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Immunology, mutations, biology

Avrum Spira, Mary L Disis, John T Schiller, Eduardo Vilar, Timothy R Rebbeck, Rafael Bejar, Trey Ideker, Janine Arts, Matthew B Yurgelun, Jill P Mesirov, Anjana Rao, Judy Garber, Elizabeth M Jaffee, Scott M Lippman
Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
Anthony L DeFranco
Antibodies are involved in the pathogenesis of many autoimmune diseases. Although the mechanisms underlying the antibody response to infection or vaccination are reasonably well understood, we still have a poor understanding of the nature of autoimmune antibody responses. The most well studied are the anti-nuclear antibody responses characteristic of systemic lupus erythematosus and studies over the past decade or so have demonstrated a critical role for signaling by TLR7 and/or TLR9 in B cells to promote these responses...
October 11, 2016: Immunology and Cell Biology
Shunichi Suzuki, Masaki Iwamoto, Michiko Hashimoto, Misae Suzuki, Michiko Nakai, Daiichiro Fuchimoto, Shoichiro Sembon, Tomoko Eguchi-Ogawa, Hirohide Uenishi, Akira Onishi
Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells...
October 1, 2016: Veterinary Immunology and Immunopathology
Joe Ryan Delaney, Dwayne G Stupack
BACKGROUND: Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs) are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC) offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20-90% of their genome altered in copy number...
2016: PloS One
Stefanie Marczok, Birgit Bortz, Chong Wang, Heike Pospisil
Carcinogenesis is a complex multifactorial, multistage process, but the precise mechanisms are not well understood. In this study, we performed a genome-wide analysis of the copy number variation (CNV), breakpoint region (BPR) and fragile sites in 2,737 tumor samples from eight tumor entities and in 432 normal samples. CNV detection and BPR identification revealed that BPRs tended to accumulate in specific genomic regions in tumor samples whereas being dispersed genome-wide in the normal samples. Hotspots were observed, at which segments with similar alteration in copy number were overlapped along with BPRs adjacently clustered...
2016: PloS One
Julie Jurczyluk, Marcia A Munoz, Oliver P Skinner, Ryan C Chai, Naveid Ali, Umaimainthan Palendira, Julian Mw Quinn, Alexandra Preston, Stuart G Tangye, Andrew J Brown, Elizabeth Argent, John B Ziegler, Sam Mehr, Michael J Rogers
Mevalonate kinase deficiency (MKD) is caused by mutations in a key enzyme of the mevalonate-cholesterol biosynthesis pathway, leading to recurrent autoinflammatory disease characterised by enhanced release of interleukin-1β (IL-1β). It is currently believed that the inflammatory phenotype of MKD is triggered by temperature-sensitive loss of mevalonate kinase activity and reduced biosynthesis of isoprenoid lipids required for the prenylation of small GTPase proteins. However, previous studies have not clearly shown any change in protein prenylation in patient cells under normal conditions...
July 5, 2016: Immunology and Cell Biology
Steffen K Meurer, Melanie Neß, Sabine Weiskirchen, Philipp Kim, Carmen G Tag, Marlies Kauffmann, Michael Huber, Ralf Weiskirchen
Mast cells (MCs) are a versatile cell type playing key roles in tissue morphogenesis and host defence against bacteria and parasites. Furthermore, they can enhance immunological danger signals and are implicated in inflammatory disorders like fibrosis. This granulated cell type originates from the myeloid lineage and has similarities to basophilic granulocytes, both containing large quantities of histamine and heparin. Immature murine mast cells mature in their destination tissue and adopt either the connective tissue (CTMC) or mucosal (MMC) type...
2016: PloS One
F Uettwiller, G Sarrabay, M P Rodero, G I Rice, E Lagrue, Y Marot, K Deiva, I Touitou, Y J Crow, P Quartier
The objective of this paper is to: describe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2 activity, cytokine expression, interferon-stimulated and neutrophil-stimulated gene signatures, and the results of CECR1 sequencing. The first patient presented with intermittent fever, cutaneous vasculitis, myalgia and muscle inflammation on MRI leading to a provisional diagnosis of periarteritis nodosa...
2016: RMD Open
Maurizio Zanetti
Telomerase reverse transcriptase (TERT) is a self-antigen that is expressed constitutively in many tumours, and is, therefore, an important target for anticancer immunotherapy. In the past 10 years, trials of immunotherapy with TERT-based vaccines have demonstrated only modest benefits. In this Perspectives, I discuss the possible immunological reasons for this limited antitumour efficacy, and propose that advances in our understanding of the genetics and biology of the involvement of TERT in cancer provides the basis for renewed interest in TERT- based immunotherapy...
June 1, 2016: Nature Reviews. Clinical Oncology
Elodie Elkaim, Benedicte Neven, Julie Bruneau, Kanako Mitsui-Sekinaka, Aurelie Stanislas, Lucie Heurtier, Carrie L Lucas, Helen Matthews, Marie-Céline Deau, Svetlana Sharapova, James Curtis, Janine Reichenbach, Catherine Glastre, David A Parry, Gururaj Arumugakani, Elizabeth McDermott, Sara Sebnem Kilic, Motoi Yamashita, Despina Moshous, Hicham Lamrini, Burkhard Otremba, Andrew Gennery, Tanya Coulter, Isabella Quinti, Jean-Louis Stephan, Vassilios Lougaris, Nicholas Brodszki, Vincent Barlogis, Takaki Asano, Lionel Galicier, David Boutboul, Shigeaki Nonoyama, Andrew Cant, Kohsuke Imai, Capucine Picard, Sergey Nejentsev, Thierry Jo Molina, Michael Lenardo, Sinisa Savic, Marina Cavazzana, Alain Fischer, Anne Durandy, Sven Kracker
BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases. OBJECTIVES: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort...
July 2016: Journal of Allergy and Clinical Immunology
Mark Plander, Bernadette Kalman
Autoimmune diseases represent a heterogeneous group of common disorders defined by complex trait genetics and environmental effects. The genetic variants usually align in immune and metabolic pathways that affect cell survival or apoptosis and modulate leukocyte function. Nevertheless, the exact triggers of disease development remain poorly understood and the current therapeutic interventions only modify the disease course. Both the prevention and the cure of autoimmune disorders are beyond our present medical capabilities...
August 2016: Autoimmunity
Christopher A Hamm, Diarmuid Moran, Kakuturu Rao, Patricia B Trusk, Karen Pry, Mark Sausen, Siân Jones, Victor E Velculescu, Massimo Cristofanilli, Sarah Bacus
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that remains poorly understood at the molecular level. Comprehensive tumor profiling was performed to understand clinically actionable alterations in IBC. Targeted next-generation sequencing (NGS) and IHC were performed to identify activated pathways in IBC tumor tissues. siRNA studies examined the impact of IBC genomic variants in cellular models. IBC tumor tissues were further characterized for immune infiltration and immune checkpoint expression by IHC...
July 2016: Molecular Cancer Therapeutics
John C Moore, David M Langenau
Allogeneic cell transplantation is the transfer of cells from one individual into another of the same species and has become an indispensable technique for studying development, immunology, regeneration and cancer biology. In experimental settings, tumor cell engraftment into immunologically competent recipients has greatly increased our understanding of the mechanisms that drive self-renewal, progression and metastasis in vivo. Zebrafish have quickly emerged as a powerful genetic model of cancer that has benefited greatly from allogeneic transplantation...
2016: Advances in Experimental Medicine and Biology
Nadine Voelxen, Claudia Wehr, Sylvia Gutenberger, Baerbel Keller, Miriam Erlacher, Cecilia Dominguez-Conde, Daniela Bertele, Florian Emmerich, Milena Pantic, Stefanie Jennings, Mirzokhid Rakhmanov, Christian Foerster, Uwe M Martens, Uwe Platzbecker, Hans-Hartmut Peter, Paul Fisch, Kaan Boztug, Hermann Eibel, Ulrich Salzer, Klaus Warnatz
Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation, and survival of B cells in vitro, yet the underlying defect remains unknown. Here, we report for the first time an attenuated activation of the canonical NF-κB and MAPK/ERK pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B cell receptor (BCR) and toll-like receptor 9 (TLR9) mediated activation remained unaffected...
April 29, 2016: Immunology and Cell Biology
Moin A Saleem, Yasuko Kobayashi
Minimal change disease (MCD) is an important cause of nephrotic syndrome and is characterized by massive proteinuria and hypoalbuminemia, resulting in edema and hypercholesterolemia. The podocyte plays a key role in filtration and its disruption results in a dramatic loss of function leading to proteinuria. Immunologic disturbance has been suggested in the pathogenesis of MCD. Because of its clinical features, such as recurrent relapse/remission course, steroid response in most patients, and rare familial cases, a genetic defect has been thought to be less likely in MCD...
2016: F1000Research
Alessandra Lo Presti, Eleonora Cella, Silvia Angeletti, Massimo Ciccozzi
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus belonging to the Togaviridae family, causing a febrile illness associated with severe arthralgia and rash. In this review, we summarized a series of articles published from 2013 to 2016 concerning CHIKV epidemiology, phylogeny, vaccine and therapies, to give an update of our most recent article written in 2014 (Lo Presti et al.,2014). CHIKV infection was first reported in 1952 from Makonde plateaus and since this time caused many outbreaks worldwide, involving the Indian Ocean region, African countries, American continent and Italy...
July 2016: Infection, Genetics and Evolution
Antonio Girolami, Maria Angelica Molina, Maria Laura Lopez Galletti, Silvia Ferrari, Luisa Sambado, Hugo Guglielmone
The objective was to investigate a family from Argentina. The proposita was a 51-year-old woman who had a moderate bleeding tendency. Some of her children showed a mild bleeding tendency. Her mother and the husband were asymptomatic. Clotting, immunological and molecular biology techniques were used. Partial thromboplastin, prothrombin, Russell Viper venom-clotting times were moderately prolonged in the proposita, whereas they were slightly prolonged in the children and in her mother. Factor X (FX) activity was about 2-3% of normal in all assay systems...
September 2016: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
C Cappi, H Brentani, L Lima, S J Sanders, G Zai, B J Diniz, V N S Reis, A G Hounie, M Conceição do Rosário, D Mariani, G L Requena, R Puga, F L Souza-Duran, R G Shavitt, D L Pauls, E C Miguel, T V Fernandez
Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder...
2016: Translational Psychiatry
Age Utt, Tania Quirin, Sirle Saul, Kirsi Hellström, Tero Ahola, Andres Merits
Chikungunya virus (CHIKV; genus Alphavirus, family Togaviridae) has recently caused several major outbreaks affecting millions of people. There are no licensed vaccines or antivirals, and the knowledge of the molecular biology of CHIKV, crucial for development of efficient antiviral strategies, remains fragmentary. CHIKV has a 12 kb positive-strand RNA genome, which is translated to yield a nonstructural (ns) or replicase polyprotein. CHIKV structural proteins are expressed from a subgenomic RNA synthesized in infected cells...
2016: PloS One
Weiping Zou, Jedd D Wolchok, Lieping Chen
PD-L1 and PD-1 (PD) pathway blockade is a highly promising therapy and has elicited durable antitumor responses and long-term remissions in a subset of patients with a broad spectrum of cancers. How to improve, widen, and predict the clinical response to anti-PD therapy is a central theme in the field of cancer immunology and immunotherapy. Oncologic, immunologic, genetic, and biological studies focused on the human cancer microenvironment have yielded substantial insight into this issue. Here, we focus on tumor microenvironment and evaluate several potential therapeutic response markers including the PD-L1 and PD-1 expression pattern, genetic mutations within cancer cells and neoantigens, cancer epigenetics and effector T cell landscape, and microbiota...
March 2, 2016: Science Translational Medicine
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