Elevated Expression of Stromal Palladin Predicts Poor Clinical Outcome in Renal Cell Carcinoma

The role that stromal renal cell carcinoma (RCC) plays in support of tumor progression is unclear. Here we sought to determine the predictive value on patient survival of several markers of stromal activation and the feasibility of a fibroblast-derived extracellular matrix (ECM) based three-dimensional (3D) culture stemming from clinical specimens to recapitulate stromal behavior in vitro. The clinical relevance of selected stromal markers was assessed using a well annotated tumor microarray where stromal-marker levels of expression were evaluated and compared to patient outcomes. Also, an in vitro 3D system derived from fibroblasts harvested from patient matched normal kidney, primary RCC and metastatic tumors was employed to evaluate levels and localizations of known stromal markers such as the actin binding proteins palladin, alpha-smooth muscle actin (α-SMA), fibronectin and its spliced form EDA. Results suggested that RCCs exhibiting high levels of stromal palladin correlate with a poor prognosis, as demonstrated by overall survival time. Conversely, cases of RCCs where stroma presents low levels of palladin expression indicate increased survival times and, hence, better outcomes. Fibroblast-derived 3D cultures, which facilitate the categorization of stromal RCCs into discrete progressive stromal stages, also show increased levels of expression and stress fiber localization of α-SMA and palladin, as well as topographical organization of fibronectin and its splice variant EDA. These observations are concordant with expression levels of these markers in vivo. The study proposes that palladin constitutes a useful marker of poor prognosis in non-metastatic RCCs, while in vitro 3D cultures accurately represent the specific patient's tumor-associated stromal compartment. Our observations support the belief that stromal palladin assessments have clinical relevance thus validating the use of these 3D cultures to study both progressive RCC-associated stroma and stroma-dependent mechanisms affecting tumorigenesis. The clinical value of assessing RCC stromal activation merits further study

Lack of CD151/integrin alpha 3 beta 1 complex is predictive of poor outcome in node-negative lobular breast carcinoma: opposing roles of CD151 in invasive lobular and ductal breast cancers

background: The proposed involvement of CD151 in breast cancer (BCa) progression is based on findings from studies in invasive ductal carcinoma (IDC). The IDC and invasive lobular carcinoma (ILC) represent distinct disease entities. Here we evaluated clinical significance of CD151 alone and in association with integrin α3β1 in patients with ILC in context of the data of our recent IDC study. methods: Expression of CD151 and/or integrin α3β1 was evaluated in ILC samples (N=117) using immunohistochemistry. The findings were analysed in relation to our results from an IDC cohort (N=182) demonstrating a prognostic value of an expression of CD151/integrin α3β1 complex in patients with HER2-negative tumours. results: Unlike in the IDCs, neither CD151 nor CD151/α3β1 complex showed any correlation with any of the ILC characteristics. Lack of both CD151 and α3β1 was significantly correlated with poor survival (P=0.034) in lymph node-negative ILC N(−) cases. The CD151−/α3β1− patients had 3.12-fold higher risk of death from BCa in comparison with the rest of the ILC N(−) patients. conclusions: Biological role of CD151/α3β1 varies between ILC and IDC. Assessment of CD151/α3β1 might help to identify ILC N(−) patients with increased risk of distant metastases

Simple scoring system to predict in-hospital mortality after surgery for infective endocarditis

BACKGROUND: Aspecific scoring systems are used to predict the risk of death postsurgery in patients with infective endocarditis (IE). The purpose of the present study was both to analyze the risk factors for in-hospital death, which complicates surgery for IE, and to create a mortality risk score based on the results of this analysis. METHODS AND RESULTS: Outcomes of 361 consecutive patients (mean age, 59.1\ub115.4 years) who had undergone surgery for IE in 8 European centers of cardiac surgery were recorded prospectively, and a risk factor analysis (multivariable logistic regression) for in-hospital death was performed. The discriminatory power of a new predictive scoring system was assessed with the receiver operating characteristic curve analysis. Score validation procedures were carried out. Fifty-six (15.5%) patients died postsurgery. BMI >27 kg/m2 (odds ratio [OR], 1.79; P=0.049), estimated glomerular filtration rate 55 mm Hg (OR, 1.78; P=0.032), and critical state (OR, 2.37; P=0.017) were independent predictors of in-hospital death. A scoring system was devised to predict in-hospital death postsurgery for IE (area under the receiver operating characteristic curve, 0.780; 95% CI, 0.734-0.822). The score performed better than 5 of 6 scoring systems for in-hospital death after cardiac surgery that were considered. CONCLUSIONS: A simple scoring system based on risk factors for in-hospital death was specifically created to predict mortality risk postsurgery in patients with IE

The Membrane-targeted Alkylphosphocholine Erufosine Interferes with Survival Signals from the Extracellular Matrix

Integrin-dependent adhesion of tumor cells to extracellular matrix proteins provides anchorage-dependent protection from cell death. In the present investigation we aimed to understand whether and how the paradigmatic membrane-targeted synthetic phospholipid analog erufosine is relevant for tumor cell adhesion to extracellular matrix proteins, cell survival and migration. The antineoplastic action of erufosine was analyzed with glioblastoma and prostate cancer cells adhering to fibronectin or collagen I using proliferation, adhesion and migration assays. The composition of adhesion contacts containing activated beta 1 integrins was studied using immunofluorescence. The importance of beta 1 integrins for the observed effects was analyzed in fibroblasts proficient or deficient in beta 1 integrin expression. Adhesion to collagen I and fibronectin increased the death threshold in serum-deprived tumor cells. Moreover, beta 1 integrin-deficient cells were more sensitive to erufosine-treatment compared to beta 1 integrin proficient cells suggesting a role of beta 1 integrins for matrix-mediated death resistance. Most importantly, erufosine disturbed the maturation of the cell adhesion complexes containing paxillin, activated beta 1 integrins and phosphorylated FAK, leading to a reduction of survival signals and inhibition of tumor cell adhesion and migration. These findings suggest that membrane-targeted synthetic phospholipids analogs may be of value for counteracting matrix-mediated treatment resistance in combined treatment approaches with radiotherapy or chemotherapy

Wolff-Parkinson-White syndrome in the elderly: clinical and electrophysiological findings

SummaryBackgroundScreening for Wolff-Parkinson-White (WPW) syndrome is recommended in children and young adults. The aim of this study was to evaluate the clinical and electrophysiological characteristics of patent WPW syndrome in subjects ≥60 years of age.MethodsFour-hundred and fifty-nine consecutive patients with WPW syndrome, aged 8–80 years, were recruited; 32 (7%) of these patients were ≥60 years of age. The clinical, electrophysiological and therapeutic data for these patients were evaluated.ResultsSixteen men and 16 women, aged 60–81 years (67±4.5), were admitted for resuscitated sudden death (1), rapid atrial fibrillation (4), syncope (4), or junctional tachycardia (13); 10 patients were asymptomatic (10). Left lateral bundles of Kent were detected more frequently in patients over 60 years (56%) than in those < 60 years of age (40.5%). Reciprocal tachycardia was induced in 58% of subjects <60 years of age and 53% of those ≥60 years old (difference not significant); atrial fibrillation was more frequent in subjects ≥ 60 years of age (37.5%vs. 19%) (p<0.05). The incidence of malignant forms of WPW syndrome was identical in older and younger subjects. Ablation of the accessory pathway was indicated 18 times; effective ablation of a left bundle of Kent required a second intervention more often in patients ≥60 years of age (22%vs. 5%) (p<0.05).ConclusionWPW syndrome is not uncommon in subjects over 60 years of age (7%). Left lateral accessory pathways, that have similar conduction properties to those in much younger subjects, are common. Ablation of the bundle of Kent is often difficult but is indicated in symptomatic subjects or those with more serious forms of WPW syndrome

Role of the RhoGTPases in the cellular receptivity and reactivity to mechanical signals including microgravity

The small G proteins of the Rho Family (RhoGTPases) are key operators in the signaling arising from extracellular matrix through integrin receptors and from membrane receptors for soluble ligands. FLight data show that microgravity affects cell architecture and gene expression leading us to assume that the signaling pathways(s) involving the RhoGTPAses might disturbed in a weightlessness environment. TO test this hypothesis in microgravityu, we created genetically engineered human fibroblasts that will be used in Biolab on the ISS