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BC: Articoli scritti da E. Danese

La diagnostica di laboratorio nella sindrome da apparente eccesso di mineralcorticoidi
The laboratory diagnosis of apparent mineralocorticoid excess (AME)
<p>The apparent mineralocorticoid excess(AME) is a rare genetic disorder caused by impaired activity of the enzyme 11&beta;-hydroxysteroid dehydrogenase type2 (11&beta;HSD2). This abnormality is associated with cortisol excess and abnormal activation of mineralocorticoidreceptor, which is usually only activated by aldosterone. More than 50 known mutations have been associated withAME; whilst some epigenetic modifications may also be involved. AME causes severe hypertension and is hencetraditionally diagnosed during the first years of life. Deficit of 11&beta;HSD2 also occur in other physiopathologicalconditions like pre-eclampsia, sodium-sensitive hypertension and kidney or hepatic impairment. The biochemicaldiagnosis is conventionally made by quantifying tetrahydroxylated metabolites of cortisol (THF and allo-THF) andcortisone (THE) expressed as THF+allo-THF/THE ratio and using home-made Gas Chromatography-MassSpectrometry methods. Nevertheless, some recent studies showed more accurate characterization of 11&beta;HSD2deficit by measuring the urinary free cortisol/cortisone ratio with Liquid Chromatography-Tandem Mass Spectrometry.A final consensus on the preferred method to diagnose AME has not been reached so far, and more studies areneeded for better defining sensitivity and specificity of these tests in some different physiopathological conditionsassociated with 11&beta;HSD2 impairment.</p>
Biochimica Clinica ; 43(3) 264-268
Rassegne - Reviews
 
Telomere shortening and PCDH10 promoter methylation in colorectal cancermucosae
<p>Background: telomerase activity and telomere length (TL) have important implications in several human diseases.Telomere shortening is associated with colorectal carcinogenesis. Recent studies also showed that protocadherin 10(PCDH10) plays a critical role in cancer cell growth, by negatively regulating telomerase activity. PCDH10isfrequently downregulated by promoter DNA methylation. The aim of this study was to investigate whether PCDH10promoter methylation was associated with TL in colorectal cancer (CRC).<br />Methods: DNA was extracted from 35 CRC and 35 adjacent normal tissues with Gentra Purgene Kit (Qiagen, Hilden,Germany). A quantitative methylation-specific PCR (MSP) based method was used to analyze a selected CpG site inPCDH10promoter. TL was evaluated with qPCR and expressed as telomere to single copy gene (T/S) ratio.Differences were assessed with Mann-Whitney test or Wilcoxon signed-ranks test when appropriate, whilstcorrelation analyses were performed with Spearman&rsquo;s test. Diagnostic performance was calculated with receiveroperating characteristics (ROC) curve analysis. The level of statistical significance was set at p &lt;0.05.<br />Results: we found that TL was significantly lower in CRC than in adjacent non-cancerous tissues (p=0.0005). Thearea under the ROC curve (AUC) for TL was 0.759 (95% Confidence Interval: 0.643-0.875, p=0.0002). AberrantPCDH10promoter methylation was detected in 100% of CRC tissues but in none of paired non-cancerous tissues.The median methylation rate in CRC tissues was 55.7% (range: 6.1-97.8%). TL was negatively correlated withPCDH10promoter methylation (r=-0.42, p=0.0002).<br />Conclusions: these results suggest a pivotal role of telomere shortening and PCDH10methylation in CRC tissues.TL may be seen as a potential biomarker in CRC diagnostics.</p>
Biochimica Clinica ; 43(3) 278-283
Contributi Scientifici - Scientific Papers
 
Meccanismi epigenetici: l’esempio del Diabete Mellito tipo 1
Epigenetics in Type 1 Diabetes Mellitus
M. Montagnana  |  G. Lippi  |  E. Danese  | 
<p>Type 1 diabetes mellitus (T1DM) is a chronic autoimmune illness characterized by insufficient production of insulin by pancreatic beta cells. This condition occurs by environmental disruption (mostly supported by viral infections or nutritional components) of immune tolerance in genetically susceptible individuals. The lack of concordance in monozygotic twins for common diseases as T1DM has led to hypothesize that epigenetics may have a pivotal role in the pathogenesis of this condition, by modulating the relationship between the genotype and the phenotype. Epigenetics is commonly defined as the regulation of gene expression through chemical changes including DNA methylation or histone modulation of noncoding RNAs, without directly involving mutational changes in DNA. Epigenetics has recently contributed to amplify our understanding of the mechanisms underlying different pathological conditions for which causes other than genetic mutations and environmental factors are involved. Epigenetic modification in T1DM may hence mediate the environmental influence on expression of genes involved in the pathogenesis of disease. Therefore, this review is focused on describing the leading epigenetic mechanisms participating to the pathogenesis and progression of T1DM, and discussing the diagnostic or prognostic role of some potentially useful epigenetic biomarkers.</p>
Biochimica Clinica ; 42(2) 097-102
Rassegne - Reviews
 
miR-199a and miR-125b expression levels in serum of women affected by epithelial ovarian cancer
<p>Recent studies show that microRNA (miRNAs) are involved in cancer by regulating cell proliferation, apoptosis and angiogenesis. Accordingly, their deregulation could contribute to cancer development and progression. It has been demonstrated that in ovarian tissue the over-expression of miR-199a and miR-125b inhibits tumor angiogenesis, a fundamental process for cancer development and growth. Aims of our study were to investigate the expression levels of miR-199a and miR-125b in serum of patients with ovarian cancer (OC) and to evaluate the correlation between miRNAs expression and traditional biomarkers [CA125 and human epididymis protein 4 (HE4)]. 32 patients with epithelial OC (54&plusmn;14 years old) and 31 healthy controls (55&plusmn;17 years old) were enrolled. Serum samples were collected prior to definitive surgical treatment and RNA extraction was performed by using the miRNeasy Serum/Plasma kit (Qiagen GmbH). miR-199a and miR-125b expression was determined by quantitative real timepolymerase chain reaction (TaqMan MicroRNA Assay, Applied Biosystems). The expression levels of miRNAs were normalized to miR-16 and calculated utilizing the 2-&Delta;Ct method. Serum levels of miR-199a and miR-125b were significantly higher in OC patients compared to controls (P=0.007 and P=0.002, respectively). A marginally statistically significant correlation was found between miR-199a and miR-125b expression levels (r=0.38, P=0.03). The ROC curve analysis of the diagnostic performance between healthy controls and OC patients revealed that HE4 had a significantly higher area under the curve (AUC=0.90) when compared to CA125 (AUC=0.85), miR-199a (AUC=0.70) and miR-125b (AUC=0.67). Anyway, the determination of circulating miRNAs may be relevant, since their expression is known to be aberrant in cancer, having potential ability to monitor tumor dynamics.</p>
Biochimica Clinica ; 40(4) 328-333
Contributi scientifici - Scientific Papers
 
Nuovi approcci diagnostici al ritardo mentale
New diagnostic approaches to mental retardation
<p>Genomic imbalances are considered the most frequent causes of mental retardation (MR). Although widespread screening with novel molecular karyotyping methods, such as multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (Array-CGH) might be desirable, effective clinical preselection is essential because of the technical complexities and cost of testing. This study focuses on a retrospective analysis of clinical features in patients with MR of unknown etiology,thereby assessing the sensitivity of a six item checklist in identifying rearranged subjects. The diagnostic powers of single techniques were also evaluated. We studied 164 subjects with MR who had completed the follow diagnostic process: karyotype and eventually fluorescence in situ hybridization (FISH) in case of suspected microdeletion syndrome, specific analysis in case of suspected X-linked or monogenic disease, MLPA for subtelomeric rearrangements in patients negative to previous tests, Array-CGH in patients negative to MLPA. A six items checklist based on relevant clinical signs was retrospectively applied. 5 patients were carrier of chromosomal abnormalities (3 detected by karyotype and 2 by FISH), 3 were affected by X-fragile syndrome, 6 had mutations, and 33 were carriers of genomic imbalances (9 detected by MLPA and 24 by Array-CGH), while 117 resulted negative to any tests. In patients with genomic imbalances and in subjects without rearrangements the median score of the checklist was 6 (range 3-9) and 4 (range 0-8), respectively (P &lt;0,0001). The ROC analysis for the diagnostic accuracy of our checklist showed an area under the curve of 0.74 (95% confidence interval: 0.65-0.83). Using a cut-off for the score of U3, 24% of patients could have been excluded without missing any genomic imbalances. This study supports the evidence that the application of a clinical checklist may improve the rate of pathological findings in patients with MR.</p>
Biochimica Clinica ; 36(3) 187-192
Contributi Scientifici - Scientific Papers
 
Determinazione della variabilità biologica dell'emoglobina A2
Determination of biological variation of hemoglobin A2.
R. Paleari  |  M. Montagnana  |  E. Danese  |  M. Tozzi  |  G.C. Guidi  |  A. Mosca  | 
<p><strong>Determination of biological variation of hemoglobin A2.</strong> We present an experimental report aimed to evaluate the biological variation of hemoglobin A2 (HbA2), a minor hemoglobin component in post-natal life, accounting for 2.5%-3.5% of the total hemoglobin in red cells, which is very relevant for the laboratory diagnosis of thalassemic syndromes. We took five blood specimens from 17 apparently healthy subjects (9 men and 8 women, ages 26-52 years) on the same day, every two weeks for two months. Samples were stored at -80 &#176;C until analysis and assayed in duplicate by Bio-Rad Variant II analyzer. Data were analyzed by the ANOVA. There were no differences in HbA2 values between men and women. HbA2 exhibited marked individuality: within- (CVI) and between-subject (CVG) biological variation were 0.7% and 7.7%, respectively. Desirable analytical goals derived from biological variation for imprecision (0.5 CVI), bias [0.25 (CVI2 + CVG2)1/2] and total error [1.65 (0.5 CVI) + 0.25 (CVI2 + CVG2)1/2]were 0.4%, 1.9%, and 3.1%, respectively. In conclusion, this is the first evidence that HbA2, as well as total hemoglobin, is under a strict homeostatic control. Our data also show that stringent analytical goals are needed for the clinical application of HbA2 measurements.</p>
Biochimica Clinica ; 35(6) 458-460
CONTRIBUTI SCIENTIFICI - CONTRIBUTI SCIENTIFICI
 
Valutazione del "risk of ovarian malignancy algorithm" (ROMA) nella stima del rischio di tumore epiteliale maligno dell'ovaio in donne con massa pelvica
The "risk of ovarian malignancy algorithm" for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass.
Biochimica Clinica ; 35(1) 30
CONTRIBUTI SCIENTIFICI - CONTRIBUTI SCIENTIFICI