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PubMed | CEINGE Advanced Biotechnologies, The Second University of Naples, University of Naples Federico II, Italian National Cancer Institute and University of Sannio
Type: Journal Article | Journal: Journal of cellular and molecular medicine | Year: 2015

CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype-phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P=NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46years) than in those without (median not reached; P=0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P=0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1.


Fabbrini E.,University of Washington | Fabbrini E.,Center for Clinical and Basic Research | Higgins P.B.,The Texas Institute | Magkos F.,University of Washington | And 9 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2013

We established a model of chronic portal vein catheterization in an awake nonhuman primate to provide a comprehensive evaluation of the metabolic response to low-carbohydrate/high-fat (LCHF; 20% carbohydrate and 65% fat) and high-carbohydrate/low-fat (HCLF; 65% carbohydrate and 20% fat) meal ingestion. Each meal was given 1 wk apart to five young adult (7.8 ± 1.3 yr old) male baboons. A [U-13C]glucose tracer was added to the meal, and a [6,6-132H2]glucose tracer was infused systemically to assess glucose kinetics. Plasma areas under the curve (AUCs) of glucose, insulin, and C-peptide in the femoral artery and of glucose and insulin in the portal vein were higher (P ≤ 0.05) after ingestion of the HCLF compared with the LCHF meal. Compared with the LCHF meal, the rate of appearance of ingested glucose into the portal vein and the systemic circulation was greater after the HCLF meal (P < 0.05). Endogenous glucose production decreased by ~40% after ingestion of the HCLF meal but was not affected by the LCHF meal (P < 0.05). Portal vein blood flow increased (P < 0.001) to a similar extent after consumption of either meal. In conclusion, a LCHF diet causes minimal changes in the rate of glucose appearance in both portal and systemic circulations, does not affect the rate of endogenous glucose production, and causes minimal stimulation of C-peptide and insulin. These observations demonstrate that LCHF diets cause minimal perturbations in glucose homeostasis and pancreatic β-cell activity. © 2013 the American Physiological Society.


Gentile I.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | Zappulo E.,University of Naples Federico II | And 5 more authors.
Reviews on Recent Clinical Trials | Year: 2014

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. Currently, it is treated with pegylated interferon (PEG-IFN) plus ribavirin, associated with a protease inhibitor in case of genotype 1 infection. However, this combination is often contraindicated and associated with severe adverse events that limit its use in clinical practice. Several drugs active against HCV are in an advanced phase of clinical development. Among these, sofosbuvir appears one of the most promising candidates for use in association with both interferon and interferon-free combinations. This review focuses on the results of several sofosbuvir-based phase III trials that have very recently become available. These studies show that the co-administration of sofosbuvir, PEG-IFN and ribavirin for 12 weeks is associated with a very high rate of sustained virological responses (SVR) (about 90%) in naïve patients with genotypes 1, 4, 5 or 6. In patients infected by genotypes 2 or 3, the interferon-free combination of sofosbuvir and ribavirin administered for 12 weeks is associated with a SVR of 97% and 56% in naïve patients, and of 86% and 30% in experienced genotype 2 or 3 patients, respectively. The safety and tolerability profile is optimal and consistent with that of the other drugs administered in the combination (ribavirin and/or interferon). In conclusion, the recent phase III trials of sofosbuvir confirm the excellent results of phase II studies in terms of efficacy and safety and will probably open a new era in the fight against HCV. © 2014 Bentham Science Publishers.


Gentile I.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | Coppola N.,The Second University of Naples | And 4 more authors.
Current Medicinal Chemistry | Year: 2014

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylatedinterferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naïve patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C. © 2014 Bentham Science Publishers.


Gentile I.,University of Naples Federico II | Buonomo A.R.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | And 4 more authors.
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1. Areas covered: This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172, a second-generation inhibitor of HCV NS3/4A protease. Expert opinion: The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89-100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection. © 2014 Informa UK, Ltd.


Gentile I.,University of Naples Federico II | Buonomo A.R.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | And 3 more authors.
Expert Opinion on Investigational Drugs | Year: 2014

Introduction: About 150,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). HCV infection can lead to liver cirrhosis, hepatocellular carcinoma and death. Treatment was based previously only on pegylated interferon combined with other antiviral drugs. Recently, the first interferon-free combination for patients with genotype 2 or 3 was approved in the USA and Europe, and several molecules are in an advanced phase of clinical development. Areas covered: This review focuses on the pharmacokinetics, pharmacodynamics and tolerability of ledipasvir, an inhibitor of HCV nonstructural 5A protein. The authors also highlight the drug's safety and resistance profile. Expert opinion: The pharmacokinetic profile and antiviral activity of ledipasvir are ideal. However, given the high rate of natural and drug-related ledipasvir-resistant HCV mutations, ledipasvir is administered in combination regimens with other antiviral drugs, which resulted in a cure rate up to 100%. While ledipasvir is effective in patients with genotype 1 chronic hepatitis C, its efficacy remains to be established in patients with genotype 4, 5 or 6, in subjects with HIV coinfection, in hemodialyzed and elderly patients and in subjects with decompensated cirrhosis. If the excellent results of combination therapy be confirmed in larger trials, hepatologists will have the possibility to cure most HCV-positive patients in the near future. © 2014 Informa UK, Ltd.


Gentile I.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | Buonomo A.R.,University of Naples Federico II | And 3 more authors.
Current Medicinal Chemistry | Year: 2013

Hepatitis C virus (HCV) infection is one of the main causes of liver disease worldwide. Its treatment is currently based on the combination of peg-interferon, ribavirin, and, for patients with genotype 1, a protease inhibitor (telaprevir or boceprevir). However, interferon-based combinations are not effective in all patients. Moreover, they are contraindicated in patients who cannot receive interferon (e.g. those with decompensated cirrhosis), and are frequently associated with adverse events. Consequently, there is a need to develop new drugs to treat HCV infection. This review focuses on preclinical and clinical data regarding sofosbuvir (GS-7977), a uridine nucleotide analogue inhibitor of HCV NS5 B polymerase that is effective against HCV genotypes 1,2, 3,4 and 6. Thanks to its excellent pharmacokinetic profile, sofosbuvir can be administered in an oral single daily dose. In vitro it exerts a potent antiviral effect against HCV. Clinical data show that combined with peg-interferon and ribavirin for 12 weeks it yields SVR of about 90% in subjects with HCV genotype 1 and about 100% in patients with HCV genotype 2 or 3. Moreover, sofosbuvir and ribavirin administered for 12 weeks yield similar high SVR rate (84% for genotype 1 and 100% for genotype 2/3 patients) as well as sofosbuvir and daclatasvir (an inhibitor of NS5A) which produce SVR rate of about 100% regardless of genotype or of ribavirin employment. Safety and tolerability of sofosbuvir appear to be excellent. In conclusion, sofosbuvir especially in interferon-free combinations represents a very promising option in the treatment of chronic hepatitis C. © 2013 Bentham Science Publishers.


Galizia G.,The Second University of Naples | Gemei M.,CEINGE Advanced Biotechnologies | Orditura M.,The Second University of Naples | Romano C.,The Second University of Naples | And 8 more authors.
Journal of Gastrointestinal Surgery | Year: 2013

Introduction: Circulating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial. Materials and Methods: Pre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells. Results: Fifty-four (71 %) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75 %) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86 %, with a reduction in the risk of tumor relapse greater than 90 %. Conclusions: High postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients. © 2013 The Society for Surgery of the Alimentary Tract.


Gentile I.,University of Naples Federico II | Borgia F.,CEINGE Advanced Biotechnologies | Borgia F.,University of Naples Federico II | Buonomo A.R.,University of Naples Federico II | And 4 more authors.
Current Medicinal Chemistry | Year: 2014

About 2.3% of the world's population is infected with hepatitis C virus (HCV) and patients have a high risk of developing liver cirrhosis and its complications. Current therapeutic strategies are based on a combination of pegylatedinterferon, ribavirin and (only for patients with genotype 1 infection) a protease inhibitor (boceprevir or telaprevir). Consequently, all these combinations have the limitations of interferon. In fact, they are contraindicated in decompensated disease and in subjects with severe comorbidities, and are associated with a high rate of side effects. Moreover, they are poorly effective in advanced disease. As complete viral eradication is associated with improved disease-free survival, several molecules are under clinical development for their potential to overcome the drawbacks of currently available treatments. This review focuses on the pharmacodynamics, pharmacokinetics, safety and tolerability of ABT-450, a potent inhibitor of non-structural 3 protease. ABT-450 is a substrate of cytochrome P450; hence its co-administration with ritonavir, a cytochrome P450 inhibitor, dramatically increases the plasma concentration and half-life of ABT-450 and allows once-daily administration. Given in monotherapy for 3 days at different doses, ABT-450 causes a mean maximum viral decline of about 4 logs. Interestingly, high doses of ABT-450 are associated with a reduced and delayed development of resistance-conferring mutations. Given in combination with other direct antiviral drugs, the sustained response rate reaches 90-95% in both naïve and treatment-experienced genotype 1 patients, and tolerability is good. In conclusion, ABT-450 is an excellent component of interferon-free combinations for the treatment of chronic HCV infection. © 2014 Bentham Science Publishers.


Iommelli F.,National Research Council Italy | De Rosa V.,National Research Council Italy | Gargiulo S.,National Research Council Italy | Panico M.,National Research Council Italy | And 10 more authors.
Clinical Cancer Research | Year: 2014

Purpose: MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3′-deoxy-3′-[18F]-fluorothymidine ([18F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC.Experimental Design: H1993 and H820 NSCLC cells with high and low levels of MET amplification, respectively, and HCC827-expressing MET, but without gene amplification, were tested for the effects of MET inhibitors on the EGFR pathway and proliferation both in vitro and in vivo. Nude mice bearing NSCLCs with and without MET amplification were subjected to [18F]FLT PET/CT before and after treatment with crizotinib or erlotinib (50 mg/kg and 100 mg/kg p.o. for 3 days).Results: H1993 cells showed high responsiveness to MET inhibitors and were resistant to erlotinib. Conversely, HCC827 cells showed high sensitivity to erlotinib and were resistant to MET inhibitors. Accordingly, H1993 tumors bearingMETamplification showed a mean reduction in [18F]FLT uptake of28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [18F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [18F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [18F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections.Conclusions: [18F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC. © 2014 American Association for Cancer Research.

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