Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin

Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell-cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell-cell and cell-matrix pathologies important for early tumor dissemination. Significance: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell-cell and cell-matrix interactions and cohesion of epithelial structure.Peer reviewe

Diabetes, periodontitis, and the subgingival microbiota

Both type 1 and type 2 diabetes have been associated with increased severity of periodontal disease for many years. More recently, the impact of periodontal disease on glycaemic control has been investigated. The role of the oral microbiota in this two-way relationship is at this stage unknown. Further studies, of a longitudinal nature and investigating a wider array of bacterial species, are required in order to conclusively determine if there is a difference in the oral microbiota of diabetics and non-diabetics and whether this difference accounts, on the one hand, for the increased severity of periodontal disease and on the other for the poorer glycaemic control seen in diabetics

Progress in cancer survival, mortality, and incidence in seven high-income countries 1995–2014 (ICBP SURVMARK-2): a population-based study

© 2019 World Health Organization Background: Population-based cancer survival estimates provide valuable insights into the effectiveness of cancer services and can reflect the prospects of cure. As part of the second phase of the International Cancer Benchmarking Partnership (ICBP), the Cancer Survival in High-Income Countries (SURVMARK-2) project aims to provide a comprehensive overview of cancer survival across seven high-income countries and a comparative assessment of corresponding incidence and mortality trends. Methods: In this longitudinal, population-based study, we collected patient-level data on 3·9 million patients with cancer from population-based cancer registries in 21 jurisdictions in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the UK) for seven sites of cancer (oesophagus, stomach, colon, rectum, pancreas, lung, and ovary) diagnosed between 1995 and 2014, and followed up until Dec 31, 2015. We calculated age-standardised net survival at 1 year and 5 years after diagnosis by site, age group, and period of diagnosis. We mapped changes in incidence and mortality to changes in survival to assess progress in cancer control. Findings: In 19 eligible jurisdictions, 3 764 543 cases of cancer were eligible for inclusion in the study. In the 19 included jurisdictions, over 1995–2014, 1-year and 5-year net survival increased in each country across almost all cancer types, with, for example, 5-year rectal cancer survival increasing more than 13 percentage points in Denmark, Ireland, and the UK. For 2010–14, survival was generally higher in Australia, Canada, and Norway than in New Zealand, Denmark, Ireland, and the UK. Over the study period, larger survival improvements were observed for patients younger than 75 years at diagnosis than those aged 75 years and older, and notably for cancers with a poor prognosis (ie, oesophagus, stomach, pancreas, and lung). Progress in cancer control (ie, increased survival, decreased mortality and incidence) over the study period was evident for stomach, colon, lung (in males), and ovarian cancer. Interpretation: The joint evaluation of trends in incidence, mortality, and survival indicated progress in four of the seven studied cancers. Cancer survival continues to increase across high-income countries; however, international disparities persist. While truly valid comparisons require differences in registration practice, classification, and coding to be minimal, stage of disease at diagnosis, timely access to effective treatment, and the extent of comorbidity are likely the main determinants of patient outcomes. Future studies are needed to assess the impact of these factors to further our understanding of international disparities in cancer survival. Funding: Canadian Partnership Against Cancer; Cancer Council Victoria; Cancer Institute New South Wales; Cancer Research UK; Danish Cancer Society; National Cancer Registry Ireland; The Cancer Society of New Zealand; National Health Service England; Norwegian Cancer Society; Public Health Agency Northern Ireland, on behalf of the Northern Ireland Cancer Registry; The Scottish Government; Western Australia Department of Health; and Wales Cancer Network

Progressive vertebral deformities despite unchanged bone mineral density in patients with sarcoidosis: a 4-year follow-up study

To evaluate the incidence of new and/or progressive vertebral deformities and changes in bone mineral density, we re-examined 66 patients with sarcoidosis after a follow-up period of four years. In 17 subjects (26%) new and/or progressive vertebral deformities were found, though BMD did not change significantly. INTRODUCTION: Previous studies from our group have shown that morphometric vertebral deformities suggestive of fractures can be found in 20% of patients with sarcoidosis, despite a normal bone mineral density (BMD). The aim of this study was to determine the incidence of new and/or progressive vertebral deformities and the evolution of BMD during the course of this disease. METHODS: BMD of the hip (DXA) and vertebral fracture assessment (VFA) with lateral single energy densitometry was performed at baseline and after 45 months in 66 patients with sarcoidosis. Potential predictors of new/ progressive vertebral deformities were assessed using logistic regression analysis. RESULTS: The BMD of the total group was unchanged after follow-up. The prevalence of vertebral deformities increased from 20 to 32% (p < 0.05); in 17 subjects (26%) new or progressive vertebral deformities were diagnosed. A lower T-score of the femoral neck [(OR = 2.5 (CI: 1.0-5.9), p < 0.05)] and mother with a hip fracture [(OR = 14.1 (CI: 1.4-142.6), p < 0.05)] were independent predictors of new/progressive deformities. CONCLUSIONS: In subjects with sarcoidosis the number of vertebral deformities increases in the course of this disease, despite unchanged BMD. The combination of low normal BMD and family history of fragility fractures confers an increased risk of the incidence of these deformities

Transfer of Health for All policy – What, how and in which direction? A two-case study

BACKGROUND: This article explores the transfer of World Health Organization's (WHO) policy initiative Health for All by the Year 2000 (HFA2000) into national contexts by using the changes in the public health policies of Finland and Portugal from the 1970's onward and the relationship of these changes to WHO policy development as test cases. Finland and Portugal were chosen to be compared as they represent different welfare state types and as the paradigmatic transition from the old to new public health is assumed to be related to the wider welfare state development. METHODS: The policy transfer approach is used as a conceptual tool to analyze the possible policy changes related to the adaptation of HFA into the national context. To be able to analyze not only the content but also the contextual conditions of policy transfer Kingdon's analytical framework of policy analysis is applied. CONCLUSIONS: Our analysis suggests that no significant change of health promotion policy resulted from the launch of HFA program neither in Finland nor in Portugal. Instead the changes that occurred in both countries were of incremental nature, in accordance with the earlier policy choices, and the adaptation of HFA program was mainly applied to the areas where there were national traditions

Electre Methods: Main Features and Recent Developments

We present main characteristics of Electre family methods, designed for multiple criteria decision aiding. These methods use as a preference model an outranking relation in the set of actions - it is constructed in result of concordance and non-discordance tests involving a specific input preference information. After a brief description of the constructivist conception in which the Electre methods are inserted, we present the main features of these methods. We discuss such characteristic features as: the possibility of taking into account positive and negative reasons in the modeling of preferences, without any need for recoding the data; using of thresholds for taking into account the imperfect knowledge of data; the absence of systematic compensation between "gains" and "losses". The main weaknesses are also presented. Then, some aspects related to new developments are outlined. These are related to some new methodological developments, new procedures, axiomatic analysis, software tools, and several other aspects. The paper ends with conclusions