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

Designing a physical activity parenting course : parental views on recruitment, content and delivery

Background Many children do not engage in sufficient levels of physical activity (PA) and spend too much time screen-viewing (SV). High levels of SV (e.g. watching TV, playing video games and surfing the internet) and low levels of PA have been associated with adverse health outcomes. Parenting courses may hold promise as an intervention medium to change children’s PA and SV. The current study was formative work conducted to design a new parenting programme to increase children’s PA and reduce their SV. Specifically, we focussed on interest in a course, desired content and delivery style, barriers and facilitators to participation and opinions on control group provision. Methods In-depth telephone interviews were conducted with thirty two parents (29 female) of 6–8 year olds. Data were analysed thematically. An anonymous online survey was also completed by 750 parents of 6–8 year old children and descriptive statistics calculated. Results Interview participants were interested in a parenting course because they wanted general parenting advice and ideas to help their children be physically active. Parents indicated that they would benefit from knowing how to quantify their child’s PA and SV levels. Parents wanted practical ideas of alternatives to SV. Most parents would be unable to attend unless childcare was provided. Schools were perceived to be a trusted source of information about parenting courses and the optimal recruitment location. In terms of delivery style, the majority of parents stated they would prefer a group-based approach that provided opportunities for peer learning and support with professional input. Survey participants reported the timing of classes and the provision of childcare were essential factors that would affect participation. In terms of designing an intervention, the most preferred control group option was the opportunity to attend the same course at a later date. Conclusions Parents are interested in PA/SV parenting courses but the provision of child care is essential for attendance. Recruitment is likely to be facilitated via trusted sources. Parents want practical advice on how to overcome barriers and suggest advice is provided in a mutually supportive group experience with expert input

Aneuploidy in pluripotent stem cells and implications for cancerous transformation

Owing to a unique set of attributes, human pluripotent stem cells (hPSCs) have emerged as a promising cell source for regenerative medicine, disease modeling and drug discovery. Assurance of genetic stability over long term maintenance of hPSCs is pivotal in this endeavor, but hPSCs can adapt to life in culture by acquiring non-random genetic changes that render them more robust and easier to grow. In separate studies between 12.5% and 34% of hPSC lines were found to acquire chromosome abnormalities over time, with the incidence increasing with passage number. The predominant genetic changes found in hPSC lines involve changes in chromosome number and structure (particularly of chromosomes 1, 12, 17 and 20), reminiscent of the changes observed in cancer cells. In this review, we summarize current knowledge on the causes and consequences of aneuploidy in hPSCs and highlight the potential links with genetic changes observed in human cancers and early embryos. We point to the need for comprehensive characterization of mechanisms underpinning both the acquisition of chromosomal abnormalities and selection pressures, which allow mutations to persist in hPSC cultures. Elucidation of these mechanisms will help to design culture conditions that minimize the appearance of aneuploid hPSCs. Moreover, aneuploidy in hPSCs may provide a unique platform to analyse the driving forces behind the genome evolution that may eventually lead to cancerous transformation

SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair

The research leading to these results is supported by Cancer Research UK (XYG, RAB, EG, PM, PE, SG, C Santos, AJR, NM, PAB, AS and C Swanton), Breast Cancer Research Foundation (C Swanton and NK), Medical Research Council (ID: G0902275 to MG and C Santos; ID: G0701935/2 to AJR and C Swanton), the Danish Cancer Society (AMM, J Bartkova and J Bartek), the Lundbeck Foundation (R93-A8990 to J Bartek), the Ministry of the interior of the Czech Republic (grant VG20102014001 to MM and J Bartek), the National Program of Sustainability (grant LO1304 to MM and J Bartek), the Danish Council for Independent Research (grant DFF-1331-00262 to J Bartek), NIHR RMH/ICR Biomedical Research Centre for Cancer (JL), the EC Framework 7 (PREDICT 259303 to XYG, EG, PM, MG, TJ and C Swanton; DDResponse 259892 to J Bartek and J Bartkova and RESPONSIFY ID:259303 to C Swanton), UCL Overseas Research Scholarship (SG). C Swanton is also supported by the European Research Council, Rosetrees Trust and The Prostate Cancer Foundation. This research is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Hepatitis C infection: eligibility for antiviral therapies

peer reviewedBackground Current treatments of chronic hepatitis C virus (HCV) are effective, but expensive and susceptible to induce significant side effects. Objectives To evaluate the proportion of HCV patients who are eligible for a treatment. Methods In a database comprising 1726 viraemic HCV patients, the files of 299 patients who presented to the same hepatologist for an initial appointment between 1996 and 2003 were reviewed. Results Patients' characteristics were age 43.1 +/- 15.6 years, 53% male and 92% Caucasian. The main risk factors were transfusion (43%) and drug use (22%). Genotypes were mostly genotype 1 (66%), genotype 3 (12%) and genotype 2 (10%). These characteristics were not different from those of the whole series of 1726 patients. A total of 176 patients (59%) were not treated, the reasons for non-treatment being medical contraindications (34%), non-compliance (25%) and normal transaminases (24%). In addition, 17% of patients declined therapy despite being considered as eligible, mainly due to fear of adverse events. Medical contraindications were psychiatric (27%), age (22%), end-stage liver disease (15%), willingness for pregnancy (13%), cardiac contraindication (7%) and others (16%). Only 123 patients (41%) were treated. A sustained viral response was observed in 41%. The treatment was interrupted in 16% for adverse events. Conclusions The majority of HCV patients are not eligible for treatment. This implies that, with current therapies, only 17% of patients referred for chronic HCV become sustained responders. Some modifications of guidelines could extend the rate of treatment (patients with normal transaminases), but an important barrier remains the patients' and the doctors' fear of adverse events

Assessment on the ownership and use of mosquito nets in Mozambique

ABSTRACT OBJECTIVE To assess the ownership and use of mosquito nets in 2014, in Mozambique. METHODS This observational and cross-sectional study assessed, in February and March 2015, 69 districts (nine of 11 provinces of Mozambique) that have benefited from the mass distribution of mosquito nets. The Lot Quality Assurance Sampling methodology was used. Each locality was denominated supervision area. The Lot Quality Assurance Sampling opts for a minimum of 19 households (in this case, we decided for a minimum of 100 households per district) from each supervision area to assess an indicator (in this case, two indicators were assessed: ownership and use of mosquito nets). Two questions guided the research: a) received a mosquito net; b) used a mosquito net the night before. RESULTS A total of 6,725 households were assessed. Eighty three percent of them had received mosquito nets in the campaign. Of the 6,232 respondents, 82.0% said they used mosquito nets the night before. The districts of the provinces with low coverage of ownership and use were Tete (69.5% and 60.0%, respectively), Zambezia (79.0% and 60.0%, respectively), and Gaza (81.6% and 70.7%, respectively). The largest coverage of ownership and use were observed in the districts of Nampula (96.7% and 93.8%, respectively) and Niassa (86.0% and 85.4% respectively). CONCLUSIONS In the districts assessed, the progression of ownership and use of mosquito nets is satisfactory. Nampula and Niassa are the only provinces where ownership and use are at desired levels

Medication knowledge, certainty, and risk of errors in health care: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Medication errors are often involved in reported adverse events. Drug therapy, prescribed by physicians, is mostly carried out by nurses, who are expected to master all aspects of medication. Research has revealed the need for improved knowledge in drug dose calculation, and medication knowledge as a whole is poorly investigated. The purpose of this survey was to study registered nurses' medication knowledge, certainty and estimated risk of errors, and to explore factors associated with good results.</p> <p>Methods</p> <p>Nurses from hospitals and primary health care establishments were invited to carry out a multiple-choice test in pharmacology, drug management and drug dose calculations (score range 0-14). Self-estimated certainty in each answer was recorded, graded from 0 = very uncertain to 3 = very certain. Background characteristics and sense of coping were recorded. Risk of error was estimated by combining knowledge and certainty scores. The results are presented as mean (±SD).</p> <p>Results</p> <p>Two-hundred and three registered nurses participated (including 16 males), aged 42.0 (9.3) years with a working experience of 12.4 (9.2) years. Knowledge scores in pharmacology, drug management and drug dose calculations were 10.3 (1.6), 7.5 (1.6), and 11.2 (2.0), respectively, and certainty scores were 1.8 (0.4), 1.9 (0.5), and 2.0 (0.6), respectively. Fifteen percent of the total answers showed a high risk of error, with 25% in drug management. Independent factors associated with high medication knowledge were working in hospitals (p < 0.001), postgraduate specialization (p = 0.01) and completion of courses in drug management (p < 0.01).</p> <p>Conclusions</p> <p>Medication knowledge was found to be unsatisfactory among practicing nurses, with a significant risk for medication errors. The study revealed a need to improve the nurses' basic knowledge, especially when referring to drug management.</p

Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin-dependent protein kinase II.

Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones

Identifying older diabetic patients at risk of poor glycemic control

BACKGROUND: Optimal glycemic control prevents the onset of diabetes complications. Identifying diabetic patients at risk of poor glycemic control could help promoting dedicated interventions. The purpose of this study was to identify predictors of poor short-term and long-term glycemic control in older diabetic in-patients. METHODS: A total of 1354 older diabetic in-patients consecutively enrolled in a multicenter study formed the training population (retrospective arm); 264 patients consecutively admitted to a ward of general medicine formed the testing population (prospective arm). Glycated hemoglobin (HbA1c) was measured on admission and one year after the discharge in the testing population. Independent correlates of a discharge glycemia ≥ 140 mg/dl in the training population were assessed by logistic regression analysis and a clinical prediction rule was developed. The ability of the prediction rule and that of admission HbA1c to predict discharge glycemia ≥ 140 mg/dl and HbA1c > 7% one year after discharge was assessed in the testing population. RESULTS: Selected admission variables (diastolic arterial pressure < 80 mmHg, glycemia = 143–218 mg/dl, glycemia > 218 mg/dl, history of insulinic or combined hypoglycemic therapy, Charlson's index > 2) were combined to obtain a score predicting a discharge fasting glycemia ≥ 140 mg/dl in the training population. A modified score was obtained by adding 1 if admission HbA1c exceeded 7.8%. The modified score was the best predictor of both discharge glycemia ≥ 140 mg/dl (sensitivity = 79%, specificity = 63%) and 1 year HbA1c > 7% (sensitivity = 72%, specificity = 71%) in the testing population. CONCLUSION: A simple clinical prediction rule might help identify older diabetic in-patients at risk of both short and long term poor glycemic control