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Genetics and immune therapy

Elaine Tan, Bassel El-Rayes
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive and lethal diseases in the world. The success of immunotherapy in other types of malignancy has led to further trials to understand better the role of immunotherapy in PDAC. However, initial studies with immunotherapy, namely, the checkpoint inhibitors, in PDAC have not been met with the same outcomes. The purpose of this review is to identify and discuss the various resistance mechanisms of PDAC to immunotherapy (pancreatic stroma, genetic predisposition/epigenetics, and the immune inhibitory cells, cytokines, soluble factors, and enzymes that comprise the tumor microenvironment) and the solutions currently being studied to overcome them...
November 17, 2018: Journal of Gastrointestinal Cancer
Chun-Pin Chiang, Julia Yu-Fong Chang, Yi-Ping Wang, Yu-Hsueh Wu, Yang-Che Wu, Andy Sun
Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases characterized by recurrent and painful ulcerations on the movable or nonkeratinized oral mucosae. Clinically, three types of RAS, namely minor, major, and herpetiform types, can be identified. RAS more commonly affects labial mucosa, buccal mucosa, and tongue. Previous studies indicate that RAS is a multifactorial T cell-mediated immune-dysregulated disease. Factors that modify the immunologic responses in RAS include genetic predisposition, viral and bacterial infections, food allergies, vitamin and microelement deficiencies, systemic diseases, hormonal imbalance, mechanical injuries, and stress...
November 14, 2018: Journal of the Formosan Medical Association, Taiwan Yi Zhi
Atul Munish Chander, Hariom Yadav, Shalini Jain, Sanjay Kumar Bhadada, Devinder Kumar Dhawan
Celiac disease (CD) is an autoimmune disorder of the small intestine, caused by gluten induced inflammation in some individuals susceptible to genetic and environmental influences. To date, pathophysiology of CD in relation to intestinal microbiota is not known well. This review relies on contribution of intestinal microbiome and oral microbiome in pathogenesis of CD based on their interactions with gluten, thereby highlighting the role of upper gastrointestinal microbiota. It has been hypothesized that CD might be triggered by additive effects of immunotoxic gluten peptides and intestinal dysbiosis (microbial imbalance) in the people with or without genetic susceptibilities, where antibiotics may be deriving dysbiotic agents...
2018: Frontiers in Microbiology
Yasmin Leshem, Emily M King, Ronit Mazor, Yoram Reiter, Ira Pastan
SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells...
November 14, 2018: Toxins
Ian Simon Olivier, Ramón Cacabelos, Vinogran Naidoo
Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND...
November 14, 2018: International Journal of Molecular Sciences
Mark G Kirchhof, Ian Landells, Chuck W Lynde, Melinda J Gooderham, Chih-Ho Hong
Atopic dermatitis (AD) is a chronic, relapsing, and remitting inflammatory skin disease whose onset typically occurs early in life. AD pathophysiology includes genetic, immune, and environmental factors contributing to chronic inflammation. A rapidly evolving understanding of the pathogenesis of AD has led to the development of several treatment options for AD in adults, including topicals, phototherapy, and systemic therapies. Here, we provide a concise summary of AD pathophysiology with a focus on implications for systemic therapy...
November 2018: Journal of Cutaneous Medicine and Surgery
Jose Antonio Lopez-Escamez, Angel Batuecas-Caletrio, Alexandre Bisdorff
Ménière's disease (MD) represents a heterogeneous group of relatively rare disorders with three core symptoms: episodic vertigo, tinnitus, and sensorineural hearing loss involving 125 to 2,000 Hz frequencies. The majority of cases are considered sporadic, although familial aggregation has been recognized in European and Korean populations, and the search for familial MD genes has been elusive until the last few years. Detailed phenotyping and cluster analyses have found several clinical predictors for different subgroups of patients, which may indicate different mechanisms, including genetic and immune factors...
2018: F1000Research
Jenny Lazarus, Tomasz Maj, J Joshua Smith, Mirna Perusina Lanfranca, Arvind Rao, Michael I D'Angelica, Lawrence Delrosario, Alexander Girgis, Casey Schukow, Jinru Shia, Ilona Kryczek, Jiaqi Shi, Isaac Wasserman, Howard Crawford, Hari Nathan, Marina Pasca Di Magliano, Weiping Zou, Timothy L Frankel
Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival...
November 15, 2018: JCI Insight
Wenbo Wu, Ting Chen
The clustered regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system functions like an adaptive immune system in a variety of microbes and has recently been engineered as a powerful tool for manipulating genomic sequences in a huge variety of cell types. In mammals, CRISPR/Cas9 has the potential to bring curative therapies to patients with genetic diseases, although it remained unknown whether suitable in vivo methods for its use are feasible. It is now appreciated that the efficient delivery of these genome-editing tools into most tissue types, including skin, remains a major challenge...
November 14, 2018: Methods in Molecular Biology
Marta Martinez-Lage, Pilar Puig-Serra, Pablo Menendez, Raul Torres-Ruiz, Sandra Rodriguez-Perales
Cancer is the second leading cause of death globally and remains a major economic and social burden. Although our understanding of cancer at the molecular level continues to improve, more effort is needed to develop new therapeutic tools and approaches exploiting these advances. Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has recently emerged as a potentially powerful tool in the arsenal of cancer therapy. Among its many applications, CRISPR-Cas9 has shown an unprecedented clinical potential to discover novel targets for cancer therapy and to dissect chemical-genetic interactions, providing insight into how tumours respond to drug treatment...
November 12, 2018: Biomedicines
Takashi Mitamura, Peixin Dong, Kei Ihira, Masataka Kudo, Hidemichi Watari
The overall survival rate of patients with early-stage endometrial cancer is relatively high; however, there are few treatment options for patients with advanced or recurrent endometrial cancer, and the prognosis of such patients remains poor. Recent progress in molecular-targeted therapies demonstrated that they have the potential to improve the long-term survival of cancer patients with appropriate biomarkers. However, the median progression-free survival of patients who received single-agent molecular-targeted therapy was <5 months, and the development of molecular-targeted therapies for endometrial cancer patients is urgently needed...
November 13, 2018: Japanese Journal of Clinical Oncology
Eugene Tulchinsky, Oleg Demidov, Marina Kriajevska, Nickolai A Barlev, Evgeny Imyanitov
Epithelial mesenchymal transition (EMT) is a reversible developmental genetic programme of transdifferentiation of polarised epithelial cells to mesenchymal cells. In cancer, EMT is an important factor of tumour cell plasticity and has received increasing attention for its role in the resistance to conventional and targeted therapies. In this paper we provide an overview of EMT in human malignancies, and discuss contribution of EMT to the development of the resistance to Epithelial Growth Factor Receptor (EGFR)-targeted therapies in non-small cell lung cancer (NSCLC)...
November 9, 2018: Biochimica et biophysica acta. Reviews on cancer
Maksim Vyacheslavovich Kvach, Fareeda M Barzak, Stefan Harjes, Henry A M Schares, Geoffrey B Jameson, Alex M Ayoub, Ramkumar Moorthy, Hideki Aihara, Reuben S Harris, Vyacheslav Filichev, Daniel A Harki, Elena Harjes
APOBEC3 enzymes form part of the innate immune system by deaminating cytosine to uracil in single-stranded DNA (ssDNA) and thereby preventing the spread of pathogenic genetic information. However, APOBEC mutagenesis is also exploited by viruses and cancer cells to increase rates of evolution, escape adaptive immune responses, and resist drugs. This raises the possibility of APOBEC3 inhibition as a strategy to augment existing antiviral and anticancer therapies. Here we show that, upon incorporation into short single-stranded (ss)DNAs, the cytidine nucleoside analog 2'-deoxy-zebularine (dZ) becomes capable of inhibiting the catalytic activity of selected APOBEC variants derived from APOBEC3A, APOBEC3B, and APOBEC3G supporting a mechanism in which ssDNA delivers dZ to the active site...
November 12, 2018: Biochemistry
Lihong Zhang, Yang Peng, Guang Peng
Mismatch repair (MMR) plays a key role in maintaining genomic stability. Mismatch repair deficiency (MMR-D) causes a molecular feature of microsatellite instability (MSI) and contributes to the development of human cancers and genetic diseases with cancer predisposition such as Lynch syndrome. Recent studies have shown that immune checkpoint blockade therapy has a promising response in MMR-D cancers regardless of the tissue of origin. Being able to identify patients with MMR-D cancers is an important challenge in clinical practice...
2018: American Journal of Cancer Research
Hayandra Ferreira Nanini, Claudio Bernardazzi, Fernando Castro, Heitor Siffert Pereira de Souza
The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation...
November 7, 2018: World Journal of Gastroenterology: WJG
Carolina Petrillo, Lucy G Thorne, Giulia Unali, Giulia Schiroli, Anna M S Giordano, Francesco Piras, Ivan Cuccovillo, Sarah J Petit, Fatima Ahsan, Mahdad Noursadeghi, Simon Clare, Pietro Genovese, Bernhard Gentner, Luigi Naldini, Greg J Towers, Anna Kajaste-Rudnitski
Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry...
October 24, 2018: Cell Stem Cell
Cyrill A Rentsch, Laurent Derré, Sarah G Dugas, Christian Wetterauer, Joël R Federer-Gsponer, George N Thalmann, Molly A Ingersoll
CONTEXT: More than 40 yr ago, bacillus Calmette-Guérin (BCG) was introduced as an adjuvant therapy following transurethral resection of papillary tumours and as a treatment for carcinoma in situ of the bladder. Some 30 yr after its introduction, BCG maintenance therapy was found to be superior to induction therapy alone, representing the most relevant clinical improvement to BCG therapy since its inception. OBJECTIVE: To review current efforts and future opportunities to improve BCG immunotherapy...
November 8, 2018: European Urology Focus
Karin Ried, Peter Fakler
Juvenile arthritis with unknown disease etiology is also known as juvenile idiopathic arthritis. Symptoms include joint pain, swelling, and stiffness, and standard treatment involves immunosuppressant medication. Here we present a case of juvenile idiopathic arthritis with severe malnutrition and worsening of symptoms, which restrained a nine-year-old girl to a wheelchair with minimal movement capacity and low energy during standard immunosuppressant therapies over the course of three years. Our innovative Pathogen Blood Test combining cytology-based microscopy and genetic analysis using a pan-fungal primer assay and sequencing identified a systemic fungal infection with Sagenomella species, closely related to Aspergillus , and a soil-dwelling highly pathogenic fungus, which had previously been linked to a fatal veterinary case of arthritis and malnutrition...
August 29, 2018: Curēus
Theresa L Whiteside
Liquid biopsy platforms are being actively developed in the biomarker field. Extracellular vesicles (EVs), especially the tumor-derived exosome (TEX) subsets of EVs, represent a platform that allows for molecular and genetic profiling of parent tumor cells. TEX are ubiquitous in body fluids of cancer patients and are promising clinically relevant surrogates of cancer cells. Areas covered: Isolation from body fluids of cancer patients and subsetting of exosomes based on immunoaffinity capture offers a means of evaluating proteins, lipids, nucleic acids and other molecular contents that are a characteristic of TEX and exosomes produced by reprogrammed normal cells...
November 8, 2018: Expert Review of Molecular Diagnostics
Shibin Zhou, Claudia Gravekamp, David Bermudes, Ke Liu
Recent advances in targeted therapy and immunotherapy have once again raised the hope that a cure might be within reach for many cancer types. Yet, most late-stage cancers are either insensitive to the therapies to begin with or develop resistance later. Therapy with live tumour-targeting bacteria provides a unique option to meet these challenges. Compared with most other therapeutics, the effectiveness of tumour-targeting bacteria is not directly affected by the 'genetic makeup' of a tumour. Bacteria initiate their direct antitumour effects from deep within the tumour, followed by innate and adaptive antitumour immune responses...
November 7, 2018: Nature Reviews. Cancer
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