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Tessitore A.,University of LAquila | Cicciarelli G.,University of LAquila | Del Vecchio F.,University of LAquila | Gaggiano A.,University of LAquila | And 9 more authors.
BMC Cancer | Year: 2015

Background: Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver. Non-alcoholic fatty liver disease (NAFLD) is a frequent chronic liver disorder in developed countries. NAFLD can progress through the more severe non alcoholic steatohepatitis (NASH), cirrhosis and, lastly, HCC. Genetic and epigenetic alterations of coding genes as well as deregulation of microRNAs (miRNAs) activity play a role in HCC development. In this study, the C57BL/6J mouse model was long term high-fat (HF) or low-fat (LF) diet fed, in order to analyze molecular mechanisms responsible for the hepatic damage progression. Methods: Mice were HF or LF diet fed for different time points, then plasma and hepatic tissues were collected. Histological and clinical chemistry assays were performed to assess the progression of liver disease. MicroRNAs' differential expression was evaluated on pooled RNAs from tissues, and some miRNAs showing dysregulation were further analyzed at the individual level. Results: Cholesterol, low and high density lipoproteins, triglycerides and alanine aminotransferase increase was detected in HF mice. Gross anatomical examination revealed hepatomegaly in HF livers, and histological analysis highlighted different degrees and levels of steatosis, inflammatory infiltrate and fibrosis in HF and LF animals, demonstrating the progression from NAFLD through NASH. Macroscopic nodules, showing typical neoplastic features, were observed in 20 % of HF diet fed mice. Fifteen miRNAs differentially expressed in HF with respect to LF hepatic tissues during the progression of liver damage, and in tumors with respect to HF non tumor liver specimens were identified. Among them, miR-340-5p, miR-484, miR-574-3p, miR-720, whose expression was never described in NAFLD, NASH and HCC tissues, and miR-125a-5p and miR-182, which showed early and significant dysregulation in the sequential hepatic damage process. Conclusions: In this study, fifteen microRNAs which were modulated in hepatic tissues and in tumors during the transition NAFLD-NASH-HCC are reported. Besides some already described, new and early dysregulated miRNAs were identified. Functional analyses are needed to validate the results here obtained, and to better define the role of these molecules in the progression of the hepatic disease. © 2015 Tessitore et al.

Fiotti N.,Unit of Clinica Medica Generale e Terapia Medica | Mearelli F.,C O Clinica Medica Generale | Ruscio M.,Unit of Laboratory Medicine | Altamura N.,Unit of Clinica Medica Generale e Terapia Medica | And 12 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2014

Background: A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. Methods: In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. Results: Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with noninfective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p < 0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7-78.9) and 78.2% (69.8-87.2), respectively, compared to the 55% (44.2-66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. Conclusions: In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.

Fabris M.,University of Udine | Zago S.,University of Udine | Liguori M.,Laboratory of Clinical Pathology | Trevisan M.T.,Unit of Laboratory Medicine | And 6 more authors.
Autoimmunity Highlights | Year: 2015

Background and aim: Anti-ZnT8 antibodies (ZnT8A) were recently proposed as a new independent serological marker in Type 1 diabetes (T1D), leading to a significant improvement of the positive predictive value of autoantibody measurement in this setting. The aim of this retrospective multicentre study was to investigate ZnT8A as a complement to the current T1D autoantibody assays in a large cohort of paediatric Italian patients. Methods: ZnT8A were assessed by ELISA in 213 T1DM paediatric patients referred to six different centres in North-East Italy. Fifty-four were analysed at disease onset, 79 within 4 years from diagnosis and 80 after 5 or more years from diagnosis. Retrospective data about islet cell autoantibodies (ICA), anti-insulin (IAA), anti-glutamate decarboxylase (GADA) and anti-protein tyrosine phosphatase IA-2 (IA-2A) antibodies were collected and compared. Results: Overall, ZnT8A showed positive results in 106/213 (49.8 %) T1D patients and were found in 10 (4.7 %) subjects previously classified as autoantibody negative based on the existing markers (GADA, IA-2A, IAA and ICA), increasing the overall diagnostic sensitivity from 85.9 to 90.6 %. ZnT8A disclosed the same sensitivity (61.1 %) at disease onset as GADA (61.1 %) and higher than IA-2A (53.7 %), with only GADA showing much persistence in the long-term follow-up. Focusing on patients at disease onset, all the ICA positive were associated with at least one positive autoantibody among GADA, IA-2A and ZnT8A, 16.7 % of whom presenting only anti-ZnT8-positive antibodies. Conclusion: This study confirms ZnT8A as an important additional and independent diagnostic marker of T1D and supports its introduction in the routine diagnostic process to replace less sensitive methods and improve the overall autoantibody sensitivity. © 2015, The Author(s).

Contiero P.,Scientific Directorate | Berrino F.,Fondazione Istituto Nazionale Tumori | Tagliabue G.,Scientific Directorate | Mastroianni A.,Unit of Laboratory Medicine | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2013

High circulating glucose has been associated with increased risk of breast cancer (BC). There may also be a link between serum glucose and prognosis in women treated for BC. We assessed the effect of peridiagnostic fasting blood glucose and body mass index (BMI) on long-term BC prognosis. We retrospectively investigated 1,261 women diagnosed and treated for stage I-III BC at the National Cancer Institute, Milan, in 1996, 1999 and 2000. Data on blood tests and follow-up were obtained by linking electronic archives, with follow-up to end of 2009. Multivariate Cox modelling estimated hazard ratios (HR) with 95 % confidence intervals (CI) for distant metastasis, recurrence and death (all causes) in relation to categorized peridiagnostic fasting blood glucose and BMI. Mediation analysis investigated whether blood glucose mediated the BMI-breast cancer prognosis association. The risks of distant metastasis were significantly higher for all other quintiles compared to the lowest glucose quintile (reference <87 mg/dL) (respective HRs: 1.99 95 % CI 1.23-3.24, 1.85 95 % CI 1.14-3.0, 1.73 95 % CI 1.07-2.8, and 1.91 95 % CI 1.15-3.17). The risk of recurrence was significantly higher for all other glucose quintiles compared to the first. The risk of death was significantly higher than reference in the second, fourth and fifth quintiles. Women with BMI ≥ 25 kg/m2 had significantly greater risks of recurrence and distant metastasis than those with BMI < 25 kg/m2, irrespective of blood glucose. The increased risks remained invariant over a median follow-up of 9.5 years. Mediation analysis indicated that glucose and BMI had independent effects on BC prognosis. Peridiagnostic high fasting glucose and obesity predict worsened short- and long-term outcomes in BC patients. Maintaining healthy blood glucose levels and normal weight may improve prognosis. © 2013 Springer Science+Business Media New York.

Sassi C.,U.S. National Institute on Aging | Sassi C.,University College London | Sassi C.,Charite - Medical University of Berlin | Sassi C.,German Center for Neurodegenerative Diseases | And 10 more authors.
Journal of Alzheimer's Disease | Year: 2016

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24ng/ml) compared to controls (142.7ng/ml) or family members non-carriers (82.0ng/ml) (p-value=0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations. © 2016 - IOS Press and the authors. All rights reserved.

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