Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

A Bayesian micro-simulation to evaluate the cost-effectiveness of interventions for mastitis control during the dry period in UK dairy herds

Importance of the dry period with respect to mastitis control is now well established although the precise interventions that reduce the risk of acquiring intramammary infections during this time are not clearly understood. There are very few intervention studies that have measured the clinical efficacy of specific mastitis interventions within a cost-effectiveness framework so there remains a large degree of uncertainty about the impact of a specific intervention and its costeffectiveness. The aim of this study was to use a Bayesian framework to investigate the cost-effectiveness of mastitis controls during the dry period. Data were assimilated from 77 UK dairy farms that participated in a British national mastitis control programme during 2009–2012 in which the majority of intramammary infections were acquired during the dry period. The data consisted of clinical mastitis (CM) and somatic cell count (SCC) records, herd management practices and details of interventions that were implemented by the farmer as part of the control plan. The outcomes used to measure the effectiveness of the interventions were i) changes in the incidence rate of clinical mastitis during the first 30 days after calving and ii) the rate at which cows gained new infections during the dry period (measured by SCC changes across the dry period from 200,000 cells/ml). A Bayesian one-step microsimulation model was constructed such that posterior predictions from the model incorporated uncertainty in all parameters. The incremental net benefit was calculated across 10,000 Markov chain Monte Carlo iterations, to estimate the cost-benefit (and associated uncertainty) of each mastitis intervention. Interventions identified as being cost-effective in most circumstances included selecting dry-cow therapy at the cow level, dry-cow rations formulated by a qualified nutritionist, use of individual calving pens, first milking cows within 24 h of calving and spreading bedding evenly in dry-cow yards. The results of this study highlighted the efficacy of specific mastitis interventions in UK conditions which, when incorporated into a costeffectiveness framework, can be used to optimize decision making in mastitis control. This intervention study provides an example of how an intuitive and clinically useful Bayesian approach can be used to form the basis of an on-farm decision support tool

Bacteriological etiology and treatment of mastitis in Finnish dairy herds

Background: The Finnish dairy herd recording system maintains production and health records of cows and herds. Veterinarians and farmers register veterinary treatments in the system. Milk samples for microbiological analysis are routinely taken from mastitic cows. The laboratory of the largest dairy company in Finland, Valio Ltd., analyzes most samples using real-time PCR. This study addressed pathogen-specific microbiological data and treatment and culling records, in combination with cow and herd characteristics, from the Finnish dairy herd recording system during 2010-2012. Results: The data derived from 240,067 quarter milk samples from 93,529 dairy cows with mastitis; 238,235 cows from the same herds served as the control group. No target pathogen DNA was detected in 12% of the samples. In 49% of the positive samples, only one target species and in 19%, two species with one dominant species were present. The most common species in the samples with a single species only were coagulase-negative staphylococci (CNS) (43%), followed by Staphylococcus aureus (21%), Streptococcus uberis (9%), Streptococcus dysgalactiae (8%), Corynebacterium bovis (7%), and Escherichia coli (5%). On average, 36% of the study cows and 6% of the control cows had recorded mastitis treatments during lactation. The corresponding proportions were 16 and 6% at drying-off. For more than 75% of the treatments during lactation, diagnosis was acute clinical mastitis. In the milk samples from cows with a recorded mastitis treatment during lactation, CNS and S. aureus were most common, followed by streptococci. Altogether, 48% of the cows were culled during the study. Mastitis was reported as the most common reason to cull; 49% of study cows and 18% of control cows were culled because of mastitis. Culling was most likely if S. aureus was detected in the milk sample submitted during the culling year. Conclusions: The PCR test has proven to be an applicable method also for large-scale use in bacterial diagnostics. In the present study, microbiological diagnosis was unequivocal in the great majority of samples where a single species or two species with one dominating were detected. Coagulase-negative staphylococci and S. aureus were the most common species. S. aureus was also the most common pathogen among the culled cows, which emphasizes the importance of preventive measures.Peer reviewe

Insights into udder health and intramammary antibiotic usage on Irish dairy farms during 2003-2010

By international standards, Ireland is a relatively small dairy producer. However, the industry plays a critical role to the national economy, accounting for approximately 3% of national gross domestic product. This paper presents insights into udder health and intramammary antibiotic usage on Irish dairy farms during 2003-2010, based on data from several sources. Three data sources were used, including data on milk recording data, intramammary antibiotic sales and animal health assessment. The milk recording data included a single unadjusted herd-level somatic cell count (SCC) value for each herd at each milk recording, being the arithmetic mean of cow-level SCC of each cow at that recording, weighted by cow-level yield. These data were used to calculate the percentage of herds each month where the unadjusted herd SCC exceeded 200,000 and 400,000 cells/mL. Two logistic generalised estimating-equations (GEE) models were developed, the outcome variable being either the probability that the monthly SCC of a herd was greater than 400,000 cells/mL or less than or equal to 200,000 cells/mL. Spring herds had a lower probability of a high SCC (> 400,000 cells/mL) during February to October compared to non-Spring herds but a higher probability between November to January. The odds of a high SCC were greater in 2005, 2006, 2009 and 2010 but less in 2007 and 2008 compared to 2004. Smaller herds had higher odds of having a high SCC compared to larger herds. We present the number of intramammary tubes and the quantity of active substance (kg) sold annually in Ireland during 2003-2010. We infer an incidence of clinical mastitis of 54.0 cases per 100 cow-years at risk, assuming 4 tubes per treatment regime, one affected quarter per cow, tubes restricted to clinical cases only and 100% of treated cases considered new cases, based on data collected on sales of in-lactation intra-mammary antibiotics. With differing assumptions, this estimate varied between 25.8 and 77.0 cases per 100 cow-years at risk. Using data on sales of dry cow therapy intra-mammary antibiotics, we also infer that most Irish dairy farmers use blanket dry cow therapy. It is important that Ireland has an objective understanding of current levels of udder health, to facilitate benchmarking and improvement into the future. Udder health is a concern on a number of Irish dairy farms. High SCC results were present throughout the year, but more marked towards the start and end of each milking season. Animal Health Ireland recently commenced a major national programme, CellCheck, in collaboration with a broad range of stakeholders, to support national SCC improvement. In this paper, relevant European and national legislation is also reviewed

Mastitis diagnostics and performance monitoring: a practical approach

In this paper a review is given of frequently used mastitis diagnostic methods in modern dairy practice. Methods used at the quarter, cow, herd and regional or national level are discussed, including their usability for performance monitoring in udder health. Future developments, such as systems in which milk-derived parameters are combined with modern analytical techniques, are discussed. It is concluded that, although much knowledge is available and science is still developing and much knowledge is available, it is not always fully exploited in practice