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T cells

Amar Patel, Lawrence Fong
Immunotherapies have emerged as a revolutionary modality for cancer treatment, and a variety of immune-based approaches are currently being investigated in the field of prostate cancer. Despite the 2010 approval of sipuleucel-T, subsequent progress in prostate cancer immunotherapy development has been limited by disappointing results with novel vaccination approaches and by prostate cancer's general resistance to immune checkpoint blockade. Nevertheless, there remains strong preclinical and clinical evidence to suggest that prostate cancer is a susceptible target for immune therapies...
March 15, 2018: Oncology (Williston Park, NY)
Sarah Löw, Tracy T Batchelor
Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma limited to the brain, spinal cord, leptomeninges, and eyes. The majority of patients are immunocompetent, with a median age of 65 years at diagnosis. Historically, whole-brain radiation therapy (WBRT) was the first and sole treatment for PCNSL. Today, due to the recognized neurotoxicity of WBRT, this modality is usually avoided in the treatment. Most chemotherapy regimens are based on high-dose methotrexate plus the anti-CD20 monoclonal antibody rituximab, leading to high response rates, but 5-year survival is still poor at approximately 30% compared with other extranodal lymphomas...
February 2018: Seminars in Neurology
Michael Platten, David A Reardon
Strategies to empower the immune system to successfully attack cancers, including vaccination approaches, adaptive T cell therapies, and immune checkpoint modulators, have recently achieved remarkable success across a spectrum of cancer indications. Nonetheless, with rare exception, only a minority of patients with a given type of cancer respond to an immunotherapeutic when administered as single-agent therapy. Although under extensive laboratory and clinical investigation, the role of these approaches for glioma patients remains to be determined...
February 2018: Seminars in Neurology
Joel D Ernst, Amber Cornelius, Ludovic Desvignes, Jacqueline Tavs, Brian A Norris
Infection with M. tuberculosis is associated with inconsistent and incomplete elimination of the bacteria, despite development of antigen-specific T cell responses. One mechanism employed by M. tuberculosis is to limit availability of antigen for activation of CD4 T cells. We examined the utility of systemic administration of epitope peptides to activate pre-existing T cells in mice infected with M. tuberculosis. We found that systemic peptide administration: 1) selectively activates T cells specific for the epitope peptide; 2) loads MHC class II on lung macrophages and dendritic cells; 3) activates CD4 T cells in the lung parenchyma; 4) has little antimycobacterial activity...
March 14, 2018: Journal of Infectious Diseases
Francesca Micoli, Paolo Costantino, Roberto Adamo
Cell surface carbohydrates have been proven optimal targets for vaccine development. Conjugation of polysaccharides to a carrier protein triggers a T-cell dependent immune response to the glycan moiety. Licensed glycoconjugate vaccines are produced by chemical conjugation of capsular polysaccharides to prevent meningitis caused by meningococcus, pneumococcus and Haemophilus influenzae type b. However, other classes of carbohydrates (O-antigens, exopolysaccharides, wall/teichoic acids) represent attractive targets for developing vaccines...
March 14, 2018: FEMS Microbiology Reviews
Jiawei Wang, Bingjiao Yang, André Leier, Tatiana T Marquez-Lago, Morihiro Hayashida, Andrea Rocker, Zhang Yanju, Tatsuya Akutsu, Kuo-Chen Chou, Richard A Strugnell, Jiangning Song, Trevor Lithgow
Motivation: Many Gram-negative bacteria use type VI secretion systems (T6SS) to export effector proteins into adjacent target cells. These secreted effectors (T6SEs) play vital roles in the competitive survival in bacterial populations, as well as pathogenesis of bacteria. Although various computational analyses have been previously applied to identify effectors secreted by certain bacterial species, there is no universal method available to accurately predict T6SS effector proteins from the growing tide of bacterial genome sequence data...
March 14, 2018: Bioinformatics
Kelsey A Herrmann, Heather T Broihier
Although retrograde neurotrophin signaling has provided an immensely influential paradigm for understanding growth factor signaling in the nervous system, recent studies indicate that growth factors also signal via cell-autonomous, or autocrine, mechanisms. Autocrine signals have been discovered in many neuronal contexts, providing insights into their regulation and function. The growing realization of the importance of cell-autonomous signaling stems from advances in both conditional genetic approaches and in sophisticated analyses of growth factor dynamics, which combine to enable rigorous in vivo dissection of signaling pathways...
March 13, 2018: Current Opinion in Neurobiology
Ruiting Lin, Siyuan Xia, Changliang Shan, Dong Chen, Yijie Liu, Xue Gao, Mei Wang, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Michael Rossi, Ragini R Kudchadkar, David H Lawson, Fadlo R Khuri, Sagar Lonial, Jing Chen
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors...
March 15, 2018: Molecular Cell
Dong-Keon Lee, Ji-Hee Kim, Joohwan Kim, Seunghwan Choi, MinSik Park, Wonjin Park, Suji Kim, Kyu-Sun Lee, Taesam Kim, Jiwon Jung, Yoon Kyung Choi, Kwon-Soo Ha, Moo-Ho Won, Timothy R Billiar, Young-Guen Kwon, Young-Myeong Kim
Regulated in development and DNA damage responses (REDD)-1, an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/- macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation...
March 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Jared T Hammill, Daniel C Scott, Jaeki Min, Michele C Connelly, Gloria Holbrook, Fangyi Zhu, Amy Matheny, Lei Yang, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit...
March 16, 2018: Journal of Medicinal Chemistry
Jared T Hammill, Deepak Bhasin, Daniel C Scott, Jaeki Min, Yizhe Chen, Yan Lu, Lei Yang, Ho Shin Kim, Michele C Connelly, Courtney Hammill, Gloria Holbrook, Cynthia Jeffries, Bhuvanesh Singh, Brenda A Schulman, R Kiplin Guy
We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg)...
March 16, 2018: Journal of Medicinal Chemistry
Hirofumi Chiba, Yoichi Kakuta, Yoshitaka Kinouchi, Yosuke Kawai, Kazuhiro Watanabe, Munenori Nagao, Takeo Naito, Motoyuki Onodera, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Katsuya Endo, Kenichi Negoro, Masao Nagasaki, Michiaki Unno, Tooru Shimosegawa
BACKGROUND: Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs...
2018: PloS One
Corina T Madreiter-Sokolowski, Armin A Sokolowski, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F Graier
Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS)...
March 16, 2018: Genes
Carolina de la Guardia, David E Stephens, Hang T Dang, Mario Quijada, Oleg V Larionov, Ricardo Lleonart
Dengue virus causes dengue fever, a debilitating disease with an increasing incidence in many tropical and subtropical territories. So far, there are no effective antivirals licensed to treat this virus. Here we describe the synthesis and antiviral activity evaluation of two compounds based on the quinoline scaffold, which has shown potential for the development of molecules with various biological activities. Two of the tested compounds showed dose-dependent inhibition of dengue virus serotype 2 in the low and sub micromolar range...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Stefanie Kroeze, Pascale Ondoa, Cissy M Kityo, Margaret Siwale, Sulaimon Akanmu, Maureen Wellington, Marleen de Jager, Prudence Ive, Kishor Mandaliya, Wendy Stevens, T Sonia Boender, Marieke E de Pundert, Kim C E Sigaloff, Peter Reiss, Ferdinand W Wit, Tobias F Rinke de Wit, Raph L Hamers
OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART). DESIGN: Multi-country prospective cohort. METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4 cell count thresholds (>200, >350 and >500 cells/μL) despite sustained viral suppression on continuous first-line ART...
March 15, 2018: AIDS
Laura Tarancon-Diez, Rebeca S De Pablo-Bernal, José Luis Jiménez, Ana I Álvarez-Ríos, Miguel Genebat, Isaac Rosado-Sánchez, María-Ángeles Muñoz-Fernández, Ezequiel Ruiz-Mateos, Manuel Leal
OBJECTIVE: Cardiovascular diseases (CVDs) are one of the main causes of morbimortality in HIV-infected patients on suppressive antiretroviral therapy. The objective of this work was to evaluate the role of single nucleotide polymorphisms (SNPs) in lipopolysaccharide (LPS) Toll-like receptor 4 (TLR4) and CVDs occurrence in HIV-infected patients. Additionally, the functional consequences of carrying these SNPs were analyzed. METHODS: The association of TLR4 SNPs, Asp299Gly/Thr399Ile with CVDs occurrence was analyzed using multivariate logistic regression models...
March 15, 2018: AIDS
Elena García-Payá, Marta Fernández, Sergio Padilla, José A García, Catalina Robledano, Victoria Ortiz DE LA Tabla, Félix Gutiérrez, Mar Masiá
OBJECTIVE: The protective effect of ART has not yet been definitively established in men who have sex with men (MSM). We aimed to characterize the factors associated with persistent HIV-1 RNA rectal shedding. METHODS: Prospective study including virologically-suppressed MSM from an HIV cohort. High-resolution anoscopy (HRA) was performed for screening of anal dysplasia, and rectal sampling for HIV-1 RNA quantification and sexually-transmitted infections (STIs) investigation through multiplex PCR...
March 15, 2018: AIDS
Alison G Abraham, Long Zhang, Keri Calkins, Adrienne Tin, Andrew Hoofnagle, Frank J Palella, Michelle M Estrella, Lisa P Jacobson, Mallory D Witt, Lawrence A Kingsley, Todd T Brown
OBJECTIVE: Despite effective antiretroviral therapy (HAART) and durable viral suppression, many HIV-infected individuals still do not achieve CD4+ cell count (CD4) normalization. Vitamin D has immunoregulatory functions, including inducing the development of T cells, and higher levels may improve CD4 rebound. DESIGN: Longitudinal study of men from the Multicenter AIDS Cohort Study who virally suppressed following HAART initiation and had pre- and post-HAART 25[OH]D and 1,25[OH]2D measurements and repeated measures of CD4...
March 15, 2018: AIDS
Jessica H Hill, Claudia Solt, Michelle T Foster
Obesity and associated metabolic co-morbidities are a worldwide public health problem. Negative health outcomes associated with obesity, however, do not arise from excessive adiposity alone. Rather, deleterious outcomes of adipose tissue accumulation are a result of how adipocytes are distributed to individual regions in the body. Due to our increased understanding of the dynamic relationship that exists between specific adipose depots and disease risk, an accurate characterization of total body adiposity as well as location is required to properly evaluate a population's disease risk...
March 16, 2018: Hormone Molecular Biology and Clinical Investigation
Lucia Romero, Jordi Cano, Julio Gomis-Tena, Beatriz Trenor, Ferran Sanz, Manuel Pastor, Javier Saiz
Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue...
March 16, 2018: Journal of Chemical Information and Modeling
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