Tumor membrane-based vaccine immunotherapy in combination with anti-CTLA-4 antibody confers protection against immune checkpoint resistant murine triple-negative breast cancer.

Triple-negative breast cancer (TNBC) afflicts women at a younger age than other breast cancers and is associated with a worse clinical outcome. This poor clinical outcome is attributed to a lack of defined targets and patient-to-patient heterogeneity in target antigens and immune responses. To address such heterogeneity, we tested the efficacy of a personalized vaccination approach for the treatment of TNBC using the 4T1 murine TNBC model.

Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP.

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK.

Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism.

Background: TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and steer the immune response through chemokine and cytokine secretion.

Activating the Nucleic Acid-Sensing Machinery for Anticancer Immunity.

Nucleic acid sensing pathways have likely evolved as part of a broad pathogen sensing strategy intended to discriminate infectious agents and initiate appropriate innate and adaptive controls. However, in the absence of infectious agents, nucleic acid sensing pathways have been shown to play positive and negative roles in regulating tumorigenesis, tumor progression and metastatic spread. Understanding the normal biology behind these pathways and how they are regulated in malignant cells and in the tumor immune environment can help us devise strategies to exploit nucleic acid sensing to manipulate anti-cancer immunity.

Prevalence of Genetic Disorders and GLUT1 Deficiency in a Ketogenic Diet Clinic.

Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively.

Long-term outcome of patients with X-linked adrenoleukodystrophy: A retrospective cohort study.

Background: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD.

Method: All patients with X-ALD diagnosed between 1989 and 2012 were included.

Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy.

We report treatment outcome of eleven patients with pyridoxine-dependent epilepsy caused by pathogenic variants in ALDH7A1 (PDE-ALDH7A1). We developed a clinical severity score to compare phenotype with biochemical features, genotype and delays in the initiation of pyridoxine. Clinical severity score included 1) global developmental delay/ intellectual disability; 2) age of seizure onset prior to pyridoxine; 3) current seizures on treatment.

Effects of anchor structure and glycosylation of Fcγ receptor III on ligand binding affinity.

Isoforms of the Fcγ receptor III (FcγRIII or CD16) are cell surface receptors for the Fc portion of IgG and important regulators of humoral immune responses. Different ligand binding kinetics of FcγRIII isoforms are obtained in three dimensions by surface plasmon resonance and in two dimensions by a micropipette adhesion frequency assay. We show that the anchor structure of CD16 isoforms isolated from the cell membrane affects their binding affinities in a ligand-specific manner.

Epileptic Encephalopathy in Childhood: A Stepwise Approach for Identification of Underlying Genetic Causes.

Epilepsy is one of the most common neurological disorders in childhood. Epilepsy associated with global developmental delay and cognitive dysfunction is defined as epileptic encephalopathy. Certain inherited metabolic disorders presenting with epileptic encephalopathy can be treated with disease specific diet, vitamin, amino acid or cofactor supplementations.

Plasma membrane vesicles decorated with glycolipid-anchored antigens and adjuvants via protein transfer as an antigen delivery platform for inhibition of tumor growth.

Antigen delivered within particulate materials leads to enhanced antigen-specific immunity compared to soluble administration of antigen. However, current delivery approaches for antigen encapsulated in synthetic particulate materials are limited by the complexity of particle production that affects stability and immunogenicity of the antigen. Herein, we describe a protein delivery system that utilizes plasma membrane vesicles (PMVs) derived from biological materials such as cultured cells or isolated tissues and a simple protein transfer technology.

Carrier frequency of guanidinoacetate methyltransferase deficiency in the general population by functional characterization of missense variants in the GAMT gene.

Guanidinoacetate methyltransferase (GAMT) deficiency is a neurodegenerative disease. Although no symptomatic patients on treatment achieved normal neurodevelopment, three asymptomatic newborns were reported with normal neurodevelopmental outcome on neonatal treatment. GAMT deficiency is therefore a candidate for newborn screening programs, but there are no studies for the carrier frequency of this disease in the general population.

Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene.

Creatine transporter deficiency (CRTR-D) is an X-linked inherited disorder of creatine transport. All males and about 50% of females have intellectual disability or cognitive dysfunction. Creatine deficiency on brain proton magnetic resonance spectroscopy and elevated urinary creatine to creatinine ratio are important biomarkers.

Diagnostic yield of genetic testing in epileptic encephalopathy in childhood.

Objective: Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic.

Methods: We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic.

Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study.

Background: Inherited neurotransmitter disorders are primary defects of neurotransmitter metabolism. The main purpose of this retrospective cohort study was to identify prevalence of inherited neurotransmitter disorders.

Methods: This retrospective cohort study does not have inclusion criteria; rather included all patients who underwent cerebrospinal fluid (CSF) homovanillic and 5-hydroxyindol acetic acid measurements.

Protein transfer-mediated surface engineering to adjuvantate virus-like nanoparticles for enhanced anti-viral immune responses.

Unlabelled: Recombinant virus-like nanoparticles (VLPs) are a promising nanoparticle platform to develop safe vaccines for many viruses. Herein, we describe a novel and rapid protein transfer process to enhance the potency of enveloped VLPs by decorating influenza VLPs with exogenously added glycosylphosphatidylinositol-anchored immunostimulatory molecules (GPI-ISMs). With protein transfer, the level of GPI-ISM incorporation onto VLPs is controllable by varying incubation time and concentration of GPI-ISMs added.

Influenza virus-like particles engineered by protein transfer with tumor-associated antigens induces protective antitumor immunity.

Delivery of antigen in particulate form using either synthetic or natural particles induces stronger immunity than soluble forms of the antigen. Among naturally occurring particles, virus-like particles (VLPs) have been genetically engineered to express tumor-associated antigens (TAAs) and have shown to induce strong TAA-specific immune responses due to their nano-particulate size and ability to bind and activate antigen-presenting cells. In this report, we demonstrate that influenza VLPs can be modified by a protein transfer technology to express TAAs for induction of effective antitumor immune responses.

The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada.

Objectives: Glycogen storage disease (GSD) types VI and IX are caused by phosphorylase system deficiencies. To evaluate the natural history and long-term treatment outcome of the patients with GSD-VI and -IX, we performed an observational retrospective case study of 21 patients with confirmed diagnosis of GSD-VI or -IX.

Methods: All patients with GSD-VI or -IX, diagnosed at The Hospital for Sick Children, were included.

Cancer CARtography: charting out a new approach to cancer immunotherapy.

Evaluation of: Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci.

Allogeneic tumor cell vaccines: the promise and limitations in clinical trials.

The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation.

Human leukocyte antigen alleles, genotypes and haplotypes frequencies in renal transplant donors and recipients from West Central India.

Background: Human leukocyte antigen (HLA) is comprised of a highly polymorphic set of genes which determines the histocompatibility of organ transplantation. The present study was undertaken to identify HLA class I and class II allele, genotype and haplotype frequencies in renal transplant recipients and donors from West Central India.

Materials And Methods: HLA typing was carried out using Polymerase Chain Reaction-Sequence Specific Primer in 552 live related and unrelated renal transplant recipients and donors.

Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model.

Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines.

Taming dendritic cells with TIM-3: another immunosuppressive strategy used by tumors.

Evaluation of: Chiba S, Baghdadi M, Akiba H et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat.

Evaluation of genetic diversity and population structure of West-Central Indian cattle breeds.

Evaluations of genetic diversity in domestic livestock populations are necessary to implement region-specific conservation measures. We determined the genetic diversity and evolutionary relationships among eight geographically and phenotypically diverse cattle breeds indigenous to west-central India by genotyping these animals for 22 microsatellite loci. A total of 326 alleles were detected, and the expected heterozygosity ranged from 0.