Time filter

Source Type

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.


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.


PubMed | CNR Institute of Neuroscience, RAS Engelhardt Institute of Molecular Biology, Sant'Anna School of Advanced Studies, Pisa Science Foundation and 4 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics. Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was on in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned off upon homing at metastatic sites. In vitro, MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition. Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.


PubMed | Joan wards Cancer Center, CNR Institute of Neuroscience, University of Naples Federico II, Marshall University and 5 more.
Type: Journal Article | Journal: 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.


PubMed | University of Rome La Sapienza, U.O.C Anatomia Patologica, Medical Genetics Unit and Bambino Gesu Childrens Hospital
Type: | Journal: Molecular cytogenetics | Year: 2015

Interstitial deletions of the long arm of chromosome 14 involving the 14q24-q32 region have been reported in less than 20 patients. Previous studies mainly attempted to delineate recognizable facial dysmorphisms; conversely, descriptions on neurological features are limited to the presence of cognitive and motor delay, but no better characterization exists.In this paper we report on a patient with a de novo interstitial deletion of 5.5Mb at 14q24.3-q31.1. The deletion encompasses 84 genes, including fourteen Mendelian genes. He presented with dysmorphic face, developmental delay, paroxysmal non-epileptic events and, subsequently, epilepsy.The clinical and molecular evaluation of this patient and the review of the literature expand the phenotype of 14q23-q32 deletion syndrome to include paroxysmal non-epileptic events and infantile-onset focal seizures.


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.


Golan-Gerstl R.,Hebrew University of Jerusalem | Cohen M.,Hebrew University of Jerusalem | Shilo A.,Hebrew University of Jerusalem | Suh S.-S.,Ohio State University | And 3 more authors.
Cancer Research | Year: 2011

The process of alternative splicing is widely misregulated in cancer, but the contribution of splicing regulators to cancer development is largely unknown. In this study, we found that the splicing factor hnRNP A2/B1 is overexpressed in glioblastomas and is correlated with poor prognosis. Conversely, patients who harbor deletions of the HNRNPA2B1 gene show better prognosis than average. Knockdown of hnRNP A2/B1 in glioblastoma cells inhibited tumor formation in mice. In contrast, overexpression of hnRNP A2/B1 in immortal cells led to malignant transformation, suggesting that HNRNPA2B1 is a putative proto-oncogene. We then identified several tumor suppressors and oncogenes that are regulated by HNRNPA2B1, among them are c-FLIP, BIN1, and WWOX, and the proto-oncogene RON. Knockdown of RON inhibited hnRNP A2/B1 mediated transformation, which implied that RON is one of the mediators of HNRNPA2B1 oncogenic activity. Together, our results indicate that HNRNPA2B1 is a novel oncogene in glioblastoma and a potential new target for glioblastoma therapy. ©2011 AACR.


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.


PubMed | U.O.C Anatomia Patologica and Laboratorio Of Genetica Medica
Type: | Journal: Molecular cytogenetics | Year: 2015

Pure interstitial duplications of chromosome band 4p16.3 represent an infrequent chromosomal finding with, to the best of our knowledge, only two patients to date reported.We report on a 13-year-old boy showing a set of dysmorphic facial features, attention deficit hyperactivity disorders, learning difficulties, speech and cognitive delays, overgrowth and musculoskeletal anomalies in whom an interstitial duplication of about 400kb in 4p16.3 was detected by SNP-array analysis. The duplication includes the complete coding sequence of FAM53A, SLBP, TMEM129 and TACC3 genes and the first exon of the FGFR3 gene. Phenotypic comparison with previously described patients harboring a microduplication of similar size and position contributes to better define the clinical correlation of 4p16.3 microduplications, suggesting the existence of a novel distinct and phenotypically recognizable syndrome. In addition, being the duplication identified in our case the smallest so far reported, it allowed us to refine the smallest region of overlap among patients to 222kb, enabling a more accurate genotype-phenotype correlation for 4p16.3 microduplications.Our case report provide clinical and molecular evidences supporting the existence of a novel 4p16.3 microduplication syndrome. The genes FAM53A, TACC3 and FGFR3 seems to play a key role in the etiology of the clinical phenotype. Interestingly, our patient is the oldest described so far and for this reason useful to delineate the long-term prognosis of these patients.


PubMed | U.O.C. Anatomia Patologica
Type: Case Reports | Journal: Pathologica | Year: 2013

Fibrous hamartoma of infancy is a soft tissue subdermal fibromatous tumour that characteristically occurs in the first years of life. It is histologically composed of three different components that are intimately admixed: well-defined bundles of fibro-myofibroblastic spindle-shaped cells, nodular proliferations of immature-looking mesenchymal cells set in a myxoid stroma, and mature adipose tissue. A wide intralesional and interlesional cellular composition is commonly observed. Fibrous hamartoma of infancy usually arises from subcutaneous tissue of the trunk, axilla, upper extremities and inguinal region. Only rarely has fibrous hamartoma of infancy been reported in genital organs, with only one case described in the labium majus. We report a rare case of fibrous hamartoma of infancy in the labium majus of a 1-year old female child. Ultrasonography revealed the presence of a mass-like lesion involving subcutaneous tissue, with ill-defined margins. We emphasize that fibrous hamartoma of infancy should be included in the differential diagnosis of soft tissue tumour-like and tumour lesions of the vulva in children. Awareness that fibrous hamartoma of infancy occurs at this site with irregular margins is important to avoid confusion with other lesions exhibiting a more aggressive behaviour.

Loading UOC Anatomia Patologica collaborators
Loading UOC Anatomia Patologica collaborators