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1.
Eur J Clin Invest ; 48(2): e12870, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29235098

RESUMO

BACKGROUND: The liver hormone hepcidin regulates iron homoeostasis that is often altered in hepatocellular carcinoma (HCC). Epigenetic phenomena control gene expression through a dynamic fashion; therefore, considering the plasticity of both iron homoeostasis and epigenetic mechanisms and their role in liver carcinogenesis, we investigated whether hepcidin gene (HAMP) expression is modulated by DNA methylation, thus affecting iron status in human HCC. MATERIALS AND METHODS: Thirty-two patients affected by nonviral HCC were enrolled, and their main clinical and biochemical characteristics were obtained. Neoplastic and homologous non-neoplastic liver tissues were analysed for HAMP promoter DNA methylation, for HAMP gene expression and for iron content. An in vitro demethylation assay with a human hepatocarcinoma cell line was performed to evaluate the role of DNA methylation on HAMP transcriptional repression. RESULTS: Gene expression and DNA methylation analyses on tissues showed that HAMP was transcriptionally repressed in HCC tissues consensually with a promoter hypermethylation. Furthermore, patients with HCC had low serum hepcidin concentrations, and HCC tissues had relative iron depletion as compared to non-neoplastic liver tissues. The cell culture model showed the functional role of DNA hypermethylation by downregulating HAMP gene expression. Through a quantitative methylation analysis on HCC tissues, we then proved that methylation at definite CpG sites within consensus sequences for specific transcription factors is possibly the mechanism underlying HAMP repression. CONCLUSIONS: This study highlights a novel role for HAMP downregulation through DNA promoter hypermethylation and emphasises the significance of epigenetics in the regulation of iron metabolism in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Metilação de DNA/fisiologia , Hepcidinas/metabolismo , Neoplasias Hepáticas/metabolismo , Regiões Promotoras Genéticas/fisiologia , Idoso , Análise de Variância , Proteínas de Transporte de Cátions/metabolismo , Regulação para Baixo/fisiologia , Feminino , Expressão Gênica/fisiologia , Hepcidinas/genética , Humanos , Deficiências de Ferro , Masculino , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Transcrição Gênica/fisiologia
2.
Hepatology ; 62(2): 496-504, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25833413

RESUMO

UNLABELLED: In addition to DNA methylation, hydroxymethylation of DNA is recognized as a novel epigenetic mark. Primary liver cancers, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), are highly prevalent but epigenetically poorly characterized, so far. In the present study we measured global methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) in HCC and CC tissues and in peripheral blood mononuclear cell (PBMC) DNA to define mCyt and hmCyt status and, accordingly, the survival rate. Both mCyt and hmCyt were measured by a liquid chromatography/tandem mass spectrometry method in neoplastic and homologous nonneoplastic tissues, i.e., liver and gallbladder, and in PBMCs of 31 HCC and 16 CC patients. Content of mCyt was notably lower in HCC than in CC tissues (3.97% versus 5.26%, respectively; P < 0.0001). Significantly reduced mCyt was also detected in HCC compared to nonneoplastic tissue (3.97% versus 4.82% mCyt, respectively; P < 0.0001), but no such difference was found for CC versus homologous nonneoplastic tissue. Hydroxymethylation was significantly decreased in HCC versus nonneoplastic liver tissue (0.044 versus 0.128, respectively; P < 0.0001) and in CC versus both liver and gallbladder nonneoplastic tissue (0.030 versus 0.124, P = 0.026, and 0.030 versus 0.123, P = 0.006, respectively). When the survival rate was evaluated according to mCyt PBMC content by Kaplan-Meier analysis, patients with mCyt ≥5.59% had a significantly higher life expectancy than those with mCyt <5.59% (P = 0.034) at a follow-up period up to 48 months. CONCLUSION: A significant DNA hypomethylation distinguishes HCC from CC, while DNA hypo-hydroxymethylation characterizes both HCC and CC, and a PBMC DNA mCyt content ≥5.59% relates to a favorable outcome in primary liver cancers.


Assuntos
Neoplasias dos Ductos Biliares/mortalidade , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidade , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidade , Metilação de DNA , Neoplasias Hepáticas/mortalidade , Idoso , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Intra-Hepáticos , Carcinoma Hepatocelular/cirurgia , Colangiocarcinoma/cirurgia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Hepatectomia/métodos , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirurgia , Masculino , Metilação , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida
3.
Diagnostics (Basel) ; 14(16)2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39202199

RESUMO

Tissue factor (TF) is a transmembrane glycoprotein that represents the fundamental physiological initiator of the coagulation cascade through its interaction with factor VII. TF belongs to the cytokine receptor protein superfamily and contributes to the transduction of cellular signaling. Therefore, TF-related pathways are involved in multiple pathophysiological processes, not only in coagulation/thrombosis but in a wider mechanisms' panorama, ranging from infective to neoplastic diseases. Consistently, the measurement of TF activity could have a diagnostic and/or prognostic meaning in different clinical conditions. However, the transmembrane localization, the expression on different cellular types and circulating extracellular vesicles, and the different conformations (encrypted and decrypted) and variants (such as the soluble alternatively spliced TF) hamper TF assessment in clinical practice. The activated factor VII-antithrombin (FVIIa-AT) complex is proposed as an indirect biomarker of the TF-FVIIa interaction and, consequently, of the functionally active TF expression. In this narrative review, we evaluate the clinical studies investigating the role of plasma concentration of FVIIa-AT in health and disease. Although without conclusive data, high FVIIa-AT concentrations predict the worst clinical outcomes in different pathologic conditions, such as cardiovascular disease and cancer, thereby suggesting that overactivation of TF-related pathways may play an unfavorable role in various clinical settings.

4.
Res Pract Thromb Haemost ; 8(1): 102310, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38282902

RESUMO

Background: Tissue factor (TF), the main initiator of the coagulation cascade, plays a role in cancer progression and prognosis. Activated factor VII-antithrombin complex (FVIIa-AT) is considered an indirect marker of TF exposure by reflecting TF-FVIIa interaction. Objectives: To assess the link between FVIIa-AT plasma levels, TF messenger RNA (mRNA) expression, and survival in cancer. Methods: TF pathway-related coagulation biomarkers were assessed in 136 patients with cancer (52 with hepatocellular carcinoma, 41 with cholangiocarcinoma, and 43 with colon cancer) undergoing surgical intervention with curative intent. TF mRNA expression analysis in neoplastic vs nonneoplastic liver tissues was evaluated in a subgroup of 91 patients with primary liver cancer. Results: FVIIa-AT levels were higher in patients with cancer than in 136 sex- and age-matched cancer-free controls. In patients with cancer, high levels of FVIIa-AT and total TF pathway inhibitor were associated with an increased mortality risk after adjustment for confounders, but only FVIIa-AT remained a predictor of mortality by including both FVIIa-AT and total TF pathway inhibitor in Cox regression (hazard ratio, 2.80; 95% CI, 1.23-6.39; the highest vs the lowest quartile). This association remained significant even after adjustment for extracellular vesicle-associated TF-dependent procoagulant activity. In the subgroup of patients with primary liver cancer, patients with high TF mRNA levels had an increased mortality risk compared with that for those with low TF mRNA levels (hazard ratio, 1.92; 95% CI, 1.03-3.57), and there was a consistent correlation among high FVIIa-AT levels, high TF mRNA levels, and increased risk of mortality. Conclusion: High FVIIa-AT levels may allow the identification of patients with cancer involving high TF expression and predict a higher mortality risk in liver cancer.

5.
Depress Anxiety ; 30(3): 259-66, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23349098

RESUMO

BACKGROUND: Carbon dioxide (CO2 ) hypersensitivity represents an individual difference response to breathing CO2 enriched air. People with a history of panic attacks or panic disorder are particularly prone to anxious response, suggesting that CO2 hypersensitivity is a robust risk marker of panic spectrum vulnerability. METHODS: Twin pairs (n = 346) from the general population-based Norwegian NIPH Mental Health Study completed a measure of anxiety before and after vital capacity inhalation of 35% CO2 air and before and after inhalation of regular air. Three hypotheses regarding genetic factors for CO2 hypersensitivity were examined: (1) a single set of genetic risk factors impacts anxiety before exposure to CO2 and these same genes constitute the only genetic influences on anxiety in response to CO2 , (2) the genetic effects on pre-CO2 anxiety are entirely different from the genetic effects on anxiety in response to exposure to CO2 (i.e., new genetic effects), and (3) pre-CO2 anxiety influences anxiety in response to CO2 as well as unique genetic factors that become activated by respiratory stimulation. RESULTS: Our results support the latter hypothesis for response to 35% CO2 , with additive genetic and unique environmental factors best fitting the data. Evidence of new genetic effects was observed, accounting for 20% unique variance in post 35% CO2 anxiety response. New genetic effects were not observed for anxiety ratings made post regular air where only preregular air anxiety ratings explained significant variance in this outcome. CONCLUSIONS: These data suggest that there are distinct genetic factors associated with responsivity to respiratory stimulation via 35% CO2 .


Assuntos
Transtornos de Ansiedade/genética , Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/efeitos adversos , Interação Gene-Ambiente , Hipersensibilidade Respiratória/genética , Adulto , Transtornos de Ansiedade/induzido quimicamente , Transtornos de Ansiedade/epidemiologia , Biomarcadores , Doenças em Gêmeos/genética , Feminino , Inquéritos Epidemiológicos , Humanos , Inalação/genética , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/epidemiologia , Fatores de Risco
6.
Clin Nutr ; 42(1): 9-17, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36473427

RESUMO

BACKGROUND & AIMS: Anorexia is a disabling symptom in cancer and we aimed at investigating the role of changes in gene expression in lung cancer patients presenting with anorexia. METHODS: Genome-wide transcriptomic profiling was assessed in PBMCs RNA from newly diagnosed lung cancer patients and in a control group. RT-qPCR was used for selected genes. RESULTS: RNA-Seq analysis revealed among groups a large number of differentially expressed genes mainly implicated in immune system regulation, oxidative stress and cytokine-mediated inflammation signaling pathways. In particular, we identified a total of 983 DEGs (843 up-regulated; 140 down-regulated) in anorexic cancer compared to controls. A selected number of DEGs including ADAM8, SMAD4, CCR4 and CLU were differentially expressed within cancer group according to the presence/absence of anorexia. In terms of RT-qPCR, ADAM8 was less expressed in cancer patients than controls (p < 0.001), and in anorexic patients vs controls (p = 0.001). The expression of SMAD4 was lower in cancer vs controls (p = 0.005), and in anorexic patients vs controls (p = 0.009). We observed lower CCR4 expression in both anorexic and non-anorexic vs control (p = 0.004, p = 0.011, respectively) and a similar trend was present for CLU. CONCLUSIONS: Our data shed new light on the role of specific genes and their associated molecular pathways as potential key mechanisms for the development of anorexia and may represent a novel landmark for understanding the complex pathophysiology of impaired appetite in cancer.


Assuntos
Anorexia , Neoplasias Pulmonares , Humanos , Anorexia/genética , Leucócitos Mononucleares , Neoplasias Pulmonares/genética , Perfilação da Expressão Gênica , Expressão Gênica , Proteínas de Membrana , Proteínas ADAM
7.
Hepatology ; 63(5): 1746-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26439221
8.
Diagnostics (Basel) ; 12(11)2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36428852

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

9.
Am J Med Genet B Neuropsychiatr Genet ; 156B(1): 79-88, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21184587

RESUMO

Heterogeneous life events (LE) precede the onset of-and potentially increase the susceptibility to-panic disorder (PD). It remains unknown whether LE can act as moderators in the context of gene-by-environment interactions (G×E) that alter the susceptibility to PD and the related trait of CO2 sensitivity, nor it is known whether such moderation may depend on occurrence of events at different epochs in life. In 712 general population twins we analyzed by Maximum Likelihood analyses of ordinal data whether life (major- and stressful) events moderate the genetic risk for PD and CO2 sensitivity, as indexed by the 35% CO2 /65% O2 challenge. For CO2 sensitivity, best-fitting models encompassed both additive and interactional effects that increased linearly with the cumulative number and severity (SEV) of events in lifetime. By analyzing the moderation effect of cumulative SEV separately for events that had occurred in adulthood (between age 18 and 37) or during childhood-adolescence (before the 18th birthday), we found evidence of G×E only within the childhood-adolescence window of risk, although twins had rated the childhood-adolescence events as significantly (P = 0.001) less severe than those having occurred during adulthood. For PD, all interactional terms could be dropped without significant worsening of the models' fit. Consistently with a diathesis-stress model, LE appear to act as moderators of the genetic variance for CO2 sensitivity. Childhood-adolescence appears to constitute a sensitive period to the action of events that concur to alter the susceptibility to this panic-related trait.


Assuntos
Dióxido de Carbono/farmacologia , Meio Ambiente , Acontecimentos que Mudam a Vida , Transtorno de Pânico/genética , Adulto , Humanos , Modelos Genéticos , Gêmeos/genética , Adulto Jovem
10.
Front Oncol ; 10: 596040, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33585212

RESUMO

BACKGROUND: Mechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC. METHODS: Forty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. MT1G and MT1H gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing. RESULTS: Patients with Cu serum concentration above the 80th percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60-18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). MT1G and MT1H gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015). CONCLUSIONS: MT1G and MT1H act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.

11.
J Am Heart Assoc ; 8(2): e010973, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30646800

RESUMO

Background Apolipoprotein CIII (apo CIII ) is a crucial player in triglyceride-rich lipoprotein metabolism, but may also act pleiotropically, provoking inflammatory responses and stimulating coagulation. Elevated apo CIII plasma levels have been associated with increased activity of coagulation factors. Since these features of prothrombotic diathesis are linked with venous thromboembolism ( VTE ), we hypothesized that apo CIII plays a role in VTE . Methods and Results We recorded nonfatal VTE events in 1020 patients (age 63.3±11.4 years; 29.1% women) with or without coronary artery disease (79.1% with coronary artery disease and 20.9% without coronary artery disease) during a long follow-up. Complete plasma lipid and apolipoproteins were available for all patients. Forty-five patients (4.4%) experienced nonfatal VTE events during a median follow-up period of 144 months. Apo CIII plasma concentration at enrollment was higher in patients with VTE compared with patients without VTE (12.2 [95% CI, 11.10-13.5] mg/dL vs 10.6 [95% CI, 10.4-10.9] mg/dL, respectively; P=0.011). Patients with apo CIII levels above the median value (10.6 mg/dL) exhibited an increased risk of VTE (incidence rate, 6.0 [95% CI , 4.0-8.0] vs 1.8 [95% CI, 0.7-2.9] VTE events/1000 person-years; unadjusted hazard ratio [ HR ], 3.42 [95% CI , 1.73-6.75]; P<0.001). This association was confirmed after adjustment for sex, age, coronary artery disease diagnosis, body mass index, hypertension, and anticoagulant treatment at enrollment ( HR , 2.66; 95% CI , 1.31-5.37 [ P=0.007]), with inclusion of lipid parameters in the Cox model (HR, 3.74; 95% CI , 1.24-11.33 [ P=0.019]), and even with exclusion of patients who died at follow-up ( HR, 3.92; 95% CI , 1.68-9.14 [ P=0.002]) or patients taking anticoagulants ( HR , 3.39; 95% CI , 1.72-6.69 [ P<0.001]). Conclusions Our results suggest that high plasma apo CIII concentrations may predict an increased risk of VTE in patients with cardiovascular disease.


Assuntos
Apolipoproteína C-III/sangue , Doença da Artéria Coronariana/complicações , Tromboembolia Venosa/sangue , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Estudos Transversais , Feminino , Seguimentos , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
12.
Clin Rheumatol ; 26(3): 440-2, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16437363

RESUMO

We describe the case of a 75-year-old Italian woman affected by dermatomyositis (DM) treated with steroid, high-dose intravenous immunoglobulins (IVIgs) and cyclophosphamide (CPX), taken orally. After a few months, the patient presented multiple red vascular skin lesions diagnosed as Kaposi sarcoma (KS). Steroid was furtherly reduced, and CPX was stopped. We put the patient on chemotherapy with intravenous infusion of vinblastine and vincristine on alternate weeks obtaining the remission of KS. DM is well controlled by a low-dosage steroid and high-dose IVIgs.


Assuntos
Dermatomiosite/complicações , Dermatomiosite/tratamento farmacológico , Imunossupressores/efeitos adversos , Prednisona/efeitos adversos , Sarcoma de Kaposi/induzido quimicamente , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Vimblastina/uso terapêutico , Vincristina/uso terapêutico
13.
PLoS One ; 12(10): e0185792, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28968444

RESUMO

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.


Assuntos
Carbono/química , Neoplasias do Colo/genética , Metilação de DNA , Neoplasias Hepáticas/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Antígenos de Histocompatibilidade Menor/genética , Idoso , Neoplasias do Colo/patologia , Feminino , Genótipo , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
15.
Front Genet ; 8: 229, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375619

RESUMO

Colon cancer is one of the most frequent solid tumor and simultaneous diagnosis of primary colon cancer and liver metastases occurs in about one fourth of cases. The current knowledge on epigenetic signatures, especially those related to hydroxymethylation in primary cancer tissue, synchronous metastasis, and blood circulating cells is lacking. This study aimed to investigate both methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) status in the DNA of individual patients from colon cancer tissue, synchronous liver metastases, and in cancer-free colon and liver tissues and leukocytes. Patients undergoing curative surgery (n = 16) were enrolled and their laboratory and clinical history data collected. The contents of mCyt and hmCyt were determined by a liquid chromatography/mass spectrometry (LC/MS/MS) method in DNA extracted from primary colon cancer, synchronous hepatic metastatic tissues and homologous cancer-free tissues, i.e., colon and liver tissues as well as leukocytes. The mCyt and hmCyt levels were compared between cancerous and cancer-free tissues, and correlations between leukocytes and colon/liver tissues for both the mCyt and hmCyt levels were evaluated. The mCyt levels were similar in primary colon cancer and liver metastasis tissues (4.69 ± 0.37% vs. 4.77 ± 0.38%, respectively, p = 0.535), and both primary and metastatic tissues were hypomethylated compared to cancer-free colon (4.98 ± 0.26%). The difference in the mCyt content between cancerous and cancer-free colon tissues was significantly lower in primary colon cancer (p = 0.004), but not in liver metastasis (p = 0.148). The hmCyt content was similar in primary colon cancer compared to liver metastasis (0.035%, C.I. 0.024-0.052% versus 0.035%, C.I. 0.021-0.058%, respectively, p = 0.905) and markedly depleted compared to the cancer-free colon (0.081%, C.I. 0.055-0.119%) with a statistically significant difference (p < 0.05) for both comparisons. The mCyt levels showed a borderline correlation between leukocytes and colon cancer tissue (Pearson's correlation coefficient = 0.51, p = 0.052) while no correlations were detected for the hmCyt levels. In conclusion, primary colon cancer and synchronous liver metastasis tissues showed a similar epigenetic status but were significantly hypomethylated and hypohydroxymethylated as compared to homologous cancer-free colon tissues.

16.
PLoS One ; 11(12): e0167534, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936032

RESUMO

Polymorphisms within one-carbon metabolism genes have been largely studied in relation to cancer risk for the function of this pathway in nucleotide synthesis and DNA methylation. Aims of this study were to explore the possible link among several common functional gene polymorphisms within one-carbon metabolism and survival rate in primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma, and to assess the additional effect of global DNA methylation on survival rate and mortality risk. Forty-seven primary liver cancer patients were genotyped for ten polymorphisms: DHFR 19bp ins/del, TS 2rpt-3rpt, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, BHMT 716 A>G, TC II 776C>G. Methylation was determined in peripheral blood mononuclear cells (PBMCs) DNA as methylcytosine (mCyt) content using LC/MS/MS. Among the polymorphisms analysed, the RFC1 80G>A (rs1051266) influenced the survival rate in primary liver cancers. The RFC1 80AA was associated to a significantly reduced survival rate (22.2%) as compared to both GG and GA genotypes (61.5% and 76% respectively, p = 0.005). When the cancer patients were stratified according to the mCyt median value as high (>5.34%) or low (≤5.34%), the concomitant presence of AA genotype and low mCyt level led to a significantly worse survival rate as compared to the G allele carriership (p<0.0001) with a higher Hazard Ratio (HR = 6.62, p = 0.001). The subjects carrying the AA genotype in association with high mCyt did not show a significant difference in survival rate as compared with the G allele carriers (p = 0.919). The RFC1 80G>A polymorphism influenced the survival rate, and the presence of RFC1 80AA genotype with low global methylation in PBMCs DNA was associated with poorer prognosis and higher mortality risk, therefore highlighting novel molecular signatures potentially helpful to define prognostic markers for primary liver cancers.


Assuntos
Carbono/metabolismo , Metilação de DNA , Predisposição Genética para Doença/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único , Proteína Carregadora de Folato Reduzido/genética , Idoso , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Taxa de Sobrevida
17.
Clin Epigenetics ; 7: 43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25945129

RESUMO

BACKGROUND: Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue. RESULTS: After merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16), iron homeostasis (HAMP), one-carbon metabolism (SHMT1), and genes with a putative, newly identified function as tumor suppressors (FAM107A, IGFALS, MT1G, MT1H, RNF180). CONCLUSIONS: A genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC. Due to the reversibility of epigenetic mechanisms by environmental/nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.

18.
J Abnorm Child Psychol ; 42(1): 63-75, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23435481

RESUMO

We investigated the etiological relationships between the three ADHD dimensions of Inattentive Problems (INP), Hyperactivity-Impulsivity Problems (HIP) and Sluggish Cognitive Tempo (SCT) as measured by the CBCL 6-18 questionnaire. Multivariate models were applied to 398 twin pairs (374 boys and 422 girls) aged 8 to 17 years (M = 13.06, SD = 2.59) belonging to the population-based Italian Twin Registry. The INP, HIP and SCT problem scores were moderately-to-substantially (range 0.29-0.47) intercorrelated. The best fitting model showed that these 3 dimensions are correlated both at the genetic (correlations' range: 0.65-0.83) and the environmental (correlations: 0.29 and 0.44) levels, but they are also distinct. While SCT showed moderate heritability and large non-shared environmental influences, variance for both INP and HIP was substantially explained by genetic influences. We also found evidence of negative sibling interaction for INP, implying that a given behavior in one twin leads to an opposite behavior in the co-twin. Our results support at the etiological level the findings of previous psychometric and longitudinal studies of ADHD, which yielded evidence of the 3 distinct-albeit correlated-problem dimensions of inattentiveness, hyperactivity-impulsivity, and sluggish cognitive tempo.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtornos Cognitivos/psicologia , Comportamento Impulsivo/psicologia , Relações Interpessoais , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Feminino , Interação Gene-Ambiente , Humanos , Itália , Masculino , Análise Multivariada , Relações entre Irmãos
19.
Front Hum Neurosci ; 8: 672, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25225476

RESUMO

From a phenomenological perspective, faces are perceived differently from objects as their perception always involves the possibility of a relational engagement (Bredlau, 2011). This is especially true for familiar faces, i.e., faces of people with a history of real relational engagements. Similarly, valence of emotional expressions assumes a key role, as they define the sense and direction of this engagement. Following these premises, the aim of the present study is to demonstrate that face recognition is facilitated by at least two variables, familiarity and emotional expression, and that perception of familiar faces is not influenced by orientation. In order to verify this hypothesis, we implemented a 3 × 3 × 2 factorial design, showing 17 healthy subjects three type of faces (unfamiliar, personally familiar, famous) characterized by three different emotional expressions (happy, hungry/sad, neutral) and in two different orientation (upright vs. inverted). We showed every subject a total of 180 faces with the instructions to give a familiarity judgment. Reaction times (RTs) were recorded and we found that the recognition of a face is facilitated by personal familiarity and emotional expression, and that this process is otherwise independent from a cognitive elaboration of stimuli and remains stable despite orientation. These results highlight the need to make a distinction between famous and personally familiar faces when studying face perception and to consider its historical aspects from a phenomenological point of view.

20.
J Abnorm Child Psychol ; 42(5): 861-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24337737

RESUMO

Reduced amplitude of the P300 event-related potential has been consistently associated with a variety of externalising problems, including conduct disorder. The few available genetically-informative studies of these relationships, however, were conducted among adolescents/adults (i.e., at an age when conduct disorder has typically already become manifest). Among 200 general population twins with a mean age of 9 years (range 6-14 years), we studied the relationship between the P300 waveform elicited by an auditory oddball task and the DSM-oriented conduct problems scale of the Child Behavior Checklist 6-18. Conduct problems scores were negatively and significantly correlated (r = -0.19, p = 0.01) with P300 amplitude; correlations between P300 amplitude and the other DSM-oriented Child Behavior Checklist scales were non-significant, except for oppositional defiant problems (p = 0.01). We found moderate heritability estimates for both P300 amplitude (0.58, CI:0.37;0.73) and conduct problems (0.52, CI:0.25;0.70). Bivariate twin analyses indicated that the covariation between these two phenotypes can be explained by additive genetic factors only, with a genetic correlation of -0.33. An association between reduced P300 amplitude and conduct problems can be substantiated already in childhood, at an age that precedes the most typical onset of conduct disorder. This relationship appears to be genetic in nature. Reduced P300 amplitude can represent a valuable marker for conduct problems, and can contribute to the early identification of children at high-risk for conduct disorder.


Assuntos
Transtorno da Conduta/fisiopatologia , Potenciais Evocados P300/fisiologia , Estimulação Acústica/métodos , Adolescente , Análise de Variância , Criança , Comportamento Infantil/fisiologia , Transtorno da Conduta/genética , Doenças em Gêmeos , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Feminino , Humanos , Masculino
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