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Genetics and immune therapy

Stephen F Murphy, Jonathan F Anker, Daniel J Mazur, Christel Hall, Anthony J Schaeffer, Praveen Thumbikat
INTRODUCTION: Chronic pelvic pain syndrome (CPPS) is a complex disorder that affects a large proportion of all men. A limited understanding of its etiology and pathogenesis is reflected by the absence of effective therapies. Although CPPS is deemed clinically non-infectious with no well-defined etiological role for microbes, bacteria is readily isolated from both healthy and patient prostate secretion and urine samples. Our laboratory has previously demonstrated that a specific gram-negative bacterial isolate can induce CPPS-like symptoms in mice...
September 21, 2018: Prostate
Mounika Addula, Victoria E D Wilson, Savio Reddymasu, Devendra K Agrawal
Functional dyspepsia (FD) is widespread with 20% prevalence worldwide and a significant economic burden due to health care cost and constraints on daily activities of patients. Despite extensive investigation, the underlying causes of dyspepsia in a majority of patients remain unknown. Common complaints include abdominal discomfort, pain, burning, nausea, early satiety, and bloating. Motor dysfunction of the gut was long considered a major cause, but recent investigations suggest immune-based pathophysiological and molecular events in the duodenum are more probable contributing factors...
September 20, 2018: Expert Review of Clinical Immunology
Ying Mu, Sunitha Kodidela, Yujie Wang, Santosh Kumar, Theodore J Cory
Combination antiretroviral therapy (ART) reduces viral load to under the limit of detection, successfully decreasing HIV-related morbidity and mortality. Due to viral mutations, complex drug combinations and different patient response, there is an increasing demand for individualized treatment options for patients. Areas covered: This review first summarizes the pharmacokinetic and pharmacodynamic profile of clinical first-line drugs, which serves as guidance for antiretroviral precision medicine. Factors which have influential effects on drug efficacy and thus precision medicine are discussed: patients' pharmacogenetic information, virus mutations, comorbidities, and immune recovery...
September 20, 2018: Expert Opinion on Pharmacotherapy
Andrew A Davis, Amy E McKee, Warren A Kibbe, Victoria M Villaflor
Precision medicine has emerged as a tool to match patients with the appropriate treatment based on the precise molecular features of an individual patient's tumor. Although examples of targeted therapies exist resulting in dramatic improvements in patient outcomes, comprehensive genomic profiling of tumors has also demonstrated the incredible complexity of molecular alterations in tissue and blood. These sequencing methods provide opportunities to study the landscape of tumors at baseline and serially in response to treatment...
May 23, 2018: American Society of Clinical Oncology Educational Book
Jun Zhao, Zhilan Xiao, Tingting Li, Huiqin Chen, Ying Yuan, Y Alan Wang, Cheng-Hui Hsiao, Diana S-L Chow, Willem W Overwijk, Chun Li
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC. We demonstrate here effective stromal modulation by a polymeric micelle-based nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine, abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel, abbreviated as PTX)...
September 21, 2018: ACS Nano
Thiru Prasanna, Fan Wu, Kum Kum Khanna, Desmond Yip, Laeeq Malik, Jane Dahlstrom, Sudha Rao
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune-directed therapies for other solid organ malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination (HR) DNA repair-deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival...
September 19, 2018: Cancer Science
Huseyin Atakan Ekiz, Shu-Chin Alicia Lai, Harika Gundlapalli, Fadi Haroun, Matthew A Williams, Alana L Welm
The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors...
2018: Oncoimmunology
Jun Yamagami
Pemphigus and pemphigoid are characterized as autoimmune blistering diseases in which immunoglobulin G autoantibodies cause blisters and erosions of the skin or mucosa or both. Recently, understanding of the pathophysiology of pemphigus and pemphigoid has been furthered by genetic analyses, characterization of autoantibodies and autoreactive B cells, and elucidation of cell-cell adhesion between keratinocytes. For the management of pemphigus and pemphigoid, the administration of systemic corticosteroids still represents the standard treatment strategy; however, evidence of the efficacy of therapies not involving corticosteroids, such as those employing anti-CD20 antibodies, is increasing...
2018: F1000Research
Esra A Akbay, James Kim
Lung cancer accounts for the greatest number of cancer deaths in the world. Tobacco smoke-associated cancers constitute the majority of lung cancer cases but never-smoker cancers comprise a significant and increasing fraction of cases. Recent genomic and transcriptomic sequencing efforts of lung cancers have revealed distinct sets of genetic aberrations of smoker and never-smoker lung cancers that implicate disparate biology and therapeutic strategies. Autochthonous mouse models have contributed greatly to our understanding of lung cancer biology and identified novel therapeutic targets and strategies in the era of targeted therapy...
August 2018: Translational Lung Cancer Research
Itziar Otano, David Escors, Anna Schurich, Harsimran Singh, Francis Robertson, Brian R Davidson, Giuseppe Fusai, Frederick A Vargas, Zhi M D Tan, Jia Y J Aw, Navjyot Hansi, Patrick T F Kennedy, Shao-An Xue, Hans J Stauss, Antonio Bertoletti, Andrea Pavesi, Mala K Maini
Checkpoint inhibitors and adoptive cell therapy provide promising options for treating solid cancers such as HBV-related HCC, but they have limitations. We tested the potential to combine advantages of each approach, genetically reprogramming T cells specific for viral tumor antigens to overcome exhaustion by down-modulating the co-inhibitory receptor PD-1. We developed a novel lentiviral transduction protocol to achieve preferential targeting of endogenous or TCR-redirected, antigen-specific CD8 T cells for shRNA knockdown of PD-1 and tested functional consequences for antitumor immunity...
August 16, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Felicitas Rataj, Fabian B T Kraus, Michael Chaloupka, Simon Grassmann, Constanze Heise, Bruno L Cadilha, Peter Duewell, Stefan Endres, Sebastian Kobold
Background: Interaction of the programmed death receptor 1 (PD-1) and its ligand, PD-L1, suppresses T cell activity and permits tumors to evade T cell-mediated immune surveillance. We have recently demonstrated that antigen-specific CD8+ T cells transduced with a PD1-CD28 fusion protein are protected from PD-1-mediated inhibition. We have now investigated the potential of PD1-CD28 fusion protein-transduced CD4+ T cells alone or in combination with CD8+ T cells for immunotherapy of pancreatic cancer and non-Hodgkin lymphoma...
2018: Frontiers in Immunology
Tagore Sunkara, Prashanth Rawla, Andrew Ofosu, Vinaya Gaduputi
Inflammatory bowel disease (IBD) is a chronic multifactorial disease that affects the gastrointestinal tract and results from an aberrant immune response toward luminal antigens in genetically susceptible people. Most of the current therapies for IBD focus on the management of the inflammation by using corticosteroids, immune modulators, and more recently, monoclonal antibodies (biological therapy). Although these therapies provide benefit in most cases, there are still a significant number of patients who do not respond or become refractory over time, suggesting the need for alternative therapeutic options...
2018: Journal of Inflammation Research
Christine L Cain
Canine perianal fistulas are painful sinus tracts and ulcers that spontaneously develop in the skin around the anus. Middle-aged German shepherd dogs are most commonly affected and may have a genetic susceptibility. Although the disease was once believed related to conformational factors and primarily managed surgically, an immune-mediated pathogenesis is now recognized. Long-term medical management with immunomodulatory agents has become standard of care for canine perianal fistulas. Perianal fistulas can be debilitating and have a negative impact on quality of life of dogs and owners...
September 11, 2018: Veterinary Clinics of North America. Small Animal Practice
David Baker, Gareth Pryce, Sandra Amor, Gavin Giovannoni, Klaus Schmierer
Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells...
September 12, 2018: Brain: a Journal of Neurology
James C Kaczmarek, Kevin J Kauffman, Owen S Fenton, Kaitlyn Sadtler, Asha K Patel, Michael W Heartlein, Frank DeRosa, Daniel G Anderson
mRNA therapeutics hold great potential for treating a variety of diseases through protein-replacement, immunomodulation, and gene editing. However, much like siRNA therapy the majority of progress in mRNA delivery has been confined to the liver. Previously, we demonstrated that poly(β-amino esters), a class of degradable polymers, are capable of systemic mRNA delivery to the lungs in mice when formulated into nanoparticles with poly(ethylene glycol)-lipid conjugates. Using experimental design, a statistical approach to optimization that reduces experimental burden, we demonstrate herein that these degradable polymer-lipid nanoparticles can be optimized in terms of polymer synthesis and nanoparticle formulation to achieve a multiple order-of-magnitude increase in potency...
September 20, 2018: Nano Letters
Jingyi Zhou, Xiaohong Tan, Yiheng Tan, Qiuyu Li, Jianjun Ma, Gangyang Wang
With the development of cancer treatments, it has become a popular research focus that mesenchymal stem (or stromal) cells (MSCs) have the functional mechanisms that influence cancer progression. One of the underestimated mechanisms is secretion of highly specialized double-membrane structures called exosomes. Mesenchymal stem cells generate several exosomes that may act as paracrine mediators by exchanging genetic information. MSC-derived exosomes are microvesicles ranging from approximately 60-200 nm in size and detected in various body fluids...
2018: Journal of Cancer
Ali McBride, John Valgus, Sandeep Parsad, Erica M Sommermann, Robert Nunan
Objective: Oncolytic immunotherapy involves the use of viruses to target and destroy cancer cells and to induce immune responses for an enhanced antitumor effect. Talimogene laherparepvec, a genetically modified herpes simplex virus type 1 (HSV-1) that selectively replicates in tumors to induce lytic cell death, tumor antigen release, and the local production of granulocyte-macrophage colony-stimulating factor (GM-CSF), has been approved for the treatment of a defined population of patients with metastatic melanoma...
October 2018: Hospital Pharmacy
L Scobie, C Galli, P Gianello, E Cozzi, H-J Schuurman
The main benefit of xenotransplantation is its potential to overcome the worldwide organ shortage experienced in allotransplantation. Allogeneic transplantation is the only successful therapy for several life-threatening diseases, with cell, tissue or organ donation only partially meeting the demand and many patients dying while waiting for treatment. With supply falling short of demand, it is foreseen that the use of porcine material may at some stage overcome the existing gap between organ availability and clinical need...
April 2018: Revue Scientifique et Technique
Maria Bottermann, Stian Foss, Laurens M van Tienen, Marina Vaysburd, James Cruickshank, Kevin O'Connell, Jessica Clark, Keith Mayes, Katie Higginson, Jack C Hirst, Martin B McAdam, Greg Slodkowicz, Edward Hutchinson, Patrycja Kozik, Jan Terje Andersen, Leo C James
Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels...
September 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hayato Iwase, Edwin C Klein, David Kc Cooper
Xenotransplantation can provide a solution to the current shortage of human organs for patients with terminal renal failure. The increasing availability of genetically engineered pigs, effective immunosuppressive therapy, and antiinflammatory therapy help to protect pig tissues from the primate immune response and can correct molecular incompatibilities. Life-supporting pig kidney xenografts have survived in NHP for more than 6 mo in the absence of markers of consumptive coagulopathy.However, few reports have focused on the physiologic aspects of life-supporting pig kidney xenografts...
September 12, 2018: Comparative Medicine
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