Project description:Immune cell metabolism is dynamically regulated in parallel with the substantial changes in cellular function that accompany immune cell activation. While these changes in metabolism are important for facilitating the increased energetic and biosynthetic demands of activated cells, immune cell metabolism also has direct roles in controlling the functions of immune cells and shaping the immune response. A theme is emerging wherein nutrients, metabolic enzymes, and metabolites can act as an extension of the established immune signal transduction pathways, thereby adding an extra layer of complexity to the regulation of immunity. This Review will outline the metabolic configurations adopted by different immune cell subsets, describe the emerging roles for metabolic enzymes and metabolites in the control of immune cell function, and discuss the therapeutic implications of this emerging immune regulatory axis.
Project description:Biomaterials employed to raise therapeutic immune responses have become a complex and active field. Historically, vaccines have been developed primarily to fight infectious diseases, but recent years have seen the development of immunologically active biomaterials towards an expanding list of non-infectious diseases and conditions including inflammation, autoimmunity, wounds, cancer, and others. This review structures its discussion of these approaches around a progression from single-target strategies to those that engage increasingly complex and multifactorial immune responses. First, the targeting of specific individual cytokines is discussed, both in terms of delivering the cytokines or blocking agents, and in terms of active immunotherapies that raise neutralizing immune responses against such single cytokine targets. Next, non-biological complex drugs such as randomized polyamino acid copolymers are discussed in terms of their ability to raise multiple different therapeutic immune responses, particularly in the context of autoimmunity. Last, biologically derived matrices and materials are discussed in terms of their ability to raise complex immune responses in the context of tissue repair. Collectively, these examples reflect the tremendous diversity of existing approaches and the breadth of opportunities that remain for generating therapeutic immune responses using biomaterials.
Project description:In order to determine whether dis-regulation of a genetic pathway could explain the increased apoptosis of parp-2-/- double positive thymocytes, the gene expression profiles in double positive thymocytes derived from wild-type and parp-2-/- mice were analysed using Affymetrix oligonucleotide chips (mouse genome 430 2.0).
Project description:Stroke is the second leading cause of death worldwide and a leading cause of disability. Most strokes are caused by occlusion of a major cerebral artery, and substantial advances have been made in elucidating how ischemia damages the brain. In particular, increasing evidence points to a double-edged role of the immune system in stroke pathophysiology. In the acute phase, innate immune cells invade brain and meninges and contribute to ischemic damage, but may also be protective. At the same time, danger signals released into the circulation by damaged brain cells lead to activation of systemic immunity, followed by profound immunodepression that promotes life-threatening infections. In the chronic phase, antigen presentation initiates an adaptive immune response targeted to the brain, which may underlie neuropsychiatric sequelae, a considerable cause of poststroke morbidity. Here, we briefly review these pathogenic processes and assess the potential therapeutic value of targeting immunity in human stroke.
Project description:Pathogenic fungi have emerged as significant causes of infectious morbidity and death in patients with acquired immunodeficiency conditions such as HIV/AIDS and following receipt of chemotherapy, immunosuppressive agents or targeted biologics for neoplastic or autoimmune diseases, or transplants for end organ failure. Furthermore, in recent years, the spread of multidrug-resistant Candida auris has caused life-threatening outbreaks in health-care facilities worldwide and raised serious concerns for global public health. Rapid progress in the discovery and functional characterization of inborn errors of immunity that predispose to fungal disease and the development of clinically relevant animal models have enhanced our understanding of fungal recognition and effector pathways and adaptive immune responses. In this Review, we synthesize our current understanding of the cellular and molecular determinants of mammalian antifungal immunity, focusing on observations that show promise for informing risk stratification, prognosis, prophylaxis and therapies to combat life-threatening fungal infections in vulnerable patient populations.
Project description:Ossification of the posterior longitudinal ligament (OPLL) is formed by heterogeneous ossification of posterior longitudinal ligament. The patho-mechanism of OPLL is still largely unknown. MicroRNAs are small nucleatides that function as regulators of gene expression in almost any biological process. However, few microRNAs are reported to have a role in the pathological process of OPLL. Therefore, we performed high-throughput microRNA sequencing and transcriptome sequencing of primary OPLL and PLL cells in order to decipher the interacting network of microRNAs in OPLL. MRNA and microRNA profiles were done using primary culture cells of human ossification of the posterior longitudinal ligament (OPLL) tissue and normal posterior longitudinal ligament (PLL) tissue.
Project description:Chromothripsis is a catastrophic event involving numerous chromosomal rearrangements in confined genomic regions of one or a few chromosomes, causing complex effects on cells via the extensive structural variation. The development of whole-genome sequencing (WGS) has promoted great progress in exploring the mechanism and effect of chromothripsis. However, the gene expression characteristics of tumors undergone chromothripsis have not been well characterized. In this study, we found that the transcriptional profile of five tumor types experiencing chromothripsis is associated with an immune evasion phenotype. A gene set variation analysis (GSVA) was used to develop a CHP score, which is based on differentially expressed gene sets in the TCGA database, revealing that chromothripsis status in multiple cancers is consistent with an abnormal tumor immune microenvironment and immune cell cytotoxicity. Evaluation using four immunotherapy datasets uncovered the ability of the CHP score to predict immunotherapy response in diverse tumor types. In addition, the CHP score was found to be related to resistance against a variety of anti-tumor drugs, including anti-angiogenesis inhibitors and platinum genotoxins, while EGFR pathway inhibitors were found to possibly be sensitizers for high CHP score tumors. Univariate COX regression analysis indicated that the CHP score can be prognostic for several types of tumors. Our study has defined gene expression characteristics of tumors with chromothripsis, supporting the controversial link between chromothripsis and tumor immunity. We also describe the potential value of the CHP score in predicting the efficacy of immunotherapy and other treatments, elevating chromothripsis as a tool in clinical practice.
Project description:Changes in cellular metabolism contribute to the development and progression of tumors, and can render tumors vulnerable to interventions. However, studies of human cancer metabolism remain limited due to technical challenges of detecting and quantifying small molecules, the highly interconnected nature of metabolic pathways, and the lack of designated tools to analyze and integrate metabolomics with other âomics data. Our study generates the largest comprehensive metabolomics dataset on a single cancer type, and provides a significant advance in integration of metabolomics with sequencing data. Our results highlight the massive re-organization of cellular metabolism as tumors progress and acquire more aggressive features. The results of our work are made available through an interactive public data portal for cancer research community. 10 RNA samples from human ccRCC tumors analyzed from the high glutathione cluster