Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion - a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for α5β1 integrin - the principle mediator of fibronectin matrix assembly (FNMA) - as an invasion suppressor of prostate cancer cells.</p> <p>Methods</p> <p>Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA.</p> <p>Results</p> <p>We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type α5 integrin or an integrin in which the cytoplasmic domain of α5 was replaced with that of α2. The α2 construct does not promote FNMA. We show that only wild-type α5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment.</p> <p>Conclusions</p> <p>We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade.</p

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk

Recognition of Depression in Older Medical Inpatients

BACKGROUND: Studies of recognition of depression in older (aged 65 or more) medical inpatients show low rates of recognition of depression by attending physicians. However, few studies have compared different measures of recognition of depression. OBJECTIVES: (1) To compare the validity of four indicators of recognition of depression and a global measure of recognition against a diagnosis of depression and (2) to explore the effect of patient characteristics on recognition of depression. METHODS: In a cohort of 264 medical inpatients 65 years and older (115 with major or minor depression, 78 with no depression), sensitivities, specificities, and diagnostic odds ratios (DOR) of 4 indicators of recognition (symptoms, diagnosis, treatment, and referral) and a global measure of recognition (any of the 4 indicators) were calculated. The associations between patient characteristics (age, sex, history of depression, antidepressant use before admission, severity of depression, comorbidity, duration of hospitalization, disability, and hospital of admission) and recognition were explored using multiple logistic regression. RESULTS: Less than half of the depressed patients were recognized. The indicator with the highest sensitivity was treatment (27.8%, 95% confidence interval [CI] 20.0–37.0), whereas the indicator with the best specificity was diagnosis (96.6%, 95% CI 91.9–98.7). The unadjusted DOR of global recognition was 2.6 (95% CI 1.5, 4.4). Less comorbidity, more severe depression symptoms, a history of depression, longer hospital stay, and antidepressant use before admission were significantly associated with better global recognition. CONCLUSION: Recognition of depression in elderly medical inpatients depends upon the indicator of recognition used

Reliability, Validity and Psychometric Properties of the Greek Translation of the Center for Epidemiological Studies-Depression (CES-D) Scale

INTRODUCTION: The aim of the current study was to assess the reliability, validity and psychometric properties of the Greek translation of the Center for Epidemiological Studies- Depression Scale (CES-D). METHODS: 40 depressed patients 29.65 ± 9.38 years old, and 120 normal controls 27.23 ± 10.62 years old entered the study. In 20 of them (12 patients and 8 controls) the instrument was re-applied 1-2 days later. Translation and Back Translation was made. Clinical Diagnosis was reached by consensus of two examiners with the use of the SCAN v.2.0 and the IPDE. Statistical Analysis included ANOVA, the Pearson Product Moment Correlation Coefficient, Principal Components Analysis and Discriminant Function Analysis and the calculation of Cronbach's alpha (α) RESULTS: Both Sensitivity and specificity exceed 90.00 at 23/24, Chronbach's alpha for the total scale was equal to 0.95. Factor analysis revealed three factors (positive affect, irritability and interpersonal relationships, depressed affect and somatic complains). The test-retest reliability was satisfactory (Pearson's R between 0.45 and 0.95 for individual items and 0.71 for total score). CONCLUSION: The Greek translation of the CES-D scale is both reliable and valid and is suitable for clinical and research use with satisfactory properties. Its properties are similar to those reported in the international literature. However one should always have in mind the limitations inherent in the use of self-report scales

Genetics and not shared environment explains familial resemblance in adult metabolomics data

Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term 'metabolomics' refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.Analytical BioScience

Genome-wide association study identifies novel genetic variants contributing to variation in blood metabolite levels

Metabolites are small molecules involved in cellular metabolism, which can be detected in biological samples using metabolomic techniques. Here we present the results of genome-wide association and meta-analyses for variation in the blood serum levels of 129 metabolites as measured by the Biocrates metabolomic platform. In a discovery sample of 7,478 individuals of European descent, we find 4,068 genome- and metabolome-wide significant (Z-test, P<1.09 × 10¯⁹) associations between single-nucleotide polymorphisms (SNPs) and metabolites, involving 59 independent SNPs and 85 metabolites. Five of the fifty-nine independent SNPs are new for serum metabolite levels, and were followed-up for replication in an independent sample (N=1,182). The novel SNPs are located in or near genes encoding metabolite transporter proteins or enzymes (SLC22A16, ARG1, AGPS and ACSL1) that have demonstrated biomedical or pharmaceutical importance. The further characterization of genetic influences on metabolic phenotypes is important for progress in biological and medical research