An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

'Who Wrote 2 Thessalonians:A Fresh Look at an Old Problem'

In light of the New Perspective on Paul, recognition of apocalyptic as a central category in Pauline theology, and the crumbling consensus concerning seven authentic epistles of Paul, it is time to reconsider the arguments for the authenticity of his letters. Here the specific question of the authorship of 2 Thessalonians is re-examined. It is noted that many of the standard arguments for or against the authenticity of 2 Thessalonians are either irrelevant or inconclusive. This discussion seeks to reveal the slender evidential basis of certain ‘classic’ arguments against the authenticity of the letter, and also to present some fresh reasons why the epistle should be regarded as written by Paul. The implications of including 2 Thessalonians among the authentic Pauline writings are then examined. In particular, it is suggested that the development in Paul’s thinking as reflected in 2 Thessalonians reveals that his theological formulations developed in response to situations in his fledgling communities. In this regard, Paul’s theological positions emerged through a negotiated response to pressing pastoral situations

Has the evolution of complexity in the amphibian papilla influenced anuran speciation rates?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72375/1/j.1420-9101.2006.01079.x.pd

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Receptor activity-modifying protein modulation of parathyroid hormone-1 receptor function and signaling

Introduction: Receptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G-protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. This study investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTH and PTH-related protein (PTHrP)-derived ligands. Methods: We employed FRET imaging to assess PTH1R interactions with RAMPs. Cell surface expression of PTH1R was evaluated in the presence of RAMPs. PTH1R-mediated cAMP accumulation, β-arrestin recruitment, and calcium signalling were measured in response to various ligands. Antibody-capture scintillation proximity assays were used to examine G-protein activation patterns. Results: PTH1R preferentially interacted with RAMP2 and, to a lesser extent, RAMP3, but not with RAMP1. RAMP3 co-expression reduced cell surface expression of PTH1R. RAMP2 significantly enhanced PTH1R-mediated signalling responses to PTH (1-34), PTHrP (1-34), PTH (1-84), and PTH (1-17) analogue ZP2307, while RAMP3 co-expression attenuated or abolished these responses. Full-length PTHrP analogues exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 increased the potency and/or efficacy of these analogues, whereas RAMP3 reduced these responses. RAMP2 differentially modulated G-protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G-protein subtype activation. Discussion: These findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach

CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic

CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival. CTCF genetic deletion occurs predominantly in poor prognosis serous subtype tumours, and this genetic deletion is associated with poor overall survival. In addition, we have shown that CTCF haploinsufficiency also occurs in poor prognosis endometrial clear cell carcinomas and has some association with endometrial cancer relapse and metastasis. Using shRNA targeting CTCF to recapitulate CTCF haploinsufficiency, we have identified a novel role for CTCF in the regulation of cellular polarity of endometrial glandular epithelium. Overall, we have identified two novel pro-tumorigenic roles (promoting cell survival and altering cell polarity) for genetic alterations of CTCF in endometrial cance

Development of a web-based, guided self-help, acceptance and commitment therapy-based intervention for weight loss maintenance: evidence-, theory-, and person-based approach.

Background: The long-term impact and cost-effectiveness of weight management programs depend on posttreatment weight maintenance. There is growing evidence that interventions based on third-wave cognitive behavioral therapy, particularly acceptance and commitment therapy (ACT), could improve long-term weight management; however, these interventions are typically delivered face-to-face by psychologists, which limits the scalability of these types of intervention. Objective: The aim of this study is to use an evidence-, theory-, and person-based approach to develop an ACT-based intervention for weight loss maintenance that uses digital technology and nonspecialist guidance to minimize the resources needed for delivery at scale. Methods: Intervention development was guided by the Medical Research Council framework for the development of complex interventions in health care, Intervention Mapping Protocol, and a person-based approach for enhancing the acceptability and feasibility of interventions. Work was conducted in two phases: phase 1 consisted of collating and analyzing existing and new primary evidence and phase 2 consisted of theoretical modeling and intervention development. Phase 1 included a synthesis of existing evidence on weight loss maintenance from previous research, a systematic review and network meta-analysis of third-wave cognitive behavioral therapy interventions for weight management, a qualitative interview study of experiences of weight loss maintenance, and the modeling of a justifiable cost for a weight loss maintenance program. Phase 2 included the iterative development of guiding principles, a logic model, and the intervention design and content. Target user and stakeholder panels were established to inform each phase of development, and user testing of successive iterations of the prototype intervention was conducted. Results: This process resulted in a guided self-help ACT-based intervention called SWiM (Supporting Weight Management). SWiM is a 4-month program consisting of weekly web-based sessions for 13 consecutive weeks followed by a 4-week break for participants to reflect and practice their new skills and a final session at week 18. Each session consists of psychoeducational content, reflective exercises, and behavioral experiments. SWiM includes specific sessions on key determinants of weight loss maintenance, including developing skills to manage high-risk situations for lapses, creating new helpful habits, breaking old unhelpful habits, and learning to manage interpersonal relationships and their impact on weight management. A trained, nonspecialist coach provides guidance for the participants through the program with 4 scheduled 30-minute telephone calls and 3 further optional calls. Conclusions: This comprehensive approach facilitated the development of an intervention that is based on scientific theory and evidence for supporting people with weight loss maintenance and is grounded in the experiences of the target users and the context in which it is intended to be delivered. The intervention will be refined based on the findings of a planned pilot randomized controlled trial

An acceptance‐based guided self‐help program for weight loss maintenance in adults who have previously completed a behavioral weight loss program: The SWiM feasibility study

Background Most weight lost during weight-loss programmes is eventually regained. Interventions based on Acceptance and Commitment Therapy (ACT) demonstrate good evidence for long-term weight loss, but are often costly and difficult to scale up. Guided self-help programmes delivered using technology and non-specialist coaches could increase scalability, but it is unclear whether delivering ACT-based interventions in this way is feasible and acceptable. Methods In this feasibility study, 61 people who recently completed a behavioral weight management intervention (BWMI) for weight management were randomly allocated to SWiM (“Supporting Weight Management”: 4-month digital guided self-help ACT-based intervention for weight loss maintenance) or a standard care group (leaflet about maintaining weight loss) using a 2:1 allocation ratio. At baseline and 6 months, participants completed measures of weight, mental health, eating behavior, and other psychosocial variables. Participants completed an intervention evaluation questionnaire. At 3 and 6 months, qualitative interviews were conducted with participants from both trial arms and SWiM coaches. The analysis integrated statistics and thematic analysis, informed by the Medical Research Council (MRC) framework for process evaluations. Since this was a feasibility study, analyses focused on process outcomes instead of interpreting statistical significance. Results Eighty-eight percent (36/41) of participants allocated to SWiM completed at least the first session and 22 (54%) completed all sessions. At 6 months, mean weight change was −2.2 (+/−6.4 SD) kg in SWiM participants and +2.2 (+/−6.6) kg in standard care participants. Descriptively, eating behavior and mental health scores improved in SWiM participants but not in standard care participants. In interviews, SWiM participants noted that they reinforced their existing knowledge while acquiring new skills and strategies, which were felt to contribute to positive behavioral changes. Conclusion The SWiM intervention is practical and well-received, and shows promise in supporting weight loss maintenance, though evaluation in a larger trial is needed to assess effectiveness. Trial Registration ISRCTN1268596