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https://www.readbyqxmd.com/read/28806575/lessons-from-ctla-4-deficiency-and-checkpoint-inhibition
#1
REVIEW
Bernice Lo, Ussama M Abdel-Motal
CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions...
August 11, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28806394/smggds-is-a-transient-nucleolar-protein-that-protects-cells-from-nucleolar-stress-and-promotes-the-cell-cycle-by-regulating-dream-complex-gene-expression
#2
P Gonyo, C Bergom, A C Brandt, S-W Tsaih, Y Sun, T M Bigley, E L Lorimer, S S Terhune, H Rui, M J Flister, R M Long, C L Williams
The chaperone protein and guanine nucleotide exchange factor SmgGDS (RAP1GDS1) is a key promoter of cancer cell proliferation and tumorigenesis. SmgGDS undergoes nucleocytoplasmic shuttling, suggesting that it has both cytoplasmic and nuclear functions that promote cancer. Previous studies indicate that SmgGDS binds cytoplasmic small GTPases and promotes their trafficking to the plasma membrane. In contrast, little is known about the functions of SmgGDS in the nucleus, or how these nuclear functions might benefit cancer cells...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28806280/integrated-analysis-of-biopsies-from-inflammatory-bowel-disease-patients-identifies-saa1-as-a-link-between-mucosal-microbes-with-th17-and-th22-cells
#3
Mei San Tang, Rowann Bowcutt, Jacqueline M Leung, Martin J Wolff, Uma M Gundra, David Hudesman, Lisa B Malter, Michael A Poles, Lea Ann Chen, Zhiheng Pei, Antonio G Neto, Wasif M Abidi, Thomas Ullman, Lloyd Mayer, Richard A Bonneau, Ilseung Cho, Pʼng Loke
BACKGROUND: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. METHODS: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD...
August 9, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28805972/in-vitro-pharmacological-characterization-of-a-novel-unbiased-nop-receptor-selective-nonpeptide-agonist-at-403
#4
Federica Ferrari, Davide Malfacini, Blair V Journigan, Mark F Bird, Claudio Trapella, Remo Guerrini, David G Lambert, Girolamo Calo', Nurulain T Zaveri
Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH-221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPγ[(35) S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28805828/mutations-in-keops-complex-genes-cause-nephrotic-syndrome-with-primary-microcephaly
#5
Daniela A Braun, Jia Rao, Geraldine Mollet, David Schapiro, Marie-Claire Daugeron, Weizhen Tan, Olivier Gribouval, Olivia Boyer, Patrick Revy, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Jennifer A Lawson, Denny Schanze, Shazia Ashraf, Jeremy F P Ullmann, Charlotte A Hoogstraten, Nathalie Boddaert, Bruno Collinet, Gaëlle Martin, Dominique Liger, Svjetlana Lovric, Monica Furlano, I Chiara Guerrera, Oraly Sanchez-Ferras, Jennifer F Hu, Anne-Claire Boschat, Sylvia Sanquer, Björn Menten, Sarah Vergult, Nina De Rocker, Merlin Airik, Tobias Hermle, Shirlee Shril, Eugen Widmeier, Heon Yung Gee, Won-Il Choi, Carolin E Sadowski, Werner L Pabst, Jillian K Warejko, Ankana Daga, Tamara Basta, Verena Matejas, Karin Scharmann, Sandra D Kienast, Babak Behnam, Brendan Beeson, Amber Begtrup, Malcolm Bruce, Gaik-Siew Ch'ng, Shuan-Pei Lin, Jui-Hsing Chang, Chao-Huei Chen, Megan T Cho, Patrick M Gaffney, Patrick E Gipson, Chyong-Hsin Hsu, Jameela A Kari, Yu-Yuan Ke, Cathy Kiraly-Borri, Wai-Ming Lai, Emmanuelle Lemyre, Rebecca Okashah Littlejohn, Amira Masri, Mastaneh Moghtaderi, Kazuyuki Nakamura, Fatih Ozaltin, Marleen Praet, Chitra Prasad, Agnieszka Prytula, Elizabeth R Roeder, Patrick Rump, Rhonda E Schnur, Takashi Shiihara, Manish D Sinha, Neveen A Soliman, Kenza Soulami, David A Sweetser, Wen-Hui Tsai, Jeng-Daw Tsai, Rezan Topaloglu, Udo Vester, David H Viskochil, Nithiwat Vatanavicharn, Jessica L Waxler, Klaas J Wierenga, Matthias T F Wolf, Sik-Nin Wong, Sebastian A Leidel, Gessica Truglio, Peter C Dedon, Annapurna Poduri, Shrikant Mane, Richard P Lifton, Maxime Bouchard, Peter Kannu, David Chitayat, Daniella Magen, Bert Callewaert, Herman van Tilbeurgh, Martin Zenker, Corinne Antignac, Friedhelm Hildebrandt
Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue...
August 14, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28805660/prolyl-hydroxylase-2-inactivation-enhances-glycogen-storage-and-promotes-excessive-neutrophilic-responses
#6
Pranvera Sadiku, Joseph A Willson, Rebecca S Dickinson, Fiona Murphy, Alison J Harris, Amy Lewis, David Sammut, Ananda S Mirchandani, Eilise Ryan, Emily R Watts, A A Roger Thompson, Helen M Marriott, David H Dockrell, Cormac T Taylor, Martin Schneider, Patrick H Maxwell, Edwin R Chilvers, Massimilliano Mazzone, Veronica Moral, Chris W Pugh, Peter J Ratcliffe, Christopher J Schofield, Bart Ghesquiere, Peter Carmeliet, Moira Kb Whyte, Sarah R Walmsley
Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28805308/lymphocyte-profile-and-cytokine-mrna-expression-in-peripheral-blood-mononuclear-cells-of-patients-with-recurrent-respiratory-papillomatosis-suggest-dysregulated-cytokine-mrna-response-and-impaired-cytotoxic-capacity
#7
Anna Holm, Olga Nagaeva, Ivan Nagaev, Christos Loizou, Göran Laurell, Lucia Mincheva-Nilsson, Karin Nylander, Katarina Olofsson
OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a relatively rare, chronic disease caused by Human Papilloma Virus (HPV) 6 and 11, and characterized by wart-like lesions in the airway affecting voice and respiratory function. The majority of HPV infections are asymptomatic and resolve spontaneously, however, some individuals are afflicted with persistent HPV infections. Failure to eliminate HPV 6 and 11 due to a defect immune responsiveness to these specific genotypes is proposed to play a major role in the development of RRP...
August 14, 2017: Immunity, Inflammation and Disease
https://www.readbyqxmd.com/read/28805251/wiskott-aldrich-syndrome-protein-emerging-mechanisms-in-immunity
#8
REVIEW
Elizabeth Rivers, Adrian J Thrasher
The Wiskott Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection...
August 14, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28805233/analytic-and-dynamic-secretory-profile-of-patient-derived-cytokine-induced-killer-cells
#9
Giulia Mesiano, Roberta Zini, Giulia Montagner, Nicoletta Bianchi, Rossella Manfredini, Antonella Chillemi, Massimo Aglietta, Giovanni Grignani, Ilaria Lampronti, Erika Fiorino, Fabio Malavasi, Dario Sangiolo, Roberto Gambari, Davide Ferrari
Adoptive immunotherapy with Cytokine Induced Killer (CIK) cells has shown antitumor activity against several kinds of cancers in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T-NK phenotype and MHC-unrestricted antitumor activity. Literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (day 1, day 14 and day 21) of CIK cells expansion...
August 9, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/28805110/lack-of-interaction-of-lopinavir-solid-drug-nanoparticles-with-cells-of-the-immune-system
#10
Neill J Liptrott, Marco Giardiello, Tom O McDonald, Steven P Rannard, Andrew Owen
AIM: We previously demonstrated that solid drug nanoparticles (SDNs) lopinavir (LPV) dispersed into aqueous media display favorable pharmacokinetics. METHODS: The impact of LPV SDNs on the function and phenotype of primary human T cells and macrophages (primary sites of HIV replication) was investigated. RESULTS: LPV significantly increased IL-1β (ninefold higher than untreated cells; p = 0.045) and TNF-α (sixfold higher than untreated cells; p = 0...
August 14, 2017: Nanomedicine
https://www.readbyqxmd.com/read/28804910/t-cell-protein-tyrosine-phosphatase-prevents-stat1-induction-of-claudin-2-expression-in-intestinal-epithelial-cells
#11
Moorthy Krishnan, Declan F McCole
T cell protein tyrosine phosphatase (TCPTP) dephosphorylates a number of substrates, including JAK-STAT (signal transducer and activator of transcription) signaling proteins, which are activated by interferon (IFN)-γ, a major proinflammatory cytokine involved in conditions such as inflammatory bowel disease. A critical function of the intestinal epithelium is formation of a selective barrier to luminal contents. The structural units of the epithelium that regulate barrier function are the tight junctions (TJs), and the protein composition of the TJ determines the tightness of the barrier...
August 14, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28804866/virally-vectored-vaccine-delivery-medical-needs-mechanisms-advantages-and-challenges
#12
Daniel D Pinschewer
Vaccines represent one of the most successful chapters in the history of medicine. Over the past decades, the advent of recombinant cDNA technology has enabled the biomedical community to genetically engineer viruses for vaccine delivery purposes. As a starting point, this review evaluates the unmet medical needs, which drive scientists and industry to exploit such fundamentally new technology for human vaccination. The author discusses the molecular functioning, production and safety profile of replication-competent and -deficient viral vector systems, representing two fundamentally distinct classes of "genetic vaccines"...
August 14, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/28804688/pivotal-regulators-of-tissue-homeostasis-and-cancer-macrophages
#13
REVIEW
Yulei Chen, Xiaobo Zhang
Macrophages are an essential component of innate immunity and play a vital role in inflammation and host defense. Based on immunological responses, the macrophages are classified into "activated" macrophage (M1 macrophages) participating in the responses of type I helper T (Th1) cells to pathogens and "alternatively activated" macrophages (M2 macrophages) in response to interleukin (IL)-4 and IL-13. In this review, we discuss the origin, classification and function of macrophages. We also discuss the mechanisms underlying polarization of different macrophage subtypes, including transcriptional, epigenetic and post-transcriptional regulation...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28804596/characterisation-of-tumour-derived-microvesicles-in-cancer-patients-blood-and-correlation-with-clinical-outcome
#14
Kerstin Menck, Annalen Bleckmann, Astrid Wachter, Bianca Hennies, Lena Ries, Matthias Schulz, Marko Balkenhol, Tobias Pukrop, Bawarjan Schatlo, Ulrike Rost, Dirk Wenzel, Florian Klemm, Claudia Binder
To evaluate whether tumour-derived microvesicles (T-MV), originating from the plasma membrane, represent suitable cancer biomarkers, we isolated MV from peripheral blood samples of cancer patients with locally advanced and/or metastatic solid tumours (n = 330, including 79 head & neck cancers, 74 lung cancers, 41 breast cancers, 28 colorectal cancers and 108 with other cancer forms) and controls (n = 103). Whole MV preparations were characterised using flow cytometry. While MV carrying the tumour-associated proteins MUC1, EGFR and EpCAM were found to be enhanced in a tumour-subtype-specific way in patients' blood, expression of the matrix metalloproteinase inducer EMMPRIN was increased independent of tumour type...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/28804539/mir-371-mir-138-mir-544-mir-145-and-mir-214-could-modulate-th1-th2-balance-in-asthma-through-the-combinatorial-regulation-of-runx3
#15
Yu-Ying Qiu, Ying-Wei Zhang, Xiu-Fen Qian, Tao Bian
Asthma is tightly related to the imbalance of Th1/Th2 cells, and Runx3 plays a pivotal role in the differentiation of T helper cells. The present study aimed to investigate dysregulated microRNAs that may target Runx3 in CD4(+) T cells from asthmatic patients and reveal Runx3 function in Th1/Th2 balance regulation. We detected the levels of Th1- and Th2-related cytokines by ELISA and analyzed the differentiation marker gene of T helper cells by qRT-PCR. Results indicated that an imbalance of Th1/Th2 cells was present in our asthmatic subject...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28804489/normalized-synergy-predicts-that-cd8-co-receptor-contribution-to-t-cell-receptor-tcr-and-pmhc-binding-decreases-as-tcr-affinity-increases-in-human-viral-specific-t-cells
#16
Chad M Williams, Alexandra A Schonnesen, Shu-Qi Zhang, Ke-Yue Ma, Chenfeng He, Tori Yamamoto, S Gail Eckhardt, Christopher A Klebanoff, Ning Jiang
The discovery of naturally occurring T cell receptors (TCRs) that confer specific, high-affinity recognition of pathogen and cancer-associated antigens remains a major goal in cellular immunotherapies. The contribution of the CD8 co-receptor to the interaction between the TCR and peptide-bound major histocompatibility complex (pMHC) has previously been correlated with the activation and responsiveness of CD8(+) T cells. However, these studies have been limited to model systems of genetically engineered hybridoma TCRs or transgenic mouse TCRs against either a single epitope or an array of altered peptide ligands...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28803862/recombinant-lcmv-vectors-induce-protective-immunity-following-homologous-and-heterologous-vaccinations
#17
Jessica Wingerath, Dmitrij Ostroumov, Norman Woller, Michael P Manns, Daniel D Pinschewer, Klaus Orlinger, Ursula Berka, Florian Kühnel, Thomas C Wirth
Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies...
July 20, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28803861/long-duration-complete-remissions-of-diffuse-large-b-cell-lymphoma-after-anti-cd19-chimeric-antigen-receptor-t%C3%A2-cell-therapy
#18
James N Kochenderfer, Robert P T Somerville, Tangying Lu, James C Yang, Richard M Sherry, Steven A Feldman, Lori McIntyre, Adrian Bot, John Rossi, Norris Lam, Steven A Rosenberg
T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed...
July 13, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28803568/history-of-child-maltreatment-and-telomere-length-in-immune-cell-subsets-associations-with-stress-and-attachment-related-hormones
#19
Christina Boeck, Sabrina Krause, Alexander Karabatsiakis, Katharina Schury, Harald Gündel, Christiane Waller, Iris-Tatjana Kolassa
Experiencing maltreatment during childhood can have long-lasting consequences for both mental and physical health. Immune cell telomere length (TL) shortening might be one link between child maltreatment (CM) experiences and adverse health outcomes later in life. While the stress hormone cortisol has been associated with TL attrition, the attachment-related hormone oxytocin may promote resilience. In 15 mothers with and 15 age- and body mass index-matched mothers without CM, we assessed TL in peripheral blood mononuclear cells and selected immune cell subsets (monocytes, naive, and memory cytotoxic T cells) by quantitative fluorescence in situ hybridization, as well as peripheral cortisol and oxytocin levels...
August 14, 2017: Development and Psychopathology
https://www.readbyqxmd.com/read/28803538/pharmacokinetics-of-tafamidis-a-transthyretin-amyloidosis-drug-in-rats
#20
Kyeong-Ryoon Lee, Jong-Woo Jeong, Hun-Chan Hyun, Jang Eunseo, Sunjoo Ahn Ahn, Sungwook Choi, Sang Hoon Joo, Sung-Sub Kim, Tae-Sung Koo
1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (Vss), and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 6...
August 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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