Oncometabolites:linking altered metabolism with cancer

The discovery of cancer-associated mutations in genes encoding key metabolic enzymes has provided a direct link between altered metabolism and cancer. Advances in mass spectrometry and nuclear magnetic resonance technologies have facilitated high-resolution metabolite profiling of cells and tumors and identified the accumulation of metabolites associated with specific gene defects. Here we review the potential roles of such "oncometabolites" in tumor evolution and as clinical biomarkers for the detection of cancers characterized by metabolic dysregulation

Vaccine safety issues at the turn of the 21st century

Global gains in vaccination coverage during the early 21st century have been threatened by the emergence of antivaccination groups that have questioned the effectiveness of vaccines to generate public distrust of vaccines and immunisation programmes. This manuscript summarises six key topics that have been at the centre of global discussions on vaccine safety during the early 21st century: thiomersal in multi-dose non-live vaccines, aluminium adjuvants used with several non-live vaccines, autism and auto-immune conditions as possible consequences of vaccination, a risk of immune overload with increasing numbers of vaccinations, and detrimental non-specific effects (NSEs) of vaccination. For each topic, we describe the hypothesis behind the public concern, the evidence reviewed by the WHO's Global Advisory Committee for Vaccine Safety (GACVS) during 1999-2019, and any significant new data that has emerged since GACVS conclusions were made. Although the scientific evidence on these issues overwhelmingly supports the safety of vaccines, communication messages to caregivers and providers need to condense and convey scientific information in an appropriate way to address concerns contributing to vaccine distrust. In addition, there is need for further studies specifically designed to address both positive and negative NSE of vaccination. The role of GACVS will be increasingly important in evaluating the evidence and engaging the global community in promoting and assuring the safety of vaccines in the decades to come as we move into an era in which we use new vaccination platforms, antigens and formulations

Off-Label Use of Transmucosal Ketamine as a Rapidacting Antidepressant: A Retrospective Chart Review

Objective: This study evaluated the effectiveness and safety of subanesthetic doses of ketamine using an off-label, transmucosal administration route in patients with treatment-resistant depression. Methods: A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant major depressive disorder. Seventeen such patients who received subanesthetic doses of ketamine were included. Patient demographics, efficacy (drug refill, clinician notes), side effects, and concurrent medications were assessed. Results: Benefit from low-dose transmucosal ketamine was noted in 76% of subjects (average age 48 years, 88% female), with a dose duration lasting 7–14 days. No notable side effects were noted. The most common classes of concurrent medications to which ketamine was added were serotonin–norepinephrine reuptake inhibitors (59%), stimulants (47%), folate replacement (47%), and benzodiazepines (47%). Conclusion: Our results provide preliminary evidence of the effectiveness and safety of lowdose transmucosal ketamine in treatment-resistant patients. A controlled, prospective pilot study is warranted to validate these findings

The emerging role of fumarate as an oncometabolite

The drive to understand how altered cellular metabolism and cancer are linked has caused a paradigm shift in the focus of cancer research. The discovery of a mutated metabolic enzyme, isocitrate dehydrogenase 1 (IDH1), that leads to accumulation of the oncometabolite 2-hydroxyglutarate, provided significant direct evidence that dysfunctional metabolism plays an important role in oncogenesis. Striking parallels exist with the Krebs cycle enzyme fumarate hydratase (FH), a tumour suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumours. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. Interestingly, our studies have questioned the role of HIF and have highlighted other candidate mechanisms, in particular the non-enzymatic modification of cysteine residues (succination) that could lead to disruption or loss of protein functions, dysfunctional cell metabolism and cell signalling. Here we discuss the evidence for proposing fumarate as an oncometabolite

A cross-sectional study of determinants of indoor environmental exposures in households with and without chronic exposure to biomass fuel smoke

BACKGROUND: Burning biomass fuels indoors for cooking is associated with high concentrations of particulate matter (PM) and carbon monoxide (CO). More efficient biomass-burning stoves and chimneys for ventilation have been proposed as solutions to reduce indoor pollution. We sought to quantify indoor PM and CO exposures in urban and rural households and determine factors associated with higher exposures. A secondary objective was to identify chronic vs. acute changes in cardiopulmonary biomarkers associated with exposure to biomass smoke. METHODS: We conducted a census survey followed by a cross-sectional study of indoor environmental exposures and cardiopulmonary biomarkers in the main household cook in Puno, Peru. We measured 24-hour indoor PM and CO concentrations in 86 households. We also measured PM(2.5) and PM(10) concentrations gravimetrically for 24 hours in urban households and during cook times in rural households, and generated a calibration equation using PM(2.5) measurements. RESULTS: In a census of 4903 households, 93% vs. 16% of rural vs. urban households used an open-fire stove; 22% of rural households had a homemade chimney; and <3% of rural households participated in a national program encouraging installation of a chimney. Median 24-hour indoor PM(2.5) and CO concentrations were 130 vs. 22 μg/m(3) and 5.8 vs. 0.4 ppm (all p<0.001) in rural vs. urban households. Having a chimney did not significantly reduce median concentrations in 24-hour indoor PM(2.5) (119 vs. 137 μg/m(3); p=0.40) or CO (4.6 vs. 7.2 ppm; p=0.23) among rural households with and without chimneys. Having a chimney did not significantly reduce median cook-time PM(2.5) (360 vs. 298 μg/m(3), p=0.45) or cook-time CO concentrations (15.2 vs. 9.4 ppm, p=0.23). Having a thatched roof (p=0.007) and hours spent cooking (p=0.02) were associated with higher 24-hour average PM concentrations. Rural participants had higher median exhaled CO (10 vs. 6 ppm; p=0.01) and exhaled carboxyhemoglobin (1.6% vs. 1.0%; p=0.04) than urban participants. CONCLUSIONS: Indoor air concentrations associated with biomass smoke were six-fold greater in rural vs. urban households. Having a homemade chimney did not reduce environmental exposures significantly. Measures of exhaled CO provide useful cardiopulmonary biomarkers for chronic exposure to biomass smoke

Cognitive representations of disability behaviours in people with mobility limitations : consistency with theoretical constructs

Disability is conceptualised as behaviour by psychological theory and as a result of bodily impairment by medical models. However, how people with disabilities conceptualise those disabilities is unclear. The purpose of this study was to examine disability representations in people with mobility disabilities. Thirteen people with mobility disabilities completed personal repertory grids (using the method of triads) applied to activities used to measure disabilities. Ten judges with expertise in health psychology then examined the correspondence between the elicited disability constructs and psychological and medical models of disability. Participants with mobility disabilities generated 73 personal constructs ofdisability. These constructs were judged consistent with the content of two psychological models, namely the theory of planned behaviour and social cognitive theory and with the main medical model of disability, the International Classification of Functioning Disability and Health.Individuals with activity limitations conceptualise activities in a manner that is compatible with both psychological and medical models. This ensures adequate communication in contexts where the medical model is relevant, e.g. clinical contexts, as well as in everyday conversation about activities and behaviours. Finally, integrated models of disability may be of value for theory driven interdisciplinary approaches to disability and rehabilitation

Human AlkB Homologue 5 Is a Nuclear 2-Oxoglutarate Dependent Oxygenase and a Direct Target of Hypoxia-Inducible Factor 1α (HIF-1α)

Human 2-oxoglutarate oxygenases catalyse a range of biological oxidations including the demethylation of histone and nucleic acid substrates and the hydroxylation of proteins and small molecules. Some of these processes are centrally involved in regulation of cellular responses to hypoxia. The ALKBH proteins are a sub-family of 2OG oxygenases that are defined by homology to the Escherichia coli DNA-methylation repair enzyme AlkB. Here we report evidence that ALKBH5 is probably unique amongst the ALKBH genes in being a direct transcriptional target of hypoxia inducible factor-1 (HIF-1) and is induced by hypoxia in a range of cell types. We show that purified recombinant ALKBH5 is a bona fide 2OG oxygenase that catalyses the decarboxylation of 2OG but appears to have different prime substrate requirements from those so far defined for other ALKBH family members. Our findings define a new class of HIF-transcriptional target gene and suggest that ALKBH5 may have a role in the regulation of cellular responses to hypoxia

Leading-effect vs. Risk-taking in Dynamic Tournaments: Evidence from a Real-life Randomized Experiment

Two 'order effects' may emerge in dynamic tournaments with information feedback. First, participants adjust effort across stages, which could advantage the leading participant who faces a larger 'effective prize' after an initial victory (leading-effect). Second, participants lagging behind may increase risk at the final stage as they have 'nothing to lose' (risk-taking). We use a randomized natural experiment in professional two-game soccer tournaments where the treatment (order of a stage-specific advantage) and team characteristics, e.g. ability, are independent. We develop an identification strategy to test for leading-effects controlling for risk-taking. We find no evidence of leading-effects and negligible risk-taking effects

The ball in play demands of international rugby union

Objectives: Rugby union is a high intensity intermittent sport, typically analysed via set time periods or rolling average methods. This study reports the demands of international rugby union via global positioning system (GPS) metrics expressed as mean ball in play (BiP), maximum BiP (max BiP), and whole match outputs. Design: Single cohort cross sectional study involving 22 international players, categorised as forwards and backs. Methods: A total of 88 GPS files from eight international test matches were collected during 2016. An Opta sportscode timeline was integrated into the GPS software to split the data into BiP periods. Metres per min (m.min-1), high metabolic load per min (HML), accelerations per min (Acc), high speed running per min (HSR), and collisions per min (Coll) were expressed relative to BiP periods and over the whole match (>60min). Results: Whole match metrics were significantly lower than all BiP metrics (p < 0.001). Mean and max BiP HML, (p < 0.01) and HSR (p < 0.05) were significantly higher for backs versus forwards, whereas Coll were significantly higher for forwards (p < 0.001). In plays lasting 61s or greater, max BiP m.min-1 were higher for backs. Max BiP m.min-1, HML, HSR and Coll were all time dependant (p < 0.05) showing that both movement metrics and collision demands differ as length of play continues. Conclusions: This study uses a novel method of accurately assessing the BiP demands of rugby union. It also reports typical and maximal demands of international rugby union that can be used by practitioners and scientists to target training of worst-case scenario's equivalent to international intensity. Backs covered greater distances at higher speeds and demonstrated higher HML, in general play as well as 'worst case scenarios'; conversely forwards perform a higher number of collisions