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Obdulia Rabal, Fernando Pastor, Helena Villanueva, Mario M Soldevilla, Sandra Hervas-Stubbs, Julen Oyarzabal
Complementing Systematic Evolution of Ligands by EXponential Enrichment (SELEX) technologies with in silico prediction of aptamer binders has attracted a lot of interest in the recent years. We propose a workflow involving 2D structure prediction, 3D RNA modeling using Rosetta and docking to the target protein with 3dRPC for: (i) prediction of the binding mode of our two previously reported potent (Kd < 50 nmol/l) murine TIM3 aptamers, and (ii) the prioritization of TIM3 aptamers that were enriched in the SELEX workflow...
October 18, 2016: Molecular Therapy. Nucleic Acids
Shu-Jing Yu, Rong Jiang, Ying Z Mazzu, Cai-Bing Wei, Zong-Liang Sun, Yu-Zhen Zhang, Lian-Di Zhou, Qi-Hui Zhang
Drug-induced liver injury (DILI) is the most common cause of acute liver failure. Disruption of the Th17/Treg balance can lead to hepatic inflammation, which causes the main symptoms of DILI. Here we investigate the protective mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) on triptolide (TP)-induced DILI that shows the Th17/Treg imbalance. Pretreatment with EGCG (5[Formula: see text]mg/kg) for 10 days before TP (0.5[Formula: see text]mg/kg) administration in mice significantly reduced the increased alanine aminotransferase (ALT) level ([Formula: see text]) induced by TP treatment...
2016: American Journal of Chinese Medicine
Bo Li, Eric Severson, Jean-Christophe Pignon, Haoquan Zhao, Taiwen Li, Jesse Novak, Peng Jiang, Hui Shen, Jon C Aster, Scott Rodig, Sabina Signoretti, Jun S Liu, X Shirley Liu
BACKGROUND: Understanding the interactions between tumor and the host immune system is critical to finding prognostic biomarkers, reducing drug resistance, and developing new therapies. Novel computational methods are needed to estimate tumor-infiltrating immune cells and understand tumor-immune interactions in cancers. RESULTS: We analyze tumor-infiltrating immune cells in over 10,000 RNA-seq samples across 23 cancer types from The Cancer Genome Atlas (TCGA). Our computationally inferred immune infiltrates associate much more strongly with patient clinical features, viral infection status, and cancer genetic alterations than other computational approaches...
2016: Genome Biology
Xuemei Feng, Juan Feng
The present study evaluated associations between the percentages of T cell immunoglobulin and mucin domain 3 (Tim3)-positive T cells and related cytokines and multiple sclerosis (MS). We collected peripheral blood samples from 30 MS patients and 30 healthy controls. Flow cytometry was used to determine the proportions of CD3(+)Tim3(+), CD4(+)Tim3(+), and CD4(+)CD25(+)Tim3(+) in peripheral blood mononuclear cells (PBMCs) and related cell subsets. The serum concentrations of galectin-9, IL-17, and IFN-γ also were determined using enzyme-linked immunosorbent assays (ELISA)...
August 17, 2016: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
Bindongo P P Dembele, Haorile Chagan-Yasutan, Toshiro Niki, Yugo Ashino, Noppadon Tangpukdee, Egawa Shinichi, Srivicha Krudsood, Shigeyuki Kano, Toshio Hattori
BACKGROUND: Galectin-9 (Gal-9) is a β-galactoside-binding lectin that interacts with sugar moieties on glycoproteins and glycolipids of cells and pathogens. Gal-9 is known as an immune modulator that induces cell death via interaction with T cell immunoglobulin and mucin domain-3 (Tim3), a co-inhibitory receptor, and it inhibits production of several pro-inflammatory cytokines (TNF, IL-6 and IL-1α) and enhances production of IL-10. To understand the immune pathology of malaria, the Gal-9 in plasma was measured...
2016: Malaria Journal
Peter J Siska, Gerritje J W van der Windt, Rigel J Kishton, Sivan Cohen, William Eisner, Nancie J MacIver, Arnon P Kater, J Brice Weinberg, Jeffrey C Rathmell
Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Leo Swadling, John Halliday, Christabel Kelly, Anthony Brown, Stefania Capone, M Azim Ansari, David Bonsall, Rachel Richardson, Felicity Hartnell, Jane Collier, Virginia Ammendola, Mariarosaria Del Sorbo, Annette Von Delft, Cinzia Traboni, Adrian V S Hill, Stefano Colloca, Alfredo Nicosia, Riccardo Cortese, Paul Klenerman, Antonella Folgori, Eleanor Barnes
An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen...
August 2, 2016: Vaccines
Tadashi Ashizawa, Akira Iizuka, Chizu Nonomura, Ryota Kondou, Chie Maeda, Haruo Miyata, Takashi Sugino, Koichi Mitsuya, Nakamasa Hayashi, Yoko Nakasu, Koji Maruyama, Ken Yamaguchi, Ikumi Katano, Mamoru Ito, Yasuto Akiyama
PURPOSE: Humanized mouse models using NOD/Shi-scid-IL2r gammanull (NOG) and NOD/LtSz-scid IL2r gamma null (NSG) mouse are associated with several limitations, such as long incubation time for stem cell engraftment and the development of xeno-graft versus host disease (xeno-GVHD) in mice injected with peripheral blood mononuclear cells (PBMCs). To solve problems, we used humanized major histocompatibility (MHC) class I and class II-deficient NOG mice (referred to as NOG-dKO) to evaluate the anti-tumor effect of anti-programmed death-1 (PD-1) antibody...
July 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qing Li, Nathan Johnston, Xiufen Zheng, Hongmei Wang, Xusheng Zhang, Dian Gao, Weiping Min
T cell exhaustion is a state of T cell dysfunction that arises during many cancer. miRNAs are one of major gene regulators which result in translational inhibition and/or mRNA degradation. We hypothesized that miRNAs exist that can silence PD1 and act as a modulator in vitro to revert exhaustive status of T cells. We demonstrated that the exhausted T cells with inhibitory receptors (IRs) are significantly increased in the melanoma-bearing mice. Meanwhile, the differentiated miRNA profiles in PD1+ exhaustive T cells were identified using a miRNA array; 11 miRNAs were observed with significant altered levels in the exhausted T cells isolated from melanoma-bearing mice...
July 20, 2016: Oncotarget
S Wang, T Wang, M-Z Li, X-L Cheng, X-L Li
OBJECTIVE: To study the expression profile and role of microRNA miR-34a in Leukemia stem cells (LSC) and during its metastasis. We examined upon the enforced expression of miR-34a in TIM3 positive leukemia stem cells and study the impact of leukemia stem cells and its metastasis. PATIENTS AND METHODS: Samples were collected from acute myeloid leukemia (AML) children along with controls. Immunohistochemistry analysis was performed with TIM3 antibody followed by Sorting of TIM3 positive cells by flow cytometry and the expression level of miR-34a was quantified by qRT-PCR assay...
July 2016: European Review for Medical and Pharmacological Sciences
Esmat Yaghoobi, Saeed Abedian, Omid Babani, Maryam Izad
BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by auto-reactive T cells against myelin antigens. T-cell immunoglobulin mucin -3 (TIM-3) is a negative regulator glycoprotein expressed by a range of immune cells, including, Th1 cells, activated CD8+ T cells and in a lower level on Th17 cells. A defect in TIM-3 regulation has been shown in multiple sclerosis patients. In humans, several single nucleotide polymorphisms (SNPs) have been identified in the TIM-3 gene and are associated with inflammatory diseases...
May 2016: Iranian Journal of Public Health
Elena Gonzalez-Gugel, Mansi Saxena, Nina Bhardwaj
A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses...
October 2016: Cancer Immunology, Immunotherapy: CII
Scott J Antonia, Johan F Vansteenkiste, Edmund Moon
Advanced-stage non-small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti-PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%-20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti-PD-1/PD-L1...
2016: American Society of Clinical Oncology Educational Book
Randy F Sweis, Stefani Spranger, Riyue Bao, Gladell P Paner, Walter M Stadler, Gary Steinberg, Thomas F Gajewski
Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1-targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non-T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell-inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8(+) T-cell infiltration...
July 2016: Cancer Immunology Research
Caroline Jochems, Massimo Fantini, Romaine I Fernando, Anna R Kwilas, Renee N Donahue, Lauren M Lepone, Italia Grenga, Young-Seung Kim, Martin W Brechbiel, James L Gulley, Ravi A Madan, Christopher R Heery, James W Hodge, Robert Newton, Jeffrey Schlom, Kwong Y Tsang
Epacadostat is a novel inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1) that suppresses systemic tryptophan catabolism and is currently being evaluated in ongoing clinical trials. We investigated the effects of epacadostat on (a) human dendritic cells (DCs) with respect to maturation and ability to activate human tumor antigen-specific cytotoxic T-cell (CTL) lines, and subsequent T-cell lysis of tumor cells, (b) human regulatory T cells (Tregs), and (c) human peripheral blood mononuclear cells (PBMCs) in vitro...
May 12, 2016: Oncotarget
Qing Fan, Tingting Gu, Peijie Li, Ping Yan, Dehong Chen, Bingchao Han
BACKGROUND: The study aimed to explore possible factors influencing wheezing in children with Mycoplasma pneumoniae pneumonia (MPP). METHODS: The study included 84 children with MPP, who were divided into two groups: wheezy group (n=40) and non-wheezy group (n=44), along with 30 age-matched healthy controls. T-cell immunoglobulin and mucin domain gene (Tim) 1, 3 and Toll-like receptor (TLR) 2, 4 were evaluated using RT-PCR. Serum IL-10, TNF-α, IFN-γ and IgE were assessed by enzyme-linked immunosorbent assay...
April 30, 2016: Heart, Lung & Circulation
Stephanie Du Four, Sarah K Maenhout, Daphné Benteyn, Brenda De Keersmaecker, Johnny Duerinck, Kris Thielemans, Bart Neyns, Joeri L Aerts
BACKGROUND: Recurrent glioblastoma is associated with a poor overall survival. Antiangiogenic therapy results in a high tumor response rate but has limited impact on survival. Immunotherapy has emerged as an efficient treatment modality for some cancers, and preclinical evidence indicates that anti-VEGF(R) therapy can counterbalance the immunosuppressive tumor microenvironment. METHODS: We collected peripheral blood mononuclear cells (PBMC) of patients with recurrent glioblastoma treated in a randomized phase II clinical trial comparing the effect of axitinib with axitinib plus lomustine and analyzed the immunophenotype of PBMC, the production of cytokines and expression of inhibitory molecules by circulating T cells...
June 2016: Cancer Immunology, Immunotherapy: CII
Matthieu Collin
INTRODUCTION: Immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies, are revolutionizing therapeutic concepts in the treatment of cancer. Said class of drugs will represent a multi-billion dollar market over the coming decade. Many companies have therefore developed important patent activities in the field. AREAS COVERED: The present review gives an overview of the patent literature during the period 2010-2015 in the field of immune checkpoint inhibitors...
May 2016: Expert Opinion on Therapeutic Patents
Shufeng Li, Jinliang Wan, William Anderson, Huaqiang Sun, Hu Zhang, Xianbo Peng, Zhaolong Yu, Teng Wang, Xinfeng Yan, Wendy Smith
Knee osteoarthritis (OA) is the most common cause of musculoskeletal pain and disability in the knee. Though traditionally thought a mechanical wear-and-tear disease, in recent years, knee OA as a low-grade, chronic inflammatory disease has been increasingly recognized. In this study, we examined the Treg responses in non-obese knee OA patients at different stages. Significantly elevated frequencies of CD4(+)CD25(+)Foxp3(+) Tregs were found in OA patients, while on the other hand, lower IL-10 secretion from Tregs in OA patients was observed...
April 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Zhu Li, Na Li, Fang Li, Zhihua Zhou, Jiao Sang, Zhao Jin, Huihui Liu, Qunying Han, Yi Lv, Zhengwen Liu
Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 -1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0...
May 3, 2016: Oncotarget
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