Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.

Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.

Combined interventions for physical activity, sleep, and diet using smartphone apps: A scoping literature review.

BACKGROUND: The use of smartphone apps to track and manage physical activity (PA), diet, and sleep is growing rapidly. Many apps aim to change individual behavior on these three key health dimensions (PA, sleep, diet) by using various interventions. Earlier reviews have examined interventions using smartphone apps for one or two of these dimensions. However, there is lack of reviews focusing on interventions for all three of these dimensions in combination with each other. This is important since the dimensions are often inter-related, and all are required for a healthy lifestyle. OBJECTIVE: The objective of this study is to conduct a review to: (1) map out the research done using smartphone app interventions targeting all three or any two of the three dimensions (PA, sleep, and diet), (2) examine if the studies consider the inter-relationships among the dimensions, and (3) identify the personalization methods implemented by the studies. METHODS: A literature search was conducted in electronic databases and libraries related to medical and informatics literature - PubMed, ScienceDirect, PsycINFO (ProQuest, Ovid) - using relevant selected keywords. Article selection and inclusion were done by removing duplicates, analyzing titles and abstracts, and then reviewing the full text of the articles. RESULTS: In the final analysis, 14 articles were selected - 2 articles focusing on PA and sleep, 8 on PA and diet, and 4 that examine or (at least) collect data of all three dimensions (PA, sleep, and diet). No research was found that focused on sleep and diet together. Of the 14 articles, only 4 build user profiles. Further, 3 of these 4 studies deliver personalized feedback based on the user's profile, with only 1 study providing automated, personalized recommendations for behavior change. Additionally, 6 of the included studies report all positive outcomes, while for 3 studies the primary outcomes are awaited. The remaining 5 studies do not report significant changes in all outcomes. In all, only 1 study examines the relationship between two (PA and diet) dimensions. No study was found to assess the relationships among the 3 dimensions.

IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response.

Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1R132H) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1R132H, TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1R132H in the context of TP53 and ATRX loss. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.