Maxwell C.A.,Catalan Institute of Nanoscience and Nanotechnology |
Maxwell C.A.,Child and Family Research Institute |
Benitez J.,Spanish National Cancer Research Center |
Benitez J.,Biomedical Research Center Network for Rare Diseases |
And 155 more authors.
PLoS Biology | Year: 2011
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio (wHR) = 1.09 (95% CI 1.02-1.16), ptrend = 0.017; and n = 3,965, wHR = 1.04 (95% CI 0.94-1.16), ptrend = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM. © 2011 Maxwell et al. Source
Sanchez-Santos R.,Complejo Hospitalario Universitario Of Pontevedra |
Corcelles Codina R.,Hospital Clinic de Barcelona |
Vilallonga Puy R.,Hospital Universitario Valld Hebron |
Delgado Rivilla S.,Hospital Clinic de Barcelona |
And 26 more authors.
Obesity Surgery | Year: 2016
Background: Complications in sleeve gastrectomy (SG) can cast a shadow over the technique’s good results and compromise its safety. The aim of this study is to identify risk factors for complications, and especially those that can potentially be modified to improve safety. Methods: A retrospective multicenter cohort study was carried out, involving the participation of 29 hospitals. Data was collected on demographic variables, associated comorbidities, technical modifications, the surgeon's experience, and postoperative morbimortality. A multivariate logistic regression analysis was carried out on risk factors (RFs) for the complications of leak/fistula, hemoperitoneum, pneumonia, pulmonary embolism, and death. Results: The following data were collected for 2882 patients: age, 43.85 ± 11.6. 32.9 % male; BMI 47.22 ± 8.79; 46.2 % hypertensive; 29.2 % diabetes2; 18.2 % smokers; bougie calibre ≥40 F 11.1 %; complications 11.7 % (2.8 % leaks, 2.7 % hemoperitoneum, 1.1 % pneumonia, 0.2 % pulmonary embolism); and death 0.6 %. RFs for complications were as follows: surgeon’s experience < 20 patients, OR 1.72 (1.32–2.25); experience > 100 patients, OR 0.78 (0.69–0.87); DM2, OR1.48(1.12–1.95); probe > 40 F, OR 0.613 (0.429–0.876). Leak RFs were the following: smoking, OR1.93 (1.1–3.41); surgeon’s experience < 20 patients, OR 2.4 (1.46–4.16); experience of 20–50 patients, OR 2.5 (1.3–4.86); experience >100 patients, OR 0.265 (0.11–0.63); distance to pylorus > 4 cm, OR 0.510 (0.29–0.91). RFs for death were as follows: smoking, OR 8.64 (2.63–28.34); DM2, OR 3.25 (1.1–9.99); distance to pylorus < 5 cm, OR 6.62 (1.63–27.02). Conclusions: The safety of SG may be compromised by nonmodifiable factors such as age >65, patient comorbidities (DM2, hypertension), and prior treatment with anticoagulants, as well as by modifiable factors such as smoking, bougie size <40 F, distance to the pylorus <4 cm, and the surgeon’s experience (<50–100 cases). © 2016 Springer Science+Business Media New York Source
Pasut G.,University of Padua |
Panisello A.,Institute of Biomedical Research of Barcelona |
Folch-Puy E.,Institute of Biomedical Research of Barcelona |
Lopez A.,University Paris - Sud |
And 6 more authors.
World Journal of Gastroenterology | Year: 2016
Liver ischemia-reperfusion injury (IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ (ischemia) is exacerbated following the return of oxygen delivery (reperfusion). IRI is a major cause of primary nonfunction after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions (antioxidants, anticytokines, etc. ) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols (PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI. © The Author(s) 2016. Source
Jurado J.C.,Hospital Universitario Canarias |
Aznar P.R.,Hospital de Manises |
Martinez R.F.,Hospital de Cabuenes |
Fernandez I.P.,Hospital de Cabuenes |
And 5 more authors.
Advances in Therapy | Year: 2011
Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Aromatase inhibitors (AI) have been extensively studied in this setting. This section summarizes the key data regarding the use of AI in advanced breast cancer. In postmenopausal women, AI are the first line of treatment for untreated patients, or those who had prior AI treatment and progress after 12 months of adjuvant therapy. A longer disease-free interval and absence of visceral disease is associated with a better response. If tumors recur in less than 12 months, it is recommended that tamoxifen (TAM) or the estrogen-receptor antagonist fulvestrant (FUL) treatment be initiated. In the second-line setting, the best option after progression is the administration of either FUL or TAM. In the third- line setting, reintroduction of AI is considered an acceptable option. In premenopausal women who have not received prior treatment or who have progressed after 12 months following adjuvant treatment, it is recommended to initiate therapy with a combination of TAM and a luteinizing hormone-releasing hormone (LHRH) analog. If there is treatment failure with the use of this combination, megestrol acetate or an LHRH agonist plus an AI may be reasonable alternatives. Intensive research is ongoing to understand the mechanisms of resistance to hormone therapy. In human epidermal growth factor receptor 2 positive-patients, combinationswith HER2 antagonists are associated with significant clinical activity. © © Springer Healthcare 2011. Source
Alonso-Espinaco V.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas |
Cuatrecasas M.,University of Barcelona |
Alonso V.,Hospital Miguel Servet |
Escudero P.,Hospital Clinico de Zaragoza |
And 11 more authors.
European Journal of Cancer | Year: 2014
Introduction Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF V600E mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC. Methods We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy. Results KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p = 0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p = 0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p = 0.01) in KRAS/BRAF WT mCRC patients. Conclusions RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy. © 2014 Elsevier Ltd. All rights reserved. Source