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Valenti L.,University of Milan | Al-Serri A.,Northumbria University | Daly A.K.,Northumbria University | Enrico Galmozzi,University of Milan | And 11 more authors.
Hepatology | Year: 2010

Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 CfiG polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] 5 3.29, 95% confidence interval [CI] 5 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P 5 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR 5 1.35, 95% CI 5 1.04-1.76), nonalcoholic steatohepatitis (OR 5 1.5, 95% CI 5 1.12-2.04), and fibrosis stage >1 (OR 5 1.5, 95% CI 5 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes. Conclusion: In patients with NAFLD, adiponutrin rs738409 CfiG genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis. Copyright © 2010 by the American Association for the Study of Liver Diseases. Source

Tortorano A.M.,University of Milan | Carminati G.,Fondazione IRCCS Ospedale Maggiore Policlinico | Tosoni A.,UOC Anatomia Patologica | Tintelnot K.,Robert Koch Institute
Mycopathologia | Year: 2015

Coccidioidomycosis is a systemic disease caused by the dimorphic fungus Coccidioides, endemic in parts of the Southwestern USA and Central and South America. Two species, Coccidioides immitis and Coccidioides posadasii, were differentiated. Primary cutaneous coccidioidomycosis (PCC) has been reported rarely. An unusual case of PCC characterized by a persistent solitary lesion diagnosed in Italy in an immunocompetent Italian nun living in Argentina is described. The isolate was identified by sequence analysis as C. posadasii. Antibody screening was negative. A total of 39 cases of PCC have been reported in the literature. Infections occurred as a consequence of traumatic implantation in a natural setting in endemic areas or of accidental inoculation in laboratory workers. Importance of accurate investigation of travel history and of occupational hazards to laboratory workers is outlined. © 2015, Springer Science+Business Media Dordrecht. Source

Romeo V.,UOC Chirurgia I | Farina M.,UOC Chirurgia I | Petrangeli S.,UOC Chirurgia I | Campagna D.,UOC Anatomia Patologica | Vitelli C.E.,UOC Chirurgia I
Clinica Terapeutica | Year: 2014

Primary Adenocarcinomas of the appendix are rare tumor. Most commonly diagnosis was made after surgical pocedure of appendicectomy for suspect acute appendicitis and the pathology report confirms appendiceal neoplasm. Laboratory exams and imaging show low sensibility and specificity for preoperative diagnosis. We report two cases of primary mucinous adenocarcinoma in caucasian men misdiagnosed as having acute appendicitis. Appendicectomy was done and excised appendix was sent for histopathological examination. Mucinous Adenocarcinoma of the appendix was confirmed after histopathological examination. Right hemicolectomy, peritonectomy and Intraoperative Hyperthermic Chemotherapy were done as a second stage procedure. The surgical treatment of these neoplasms depends from the histological stage and local presentation. Cytoreductive surgery associated with Intraoperative Hyperthermic Chemotherapy show best results in advanced cases. © 2014. Società Editrice Universo (SEU). Source

Valenti L.,University of Milan | Canavesi E.,University of Milan | Galmozzi E.,University of Milan | Dongiovanni P.,University of Milan | And 5 more authors.
Journal of Hepatology | Year: 2010

Background & Aims: Parenchymal liver siderosis is associated with increased fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to assess whether a panel of genetic variants previously reported to influence iron metabolism, including the C282Y/H63D HFE, the PiZ/PiS alpha1-antitrypsin, the IVS1-24 ferroportin polymorphisms, and the beta-thalassemia trait, may be able to predict the presence of parenchymal siderosis and of progressive fibrosis in NAFLD. Methods: We considered 274 Italian patients with biopsy-proven NAFLD. Genetic polymorphisms were searched for by sequence allele specific-polymerase chain reaction and restriction analysis, whereas beta-trait was determined according to blood count and HbA2 determination. Results: Parenchymal iron deposition was predominantly observed in 32 (11.7%) patients. Heterozygosity for the C282Y (OR 1.87, 95% CI 1.04-3.25), homozygosity for the H63D HFE (OR 2.31, 95% CI 1.04-4) mutations, and the beta-thalassemia trait (OR 2.57 95% CI 1.49-4.47) were all predominantly associated with parenchymal siderosis, independently of age, sex, body mass index, alcohol intake, ferritin, and transferrin saturation. Sixty-three percent of patients with hepatocellular siderosis were positive for at least one of the aforementioned genetic variants. The beta-thalassemia trait had the highest positive and the lowest negative likelihood ratios for predominantly parenchymal iron accumulation (5.05 and 0.74, respectively), and was independently associated with moderate/severe fibrosis (OR 2.50, 95% CI 1.26-5.19). Conclusions: In patients with NAFLD, predominant hepatocellular iron deposition is often related to genetic factors, among which beta-globin mutations play a major role, predisposing to parenchymal iron accumulation and to progressive liver fibrosis. © 2010 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. Source

Morra F.,CNR Institute of Neuroscience | Morra F.,University of Naples Federico II | Luise C.,CNR Institute of Neuroscience | Merolla F.,CNR Institute of Neuroscience | And 16 more authors.
Oncotarget | Year: 2015

CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet. We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response. Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy. Source

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