WNT7B mediates autocrine Wnt/β-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma

Developmental and cancer models show Wnt/β-catenin-dependent signaling mediates diverse phenotypic outcomes in the pancreas that are dictated by context, duration and strength of activation. While generally assumed to be pro-tumorigenic, it is unclear to what extent dysregulation of Wnt/β-catenin signaling impacts tumor progression in pancreatic adenocarcinoma (PDAC). In the present study, Wnt/β-catenin activity was characterized across a spectrum of PDAC cell lines and primary tumors. Reporter and gene expression based assays revealed wide heterogeneity in Wnt/β-catenin transcriptional activity across PDAC cell lines and patient tumors, as well as variable responsiveness to exogenous Wnt ligand stimulation. An experimentally-generated, pancreas-specific gene expression signature of Wnt/β-catenin transcriptional activation was used to stratify pathway activation across a cohort of resected, early stage PDAC tumors (N=41). In this cohort, higher Wnt/β-catenin activation was found to significantly correlate with lymphvascular invasion and worse disease specific survival (median survival time 20.3 versus 43.9 months, log rank P=0.03). Supporting the importance of Wnt ligand in mediating autocrine Wnt signaling, Wnt/β-catenin activity was significantly inhibited in PDAC cell lines by WLS gene silencing and the small molecule inhibitor IWP-2, both of which functionally block Wnt ligand processing and secretion. Transcriptional profiling revealed elevated expression of WNT7B occurred in PDAC cell lines with high levels of cell autonomous Wnt/β-catenin activity. Gene knockdown studies in AsPC-1 and HPAF-2 cell lines confirmed WNT7B mediated cell autonomous Wnt/β-catenin activation, as well as an anchorage-independent growth phenotype. Our findings indicate WNT7B can serve as a primary determinant of differential Wnt/β-catenin activation in PDAC. Disrupting the interaction between Wnt ligands and their receptors may be a particularly suitable approach for therapeutic modulation of Wnt/β-catenin signaling in PDAC and other cancer contexts where Wnt activation is mediated by ligand expression rather than mutations in canonical pathway members

Latent provisions for building information modeling (BIM) contracts: a social network analysis approach

The effective adoption and use of Building Information Modeling (BIM) require appropriate contract design to fairly allocate the contracting parties’ rights and responsibilities. Several standards for BIM protocols and contracts have been developed for the industry. However, the awareness and the use of these are rather limited, leading to unclear provisions in BIM contracts. Therefore, the research aims to identify the influential legal aspects that serve as the latent contract provisions in BIM contracts. A questionnaire survey was conducted to survey experts and active BIM users in construction projects. The data were analyzed using social network analysis (SNA) by assuming interdependent relationships among various the legal aspects in BIM contacts. The key legal aspects associated with BIM contracts pertain to the roles and responsibilities of the project participants. The results also reveal that data security is the center of all latent legal aspects in the contracts. The study provides significant new insights into clarifying the required contract provisions in BIM contracts

International study of definitions of English-language terms for suicidal behaviours: protocol of an opinion survey

Introduction The objective of present paper is to outline the methodology of the International Study of Definitions of English-Language Terms for Suicidal Behaviours (ISDELTSB). The aim of the study is to survey existing English language terms and definitions used around the world for suicidal behaviour. Methods and analysis The ISDELTSB is a worldwide survey based on one ‘designated expert’ per each WHO-registered country. ‘Experts’ were contacted through the International Association for Suicide Prevention (IASP), the World Psychiatric Association and the World Organization of Family Doctors. Each individual was sent an invitation to participate and a link to an online questionnaire. A comparison sample was created by inviting all IASP members to respond to the questionnaire. The questionnaire was designed to assess respondents’ preferences about a particular set of terms and definitions by using the four major criteria of the definition of suicide identified in the literature (outcome, intent, knowledge and agency). The questionnaire used a multiple-choice question format. Participants were asked to choose one term in the list for each of the proposed definitions. Statements and definitions in the questionnaire were elaborated using the four main features of the definition of suicide, starting by the definitions and terms for which there is already a certain degree of consensus and then progressing to definitions and terms less agreed on. Ethics and dissemination The study protocol obtained approval of Griffith University’s Ethics Committee (ethics reference number 2017/601) and in accordance with the Australian National Statement on Ethical Conduct in Human Research. Respondents are asked if they accept to be personally acknowledged in any output originating from this study, and if so to provide their full name, title and affiliations. If respondents do not accept, they are informed that the conduct of this research respects Griffith University’s Privacy Plan and that identified personal information is confidential and that anonymity will at all times be safeguarded. As detailed in the questionnaire cover letter, by answering the online or paper version of the questionnaire, respondents express their consent to participate. Dissemination of results will be done through a peer-reviewed journal article publication. This study aims to map the international use of definitions and terms for suicidal behaviour and ideation and favour the future use of an internationally shared set of terms and definitions. This will hopefully avoid undue duplication of efforts and reliably permit meta-analysis of data produced in different countries

A review of the gobioid fishes of Japan, with descriptions of twenty-one new species

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Optimizing suicide prevention programs and their implementation in Europe (OSPI Europe): an evidence-based multi-level approach

Background Suicide and non-fatal suicidal behaviour are significant public health issues in Europe requiring effective preventive interventions. However, the evidence for effective preventive strategies is scarce. The protocol of a European research project to develop an optimized evidence based program for suicide prevention is presented. Method The groundwork for this research has been established by a regional community based intervention for suicide prevention that focuses on improving awareness and care for depression performed within the European Alliance Against Depression (EAAD). The EAAD intervention consists of (1) training sessions and practice support for primary care physicians,(2) public relations activities and mass media campaigns, (3) training sessions for community facilitators who serve as gatekeepers for depressed and suicidal persons in the community and treatment and (4) outreach and support for high risk and self-help groups (e.g. helplines). The intervention has been shown to be effective in reducing suicidal behaviour in an earlier study, the Nuremberg Alliance Against Depression. In the context of the current research project described in this paper (OSPI-Europe) the EAAD model is enhanced by other evidence based interventions and implemented simultaneously and in standardised way in four regions in Ireland, Portugal, Hungary and Germany. The enhanced intervention will be evaluated using a prospective controlled design with the primary outcomes being composite suicidal acts (fatal and non-fatal), and with intermediate outcomes being the effect of training programs, changes in public attitudes, guideline-consistent media reporting. In addition an analysis of the economic costs and consequences will be undertaken, while a process evaluation will monitor implementation of the interventions within the different regions with varying organisational and healthcare contexts. Discussion This multi-centre research seeks to overcome major challenges of field research in suicide prevention. It pools data from four European regions, considerably increasing the study sample, which will be close to one million. In addition, the study will gather important information concerning the potential to transfer this multilevel program to other health care systems. The results of this research will provide a basis for developing an evidence-based, efficient concept for suicide prevention for EU-member states

Outcome assessment of a complex mental health intervention in the workplace. Results from the MENTUPP pilot study

ObjectiveMulticomponent interventions are recommendable to achieve the greatest mental health benefits, but are difficult to evaluate due to their complexity. Defining long-term outcomes, arising from a Theory of Change (ToC) and testing them in a pilot phase, is a useful approach to plan a comprehensive and meaningful evaluation later on. This article reports on the pilot results of an outcome evaluation of a complex mental health intervention and examines whether appropriate evaluation measures and indicators have been selected ahead of a clustered randomised control trial (cRCT).MethodsThe MENTUPP pilot is an evidence-based intervention for Small and Medium Enterprises (SMEs) active in three work sectors and nine countries. Based on our ToC, we selected the MENTUPP long-term outcomes, which are reported in this article, are measured with seven validated scales assessing mental wellbeing, burnout, depression, anxiety, stigma towards depression and anxiety, absenteeism and presenteeism. The pilot MENTUPP intervention assessment took place at baseline and at 6 months follow-up.ResultsIn total, 25 SMEs were recruited in the MENTUPP pilot and 346 participants completed the validated scales at baseline and 96 at follow-up. Three long-term outcomes significantly improved at follow-up (p < 0.05): mental wellbeing, symptoms of anxiety, and personal stigmatising attitudes towards depression and anxiety.ConclusionsThe results of this outcome evaluation suggest that MENTUPP has the potential to strengthen employees’ wellbeing and decrease anxiety symptoms and stigmatising attitudes. Additionally, this study demonstrates the utility of conducting pilot workplace interventions to assess whether appropriate measures and indicators have been selected. Based on the results, the intervention and the evaluation strategy have been optimised

International study of definitions of English-language terms for suicidal behaviours: a survey exploring preferred terminology.

Objectives Explore international consensus on nomenclatures of suicidal behaviours and analyse differences in terminology between high-income countries (HICs) and low/middle-income countries (LMICs). Design An online survey of members of the International Organisation for Suicide Prevention (IASP) used multiple-choice questions and vignettes to assess the four dimensions of the definition of suicidal behaviour: outcome, intent, knowledge and agency. Setting International. Participants Respondents included 126 individuals, 37 from 30 LMICs and 89 from 33 HICs. They included 40 IASP national representatives (65% response rate), IASP regular members (20% response rate) and six respondents from six additional countries identified by other organisations. Outcome measures Definitions of English-language terms for suicidal behaviours. Results The recommended definition of ‘suicide’ describes a fatal act initiated and carried out by the actors themselves. The definition of ‘suicide attempt’ was restricted to non-fatal acts with intent to die, whereas definition of ‘self-harm’ more broadly referred to acts with varying motives, including the wish to die. Almost all respondents agreed about the definitions of ‘suicidal ideation’, ‘death wishes’ and ‘suicide plan’. ‘Aborted suicide attempt’ and ‘interrupted suicide attempt’ were not considered components of ‘preparatory suicidal behaviour’. There were several differences between representatives from HICs and LMICs. Conclusion This international opinion survey provided the basis for developing a transcultural nomenclature of suicidal behaviour. Future developments of this nomenclature should be tested in larger samples of professionals, including LMICs may be a challenge