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Castel Guelfo di Bologna, Italy

Valente S.,University of Bologna | Alviano F.,Diagnostic and Specialty Medicine | Ciavarella C.,University of Bologna | Buzzi M.,University of Bologna | And 4 more authors.
Stem Cell Research and Therapy | Year: 2014

Introduction. Regenerative medicine challenges researchers to find noncontroversial, safe and abundant stem cell sources. In this context, harvesting from asystolic donors could represent an innovative and unlimited reservoir of different stem cells. In this study, cadaveric vascular tissues were established as an alternative source of human cadaver mesenchymal stromal/stem cells (hC-MSCs). We reported the successful cell isolation from postmortem arterial segments stored in a tissue-banking facility for at least 5 years. Methods. After thawing, hC-MSCs were isolated with a high efficiency (12 × 10§ssup§6§esup§) and characterized with flow cytometry, immunofluorescence, molecular and ultrastructural approaches. Results: In early passages, hC-MSCs were clonogenic, highly proliferative and expressed mesenchymal (CD44, CD73, CD90, CD105, HLA-G), stemness (Stro-1, Oct-4, Notch-1), pericyte (CD146, PDGFR-β, NG2) and neuronal (Nestin) markers; hematopoietic and vascular markers were negative. These cells had colony and spheroid-forming abilities, multipotency for their potential to differentiate in multiple mesengenic lineages and immunosuppressive activity to counteract proliferation of phytohemagglutinin-stimulated blood mononuclear cells. Conclusions: The efficient procurement of stem cells from cadaveric sources, as postmortem vascular tissues, demonstrates that such cells can survive to prolonged ischemic insult, anoxia, freezing and dehydration injuries, thus paving the way for a scientific revolution where cadaver stromal/stem cells could effectively treat patients demanding cell therapies. © 2014 Valente et al.; licensee BioMed Central Ltd.

Marco M.D.,Diagnostic and Specialty Medicine | Grassi E.,Diagnostic and Specialty Medicine | Vecchiarelli S.,Diagnostic and Specialty Medicine | Macchini M.,Diagnostic and Specialty Medicine | And 6 more authors.
Molecular Medicine Reports | Year: 2015

The aim of the current study was to implement whole transcriptome massively parallel sequencing (RNASeq) and copy number analysis to investigate the molecular biology of pancreatic ductal adenocarcinoma (PDAC). Samples from 16 patients with PDAC were collected by ultrasound-guided biopsy or from surgical specimens for DNA and RNA extraction. All samples were analyzed by RNASeq performed at 75x2 base pairs on a HiScanSQ Illumina platform. Single-nucleotide variants (SNVs) were detected with SNVMix and filtered on dbSNP, 1000 Genomes and Cosmic. Non-synonymous SNVs were analyzed with SNPs&GO and PROVEAN. A total of 13 samples were analyzed by high resolution copy number analysis on an Affymetrix SNP array 6.0. RNAseq resulted in an average of 264 coding non-synonymous novel SNVs (ranging from 146-374) and 16 novel insertions or deletions (In/Dels) (ranging from 6-24) for each sample, of which a mean of 11.2% were disease-associated and somatic events, while 34.7% were frameshift somatic In/Dels. From this analysis, alterations in the known oncogenes associated with PDAC were observed, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (93.7%) and inactivation of cyclin-dependent kinase inhibitor 2A (CDKN2A) (50%), mothers against decapentaplegic homolog 4 (SMAD4) (50%), and tumor protein 53 (TP53) (56%). One case that was negative for KRAS exhibited a G13D neuroblastoma RAS viral oncogene homolog mutation. In addition, gene fusions were detected in 10 samples for a total of 23 different intra- or inter-chromosomal rearrangements, however, a recurrent fusion transcript remains to be identified. SNP arrays identified macroscopic and cryptic cytogenetic alterations in 85% of patients. Gains were observed in the chromosome arms 6p, 12p, 18q and 19q which contain KRAS, GATA binding protein 6, protein kinase B and cyclin D3. Deletions were identified on chromosome arms 1p, 9p, 6p, 18q, 10q, 15q, 17p, 21q and 19q which involve TP53, CDKN2A/B, SMAD4, runt-related transcription factor 2, AT-rich interactive domain-containing protein 1A, phosphatase and tensin homolog and serine/threonine kinase 11. In conclusion, genetic alterations in PDCA were observed to involve numerous pathways including cell migration, transforming growth factor-β signaling, apoptosis, cell proliferation and DNA damage repair. However, signaling alterations were not observed in all tumors and key mutations appeared to differ between PDAC cases.

Kolovou G.,Onassis Cardiac Surgery Center | Barzilai N.,Yeshiva University | Caruso C.,University of Palermo | Sikora E.,Nencki Institute of Experimental Biology | And 9 more authors.
Current Vascular Pharmacology | Year: 2014

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Human life span is mainly dependent on environmental and genetic factors. Favourable modifications of lifestyle factors (e.g. physical activity, diet and not smoking) and healthcare (e.g. effective vascular disease prevention) have also increased human life span. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better health during their lifespan compared with contemporaries who died at a younger age?, 3) Do centenarians have protective modifications of body composition, fat distribution and energy expenditure, maintain high physical and cognitive function, and sustained engagement in social and productive activities?, 4) Do centenarians have genes which contribute to longevity?, 5) Do centenarians benefit from epigenetic phenomena?, 6) Is it possible to influence the transgenerational epigenetic inheritance (epigenetic memory) which leads to longevity?, 7) Is the influence of nutrigenomics important for longevity?, 8) Do centenarians benefit more from drug treatment, particularly in primary prevention?, and, 9) Are there any potential goals for drug research? Many definitions of successful ageing have been proposed, but at present there is no consensus definition. Such definitions may need to differentiate between “Longevity Syndrome” and “Exceptional Longevity”. © 2014 Bentham Science Publishers.

Sazzini M.,Laboratory of Molecular Anthropology | Sazzini M.,Center for Genome Biology | Garagnani P.,Diagnostic and Specialty Medicine | Garagnani P.,University of Bologna | And 19 more authors.
Clinical and Experimental Rheumatology | Year: 2015

Objective. Behçet's disease is a multifactorial vasculitis that shows its highest prevalence in geographical areas historically involved in the Silk Road, suggesting that it might have originated somewhere along these ancient trade routes. This study aims to provide a first clue towards genetic evidence for this hypothesis by testing it via an anthropological evolutionary genetics approach. Methods. Behçet's disease variation at ancestry informative mitochondrial DNA control region and haplogroup diagnostic sites was characterised in 185 disease subjects of Italian descent and set into the Eurasian mitochondrial landscape by comparison with nearly 9,000 sequences representative of diversity observable in Italy and along the main Silk Road routes. Results. Dissection of the actual genetic ancestry of disease individuals by means of population structure, spatial autocorrelation and haplogroup analyses revealed their closer relationships with some Middle Eastern and Central Asian groups settled along the Silk Road than with healthy Italians. Conclusion. These findings support the hypothesis that the Behçet's disease genetic risk has migrated to western Eurasia in parallel with ancestry components typical of Silk Road-related groups. This provided new insights that are useful to improve the understanding of disease origins and diffusion, as well as to inform future association studies aimed at properly accounting for the actual genetic ancestry of the examined Behçet's disease samples in order to minimise the detection of spurious associations and to improve the identification of genetic variants with actual clinical relevance. © Clinical and Experimental Rheumatology 2015.

Capri M.,Diagnostic and Specialty Medicine | Santoro A.,Diagnostic and Specialty Medicine | Garagnani P.,CIG | Bacalini M.G.,CIG | And 5 more authors.
Current Vascular Pharmacology | Year: 2014

Human longevity is a complex trait in which genetics, epigenetics, environmental and stochasticity differently contribute. To disentangle the complexity, our studies on genetics of longevity were, at the beginning, mainly focused on the extreme phenotypes, i.e. centenarians who escaped the major age-related diseases compared with cross sectional cohorts. Recently, we implemented this model by studying centenarians’ offspring and offspring of non-long lived parents. In association, during studies on many candidate genes SNPs, positively or negatively correlated with longevity have been identified. The results obtained on Insulin-like Growth Factor 1 Receptor (IGF1R) polymorphisms showed a correlation between specific genetic variants combinations and the low plasma level of IGF1 in centenarians, suggesting an impact of the IGF-I/insulin pathway on human longevity. This pathway together with mammalian target of rapamycin (mTOR) will be reviewed as being the most promising for longevity. Further, we will summarise the role of apolipoprotein E (APOE) variants in human longevity since the results of the large European project GEHA (Genetics of Healthy Aging) indicate APOE among the chromosomal loci associated with longevity. On the other hand, the identification of longevity-related genes does not explain the mechanisms of healthy aging and longevity rather pose questions on epigenetic contribution, gene regulation and the interactions with essential genomes, i.e. mitochondrial DNA and microbiota. To fully disentangle what appears to be an endless quest, all the components of the complexity of human longevity genetics are taken into account. © 2014 Bentham Science Publishers.

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