Decreased transcription-coupled nucleotide excision repair capacity is associated with increased p53- and MLH1-independent apoptosis in response to cisplatin

Abstract Background One of the most commonly used classes of anti-cancer drugs presently in clinical practice is the platinum-based drugs, including cisplatin. The efficacy of cisplatin therapy is often limited by the emergence of resistant tumours following treatment. Cisplatin resistance is multi-factorial but can be associated with increased DNA repair capacity, mutations in p53 or loss of DNA mismatch repair capacity. Methods RNA interference (RNAi) was used to reduce the transcription-coupled nucleotide excision repair (TC-NER) capacity of several prostate and colorectal carcinoma cell lines with specific defects in p53 and/or DNA mismatch repair. The effect of small inhibitory RNAs designed to target the CSB (Cockayne syndrome group B) transcript on TC-NER and the sensitivity of cells to cisplatin-induced apoptosis was determined. Results These prostate and colon cancer cell lines were initially TC-NER proficient and RNAi against CSB significantly reduced their DNA repair capacity. Decreased TC-NER capacity was associated with an increase in the sensitivity of tumour cells to cisplatin-induced apoptosis, even in p53 null and DNA mismatch repair-deficient cell lines. Conclusion The present work indicates that CSB and TC-NER play a prominent role in determining the sensitivity of tumour cells to cisplatin even in the absence of p53 and DNA mismatch repair. These results further suggest that CSB represents a potential target for cancer therapy that may be important to overcome resistance to cisplatin in the clinic

Methane drizzle on Titan

Saturn's moon Titan shows landscapes with fluvial features(1) suggestive of hydrology based on liquid methane. Recent efforts in understanding Titan's methane hydrological cycle have focused on occasional cloud outbursts near the south pole(2-4) or cloud streaks at southern mid-latitudes(5,6) and the mechanisms of their formation. It is not known, however, if the clouds produce rain or if there are also non-convective clouds, as predicted by several models(7-11). Here we show that the in situ data on the methane concentration and temperature profile in Titan's troposphere point to the presence of layered optically thin stratiform clouds. The data indicate an upper methane ice cloud and a lower, barely visible, liquid methane-nitrogen cloud, with a gap in between. The lower, liquid, cloud produces drizzle that reaches the surface. These non-convective methane clouds are quasi-permanent features supported by the global atmospheric circulation, indicating that methane precipitation occurs wherever there is slow upward motion. This drizzle is a persistent component of Titan's methane hydrological cycle and, by wetting the surface on a global scale, plays an active role in the surface geology of Titan.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62668/1/nature04948.pd

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Management of chronic obstructive pulmonary disease in India: a systematic review.

OBJECTIVES: Chronic diseases are fast becoming the largest health burden in India. Despite this, their management in India has not been well studied. We aimed to systematically review the nature and efficacy of current management strategies for chronic obstructive pulmonary disease (COPD) in India. METHODS: We used database searches (MEDLINE, EMBASE, IndMED, CENTRAL and CINAHL), journal hand-searches, scanning of reference lists and contact with experts to identify studies for systematic review. We did not review management strategies aimed at chronic diseases more generally, nor management of acute exacerbations. Due to the heterogeneity of reviewed studies, meta-analysis was not appropriate. Thus, narrative methods were used. SETTING: India. PARTICIPANTS: All adult populations resident in India. MAIN OUTCOME MEASURES: 1. Trialled interventions and outcomes 2. Extent and efficacy of current management strategies 3. Above outcomes by subgroup. RESULTS: We found information regarding current management - particularly regarding the implementation of national guidelines and primary prevention - to be minimal. This led to difficulty in interpreting studies of management strategies, which were varied and generally of positive effect. Data regarding current management outcomes were very few. CONCLUSIONS: The current understanding of management strategies for COPD in India is limited due to a lack of published data. Determination of the extent of current use of management guidelines, availability and use of treatment, and current primary prevention strategies would be useful. This would also provide evidence on which to interpret existing and future studies of management outcomes and novel interventions

Predictors of Treatment Attrition Among an Outpatient Clinic Sample of Youths With Clinically Significant Anxiety

Predictors of treatment attrition were examined in a sample of 197 youths (ages 5–18) with clinically-significant symptoms of anxiety seeking psychotherapy services at a community-based outpatient mental health clinic (OMHC). Two related definitions of attrition were considered: (a) clinician-rated dropout (CR), and (b) CR dropout qualified by phase of treatment (pre, early, or late phases) (PT). Across both definitions, rates of attrition in the OMHC sample were higher than those for anxious youths treated in randomized controlled trials, and comorbid depression symptoms predicted dropout, with a higher rate of depressed youths dropping out later in treatment (after 6 sessions). Using the PT definition, minority status also predicted attrition, with more African-American youths lost pre-treatment. Other demographic (age, gender, single parent status) and clinical (externalizing symptoms, anxiety severity) characteristics were not significantly associated with attrition using either definition. Implications for services for anxious youths in public service settings are discussed. Results highlight the important role of comorbid depression in the treatment of anxious youth and the potential value of targeted retention efforts for ethnic minority families early in the treatment process

The Eye of the Beholder: Youths and Parents Differ on What Matters in Mental Health Services

The goal of this study was to examine the degree to which youths and caregivers attend to different factors in evaluating their experiences with mental health programs. Youth (n = 251) receiving mental health services at community agencies and their caregivers (n = 275) were asked open-ended questions regarding the positive and negative aspects of the services. Qualitative analyses revealed some agreement but also divergence between youth and caregivers regarding the criteria by which services were evaluated and aspects of services that were valued most highly. Youths’ positive comments primarily focused on treatment outcomes while caregivers focused more on characteristics of the program and provider. Youths’ negative comments reflected dissatisfaction with the program, provider, and types of services offered while caregivers expressed dissatisfaction mainly with program characteristics. Results support the importance of assessing both youth and caregivers in attempts to understand the factors used by consumers to evaluate youth mental health services

Regulation of Glucose Homeostasis by KSR1 and MARK2

Protein scaffolds control the intensity and duration of signaling and dictate the specificity of signaling through MAP kinase pathways. KSR1 is a molecular scaffold of the Raf/MEK/ERK MAP kinase cascade that regulates the intensity and duration of ERK activation. Relative to wild-type mice, ksr1-/- mice are modestly glucose intolerant, but show a normal response to exogenous insulin. However, ksr1-/- mice also demonstrate a three-fold increase in serum insulin levels in response to a glucose challenge, suggesting a role for KSR1 in insulin secretion. The kinase MARK2 is closely related to C-TAK1, a known regulator of KSR1. Mice lacking MARK2 have an increased rate of glucose disposal in response to exogenous insulin, increased glucose tolerance, and are resistant to diet-induced obesity. mark2-/-ksr1-/- (DKO) mice were compared to wild type, mark2-/-, and ksr1-/- mice for their ability to regulate glucose homeostasis. Here we show that disruption of KSR1 in mark2-/- mice reverses the increased sensitivity to exogenous insulin resulting from MARK2 deletion. DKO mice respond to exogenous insulin similarly to wild type and ksr1-/- mice. These data suggest a model whereby MARK2 negatively regulates insulin sensitivity in peripheral tissue through inhibition of KSR1. Consistent with this model, we found that MARK2 binds and phosphorylates KSR1 on Ser392. Phosphorylation of Ser392 is a critical regulator of KSR1 stability, subcellular location, and ERK activation. These data reveal an unexpected role for the molecular scaffold KSR1 in insulin-regulated glucose metabolism