Hypoxia-Induced Invadopodia Formation Involves Activation of NHE-1 by the p90 Ribosomal S6 Kinase (p90RSK)

The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na+/H+ exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na+/H+ exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK), which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Toward conservational anthropology: addressing anthropocentric bias in anthropology

Anthropological literature addressing conservation and development often blames 'conservationists' as being neo-imperialist in their attempts to institute limits to commercial activities by imposing their post-materialist eco-ideology. The author argues that this view of conservationists is ironic in light of the fact that the very notion of 'development' is arguably an imposition of the (Western) elites. The anthropocentric bias in anthropology also permeates constructivist ethnographies of human-animal 'interactions,' which tend to emphasize the socio-cultural complexity and interconnectivity rather than the unequal and often extractive nature of this 'interaction.' Anthropocentrism is argued to be counteractive to reconciling conservationists' efforts at environmental protection with the traditional ontologies of the interdependency of human-nature relationship

How sulphate-reducing microorganisms cope with stress: lessons from systems biology

Sulphate-reducing microorganisms (SRMs) are a phylogenetically diverse group of anaerobes encompassing distinct physiologies with a broad ecological distribution. As SRMs have important roles in the biogeochemical cycling of carbon, nitrogen, sulphur and various metals, an understanding of how these organisms respond to environmental stresses is of fundamental and practical importance. In this Review, we highlight recent applications of systems biology tools in studying the stress responses of SRMs, particularly Desulfovibrio spp., at the cell, population, community and ecosystem levels. The syntrophic lifestyle of SRMs is also discussed, with a focus on system-level analyses of adaptive mechanisms. Such information is important for understanding the microbiology of the global sulphur cycle and for developing biotechnological applications of SRMs for environmental remediation, energy production, biocorrosion control, wastewater treatment and mineral recovery

SCHOOL-BASED EHEALTH INTERVENTIONS TARGETING MULTIPLE RISK BEHAVIORS AMONG ADOLESCENTS: A SYSTEMATIC REVIEW

BACKGROUND: Lifestyle risk behaviours typically emerge during adolescence, track into adulthood, and commonly co-occur. Interventions targeting multiple risk behaviours in adolescents have the potential to efficiently improve health outcomes, yet further evidence is required to determine their effect. We reviewed the effectiveness of eHealth school-based interventions targeting multiple lifestyle risk behaviours. METHODS: In this systematic review and meta-analysis, we searched Ovid MEDLINE, Embase, PsycINFO, and the Cochrane Library databases between Jan 1, 2000, and March 14, 2019, with no language restrictions, for publications on school-based eHealth multiple health behaviour interventions in humans. We also screened the grey literature for unpublished data. Eligible studies were randomised controlled trials of eHealth (internet, computers, tablets, mobile technology, or tele-health) interventions targeting two or more of six behaviours of interest: alcohol use, smoking, diet, physical activity, sedentary behaviour, and sleep. Primary outcomes of interest were the prevention or reduction of unhealthy behaviours, or improvement in healthy behaviours of the six behaviours. Outcomes were summarised in a narrative synthesis and combined using random-effects meta-analysis. This systematic review is registered with PROSPERO, identifier CRD42017072163. FINDINGS: Of 10 571 identified records, 22 publications assessing 16 interventions were included, comprising 18 873 students, of whom on average 56·2% were female, with a mean age of 13·41 years (SD 1·52). eHealth school-based multiple health behaviour change interventions significantly increased fruit and vegetable intake (standard mean difference 0·11, 95% CI 0·03 to 0·19; p=0·007) and both accelerometer-measured (0·33, 0·05 to 0·61; p=0·02) and self-reported (0·14, 0·05 to 0·23; p=0·003) physical activity, and reduced screen time (-0·09, -0·17 to -0·01; p=0·03) immediately after the intervention; however, these effects were not sustained at follow-up when data were available. No effect was seen for alcohol or smoking, fat or sugar-sweetened beverage or snack consumption. No studies examined sleep or used mobile health interventions. The risk of bias in masking of final outcome assessors and selective outcome reporting was high or unclear across studies and overall we deemd the quality of evidence to be low to very low. INTERPRETATION: eHealth school-based interventions addressing multiple lifestyle risk behaviours can be effective in improving physical activity, screen time, and fruit and vegetable intake. However, effects were small and only evident immediately after the intervention. Further high quality, adolescent-informed research is needed to develop eHealth interventions that can modify multiple behaviours and sustain long-term effects

Early Effects of Smoking Cessation and Weight Gain on Plasma Adiponectin Levels and Insulin Resistance

Background Tobacco smoking is a major risk factor for atherosclerotic and cardiovascular disease. Studies have found evidence that smoking cessation is associated with weight gain, which is itself a leading cause of cardiovascular disease. Aim The present study sought to determine how smoking cessation and associated weight gain affect adiponectin levels and insulin resistance. Methods Fifty-two male habitual smokers were treated for 2 months with transdermal nicotine patches, and the 28 subjects who successfully quit smoking were analyzed. Subjects were divided into two sub-groups according to their weight change: weight maintainers and weight gainers. Serum adiponectin levels and the homeostasis model assessment ratio (HOMA-R) were evaluated at the beginning of the study, and at 1 week and 9 weeks after cessation of patch use. Results In weight gainers (n=18), serum adiponection levels tended to increase at 1 week after the end of treatment (mean difference 0.4±1.0 μg/mL, p=0.08). Moreover, after 9 weeks, adiponectin levels were significantly decreased in weight gainers (mean difference between 1 week and 9 weeks 0.8±0.9 μg/mL, p=0.002). In weight maintainers, adiponectin levels increased slightly after smoking cessation, but changes were not significant. In weight gainers, HOMA-R index was significantly increased (mean difference between baseline and 9 weeks 0.4±0.7, p=0.01), while in weight maintainers, HOMA-R index showed no differences throughout the study. Conclusion Our findings suggest that the adverse effects of weight gain attenuate some of the beneficial effects of smoking cessation