dense shell, PPI-m DS) were shown to be biocompatible in cellular models, which is important for their application in drug delivery. We decided to verify also their inherent bioactivity, including immunomodulatory activity, for potential clinical applications. We tested their effects on the THP-1 monocytic cell line model of innate immunity effectors. METHODS: To estimate the cytotoxicity of dendrimers the reasazurin assay was performed...
October 20, 2016: Pharmaceutical Research
Levi Todd, Natalie Squires, Lilianna Suarez, Andy J Fischer
Müller glia are capable of de-differentiating and proliferating to become Müller glia-derived progenitor cells (MGPCs) with the ability to regenerate retinal neurons. One of the cell-signaling pathways that drives the reprogramming of Müller glia into MGPCs in the zebrafish retina is the Jak/Stat-pathway. However, nothing is known about the influence of Jak/Stat-signaling during the formation of MGPCs in the retinas of warm-blooded vertebrates. Accordingly, we examined whether Jak/Stat-signaling influences the formation of MGPCs and differentiation of progeny in the avian retina...
October 19, 2016: Scientific Reports
Liang Leng, Xiaojun Zhong, Guan Sun, Wen Qiu, Lei Shi
Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive to TMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro...
October 18, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Eva Maria Putz, Andrea Majoros, Dagmar Gotthardt, Michaela Prchal-Murphy, Eva Maria Zebedin-Brandl, Daniela Alexandra Fux, Andreas Schlattl, Robert D Schreiber, Sebastian Carotta, Mathias Müller, Christopher Gerner, Thomas Decker, Veronika Sexl
STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here, we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing a Stat1-Y701F mutant. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity as verified by RNA-seq analysis...
2016: Oncoimmunology
Prithviraj Bose, Srdan Verstovsek
The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) mainly comprise polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF, primary or post-PV/ET). Therapy in PV and ET focuses on minimizing thrombosis and bleeding risk, while in MF, prolongation of survival is an important goal. Different cytoreductive agents are employed in high risk PV and ET, while the JAK inhibtior ruxolitinib is the cornerstone of therapy in MF. Histone deacetylase inhibitors (HDACi) are pleiotropic agents with diverse epigenetic and non-epigenetic actions, selectively in transformed cells...
October 18, 2016: Expert Opinion on Investigational Drugs
Guoliang Wang, Jingchao Zhang, Danhua Dui, Haoyuan Ren, Jin Liu
The pathogenesis of severe acute pancreatitis (SAP) remains unclear. The Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway is important for various cytokines and growth factors. This study investigated the effect of the late inflammatory factor high mobility group box 1 (HMGB1) on the activation of JAK2/STAT3 in pancreatic acinar cells and the inhibitory effects of AG490 (a JAK2 inhibitor) and rapamycin (a STAT3 inhibitor) on this pathway. Rat pancreatic acinar cells were randomly divided into the control, HMGB1, AG490, and rapamycin groups...
October 18, 2016: Bosnian Journal of Basic Medical Sciences
Naeim Ehtesham, Fariborz Khorvash, Majid Kheirollahi
MicroRNAs (miRNAs) are crucial to the immunopathogenesis of multiple sclerosis (MS). The mechanism of action of interferon beta (IFN-β) in relapsing-remitting (RR) MS patients is largely unknown. miR-145 and miR-20a-5p previously reported as diagnosis biomarker in treatment naïve RRMS patients and their expression after IFN-β therapy might be indicative of molecular mechanism of IFN-β. Cross-talking between JAK/STAT pathway and complementary pathways like MAPK is important in IFN-β signaling. Here, in order to clarify the ambiguous molecular mechanism of IFN-β and evaluate the potential use of them as a biomarker for monitoring of therapy, we investigated the expression of miR-145 and miR-20a-5p in blood sample of 15 treatment naïve RRMS patients, 15 IFN-β-treated RRMS patients, and 15 healthy volunteers (HVs)...
October 17, 2016: Journal of Molecular Neuroscience: MN
Steven Wang, Jie Yan, Guangde Zhou, Rebecca Heintzelman, J Steve Hou
Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies characterized by unchecked proliferation of differentiated myeloid cells. The most common BCR-ABL1-negative MPNs are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The discovery of JAK2 V617F mutation has improved our understanding of the molecular basis of MPN. The high frequency of JAK2 mutation in MPN makes JAK2 mutation testing an essential diagnostic tool and potential therapeutic target for MPN. Here, we present a rare case of a 34-year-old patient who was initially diagnosed with acute myeloid leukemia (AML) with mutated NPM1...
2016: Case Reports in Hematology
Yuan Seng Wu, Ivy Chung, Won Fen Wong, Atsushi Masamune, Maw Shin Sim, Chung Yeng Looi
BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process...
October 14, 2016: Biochimica et Biophysica Acta
Michael J Feldman, Saman Sizdahkhani, Nancy A Edwards, Marsha J Merrill, Abhik Ray-Chaudhury, Zhengping Zhuang, Russell R Lonser, Edward H Oldfield, Prashant Chittiboina
von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1α or 2α upregulation...
October 17, 2016: Scientific Reports
A J Kivitz, S R Gutierrez-Ureña, J Poiley, M C Genovese, R Kristy, K Shay, X Wang, J P Garg, A Zubrzycka-Sienkiewicz
OBJECTIVE: To evaluate efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS: In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (N=378) were treated with peficitinib 25 mg, 50 mg, 100 mg, 150 mg + MTX, or matching placebo + MTX once daily for 12 weeks (NCT01554696)...
October 16, 2016: Arthritis & Rheumatology
Shai S Shen-Orr, David Furman, Brian A Kidd, Francois Hadad, Patricia Lovelace, Ying-Wen Huang, Yael Rosenberg-Hasson, Sally Mackey, Fatemeh A Gomari Grisar, Yishai Pickman, Holden T Maecker, Yueh-Hsiu Chien, Cornelia L Dekker, Joseph C Wu, Atul J Butte, Mark M Davis
Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ...
October 12, 2016: Cell Systems
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Yuhei Hamaguchi, Akira Mori, Yasuhiro Fujimoto, Takashi Ito, Taku Iida, Shintaro Yagi, Hideaki Okajima, Toshimi Kaido, Shinji Uemoto
BACKGROUND: The present study aimed to investigate the impact of the duration of hepatic pedicle clamping (HPC) on tumor growth after major hepatectomy in a rat model. METHODS: Rats were divided into 4 groups according to the length of HPC during 70% partial hepatectomy followed by N1S1 tumor cell implantation: group 1, without HPC; group 2, with 5-min HPC; group 3, 10-min HPC; and group 4, 15-min HPC. At three weeks after tumor cell implantation, liver tumor growth and its possible mechanisms were investigated...
October 13, 2016: Journal of Hepato-biliary-pancreatic Sciences
E Waanders, B Scheijen, M C J Jongmans, H Venselaar, S V van Reijmersdal, A H A van Dijk, A Pastorczak, R D A Weren, C E van der Schoot, M van de Vorst, E Sonneveld, N Hoogerbrugge, V H J van der Velden, B Gruhn, P M Hoogerbrugge, J J M van Dongen, A G van Kessel, F N van Leeuwen, R P Kuiper
The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family...
October 13, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Domenico Albino, Gianluca Civenni, Simona Rossi, Abhishek Mitra, Carlo V Catapano, Giuseppina M Carbone
Metastatic prostate cancer represents a yet unsolved clinical problem due to the high frequency of relapse and treatment resistance. Understanding the pathways that lead to prostate cancer progression is an important task to prevent this deadly disease. The ETS transcription factor ESE3/EHF has an important role in differentiation of human prostate epithelial cells. Loss of ESE3/EHF in prostate epithelial cells determines transformation, epithelial-to-mesenchymal transition (EMT) and acquisition of stem-like properties...
October 8, 2016: Oncotarget
Sabine Blum, Filipe Martins, Lorenzo Alberio
The discovery of JAK2 V617F mutation in the mid-2000s started to fill the gap between clinical presentation of polycythemia vera (PV), first described by Vaquez at the end of the 19th century, and spontaneous erythroid colony formation, reported by Prchal and Axelrad in the mid-1970s. The knowledge on this mutation brought an important insight to our understanding of PV pathogenesis and led to a revision of the World Health Organization diagnostic criteria in 2008. JAK-STAT is a major signaling pathway implicated in survival and proliferation of hematopoietic precursors...
2016: Journal of Blood Medicine
Yang-Yang He, Yu Yan, Hui-Fang Zhang, Yi-Huang Lin, Yu-Cai Chen, Yi Yan, Ping Wu, Jian-Song Fang, Shu-Hui Yang, Guan-Hua Du
Systemic lupus erythematosus (SLE), with a high incidence rate and insufficient therapy worldwide, is a complex disease involving multiple organs characterized primarily by inflammation due to deposition of immunocomplexes formed by production of autoantibodies. The mechanism of SLE remains unclear, and the disease still cannot be cured. We used pristane to induce SLE in female BALB/c mice. Methyl salicylate 2-O-β-d-lactoside (MSL; 200, 400, and 800 mg/kg) was orally administered 45 days after pristane injection for 4...
2016: Drug Design, Development and Therapy
Min Huang, Zhongjie Chen, Lu Zhang, Zhimin Huang, Yiying Chen, Jianrong Xu, Jian Zhang, Xiaohong Shu
It is now established that the specificity in signaling of signal transducer and activator of transcription 3 (STAT3) is mediated by the SH2 domain of STAT3, which mediates its interaction with the phosphopeptide docking sites displayed by receptors and JAKs, dimerization and subsequent DNA binding. Thus, we aimed to identify and design a class of strong potential small molecular inhibitors of STAT3 for the discovery and development of novel anticancer agents. Several classes of small molecules have been identified as STAT3 inhibitors after structure-based screening of the STAT3 SH2 domain...
September 30, 2016: Bioorganic & Medicinal Chemistry Letters
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