[Show abstract][Hide abstract] ABSTRACT: Gliomas represent a disparate group of tumours for which there are to date no cure. Thus, there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA (miRNA) profile of 8 WHO grade II gliomas and 24 higher grade tumours (2 WHO grade III and 22 glioblastomas) by using the Affymetrix GeneChip miRNA Array v. 1.0. A relative quantification method (RT-qPCR) with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas (TCGA) datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours. RT-qPCR confirmed the differential expression in the two patients' groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme (GBM) and Lower Grade Glioma (LGG) datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover, in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses (HR 1.19, p = 0.04, and HR 1.18, p = 0.029 respectively). Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas. Copyright: ß 2014 Barbano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. The array data have been deposited at the ArrayExpress archive, accession number E-MTAB-1840. Funding: Ricerca Corrente 2013 funding was granted by the Italian Ministry of Health. This work was also supported by ''561000'' voluntary contributions, ''Progetto Operativo Nazionale,'' PON 2011-2014 VIRTUALAB (PON01_01297). S.V. is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC – IG13585) and Ministero dell'Istruzione, dell'Università e della Ricerca Progetti di Ricerca di Interesse Nazionale (PRIN 2010) and The National Council of Research of Italy CNR EPIGEN grants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
[Show abstract][Hide abstract] ABSTRACT: Background
The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood.While high serum adiponectin is associated with increased CV mortality in the general population, no data are available in type 2 diabetes.We here investigated whether this counterintuitive association was observable also in diabetic patients and whether it was sex-specific.Methods
Three prospective cohorts were analyzed: 1) Gargano Heart Study (GHS; 359 patients, 58 events/1,934 person-years; py); 2) Health Professional Follow-up Study (HPFS; 833 men, 146 events/10,024 py); 3) Nurses¿ Health Study (NHS; 902 women, 144 events/15,074 py).ResultsIn GHS serum adiponectin predicted CV mortality in men (hazard ratio, HR, and 95% CI per standard deviation, SD, increment¿=¿1.54, 1.19-2.01), but not women (HR¿=¿0.98, 0.48-2.01).Circulating adiponectin predicted CV mortality in men from HPFS (HR¿=¿1.44, 1.21-1.72), but not in women from NHS (HR¿=¿1.08, 0.86-1.35), used as replication samples. In a pooled analysis, HRs were 1.47 (1.27-1.70) in 1,075 men and 1.07 (0.86-1.33) in 1,019 women (p for HRs heterogeneity across sexes¿=¿0.018).Conclusions
This is the first report showing that high circulating adiponectin predicts increased CV mortality in men, but not in women with type 2 diabetes. Further studies are necessary to unravel the mechanisms through which adiponectin influences CV mortality in a sex-specific manner.
[Show abstract][Hide abstract] ABSTRACT: Background
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy, characterized by largely unsatisfactory responses to the currently available therapeutic strategies. In this study we evaluated the expression of genes involved in gemcitabine uptake in a selected cohort of patients with PDAC, with well-defined clinical-pathological features.MethodsmRNA levels of hENT1, CHOP, MRP1 and DCK were evaluated by means of qRT-PCR in matched pairs of tumor and adjacent normal tissue samples collected from PDAC patients treated with gemcitabine after surgical tumor resection. To detect possible interaction between gene expression levels and to identify subgroups of patients at different mortality/progression risk, the RECursive Partitioning and Amalgamation (RECPAM) method was used.ResultsRECPAM analysis showed that DCK and CHOP were most relevant variables for the identification of patients with different mortality risk, while hENT1 and CHOP were able to identify subgroups of patients with different disease progression risk. Conclusion: hENT1, CHOP, MRP1 and DCK appear correlated to PDAC, and this interaction might influence disease behavior.
Journal of translational medicine. 09/2014; 12(1):248.
[Show abstract][Hide abstract] ABSTRACT: In seeking more specific biomarkers of the cystic fibrosis (CF) lung inflammatory disease that would be sensitive to antibiotic therapy, we sought to evaluate the gene expression profiles of neutrophils in CF patients before treatment in comparison with non-CF healthy individuals and after antibiotic treatment. Genes involved in neutrophil-mediated inflammation, i.e. chemotaxis, respiratory burst, apoptosis, and granule exocytosis, were the targets of this study. Microarray analysis was carried out in blood and airway neutrophils from CF patients and in control subjects. A fold change (log) threshold of 1.4 and a cut-off of p,0.05 were utilized to identify significant genes. Community networks and principal component analysis were used to distinguish the groups of controls, pre-and post-therapy patients. Control subjects and CF patients before therapy were readily separated, whereas a clear distinction between patients before and after antibiotic therapy was not possible. Blood neutrophils before therapy presented 269 genes down-regulated and 56 up-regulated as compared with control subjects. Comparison between the same patients before and after therapy showed instead 44 genes down-regulated and 72 up-regulated. Three genes appeared to be sensitive to therapy and returned to ''healthy'' condition: phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), hydrogen voltage-gated channel 1 (HVCN1), and b-arrestin 1 (ARRB1). The up-regulation of these genes after therapy were confirmed by real time PCR. In airway neutrophils, 1029 genes were differentially expressed post-vs pre-therapy. Of these, 30 genes were up-regulated and 75 down-regulated following antibiotic treatment. However, biological plausibility determined that only down-regulated genes belonged to the gene classes studied for blood neutrophils. Finally, it was observed that commonly expressed genes showed a greater variability in airway neutrophils than that found in blood neutrophils, both before and after therapy. These results indicate more specific targets for future interventions in CF patients involving respiratory burst, apoptosis, and granule exocytosis.
[Show abstract][Hide abstract] ABSTRACT: This study tried to replicate in a large sample of white patients with type 2 diabetes (T2D) from Italy a previously reported association of the IRS1 G972R polymorphism with failure to oral antidiabetes drugs (OAD). A total of 2,409 patients from four independent studies were investigated. Case subjects (n = 1,193) were patients in whom, because of uncontrolled diabetes (i.e., HbA1c >8%), insulin therapy had been added either on, or instead of, maximal or near-maximal doses of OAD, mostly metformin and sulfonylureas; control subjects (n = 1,216) were patients with HbA1c <8% in the absence of insulin therapy. The IRS1 G972R polymorphism was typed by TaqMan allele discrimination. In all samples, individuals carrying the IRS1 R972 risk variant tended to be more frequent among case than control subjects, though reaching statistical significance only in one case. As no IRS1 G972R-by-study sample interaction was observed, data from the four samples were analyzed together; a significant association was observed (allelic odds ratio [OR] 1.30, 95% CI 1.03-1.63). When our present data were meta-analyzed with those obtained in a previous study, an overall R972 allelic OR of 1.37 (1.12-1.69) was observed. This study confirms in a large and ethnically homogeneous sample that IRS1 G972R polymorphism is associated with failure to OAD among patients with T2D.
[Show abstract][Hide abstract] ABSTRACT: MicroRNA-10b (miR-10b) has a prominent role in regulating tumor invasion and metastasis by targeting the HOXD10 transcriptional repressor and has been found up-regulated in several tumor types.
[Show abstract][Hide abstract] ABSTRACT: Using diffusion tensor magnetic resonance imaging (DT MRI), we analyzed the architectural integrity of the brain white matter (WM) from a large cohort of MS patients to identify the structural substrates of the concomitant presence of depression and fatigue.
Brain dual-echo, 3D T1-weighted and DT MRI scans were acquired from 147 MS patients and 90 gender- and age-matched healthy controls (HCs). Patients were stratified by the presence of depression (92 depressed (D), 55 not depressed (nD)) and fatigue (81 fatigued (F), 66 not fatigued (nF)). Sixty-five patients had co-occurrence of depression and fatigue (DF). Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). Tract-specific analyses were run in brain WM tracts using standard-space templates.
Whole-brain voxel-wise analysis yielded no significant differences between patient subgroups. At tract-specific analysis, DF patients had reduced fractional anisotropy (FA) of the forceps minor. Reduced FA of the right anterior thalamic radiation and right uncinate fasciculus was found in F-MS vs not F-MS patients after correcting for depression. No significant differences were found between D vs not D-MS patients, after correcting for fatigue.
This study provides evidence for partially overlapping damage to frontal and fronto-temporal pathways underlying depression and fatigue in MS.
[Show abstract][Hide abstract] ABSTRACT: Background and purposeTo evaluate whether cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels could predict the time to generalization (TTG) in amyotrophic lateral sclerosis (ALS).Methods
Cerebrospinal fluid NFL levels of 37 cases of sporadic ALS were measured and the time of symptom spreading from spinal or bulbar localization to both (TTG) was evaluated in all patients.ResultsKaplan−Meier analysis showed a short TTG in patients with high NFL levels (log-rank test chi-squared = 19.4, P < 0.0001). In a multivariate regression model patients with NFL levels above the median had an eight-fold higher risk of generalization (adjusted hazard ratio 7.9, 95% confidence interval 2.9–21.4, P < 0.0001) compared with those with NFL levels below the median.Conclusions
This study shows that in sporadic ALS NFL, a marker of neurodegeneration, is correlated with TTG, a clinical intermediate parameter of survivorship.
European Journal of Neurology 04/2014; · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: White matter (WM) tract alterations were assessed in patients with progressive supranuclear palsy (PSP) relative to healthy controls and patients with idiopathic Parkinson's disease (PD) to explore the relationship of WM tract damage with clinical disease severity, performance on cognitive tests, and apathy. 37 PSP patients, 41 PD patients, and 34 healthy controls underwent an MRI scan and clinical testing to evaluate physical disability, cognitive impairment, and apathy. In PSP, the contribution of WM tract damage to global disease severity and cognitive and behavioural disturbances was assessed using Random Forest analysis. Relative to controls, PSP patients showed diffusion tensor (DT) MRI abnormalities of the corpus callosum, superior cerebellar peduncle (SCP), cingulum and uncinate fasciculus bilaterally, and right inferior longitudinal fasciculus. Corpus callosum and SCP DT MRI measures distinguished PSP from PD patients with high accuracy (area under the curve ranging from 0.89 to 0.72). In PSP, DT MRI metrics of the corpus callosum and superior cerebellar peduncles were the best predictors of global disease severity scale scores. DT MRI metrics of the corpus callosum, right superior longitudinal and inferior longitudinal fasciculus, and left uncinate were the best predictors of executive dysfunction. In PSP, apathy severity was related to the damage to the corpus callosum, right superior longitudinal, and uncinate fasciculi. In conclusion, WM tract damage contributes to the motor, cognitive, and behavioural deficits in PSP. DT MRI offers markers for PSP diagnosis, assessment, and monitoring.
Journal of Neurology 03/2014; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary palmar hyperhidrosis is a distressing and disabling condition that can produce social, psychological and occupational problems. Although the use of botulinum toxin type A (BoNT-A) has been reported as an efficacious and safe intervention to improve palmar hyperhidrosis, only one study concerned botulinum toxin type B (BoNT-B) in this disorder. The aim of study was to evaluate the efficacy and safety of BoNT-B in treating primary palmar hyperhidrosis. Participants were injected with 5,000 IU of BoNT-B in each palm. Visual analogue test (VAS) to evaluate the intensity of decrease in sweat production, Minor's iodine starch test and measurement of paper towels' weight were used to ascertain palmar sweating at baseline, 4, 12 and 24 weeks after BoNT-B injections by a blind examiner. Thirty-two subjects (12 males, 20 females, mean age 31 ± 11) were enrolled. Significant reduction of palmar sweating was detected after BoNT-B injection: 2.9 ± 1.4, 0.3 ± 0.4, 0.9 ± 0.8, and 2.1 ± 1.5 g (p < 0.001) of paper towels' weight for the right palm at baseline, 4, 12 and 24 weeks; and 2.8 ± 1.7, 0.5 ± 0.6, 0.8 ± 0.7, and 1.8 ± 1.25 g (p < 0.001) at same time, respectively for the left palm. Significant reduction of mean VAS values were also detected after BoNT-B injections: 8.6 ± 1.1, 0.6 ± 0.8, 3.5 ± 2.5, and 7.1 ± 2.4 (p < 0.0001) at baseline, 4, 12 and 24 weeks, respectively. Mild side effects consisting in local pain and hand weakness were observed in 4 (12.5 %) subjects. The findings indicated that the use of 5,000 IU BoNT-B injection in each palm was safe and significantly improved the severity of palmar hyperhidrosis.
Archives for Dermatological Research 02/2014; · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims
Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors.
Methods and results
Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 ± 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models.
At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11–2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17–4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring-Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005).
Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors.
[Show abstract][Hide abstract] ABSTRACT: To investigate grey (GM) and white matter (WM) abnormalities and their effects on cognitive and behavioral deficits in a large, phenotypically and genotypically well-characterized cohort of classic adult (aDM1, age at onset ≥20 years) or juvenile (jDM1, age at onset <20 years) patients with myotonic dystrophy type 1 (DM1).
PLoS ONE 01/2014; 9(8):e104697. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The FRAX algorithm is a diffused tool to assess fracture risk, but it has not been clinically applied in European patients with diabetes. We investigated FRAX-estimated fracture risk in patients with type 2 diabetes mellitus (DM), compared to concomitantly enrolled control subjects (CS).
In our multi-centric cross-sectional study we assessed the FRAX scores of 974 DM and 777 CS from three Italian Diabetes outpatient Clinics, and in DM we tested the association between parameters and complications of the disease and FRAX scores.
DM had significantly lower FRAX-estimated probability of both major osteoporotic fracture (MOF) and hip fracture (HF) than CS (6.35 ± 5.07% vs 7.75 ± 6.93%, p < 0.001, and 2.17 ± 3.07% vs 2.91 ± 4.56%, p = 0.023, respectively). When grouping by gender, such differences were found only in men. In DM, the frequency of previous fracture was higher than in CS (29.88% vs 20.46%, p < 0.001). In diabetics, age, sex, BMI, HbA1c and hypoglycemia significantly associated with FRAX-scores; gender-specific regression models differed. Among DM, the tree-based regression (CART) analysis identified groups of patients with different mean FRAX scores. In female DM aged >65 with or without obesity, MOF > 20% was found in 5.66% and 13.53%, and HF > 3% in 40.57% and 63.91% of patients, respectively.
DM had mean FRAX scores lower than CS, despite the higher number of previous fractures. Some features and complications of DM did associate with FRAX scores. Among DM patients, the CART analysis identified subgroups with higher FRAX scores. However, despite its potential utility, concerns still remain for using FRAX in DM patients. This article is protected by copyright. All rights reserved.
Diabetes/Metabolism Research and Reviews 12/2013; · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the value of conventional and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage, and their 12-month change, in predicting long-term disability and cognitive impairment in multiple sclerosis (MS).
Conventional and MT MRI brain scans were obtained at baseline and at 12 months in 73 patients, who were followed prospectively with clinical visits and rating of the Expanded Disability Status Scale score and the MS severity score (MSSS) for a median period of 13.3 years. At 13-year follow-up, a neuropsychological assessment was also performed when possible. T2-hyperintense and T1-hypointense lesion volumes, GM fraction (GMF), WM fraction, thalamic fraction, average lesion MT ratio (MTR), average GM MTR, average normal-appearing WM MTR, and thalamic MTR were measured. Random forest and multivariable analyses were performed to identify the predictors of neurologic deterioration and cognitive impairment at 13 years.
At 13-year follow-up, 66% of patients showed significant worsening of disability and 37% had worsened cognitively. The multivariable model, in which Expanded Disability Status Scale deterioration at final follow-up was the dependent variable, identified baseline GMF (odds ratio [OR] = 0.79, p = 0.01) as the only predictor of worsening of disability (C-index = 0.69). Baseline disease duration (OR = 1.50, p = 0.08) and average GM MTR (OR = 0.87, p = 0.03) were independent variables associated with cognitive deterioration (C-index = 0.97). Baseline MSSS (β = 0.50, p < 0.0001) and baseline GMF (β = -0.32, p = 0.0005) predicted MSSS at follow-up (r(2) = 0.45).
GM damage is one of the key factors associated with long-term accumulation of disability and cognitive impairment in MS.
[Show abstract][Hide abstract] ABSTRACT: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association.
The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448).
Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05).
Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.