Scientific Institute of Hospitalization and Treatment

Rionero in Vulture, Italy

Scientific Institute of Hospitalization and Treatment

Rionero in Vulture, Italy
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Ravegnini G.,University of Bologna | Zolezzi Moraga J.M.,University of Bologna | Zolezzi Moraga J.M.,University of Tarapacá | Maffei F.,University of Bologna | And 6 more authors.
International Journal of Molecular Sciences | Year: 2015

One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (_ = _0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Simeon V.,Scientific Institute of Hospitalization and Treatment | Todoerti K.,Scientific Institute of Hospitalization and Treatment | La Rocca F.,Scientific Institute of Hospitalization and Treatment | Caivano A.,Scientific Institute of Hospitalization and Treatment | And 6 more authors.
International Journal of Molecular Sciences | Year: 2015

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL). © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Ravegnini G.,University of Bologna | Nannini M.,University of Bologna | Simeon V.,Scientific Institute of Hospitalization and Treatment | Sammarini G.,University of Bologna | And 9 more authors.
Tumor Biology | Year: 2016

DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST. © 2016 International Society of Oncology and BioMarkers (ISOBM)


PubMed | Unit of Epidemiology and Biostatistics, Scientific Institute of Hospitalization and Treatment and University of Bologna
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2015

One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients ( = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment.


PubMed | Scientific Institute of Hospitalization and Treatment and University of Milan
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2015

Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) which may represent a valid model for high-risk MM. This disease is associated with a very poor prognosis, and unfortunately, it has not significantly improved during the last three decades. New high-throughput technologies have allowed a better understanding of the molecular basis of this disease and moved toward risk stratification, providing insights for targeted therapy studies. This knowledge, added to the pharmacogenetic profile of new and old agents in the analysis of efficacy and safety, could contribute to help clinical decisions move toward a precision medicine and a better clinical outcome for these patients. In this review, we describe the available literature concerning the genomic characterization and pharmacogenetics of plasma cell leukemia (PCL).


PubMed | Scientific Institute of Hospitalization and Treatment and University of Bologna
Type: Journal Article | Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | Year: 2016

DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P=0.018), metastatic status at onset (P=0.035) and mitotic index (P=0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P=0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P=0.005 and P=0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60% lower risk to die compared to the wild-type carriers (P=0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P=0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.


Conti V.,University of Salerno | Russomanno G.,University of Salerno | Corbi G.,University of Molise | Toro G.,Martiri Del Villa Malta Hospital | And 9 more authors.
International Journal of Molecular Sciences | Year: 2015

The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (Δt-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the Δt-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the Δt-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized. © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Conti V.,University of Salerno | Corbi G.,University of Molise | Simeon V.,Scientific Institute of Hospitalization and Treatment | Russomanno G.,University of Salerno | And 4 more authors.
Aging Clinical and Experimental Research | Year: 2015

Background: Oxidative stress is strongly associated with aging and age-related diseases and plays a crucial role in endothelial dysfunction development. Aim: To better understand the molecular mechanisms of aging and stress response in humans, we examined changes to young and older human endothelial cells over time (72, 96 and 120 h), before and after H2O2-induced stress. Methods: We measured the expression of the deacetylase Sirtuin 1 (Sirt1) and its transcriptional target Forkhead box O3a (Foxo3a); TBARS, a well-known marker of overall oxidative stress, and catalase activity as index of antioxidation. Moreover, we quantified levels of cellular senescence by senescence-associated β galactosidase (SA-βgal) assay. Results: Under oxidative stress induction older cells showed a progressive decrease of Sirt1 and Foxo3a expression, persistently high TBARS levels with high, but ineffective Cat activity to counteract such levels. In addition cellular senescence drastically increased in older cells compared with Young cells both in presence and in the absence of oxidative stress. Discussion: By following the cell behavior during the time course, we can hypothesize that while in young cells an oxidative stress induction stimulated an adequate response through activation of molecular factor crucial to counteract oxidative stress, the older cells are not able to adequately adapt themselves to external stress stimuli. Conclusions: During their life, endothelial cells impair the ability to defend themselves from oxidative stress stimuli. This dysfunction involves the pathway of Sirt1 a critical regulator of oxidative stress response and cellular lifespan, underlining its crucial role in endothelial homeostasis control during aging and age-associated diseases. © 2015, Springer International Publishing Switzerland.


PubMed | Scientific Institute of Hospitalization and Treatment, University of Molise, University of Naples Federico II, Parthenope University of Naples and 2 more.
Type: Journal Article | Journal: International journal of molecular sciences | Year: 2015

The present study investigated the effect of two single nucleotide polymorphisms (SNPs) of the vitamin D receptor (VDR) gene, rs1544410 A/G and rs2228570 C/T, in modulating bone mineral density (BMD) and the response to treatment with bisphosphonates or strontium ranelate in postmenopausal osteoporosis (PMO). Four hundred eighteen postmenopausal women from Southern Italy treated with bisphosphonates or strontium ranelate for three years were enrolled and stratified according to their genotype. Changes in BMD were expressed as the delta t-score (t-score). Allelic frequencies for rs1544410 A/GSNP were 11.2% AA, 50.0% GA and 38.8% GG; for rs2228570 C/TSNP were 54.8% CC, 39.5% TC and 5.7% TT. TT carriers showed a lower t-score than TC and CC (both p < 0.02) genotypes and were more responsive to the therapy when compared to both TC (p < 0.02) and CC (p < 0.05) carriers. Specifically, TT carriers receiving alendronate demonstrated a significant improvement of the t-score compared to TC and CC (both p < 0.0001) carriers. After adjustment for confounders, the t-score showed evidence of a statistically significant positive association with TT in all treatments considered. Therapy response was independent of rs1544410 A/G SNP; instead, rs2228570 C/TSNP was associated with a better response to antiresorptive treatment, thus suggesting that the therapy for PMO should be personalized.


PubMed | Unit of Epidemiology and Biostatistics, Scientific Institute of Hospitalization and Treatment and University of Bologna
Type: | Journal: Angiogenesis | Year: 2016

The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P<0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P=0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P=0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P=0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade 3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.

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