Integrins as therapeutic targets: lessons and opportunities.

The integrins are a large family of cell adhesion molecules that are essential for the regulation of cell growth and function. The identification of key roles for integrins in a diverse range of diseases, including cancer, infection, thrombosis and autoimmune disorders, has revealed their substantial potential as therapeutic targets. However, so far, pharmacological inhibitors for only three integrins have received marketing approval. This article discusses the structure and function of integrins, their roles in disease and the chequered history of the approved integrin antagonists. Recent advances in the understanding of integrin function, ligand interaction and signalling pathways suggest novel strategies for inhibiting integrin function that could help harness their full potential as therapeutic targets

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Metabolic activity of subterranean microbial communities in deep granitic groundwater supplemented with methane and H 2

It was previously concluded that opposing gradients of sulphate and methane, observations of 16S ribosomal DNA sequences displaying great similarity to those of anaerobic methane-oxidizing Archaea and a peak in sulphide concentration in groundwater from a depth of 250-350 m in Olkiluoto, Finland, indicated proper conditions for methane oxidation with sulphate. In the present research, pressure-resistant, gas-tight circulating systems were constructed to enable the investigation of attached and unattached anaerobic microbial populations from a depth of 327 m in Olkiluoto under in situ pressure (2.4 MPa), diversity, dissolved gas and chemistry conditions. Three parallel flow cell cabinets were configured to allow observation of the influence on microbial metabolic activity of 11 mM methane, 11 mM methane plus 10 mM H 2 or 2.1 mM O 2 plus 7.9 mM N 2 (that is, air). The concentrations of these gases and of organic acids and carbon, sulphur chemistry, pH and E h, ATP, numbers of cultivable micro-organisms, and total numbers of cells and bacteriophages were subsequently recorded under batch conditions for 105 days. The system containing H 2 and methane displayed microbial reduction of 0.7 mM sulphate to sulphide, whereas the system containing only methane resulted in 0.2 mM reduced sulphate. The system containing added air became inhibited and displayed no signs of microbial activity. Added H 2 and methane induced increasing numbers of lysogenic bacteriophages per cell. It appears likely that a microbial anaerobic methane-oxidizing process coupled to acetate formation and sulphate reduction may be ongoing in aquifers at a depth of 250-350 m in Olkiluoto. \ua9 2013 International Society for Microbial Ecology All rights reserved

Creatine supplementation does not enhance submaximal aerobic training adaptations in healthy young men and women

The benefits of dietary creatine supplementation on muscle performance are generally related to an increase in muscle phosphocreatine content. However, creatine supplementation may benefit endurance sports through increased glycogen re-synthesis following exercise. This study investigated the effect of creatine supplementation on muscle glycogen content, submaximal exercise fuel utilisation and endurance performance following 4 weeks of endurance training. Thirteen healthy, physically active, non-vegetarian subjects volunteered to take part and completed the study. Subjects were supplemented with either creatine monohydrate (CREAT, n = 7) or placebo-maltodextrin (CON, n = 6). Submaximal fuel utilisation and endurance performance were assessed before and after a 4 week endurance training program. Muscle biopsies were also collected before and following training for assessment of muscle creatine and glycogen content. Training increased quadriceps glycogen content to the same degree (approximately 20%) in both groups (P = 0.04). There was a significant training effect on submaximal fuel utilisation and improved endurance performance. However, there was no significant treatment effect of creatine supplementation. Creatine supplementation does not effect metabolic adaptations to endurance training.T. F. Reardon, P. A. Ruell, M. A. Fiatarone Singh, C. H. Thompson, K. B. Roone

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4–6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically ‘cold’ tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone—a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma—generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma

Advances in the molecular genetics of gliomas - implications for classification and therapy

Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers — together with classic histological features — in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology