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Savastano S.,University of Naples Federico II | Di Somma C.,IRCCS SDN | Colao A.,University of Naples Federico II | Barrea L.,Coleman and IOS srl | And 4 more authors.
Growth Hormone and IGF Research | Year: 2015

Background: The main components of GH/insulin-like growth factor (IGF)-1 axis and Sirtuin 4 (Sirt4), highly expressed in liver and skeletal muscle mitochondria, serve as active regulators of mitochondrial oxidative capacity with opposite functions. In obesity both GH/IGF-1 status and serum Sirt4 levels, likely mirroring its reduced mitochondrial expression, might be altered. Objective: To evaluate the association between circulating levels of Sirt4, body composition, metabolic parameters and cardio-metabolic risk profile in obese patients according to their different GH/IGF-1 status. Design: Cross-sectional study with measurement of serum Sirt4, GH after GH releasing hormone (GHRH)+Arginine test, IGF-1 and assessment of body composition, glucose and lipid metabolism in 50 class II-III obese subjects (BMI 35.6 to 62.1kg/m2) and 15 normal weight subjects. Low GH secretion and IGF-1 were defined using pre-determined cutoff-points. The Homeostatic Metabolic Assessment of insulin resistance index and Visceral adiposity index were also calculated. The association of Sirt4 with peak stimulated GH and IGF-1, body composition, metabolic parameters and cardio-metabolic risk profile was assessed. Results: Serum Sirt4 was inversely related to anthropometric and metabolic parameters and positively related to peak GH and IGF-1. After adjusting for peak GH and IGF-1, the relationships between Sirt4 and BMI became not significant. At multiple regression analysis IGF-1 (p < 0.001) was the independent predictor for Sirt4. Conclusion: There was a close relationship between low IGF-1 and low serum Sirt4. This observation suggested that in obese patients, low GH/IGF-1 status was likely associated with a major compensatory decrease in circulating levels of Sirt4 to oppose to its negative regulator effect on mitochondrial oxidative capacity. © 2014 Elsevier Ltd.


D'Apolito O.,University of Foggia | Garofalo D.,University of Foggia | Gelzo M.,University of Naples Federico II | Paris D.,CNR Institute of Biomolecular Chemistry | And 8 more authors.
Metabolomics | Year: 2014

Hepatocellular carcinoma (HCC) is a very aggressive neoplasia requiring early and accurate diagnosis to improve patient outcomes with timely treatment. The liver is also very frequently colonized by metastases, and the most frequent differential diagnosis is HCC against intrahepatic cholangiocarcinoma or metastatic adenocarcinoma. Metabolomics is a powerful tool for identification of altered biomarkers in cancer, and to evaluate the efficacy of drug treatments. Here we analyzed by HILIC-MS/MS methylated arginines, basic amino acids (Arg, Cit, Orn), and their ratios in the extracts of primary HCC tissues, liver metastases from colorectal carcinoma (MET), cirrhotic related hepatitis-C-virus (CIR), and non-cirrhotic normal liver (NT) adjacent tissues. We found high levels of Arg (p < 0.0001) and Arg/Orn (p < 0.01) in MET compared to other tissues. In MET, compared to NT and CIR, Arg concentration was fivefold higher, while in HCC it was twofold higher. ADMA increased twofold compared to NT and CIR, while in HCC it was 50 % higher. Arg/Cit and ADMA/SDMA ratios were significantly higher in MET compared to NT and CIR (p < 0.005). Arg/Orn, Arg/Cit, and ADMA/SDMA ratios increased progressively from NT, CIR, HCC, to MET tissues. Arg/Cit correlated significantly with Arg/Orn ratios (r = 0.77; p < 0.0001), and discriminates tumor from non-tumor samples. In addition, the discriminant lactate/glucose ratio we previously found by NMR, also correlated significantly with the Arg levels (r = 0.64; p < 0.0001), and discriminated MET from all other tissues. The results indicated that Arg in MET is higher than other tissue classes, suggesting that, together with the lactate/glucose ratio, it can be considered a further biomarker for HCC-metastases differentiation. © 2014 Springer Science+Business Media New York.


Carotenuto P.,Centro Ricerche Oncologiche Of Mercogliano | Roma C.,Centro Ricerche Oncologiche Of Mercogliano | Rachiglio A.M.,Centro Ricerche Oncologiche Of Mercogliano | Tatangelo F.,Surgical Pathology Unit | And 5 more authors.
Pharmacogenomics | Year: 2010

Aims: Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy. Materials & methods: We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen® kit (DxS Ltd). Results & conclusion: The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin-fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells. © 2010 Future Medicine Ltd.


De Marino S.,University of Naples Federico II | Festa C.,University of Naples Federico II | Zollo F.,University of Naples Federico II | Rusolo F.,Centro Ricerche Oncologiche Of Mercogliano | And 5 more authors.
Phytochemistry Letters | Year: 2014

Phytochemical investigation of polar extract from Juniperus oxycedrus spp. oxycedrus berries leds to the isolation of one new monoterpene glucoside (3R,6E)-3,7 dimethyl 8-hydroxy-6-octenoic acid 8-O-β-d-glucopyranoside along with seven known components, some of them were initially isolated from Juniperus communis L. berries. Their structures were established on the basis of extensive 1D and 2D NMR (1H, 13C, COSY, HMBC, HSQC, ROESY) and ESI-MS studies. The n-butanol fraction and isolated components, shikimic acid (2), compound 3, 4 and 5 were evaluated, in vitro, for their effect on cell viability against human malignant melanoma (A375), breast (MCF-7) and lung (H460) cancer cell lines. Shikimic acid exhibited selective effect on cell viability only against breast MCF-7 cell lines reaching IC50 value at dose of 30 μM and also induced the level decrease of vascular endothelial growth factor (VEGF) and five pro-inflammatory cytokines suggesting its potential anti-inflammatory effect. © 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.


Tarantino G.,University of Naples Federico II | Tarantino G.,Centro Ricerche Oncologiche Of Mercogliano
Hormone Molecular Biology and Clinical Investigation | Year: 2014

When dealing with the treatment of obesity-linked illnesses-in particular nonalcoholic fatty liver disease-beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition. © 2014 by De Gruyter.


PubMed | Centro Ricerche Oncologiche Of Mercogliano
Type: Clinical Trial | Journal: Pharmacogenomics | Year: 2010

Patients with metastatic colorectal carcinoma (mCRC) carrying activating mutations of the KRAS gene do not benefit from treatment with anti-EGF receptor monoclonal antibodies. Therefore, KRAS mutation testing of mCRC patients is mandatory in the clinical setting to aid in the choice of appropriate therapy.We developed a cost-effective approach for the determination of KRAS mutations in codons 12 and 13 in clinical practice based on a sensitive PCR/sequencing technique and the commercially available real-time PCR-based Therascreen kit (DxS Ltd).The PCR/sequencing test was able to detect 10% mutant DNA in a background of wild-type DNA. By using this assay, we determined the mutational status of KRAS in 527 out of 540 (97.6%) formalin-fixed paraffin-embedded tissues from mCRC patients. PCR/sequencing was not conclusive in 13 cases, in which low-intensity peaks suggestive of potential mutations were identified. The DxS assay, which showed a sensitivity of 1%, identified mutations in 11 out of 13 inconclusive cases. Interestingly, five of these 11 cases showed high levels of DNA fragmentation. No significant difference was found in the ability of PCR/sequencing and DxS to identify KRAS mutations within 160 cases with more than 30% tumor cells. However, in 24 samples with less than 30% tumor cells, DxS showed an higher sensitivity. In conclusion, our findings suggest that PCR/sequencing can be used for mutational analysis of the majority of tumor samples that have more than 30% tumor cell content, whereas more sensitive and expensive tests should be reserved for inconclusive cases and for samples with a low amount of tumor cells.

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