Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients

Plasma triglyceride concentrations are rapidly reduced following individual bouts of endurance exercise in women

It is known that chronic endurance training leads to improvements in the lipoprotein profile, but less is known about changes that occur during postexercise recovery acutely. We analyzed triglyceride (TG), cholesterol classes and apolipoproteins in samples collected before, during and after individual moderate- and hard-intensity exercise sessions in men and women that were isoenergetic between intensities. Young healthy men (n = 9) and young healthy women (n = 9) were studied under three different conditions with diet unchanged between trials: (1) before, during and 3 h after 90 min of exercise at 45% VO2peak (E45); (2) before, during and 3 h after 60 min of exercise at 65% VO2peak (E65), and (3) in a time-matched sedentary control trial (C). At baseline, high-density lipoprotein cholesterol (HDL-C) was higher in women than men (P < 0.05). In men and in women, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and LDL peak particle size were unaltered by exercise either during exertion or after 3 h of recovery. In women, but not in men, average plasma TG was significantly reduced below C at 3 h postexercise by approximately 15% in E45 and 25% in E65 (P < 0.05) with no significant difference between exercise intensities. In summary, plasma TG concentration rapidly declines following exercise in women, but not in men. These results demonstrate an important mechanism by which each individual exercise session may incrementally reduce the risk for cardiovascular disease (CVD) in women

New Zealand blackcurrant extract enhances fat oxidation during prolonged cycling in endurance-trained females.

PURPOSE: New Zealand blackcurrant (NZBC) extract has previously been shown to increase fat oxidation during prolonged exercise, but this observation is limited to males. We examined whether NZBC intake also increases fat oxidation during prolonged exercise in females, and whether this was related to greater concentrations of circulating fatty acids. METHODS: In a randomised, crossover, double-blind design, 16 endurance-trained females (age: 28 ± 8 years, BMI: 21.3 ± 2.1 kg·m-2, VO2max: 43.7 ± 1.1 ml·kg-1·min-1) ingested 600 mg·day-1NZBC extract (CurraNZ™) or placebo (600 mg·day-1microcrystalline cellulose) for 7 days. On day 7, participants performed 120 min cycling at 65% VO2max, using online expired air sampling with blood samples collected at baseline and at 15 min intervals throughout exercise for analysis of glucose, NEFA and glycerol. RESULTS: NZBC extract increased mean fat oxidation by 27% during 120 min moderate-intensity cycling compared to placebo (P = 0.042), and mean carbohydrate oxidation tended to be lower (P = 0.063). Pre-exercise, plasma NEFA (P = 0.034) and glycerol (P = 0.051) concentrations were greater following NZBC intake, although there was no difference between conditions in the exercise-induced increase in plasma NEFA and glycerol concentrations (P > 0.05). Mean fat oxidation during exercise was moderately associated with pre-exercise plasma NEFA concentrations (r = 0.45, P = 0.016). CONCLUSIONS: Intake of NZBC extract for 7 days elevated resting concentrations of plasma NEFA and glycerol, indicative of higher lipolytic rates, and this may underpin the observed increase in fat oxidation during prolonged cycling in endurance-trained females

Juggling to find balance: hearing the voices of undergraduate student nurses.

BACKGROUND: Accounts of stress are common among students on nursing programmes. Prolonged high levels of stress can contribute to poor learning, the development of detrimental health behaviours, attrition and burnout. AIMS: To examine the health and wellbeing implications of undertaking a BSc nursing degree in the UK for first-year students. METHODS: Qualitative narrative analysis of 100 written student reflections on the influences on their health and wellbeing was undertaken. FINDINGS: Nursing students must juggle multiple competing demands on their physical capabilities, personal resources, income and time. Students are constantly seeking to achieve balance and personal equilibrium through the use of a variety of coping strategies. CONCLUSION: This work calls upon the profession, the nursing regulator, nursing programmes within higher education institutions and health Trusts to review the framework and content of undergraduate BSc nurse education. Programme requirements should enhance the health and wellbeing of students while simultaneously delivering education and practice opportunities necessary to meet professional requirements

Optimizing a Massive Parallel Sequencing Workflow for Quantitative miRNA Expression Analysis

BACKGROUND: Massive Parallel Sequencing methods (MPS) can extend and improve the knowledge obtained by conventional microarray technology, both for mRNAs and short non-coding RNAs, e.g. miRNAs. The processing methods used to extract and interpret the information are an important aspect of dealing with the vast amounts of data generated from short read sequencing. Although the number of computational tools for MPS data analysis is constantly growing, their strengths and weaknesses as part of a complex analytical pipe-line have not yet been well investigated. PRIMARY FINDINGS: A benchmark MPS miRNA dataset, resembling a situation in which miRNAs are spiked in biological replication experiments was assembled by merging a publicly available MPS spike-in miRNAs data set with MPS data derived from healthy donor peripheral blood mononuclear cells. Using this data set we observed that short reads counts estimation is strongly under estimated in case of duplicates miRNAs, if whole genome is used as reference. Furthermore, the sensitivity of miRNAs detection is strongly dependent by the primary tool used in the analysis. Within the six aligners tested, specifically devoted to miRNA detection, SHRiMP and MicroRazerS show the highest sensitivity. Differential expression estimation is quite efficient. Within the five tools investigated, two of them (DESseq, baySeq) show a very good specificity and sensitivity in the detection of differential expression. CONCLUSIONS: The results provided by our analysis allow the definition of a clear and simple analytical optimized workflow for miRNAs digital quantitative analysis

Cationic polyamines inhibit anthrax lethal factor protease

BACKGROUND: Anthrax is a human disease that results from infection by the bacteria, Bacillus anthracis and has recently been used as a bioterrorist agent. Historically, this disease was associated with Bacillus spore exposure from wool or animal carcasses. While current vaccine approaches (targeted against the protective antigen) are effective for prophylaxis, multiple doses must be injected. Common antibiotics that block the germination process are effective but must be administered early in the infection cycle. In addition, new therapeutics are needed to specifically target the proteolytic activity of lethal factor (LF) associated with this bacterial infection. RESULTS: Using a fluorescence-based assay to identify and characterize inhibitors of anthrax lethal factor protease activity, we identified several chemically-distinct classes of inhibitory molecules including polyamines, aminoglycosides and cationic peptides. In these studies, spermine was demonstrated for the first time to inhibit anthrax LF with a K(i )value of 0.9 ± 0.09 μM (mean ± SEM; n = 3). Additional linear polyamines were also active as LF inhibitors with lower potencies. CONCLUSION: Based upon the studies reported herein, we chose linear polyamines related to spermine as potential lead optimization candidates and additional testing in cell-based models where cell penetration could be studied. During our screening process, we reproducibly demonstrated that the potencies of certain compounds, including neomycin but not neamine or spermine, were different depending upon the presence or absence of nucleic acids. Differential sensitivity to the presence/absence of nucleic acids may be an additional point to consider when comparing various classes of active compounds for lead optimization

Histopathology of Growth Anomaly Affecting the Coral, Montipora capitata: Implications on Biological Functions and Population Viability

Growth anomalies (GAs) affect the coral, Montipora capitata, at Wai'ōpae, southeast Hawai'i Island. Our histopathological analysis of this disease revealed that the GA tissue undergoes changes which compromise anatomical machinery for biological functions such as defense, feeding, digestion, and reproduction. GA tissue exhibited significant reductions in density of ova (66.1–93.7%), symbiotic dinoflagellates (38.8–67.5%), mesenterial filaments (11.2–29.0%), and nematocytes (28.8–46.0%). Hyperplasia of the basal body wall but no abnormal levels of necrosis and algal or fungal invasion was found in GA tissue. Skeletal density along the basal body wall was significantly reduced in GAs compared to healthy or unaffected sections. The reductions in density of the above histological features in GA tissue were collated with disease severity data to quantify the impact of this disease at the colony and population level. Resulting calculations showed this disease reduces the fecundity of M. capitata colonies at Wai'ōpae by 0.7–49.6%, depending on GA severity, and the overall population fecundity by 2.41±0.29%. In sum, GA in this M. capitata population reduces the coral's critical biological functions and increases susceptibility to erosion, clearly defining itself as a disease and an ecological threat

Women Have Higher Protein Content of β-Oxidation Enzymes in Skeletal Muscle than Men

It is well recognized that compared with men, women have better ultra-endurance capacity, oxidize more fat during endurance exercise, and are more resistant to fat oxidation defects i.e. diet-induced insulin resistance. Several groups have shown that the mRNA and protein transcribed and translated from genes related to transport of fatty acids into the muscle are greater in women than men; however, the mechanism(s) for the observed sex differences in fat oxidation remains to be determined. Muscle biopsies from the vastus lateralis were obtained from moderately active men (N = 12) and women (N = 11) at rest to examine mRNA and protein content of genes involved in lipid oxidation. Our results show that women have significantly higher protein content for tri-functional protein alpha (TFPα), very long chain acyl-CoA dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) (P<0.05). There was no significant sex difference in the expression of short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), or peroxisome proliferator activated receptor alpha (PPARα), or PPARγ, genes potentially involved in the transcriptional regulation of lipid metabolism. In conclusion, women have more protein content of the major enzymes involved in long and medium chain fatty acid oxidation which could account for the observed differences in fat oxidation during exercise

Gender Differences in Carbohydrate Metabolism and Carbohydrate Loading

Prior to endurance competition, many endurance athletes participate in a carbohydrate loading regimen in order to help delay the onset of fatigue. The "classic" regimen generally includes an intense glycogen depleting training period of approximately two days followed by a glycogen loading period for 3–4 days, ingesting approximately 60–70% of total energy intake as carbohydrates, while the newer method does not consist of an intense glycogen depletion protocol. However, recent evidence has indicated that glycogen loading does not occur in the same manner for males and females, thus affecting performance. The scope of this literature review will include a brief description of the role of estradiol in relation to metabolism and gender differences seen in carbohydrate metabolism and loading

Continuous low- to moderate-intensity exercise training is as effective as moderate- to high-intensity exercise training at lowering blood HbA1c in obese type 2 diabetes patients

Aims/hypothesis: Exercise represents an effective interventional strategy to improve glycaemic control in type 2 diabetes patients. However, the impact of exercise intensity on the benefits of exercise training remains to be established. In the present study, we compared the clinical benefits of 6 months of continuous low- to moderate-intensity exercise training with those of continuous moderate- to high-intensity exercise training, matched for energy expenditure, in obese type 2 diabetes patients. Methods: Fifty male obese type 2 diabetes patients (age 59∈±∈8 years, BMI 32∈± ∈4 kg/m2) participated in a 6 month continuous endurance-type exercise training programme. All participants performed three supervised exercise sessions per week, either 55 min at 50% of whole body peak oxygen uptake left(VO2peak) (low to moderate intensity) or 40 min at 75% of VO2peak (moderate to high intensity). Oral glucose tolerance, blood glycated haemoglobin, lipid profile, body composition, maximal workload capacity, whole body and skeletal muscle oxidative capacity and skeletal muscle fibre type composition were assessed before and after 2 and 6 months of intervention. Results: The entire 6 month intervention programme was completed by 37 participants. Continuous endurance-type exercise training reduced blood glycated haemoglobin levels, LDL-cholesterol concentrations, body weight and leg fat mass, and increased VO2peak, lean muscle mass and skeletal muscle cytochrome c oxidase and citrate synthase activity (p∈<∈0. 05). No differences were observed between the groups training at low to moderate or moderate to high intensity. Conclusions/interpretation: When matched for energy cost, prolonged continuous low- to moderate-intensity endurance-type exercise training is equally effective as continuous moderate- to high-intensity training in lowering blood glycated haemoglobin and increasing whole body and skeletal muscle oxidative capacity in obese type 2 diabetes patients. © 2009 Springer-Verlag