p130Cas is an essential transducer element in ErbB2 transformation

The ErbB2 oncogene is often overexpressed in breast tumors and associated with poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration, and proliferation in normal and pathological cells. The functional role of p130Cas in ErbB2-dependent breast tumorigenesis was assessed by its silencing in breast cancer cells derived from mouse mammary tumors overexpressing ErbB2 (N202-1A cells), and by its reexpression in ErbB2-transformed p130Cas-null mouse embryonic fibroblasts. We demonstrate that p130Cas is necessary for ErbB2-dependent foci formation, anchorage-independent growth, and in vivo growth of orthotopic N202-1A tumors. Moreover, intranipple injection of p130Cas-stabilized siRNAs in the mammary gland of Balbc-NeuT mice decreases the growth of spontaneous tumors. In ErbB2-transformed cells, p130Cas is a crucial component of a functional molecular complex consisting of ErbB2, c-Src, and Fak. In human mammary cells, MCF10A.B2, the concomitant activation of ErbB2, and p130Cas overexpression sustain and strengthen signaling, leading to Rac1 activation and MMP9 secretion, thus providing invasive properties. Consistently, p130Cas drives N202-1A cell in vivo lung metastases colonization. These results demonstrate that p130Cas is an essential transducer in ErbB2 transformation and highlight its potential use as a novel therapeutic target in ErbB2 positive human breast cancers.-Cabodi, S., Tinnirello, A., Bisaro, B., Tornillo, G., Camacho-Leal, M. P., Forni, G., Cojoca, R., Iezzi, M., Amici, A., Montani, M., Eva, A., Di Stefano, P., Muthuswamy, S. K., Tarone, G., Turco, E., Defilippi, P. p130Cas is an essential transducer element in ErbB2 transformation

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

New alternative splicing BCR/ABL-OOF shows an oncogenic role by lack of inhibition of BCR GTPase activity and an increased of persistence of Rac activation in chronic myeloid leukemia

In Chronic Myeloid Leukemia 80% of patients present alternative splice variants involving BCR exons 1, 13 or 14 and ABL exon 4, with a consequent impairment in the reading frame of the ABL gene. Therefore BCR/ABL fusion proteins (BCR/ABL-OOF) are characterized by an in-frame BCR portion followed by an amino acids sequence arising from the out of frame (OOF) reading of the ABL gene. The product of this new transcript contains the characteristic BCR domains while lacking the COOH-terminal Rho GTPase GAP domain. The present work aims to characterize the protein functionality in terms of cytoskeleton (re-)modelling, adhesion and activation of canonical oncogenic signalling pathways. Here, we show that BCR/ABL-OOF has a peculiar endosomal localization which affects EGF receptor activation and turnover. Moreover, we demonstrate that BCR/ABL-OOF expression leads to aberrant cellular adhesion due to the activation of Rac GTPase, increase in cellular proliferation, migration and survival. When overexpressed in a BCR/ABL positive cell line, BCR/ABL-OOF induces hyperactivation of Rac signaling axis offering a therapeutic window for Rac-targeted therapy. Our data support a critical role of BCR/ABL-OOF in leukemogenesis and identify a subset of patients that may benefit from Rac-targeted therapies

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction

Background: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cardiac troponin (cTn) assays. However, it remains to be determined how to diagnose, risk stratify and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. Methods: Patients presenting to the Emergency Department with chest pain, enrolled in the CHOPIN study, were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic (ROC) curve analysis. The biomarkers analyzed were cTnI, copeptin, mid-regional pro-atrial natriuretic peptide (MRproANP), C-terminal pro-endothelin-1 (CT-proET1), mid-regional pro-adrenomedullin (MRproADM) and procalcitonin. Prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (MACE: a composite of acute MI, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. Results: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, while those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the ROC curve (AUC) for the diagnosis of T2MI was higher for CT-proET1, MRproADM and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, p = 0.294). Addition of biomarkers to the clinical model yielded the highest AUC (0.917). Other biomarkers, but not cTnI, were associated with mortality and MACE at 180-day among all patients, with no interaction between the diagnosis of T1MI or T2MI. Conclusions: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. Additionally, all biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of type of MI

Risk factors for cardiovascular disease across the spectrum of older age: The Cardiovascular Health Study

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age. METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP). RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45). CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age

Oncoplastic and reconstructive surgery in SENONETWORK Italian breast centers: lights and shadows

Highlights: • Despite the significance of oncoplastic procedure, an italian database is lacking. • Senonetwork established a multidisciplinary survey to assess their safety and efficacy. • Reconstructive outcomes were positive across low and high-volume centers. • After mastectomy, implant-based techniques are common. DTI reconstruction is advantageuos. • This contributes to the global understanding of effective strategies against breast cancer

Chronic Kidney Disease and Coronary Artery Disease: JACC State-of-the-Art Review

Chronic kidney disease (CKD) is a major risk factor for coronary artery disease (CAD). As well as their high prevalence of traditional CAD risk factors, such as diabetes and hypertension, persons with CKD are also exposed to other nontraditional, uremia-related cardiovascular disease risk factors, including inflammation, oxidative stress, and abnormal calcium-phosphorus metabolism. CKD and end-stage kidney disease not only increase the risk of CAD, but they also modify its clinical presentation and cardinal symptoms. Management of CAD is complicated in CKD patients, due to their\ua0likelihood of comorbid conditions and potential for side effects during interventions. This summary of the Kidney\ua0Disease: Improving Global Outcomes (KDIGO) Controversies Conference on CAD and CKD (including end-stage\ua0kidney disease and\ua0transplant recipients) seeks to improve understanding of the epidemiology, pathophysiology, diagnosis, and\ua0treatment of CAD in CKD and to identify knowledge gaps, areas of controversy, and\ua0priorities for research

Elevated plasma levels of cardiac troponin-I predict left ventricular systolic dysfunction in patients with myotonic dystrophy type 1:A multicentre cohort follow-up study

Objective: High sensitivity plasma cardiac troponin-I (cTnI) is emerging as a strong predictor of cardiac events in a variety of settings. We have explored its utility in patients with myotonic dystrophy type 1 (DM1). Methods: 117 patients with DM1 were recruited from routine outpatient clinics across three health boards. A single measurement of cTnI was made using the ARCHITECT STAT Troponin I assay. Demographic, ECG, echocardiographic and other clinical data were obtained from electronic medical records. Follow up was for a mean of 23 months. Results: Fifty five females and 62 males (mean age 47.7 years) were included. Complete data were available for ECG in 107, echocardiography in 53. Muscle Impairment Rating Scale score was recorded for all patients. A highly significant excess (p = 0.0007) of DM1 patients presented with cTnI levels greater than the 99th centile of the range usually observed in the general population (9 patients; 7.6%). Three patients with elevated troponin were found to have left ventricular systolic dysfunction (LVSD), compared with four of those with normal range cTnI (33.3% versus 3.7%; p = 0.001). Sixty two patients had a cTnI level &#60; 5ng/L, of whom only one had documented evidence of LVSD. Elevated cTnI was not predictive of severe conduction abnormalities on ECG, or presence of a cardiac device, nor did cTnI level correlate with muscle strength expressed by Muscle Impairment Rating Scale score. Conclusions: Plasma cTnI is highly elevated in some ambulatory patients with DM1 and shows promise as a tool to aid cardiac risk stratification, possibly by detecting myocardial involvement. Further studies with larger patient numbers are warranted to assess its utility in this setting

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7