Efficacy of Antioxidant Treatment in Reducing Resistin Serum Levels: A Randomized Study

OBJECTIVES: Few in vitro studies have examined the participation of resistin, a recently discovered adipokine, in oxidative processes. We investigated whether in vivo treatment with the antioxidant vitamin C might affect resistin serum levels. DESIGN: Randomized prospective open trial. SETTING: San Giovanni Battista Hospital, Turin, Italy. PARTICIPANTS: Eighty healthy individuals. INTERVENTION: Administration of 2 g of ascorbic acid orally for 2 wk (n = 40; experimental group) or no supplementation (n = 40; control group). OUTCOME MEASURES: The primary end point was the between-group difference in the before–after change in resistin serum level after vitamin C supplementation. Secondary endpoints were the within- and between-group changes in glucose, insulin, lipid parameters, C-reactive protein fasting values, and markers of oxidative stress. RESULTS: In the experimental group, vitamin C supplementation was significantly associated with both resistin concentration reduction (from 4.3 ± 1.5 to 2.9 ± 0.8 ng/ml; 95% confidence interval [CI] −1.87, −1.03) and ascorbic acid level increase (from 9.4 ± 2.9 to 19.0 ± 5.2 mg/l; 95% CI 7.9, 11.2). In the control group, resistin levels did not change significantly (from 4.2 ± 1.0 to 4.3 ± 0.9 ng/ml; 95% CI −0.07, 0.37). The between-group differences were highly significant (p < 0.001). Vitamin C supplementation was also associated with a statistically significant reduction in nitrotyrosine level and incremental increase in reduced glutathione. In a linear regression model, within-individual changes in vitamin C concentrations were inversely correlated with changes in resistin levels in both groups (each unit increase of vitamin C corresponded to a decrease of about 0.10 units of resistin levels (95% CI 0.13, 0.08; p < 0.001). CONCLUSION: This is to our knowledge the first randomized trial in humans that has demonstrated that short-term vitamin C supplementation could significantly reduce resistin levels, independent of changes in inflammatory or metabolic variables. Future investigations of resistin participation in oxidative processes are warranted

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis

Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing (WGS) data from nearly 10,000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n=6 from 5 families), AAGGC (n=2 from 1 family), AGAGG (n=1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, here we show a pathogenic role for large AAAGG repeat configuration expansions (n=5). Long read sequencing was used to fully characterise the entire repeat sequence and revealed a pure AGGGC expansion in six patients, whereas the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs seem to have arisen from a common haplotype and are predicted to form highly stable G quadruplexes, which have been previously demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions, since the AAAGG motif when very large (>500 repeats) or in the presence of AAGGG interruptions. Accurate sizing and full sequencing of the satellite repeat with long read is recommended in clinically selected cases, in order to achieve an accurate molecular diagnosis and counsel patients and their families

Vittorio Grevi - Scritti per il <<Corriere>> 1988-2010

Il volume contiene una selezione ragionata - preceduta da una prefazione di Virginio Rognoni - degli articoli di argomento giuridico scritti da Vittorio Grevi per Il Corriere della Sera nell'arco di tempo compreso tra il 1988 e il 2010, completata dall'indice generale di tutti gli articoli pubblicati, e dall'indice dei nomi citati

Endless

According to the artist, "Endless is an open book, a shared portrait that will be composed over time, recounting stories, relationships and visions through the different experiences of my life"

Genetic and epigenetic analyses guided by high resolution whole-genome SNP array reveals a possible role of CHEK2 in Wilms tumour susceptibility.

Wilms tumour (WT), the most frequent malignant childhood renal tumour, shows a high degree of genetic and epigenetic heterogeneity. Loss of imprinting on chromosome 11p15 is found in a large fraction of cases and mutations in a few genes, including WT1, CTNNB1, WTX, TP53 and, more recently, SIX1, SIX2 and micro RNA processing genes (miRNAPGs), have been observed. However, these alterations are not sufficient to describe the entire spectrum of genetic defects underlying WT development. We inspected data obtained from a previously performed genome-wide single nucleotide polymorphism (SNP) array analysis on 96 WT samples. By selecting focal regions commonly involved in chromosomal anomalies, we identified genes with a possible role in WT development, based on the prior knowledge of their biological relevance, including MYCN, DIS3L2, MIR562, HACE1, GLI3, CDKN2A and CDKN2B, PALB2, and CHEK2. The MYCN hotspot mutation c.131C&gt;T was detected in seven cases (7.3%). Full sequencing of the remaining genes disclosed 16 rare missense variants and a splicing mutation. Most of these were present at the germline level. Promoter analysis of HACE1, CDKN2A and CDKN2B disclosed partial methylation affecting HACE1 in a consistent fraction of cases (85%). Interestingly, of the four missense variants identified in CHEK2, three were predicted to be deleterious by in silico analyses, while an additional variant was observed to alter mRNA splicing, generating a functionally defective protein. Our study adds additional information on putative WT genes, and adds evidences involving CHEK2 in WT susceptibility

Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors