Endothelin-1 Drives Epithelial-Mesenchymal Transition In Hypertensive Nephroangiosclerosis

BACKGROUND: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelin‐1 (ET‐1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ET‐1. METHODS AND RESULTS: Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin II–dependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ET‐1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of E‐cadherin and α‐smooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HK‐2 proximal tubular cells expressing the ET(B) receptor subtype, the effects of ET‐1 with or without ET‐1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased E‐cadherin and increased αSMA expression. Irbesartan and the mixed ET‐1 receptor antagonist bosentan prevented these changes in a blood pressure–independent fashion (P < 0.001 for both versus controls). In HK‐2 cells ET‐1 blunted E‐cadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ET(B) receptor antagonist BQ‐788. Evidence for involvement of the Rho‐kinase signaling pathway and dephosphorylation of Yes‐associated protein in EMT was also found. CONCLUSIONS: In angiotensin II–dependent hypertension, ET‐1 acting via ET(B) receptors and the Rho‐kinase and Yes‐associated protein induces EMT and thereby renal fibrosis

WALL SHEAR STRESS TOPOLOGICAL SKELETON IDENTIFICATION IN CARDIOVASCULAR FLOWS: A PRACTICAL APPROACH

The observed co-localization of “disturbed” hemodynamics and atherosclerotic lesion prevalence has led to the identification of low and oscillatory Wall Shear Stress (WSS) as a biomechanical localizing factor for vascular dysfunction. However, recent evidences have underlined how consideration of only “low and oscillatory” WSS may oversimplify the complex hemodynamic milieu to which the endothelium is exposed. In this context, recent studies have highlighted the relevance of WSS fixed points, and the stable and unstable manifolds that connect them. These WSS topological features have a strong link with flow features like flow stagnation, separation, and recirculation, which are usually classified as “disturbed” flow. Technically, a fixed point of a vector field is a point where the vector field vanishes, while unstable/stable vector field manifolds identify contraction/expansion regions linking the fixed points. The set of fixed points and their connections form the topological skeleton of a vector field. The presence of WSS fixed points and of WSS contraction/expansion regions, highlighted by WSS manifolds, might induce focal vascular responses relevant for, e.g., early atherosclerosis, or, aneurysm rupture. For these reasons, the topological skeleton analysis of the WSS vector field is of great interest and motivates the study present herein. Lagrangian techniques have been recently proposed to identify WSS manifolds but have certain practical limitations. A Eulerian approach has also been suggested, but only for 2D analytical fields. Here we propose and demonstrate the use of a simple Eulerian approach for identifying WSS topological skeleton on 3D surfaces

Founder mutations in BRCA1 and BRCA2 genes

BRCA1 and BRCA2 germline mutations contribute to a significant number of familial and hereditary breast and/or ovarian cancers. The proportion of high-risk families with breast and/or ovarian cancer cases due to mutations in these tumor suppressor genes varies widely among populations. In some population, a wide spectrum of different mutations in both genes are present, whereas in other groups specific mutations in BRCA1 and BRCA2 have been reported with high frequency. Most of these mutations are prevalent in restricted populations as consequence of a founder effect. The comparison of haplotypes between families with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event or whether they have arisen independently more than once. Here, we review some of the most well-known and significant examples of founder mutations in BRCA genes found in European and non-European populations. In conclusion, the identification of the ethnic group of families undergoing genetic counseling enables the geneticist and oncologist to make more specific choices, leading to simplify the clinical approach to genetic testing carried out on members of high-risk families. Futhermore, the high frequency of founder mutations, allowing to analyze a large number of cases, might provide accurate information regarding their penetrance

Computational hemodynamics & complex networks integrated platform to study intravascular flow in the carotid bifurcation

The well-established role of hemodynamics in cardiovascular disease [1] makes the study of cardiovascular flows of wide interest. Here we apply for the first time a method based on complex networks (CNs) theory [2] to investigate and characterize quantitatively the complexity of cardiovascular flows. The rationale lies in the ability of CNs to explore the complexity of physical systems, such as 4D cardiovascular flows, in a synthetic and effective manner. CN-based approaches have already proven useful for data-driven learning of dynamical processes that are hidden to other analysis techniques. In detail, a dataset of 10 patient-specific computational hemodynamics models of human carotid bifurcation (CB) is considered here. Quantitative metrics derived from CNs theory are applied to two fluid mechanics quantities describing the intricate intravascular hemodynamics. These are (1) the so-called axial velocity, i.e. the blood velocity component aligned with the main flow direction, as identified by the vessels centerline, and (2) the kinetic helicity density, a measure of pitch and torsion of the streaming blood. The obtained results suggest the potency of CNs in unveiling fundamental organization principles in cardiovascular flows

Specific TP53 and/or Ki-ras mutations as independent predictors of clinical outcome in sporadic colorectal adenocarcinomas: results of a 5-year Gruppo Oncologico dell'Italia Meridionale (GOIM) prospective study.

BACKGROUND: Although Ki-ras and TP53 mutations have probably been the genetic abnormalities most exhaustively implicated and studied in colorectal cancer (CRC) progression, their significance in terms of disease relapse and overall survival has not yet clearly been established. PATIENTS AND METHODS: A prospective study was carried out on paired tumor and normal colon tissue samples from a consecutive series of 160 previously-untreated patients, undergoing resective surgery for primary operable sporadic CRC. Mutations within the TP53 (exons 5-8) and Ki-ras (exon 2) genes were detected by PCR-SSCP analyses following sequencing. RESULTS: Mutation analyses of exons 5 to 8 of the TP53 gene showed mutations in 43% (68/160) of the cases, while mutation analyses of exon 2 of the Ki-ras gene showed mutations in 46% (74/160) of the cases. Multivariate analyses showed that clinical outcome were strongly associated with the presence of specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13. CONCLUSION: Specific TP53 mutations in L3 domain alone (only in DFS) or in combination with specific Ki-ras mutations at codon 13 are associated with a worse prognosis in sporadic CRC

Wall shear stress topological skeleton analysis in cardiovascular flows: Methods and applications

A marked interest has recently emerged regarding the analysis of the wall shear stress (WSS) vector field topological skeleton in cardiovascular flows. Based on dynamical system theory, the WSS topological skeleton is composed of fixed points, i.e., focal points where WSS locally vanishes, and unstable/stable manifolds, consisting of contraction/expansion regions linking fixed points. Such an interest arises from its ability to reflect the presence of near-wall hemodynamic features associated with the onset and progression of vascular diseases. Over the years, Lagrangian-based and Eulerianbased post-processing techniques have been proposed aiming at identifying the topological skeleton features of the WSS. Here, the theoretical and methodological bases supporting the Lagrangian- and Eulerian-based methods currently used in the literature are reported and discussed, highlighting their application to cardiovascular flows. The final aim is to promote the use of WSS topological skeleton analysis in hemodynamic applications and to encourage its application in future mechanobiology studies in order to increase the chance of elucidating the mechanistic links between blood flow disturbances, vascular disease, and clinical observations

BRCA1 genetic testing in 106 breast and ovarian cancer families from southern Italy (Sicily): a mutation analyses.

PURPOSE: To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile. EXPERIMENTAL DESIGN: A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the "Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors" at the University of Palermo. Genetic counselling allowed us to recruit a total of 106 unrelated families affected with breast and/or ovarian cancer screened for mutations occurring in the whole BRCA1 gene by automatic direct sequencing. RESULTS: Germline BRCA1 mutations were found in 17 of 106 (16%) Sicilian families. The HBOC profile had a major frequency (66%) of mutations (P < 0.01). A total of 28 sequence variants was identified. Seven of these were pathogenic, 5 unknown biological variant (UV) and 16 polymorphisms. We also identified a pathological mutation (4843delC) as a possible Sicilian founder mutation. CONCLUSIONS: The present study is the first BRCA1 disease-associated mutations analysis in Southern Italian families. The early age of onset of such tumors and the association with the HBOC familial profile could be two valid screening factors for the identification of BRCA1 mutation carriers. Finally, we identified a BRCA1 mutation with a possible founder effec