Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

BACKGROUND: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors. METHODS: The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants. RESULTS: We demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion. CONCLUSIONS: These studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations

Stability and change in the mental health of New Zealand secondary school students 2007–2012: Results from the national adolescent health surveys

Objective: To describe the self-reported mental health of New Zealand secondary school students in 2012 and to investigate changes between 2007 and 2012. Methods: Nationally representative health and wellbeing surveys of students were completed in 2007 (n=9107) and 2012 (n=8500). Logistic regressions were used to examine the associations between mental health and changes over time. Prevalence data and adjusted odds ratios are presented. Results: In 2012, approximately three-quarters (76.2%, 95% CI 74.8–77.5) of students reported good overall wellbeing. By contrast (also in 2012), some students reported self-harming (24.0%, 95% CI 22.7–25.4), depressive symptoms (12.8%, 95% CI 11.6–13.9), 2 weeks of low mood (31%, 95% CI 29.7–32.5), suicidal ideation (15.7%, 95% 14.5–17.0), and suicide attempts (4.5%, 95% CI 3.8–5.2). Between 2007 and 2012, there appeared to be slight increases in the proportions of students reporting an episode of low mood (OR 1.14, 95% CI 1.06–1.23, p=0.0009), depressive symptoms (OR 1.16, 95% CI 1.03–1.30, p=0.011), and using the Strengths and Difficulties Questionnaire - emotional symptoms (OR 1.38, 95% CI 1.23–1.54, p<0.0001), hyperactivity (OR 1.16, 95% CI 1.05–1.29, p=0.0051), and peer problems (OR 1.27, 95% CI 1.09–1.49, p=0.0022). The proportion of students aged 16 years or older reporting self-harm increased slightly between surveys, but there was little change for students aged 15 years or less (OR 1.29, 95% CI 1.15–1.44 and OR 1.10, 95% 0.98–1.23, respectively, p=0.0078). There were no changes in reported suicidal ideation and suicide attempts between 2007 and 2012. However, there has been an improvement in self-reported conduct problems since 2007 (OR 0.78, 95% CI 0.70–0.87, p<0.0001). Conclusions: The findings suggest a slight decline in aspects of self-reported mental health amongst New Zealand secondary school students between 2007 and 2012. There is a need for ongoing monitoring and for evidence-based, accessible interventions that prevent mental ill health and promote psychological wellbeing

National Mesothelioma Virtual Bank: A standard based biospecimen and clinical data resource to enhance translational research

Background: Advances in translational research have led to the need for well characterized biospecimens for research. The National Mesothelioma Virtual Bank is an initiative which collects annotated datasets relevant to human mesothelioma to develop an enterprising biospecimen resource to fulfill researchers' need. Methods: The National Mesothelioma Virtual Bank architecture is based on three major components: (a) common data elements (based on College of American Pathologists protocol and National North American Association of Central Cancer Registries standards), (b) clinical and epidemiologic data annotation, and (c) data query tools. These tools work interoperably to standardize the entire process of annotation. The National Mesothelioma Virtual Bank tool is based upon the caTISSUE Clinical Annotation Engine, developed by the University of Pittsburgh in cooperation with the Cancer Biomedical Informatics Grid™ (caBIG™, see http://cabig.nci.nih.gov). This application provides a web-based system for annotating, importing and searching mesothelioma cases. The underlying information model is constructed utilizing Unified Modeling Language class diagrams, hierarchical relationships and Enterprise Architect software. Result: The database provides researchers real-time access to richly annotated specimens and integral information related to mesothelioma. The data disclosed is tightly regulated depending upon users' authorization and depending on the participating institute that is amenable to the local Institutional Review Board and regulation committee reviews. Conclusion: The National Mesothelioma Virtual Bank currently has over 600 annotated cases available for researchers that include paraffin embedded tissues, tissue microarrays, serum and genomic DNA. The National Mesothelioma Virtual Bank is a virtual biospecimen registry with robust translational biomedical informatics support to facilitate basic science, clinical, and translational research. Furthermore, it protects patient privacy by disclosing only de-identified datasets to assure that biospecimens can be made accessible to researchers. © 2008 Amin et al; licensee BioMed Central Ltd

Risk factors for presentation to hospital with severe anaemia in Tanzanian children: a case-control study.

In malaria endemic areas anaemia is a usually silent condition that nevertheless places a considerable burden on health services. Cases of severe anaemia often require hospitalization and blood transfusions. The objective of this study was to assess risk factors for admission with anaemia to facilitate the design of anaemia control programmes. We conducted a prospective case-control study of children aged 2-59 months admitted to a district hospital in southern Tanzania. There were 216 cases of severe anaemia [packed cell volume (PCV) < 25%] and 234 age-matched controls (PCV > or = 25%). Most cases [55.6% (n = 120)] were < 1 year of age. Anaemia was significantly associated with the educational level of parents, type of accommodation, health-seeking behaviour, the child's nutritional status and recent and current medical history. Of these, the single most important factor was Plasmodium falciparum parasitaemia [OR 4.3, 95% confidence interval (CI) 2.9-6.5, P < 0.001]. Multivariate analysis showed that increased recent health expenditure [OR 2.2 (95% CI 1.3-3.9), P = 0.005], malnutrition [OR 2.4 (95%CI 1.3-4.3), P < 0.001], living > 10 km from the hospital [OR 3.0 (95% CI 1.9-4.9), P < 0.001], a history of previous blood transfusion [OR 3.8 (95% CI 1.7-9.1), P < 0.001] and P. falciparum parasitaemia [OR 9.5 (95% CI 4.3-21.3), P < 0.001] were independently related to risk of being admitted with anaemia. These findings are considered in terms of the pathophysiological pathway leading to anaemia. The concentration of anaemia in infants and problems of access to health services and adequate case management underline the need for targeted preventive strategies for anaemia control