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

Suppression of Lung Tumorigenesis by Leucine Zipper/EF Hand–Containing Transmembrane-1

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. However, a previous study demonstrated that LETM1 served as an anchor protein for complex formation between mitochondria and ribosome, and regulated mitochondrial biogenesis.Therefore, we examine the possibility that LETM1 may function to regulate mitochondria and lung tumor growth. In this study, we addressed this question by studying in the effect of adenovirus-mediated LETM1 in the lung cancer cell and lung cancer model mice. To investigate the effects of adenovirus-LETM1 in vitro, we infected with adenovirus-LETM1 in A549 cells. Additionally, in vivo effects of LETM1 were evaluated on K-ras(LA1) mice, human non-small cell lung cancer model mice, by delivering the LETM1 via aerosol through nose-only inhalation system. The effects of LETM1 on lung cancer growth and AMPK related signals were evaluated. Adenovirus-mediated overexpression of LETM1 could induce destruction of mitochondria of lung cancer cells through depleting ATP and AMPK activation. Furthermore, adenoviral-LETM1 also altered Akt signaling and inhibited the cell cycle while facilitating apoptosis. Theses results demonstrated that adenovirus-LETM1 suppressed lung cancer cell growth in vitro and in vivo.Adenovirus-mediated LETM1 may provide a useful target for designing lung tumor prevention and treatment

The first whole genome and transcriptome of the cinereous vulture reveals adaptation in the gastric and immune defense systems and possible convergent evolution between the Old and New World vultures

Background: The cinereous vulture, Aegypius monachus, is the largest bird of prey and plays a key role in the ecosystem by removing carcasses, thus preventing the spread of diseases. Its feeding habits force it to cope with constant exposure to pathogens, making this species an interesting target for discovering functionally selected genetic variants. Furthermore, the presence of two independently evolved vulture groups, Old World and New World vultures, provides a natural experiment in which to investigate convergent evolution due to obligate scavenging. Results: We sequenced the genome of a cinereous vulture, and mapped it to the bald eagle reference genome, a close relative with a divergence time of 18 million years. By comparing the cinereous vulture to other avian genomes, we find positively selected genetic variations in this species associated with respiration, likely linked to their ability of immune defense responses and gastric acid secretion, consistent with their ability to digest carcasses. Comparisons between the Old World and New World vulture groups suggest convergent gene evolution. We assemble the cinereous vulture blood transcriptome from a second individual, and annotate genes. Finally, we infer the demographic history of the cinereous vulture which shows marked fluctuations in effective population size during the late Pleistocene. Conclusions: We present the first genome and transcriptome analyses of the cinereous vulture compared to other avian genomes and transcriptomes, revealing genetic signatures of dietary and environmental adaptations accompanied by possible convergent evolution between the Old World and New World vulturesopen

Stretching Actin Filaments within Cells Enhances their Affinity for the Myosin II Motor Domain

To test the hypothesis that the myosin II motor domain (S1) preferentially binds to specific subsets of actin filaments in vivo, we expressed GFP-fused S1 with mutations that enhanced its affinity for actin in Dictyostelium cells. Consistent with the hypothesis, the GFP-S1 mutants were localized along specific portions of the cell cortex. Comparison with rhodamine-phalloidin staining in fixed cells demonstrated that the GFP-S1 probes preferentially bound to actin filaments in the rear cortex and cleavage furrows, where actin filaments are stretched by interaction with endogenous myosin II filaments. The GFP-S1 probes were similarly enriched in the cortex stretched passively by traction forces in the absence of myosin II or by external forces using a microcapillary. The preferential binding of GFP-S1 mutants to stretched actin filaments did not depend on cortexillin I or PTEN, two proteins previously implicated in the recruitment of myosin II filaments to stretched cortex. These results suggested that it is the stretching of the actin filaments itself that increases their affinity for the myosin II motor domain. In contrast, the GFP-fused myosin I motor domain did not localize to stretched actin filaments, which suggests different preferences of the motor domains for different structures of actin filaments play a role in distinct intracellular localizations of myosin I and II. We propose a scheme in which the stretching of actin filaments, the preferential binding of myosin II filaments to stretched actin filaments, and myosin II-dependent contraction form a positive feedback loop that contributes to the stabilization of cell polarity and to the responsiveness of the cells to external mechanical stimuli

Differences between seven measures of self-reported numbers of clients of female sex workers in southern India: implications for individual- and population-level analysis.

Quantifying sexual activity of sub-populations with high-risk sexual behaviour is important in understanding HIV epidemiology. This study examined inconsistency of seven outcomes measuring self-reported clients per month (CPM) of female sex workers (FSWs) in southern India and implications for individual/population-level analysis. Multivariate negative binomial regression was used to compare key social/environmental factors associated with each outcome. A transmission dynamics model was used to assess the impact of differences between outcomes on population-level FSW/client HIV prevalence. Outcomes based on 'clients per last working day' produced lower estimates than those based on 'clients per typical day'. Although the outcomes were strongly correlated, their averages differed by approximately two-fold (range 39.0-79.1 CPM). The CPM measure chosen did not greatly influence standard epidemiological 'risk factor' analysis. Differences across outcomes influenced HIV prevalence predictions. Due to this uncertainty, we recommend basing population-based estimates on the range of outcomes, particularly when assessing the impact of interventions

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Measurement of quarkonium production in proton–lead and proton–proton collisions at 5.02 TeV with the ATLAS detector

The modification of the production of J/ψ, ψ(2S), and Υ(nS) (n=1,2,3) in p+Pb collisions with respect to their production in pp collisions has been studied. The p+Pb and pp datasets used in this paper correspond to integrated luminosities of 28 nb−1 and 25 pb−1 respectively, collected in 2013 and 2015 by the ATLAS detector at the LHC, both at a centre-of-mass energy per nucleon pair of 5.02 TeV. The quarkonium states are reconstructed in the dimuon decay channel. The yields of J/ψ and ψ(2S) are separated into prompt and non-prompt sources. The measured quarkonium differential cross sections are presented as a function of rapidity and transverse momentum, as is the nuclear modification factor, RpPb for J/ψ and Υ(nS). No significant modification of the J/ψ production is observed while Υ(nS) production is found to be suppressed at low transverse momentum in p+Pb collisions relative to pp collisions. The production of excited charmonium and bottomonium states is found to be suppressed relative to that of the ground states in central p+Pb collisions

Search for excited electrons singly produced in proton–proton collisions at \sqrt{s} = 13 TeV with the ALAS experiment at the LHC

A search for excited electrons produced in pp collisions at s√ = 13 TeV via a contact interaction qq¯→ee∗ is presented. The search uses 36.1 fb −1 of data collected in 2015 and 2016 by the ATLAS experiment at the Large Hadron Collider. Decays of the excited electron into an electron and a pair of quarks ( eqq¯ ) are targeted in final states with two electrons and two hadronic jets, and decays via a gauge interaction into a neutrino and a W boson ( νW ) are probed in final states with an electron, missing transverse momentum, and a large-radius jet consistent with a hadronically decaying W boson. No significant excess is observed over the expected backgrounds. Upper limits are calculated for the pp→ee∗→eeqq¯ and pp→ee∗→eνW production cross sections as a function of the excited electron mass me∗ at 95% confidence level. The limits are translated into lower bounds on the compositeness scale parameter Λ of the model as a function of me∗ . For me∗<0.5 TeV , the lower bound for Λ is 11 TeV . In the special case of me∗=Λ , the values of me∗<4.8 TeV are excluded. The presented limits on Λ are more stringent than those obtained in previous searches