Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease

Do Daily Activities Impact Gas Tamponade - Retina Contact after Pars Plana Vitrectomy? A Computational Fluid Dynamics Study

Purpose:To calculate the retinal surface alternatively in contact with gas and aqueous because of fluid sloshing during daily activities such as ocular saccade, turning the head, standing up, and being a passenger of a braking car.Methods:Fluid dynamics of aqueous and gas tamponade was reproduced using computational methods using the OpenFOAM open-source library. The double-fluid dynamics was simulated by the volume of fluid method and setting the contact angle at the aqueous-gas-retina interface.Results:Sloshing increased the retinal surface in contact with aqueous by 13% to 16% regardless of fill rate and standing up determined the largest area of wet retina, followed by car braking, head rotation, and ocular saccade (P < 0.001). All activities except the ocular saccade determined a significant increase in the surface of retina in contact with the aqueous (P < 0.005). Car braking induced the highest shear stress (6.06 Pa); standing up determined the highest specific impulse and saccade the lowest.Conclusion:Daily activities instantaneously reduce the amount of retina consistently in contact with gas tamponade and increase shear stress giving aqueous a potential access to the subretinal space regardless of patients' compliance

Physical and Mental Fatigue Reduce Psychomotor Vigilance in Professional Football Players

Purpose: Professional football players experience both physical and mental fatigue (MF). The main aims of this randomized crossover study were to investigate the effect of MF on repeated-sprint ability (RSA) and the effects of both physical fatigue and MF on psychomotor vigilance. Methods: Seventeen male professional football players performed 10 maximal 20-m shuttle sprints interspaced by incomplete recovery (RSA test). Running speed, heart rate, brain oxygenation, and rating of perceived exertion were monitored during each sprint. The RSA test was preceded by either a 30-minute Stroop task to induce MF or by watching a documentary for 30 minutes (control [CON]) in a randomized counterbalanced order. Participants performed a psychomotor vigilance test at baseline, after the cognitive task (MF or CON), and after the RSA test. Results: Heart rate and rating of perceived exertion significantly increased, while running speed and brain oxygenation significantly decreased over the repeated sprints (P .001) with no significant differences between conditions. Response speed during the psychomotor vigilance test significantly declined after the Stroop task but not after CON (P = .001). Response speed during the psychomotor vigilance test declined after the RSA test in both conditions (P .001) and remained lower in the MF condition compared to CON (P = .012). Conclusions: MF does not reduce RSA. However, the results of this study suggest that physical fatigue and MF have negative and cumulative effects on psychomotor vigilance. Therefore, strategies to reduce both physical fatigue and MF should be implemented in professional football players

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R2 =0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10-8; and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT

New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII

In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a-m). All synthesized compounds, with the exception of compound EMAC10101k, preferentially inhibit off-target hCA II isoform. Within the series, compound EMAC10101d, bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors

Epigenetics, stem cells, and autophagy: Exploring a path involving miRNA

MiRNAs, a small family of non-coding RNA, are now emerging as regulators of stem cell pluripotency, differentiation, and autophagy, thus controlling stem cell behavior. Stem cells are undifferentiated elements capable to acquire specific phenotype under different kind of stimuli, being a main tool for regenerative medicine. Within this context, we have previously shown that stem cells isolated from Wharton jelly multipotent stem cells (WJ-MSCs) exhibit gender differences in the expression of the stemness related gene OCT4 and the epigenetic modulator gene DNA-Methyltransferase (DNMT1). Here, we further analyze this gender difference, evaluating adipogenic and osteogenic differentiation potential, autophagic process, and expression of miR-145, miR-148a, and miR-185 in WJ-MSCs derived from males and females. These miRNAs were selected since they are involved in OCT4 and DNMT1 gene expression, and in stem cell differentiation. Our results indicate a difference in the regulatory circuit involving miR-148a/DNMT1/OCT4 autophagy in male WJ-MSCs as compared to female cells. Moreover, no difference was detected in the expression of the two-differentiation regulating miRNA (miR-145 and miR-185). Taken together, our results highlight a different behavior of WJ-MSCs from males and females, disclosing the chance to better understand cellular processes as autophagy and stemness, usable for future clinical applications

The value of some Corsican sub-populations for genetic association studies

<p>Abstract</p> <p>Background</p> <p>Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations.</p> <p>Methods</p> <p>Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb). We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate.</p> <p>Results</p> <p>the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1) the presence of a particular haplotype with high frequency; 2) the derivation from a common genetic pool of the sub-populations examined in the present study.</p> <p>Conclusion</p> <p>These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.</p

!CHAOS: A cloud of controls

The paper is aimed to present the !CHAOS open source project aimed to develop a prototype of a national private Cloud Computing infrastructure, devoted to accelerator control systems and large experiments of High Energy Physics (HEP). The !CHAOS project has been financed by MIUR (Italian Ministry of Research and Education) and aims to develop a new concept of control system and data acquisition framework by providing, with a high level of abstraction, all the services needed for controlling and managing a large scientific, or non-scientific, infrastructure. A beta version of the !CHAOS infrastructure will be released at the end of December 2015 and will run on private Cloud infrastructures based on OpenStack

Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes: an Italian multicenter study

OBJECTIVE— To estimate the prevalence of biopsy-confirmed celiac disease in Italian children and adolescents with type 1 diabetes and to assess whether age at onset of type 1 diabetes is independently associated with diagnosis of celiac disease. RESEARCH DESIGNANDMETHODS— The study group was a clinic-based cohort of children and adolescents with type 1 diabetes cared for in 25 Italian centers for childhood diabetes. Yearly screening for celiac disease was performed using IgA/IgG anti-gliadin and IgA anti-endomysium antibodies. RESULTS— Of the 4,322 children and adolescents (age 11.8 4.2 years) identified with type 1 diabetes, biopsy-confirmed celiac disease was diagnosed in 292 (prevalence 6.8%, 95% confidence interval [CI] 6.0 –7.6), with a higher risk seen in girls than in boys (odds ratio [OR] 1.93, 1.51–2.47). In 89% of these, diabetes was diagnosed before celiac disease. In logistic regression analyses, being younger at onset of diabetes, being female, and having a diagnosis of a thyroid disorder were independently associated with the risk of having diabetes and celiac disease. In comparison with subjects who were older than 9 years at onset of diabetes, subjects who were younger than 4 years at onset had an OR of 3.27 (2.20–4.85). CONCLUSIONS— We have provided evidence that 1) the prevalence of biopsy-confirmed celiac disease in children and adolescents with type 1 diabetes is high (6.8%); 2) the risk of having both diseases is threefold higher in children diagnosed with type 1 diabetes at age 4 years than in those age 9 years; and 3) girls have a higher risk of having both diseases than boys