| 1. |
- Glasbey, JC, et al.
(author)
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- 2021
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swepub:Mat__t
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| 2. |
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| 3. |
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| 4. |
- Ravaioli, A, et al.
(author)
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p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.
- 2008
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In: Annals of oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 19:4, s. 660-668
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Journal article (peer-reviewed)abstract
- BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.
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| 5. |
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| 6. |
- Lindström, Björn, et al.
(author)
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Fast failures in the LHC and the future high luminosity LHC
- 2020
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In: Physical Review Accelerators and Beams. - : AMER PHYSICAL SOC. - 2469-9888. ; 23:8
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Journal article (peer-reviewed)abstract
- An energy of 362 MJ is stored in each of the two LHC proton beams for nominal beam parameters. This will be further increased to about 700 MJ in the future high luminosity LHC (HL-LHC) and uncontrolled beam losses represent a significant hazard for the integrity and safe operation of the machine. In this paper, a number of failure mechanisms that can lead to a fast increase of beam losses are analyzed. Most critical are failures in the magnet protection system, namely the quench heaters and a novel protection system called coupling-loss induced quench (CLIQ). An important outcome is that magnet protection has to be evaluated for its impact on the beam and designed accordingly. In particular, CLIQ, which is to protect the new HL-LHC triplet magnets, constitutes the fastest known failure in the LHC if triggered spuriously. A schematic change of CLIQ to mitigate the hazard is presented. A loss of the beam-beam kick due to the extraction of one beam is another source of beam losses with a fast onset. A significantly stronger impact is expected in the upcoming LHC Run III and HL-LHC as compared to the current LHC, mainly due to the increased bunch intensity. Its criticality and mitigation methods are discussed. It is shown that symmetric quenches in the superconducting magnets for the final focusing triplet can have a significant impact on the beam on short timescales. The impact on the beam due to failures of the beam-beam compensating wires as well as coherent excitations by the transverse beam damper are also discussed.
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| 7. |
- Ravaioli, F, et al.
(author)
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DNA Methylation Analysis of Ribosomal DNA in Adults With Down Syndrome
- 2022
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In: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 13, s. 792165-
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Journal article (peer-reviewed)abstract
- Control of ribosome biogenesis is a critical aspect of the regulation of cell metabolism. As ribosomal genes (rDNA) are organized in repeated clusters on chromosomes 13, 14, 15, 21, and 22, trisomy of chromosome 21 confers an excess of rDNA copies to persons with Down syndrome (DS). Previous studies showed an alteration of ribosome biogenesis in children with DS, but the epigenetic regulation of rDNA genes has not been investigated in adults with DS so far. In this study, we used a targeted deep-sequencing approach to measure DNA methylation (DNAm) of rDNA units in whole blood from 69 adults with DS and 95 euploid controls. We further evaluated the expression of the precursor of ribosomal RNAs (RNA45S) in peripheral blood mononuclear cells (PBMCs) from the same subjects. We found that the rDNA promoter tends to be hypermethylated in DS concerning the control group. The analysis of epihaplotypes (the combination of methylated and unmethylated CpG sites along the same DNA molecule) showed a significantly lower intra-individual diversity in the DS group, which at the same time was characterized by a higher interindividual variability. Finally, we showed that RNA45S expression is lower in adults with DS. Collectively, our results suggest a rearrangement of the epigenetic profile of rDNA in DS, possibly to compensate for the extranumerary rDNA copies. Future studies should assess whether the regulation of ribosome biogenesis can contribute to the pathogenesis of DS and explain the clinical heterogeneity characteristic of the syndrome.
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| 10. |
- Gensous, N, et al.
(author)
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A Targeted Epigenetic Clock for the Prediction of Biological Age
- 2022
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In: Cells. - : MDPI AG. - 2073-4409. ; 11:24
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Journal article (peer-reviewed)abstract
- Epigenetic clocks were initially developed to track chronological age, but accumulating evidence indicates that they can also predict biological age. They are usually based on the analysis of DNA methylation by genome-wide methods, but targeted approaches, based on the assessment of a small number of CpG sites, are advisable in several settings. In this study, we developed a targeted epigenetic clock purposely optimized for the measurement of biological age. The clock includes six genomic regions mapping in ELOVL2, NHLRC1, AIM2, EDARADD, SIRT7 and TFAP2E genes, selected from a re-analysis of existing microarray data, whose DNA methylation is measured by EpiTYPER assay. In healthy subjects (n = 278), epigenetic age calculated using the targeted clock was highly correlated with chronological age (Spearman correlation = 0.89). Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of increased (persons with Down syndrome, n = 62) and decreased (centenarians, n = 106; centenarians’ offspring, n = 143; nutritional intervention in elderly, n = 233) biological age, respectively. These results support the potential of our targeted epigenetic clock as a new marker of biological age and open its evaluation in large cohorts to further promote the assessment of biological age in healthcare practice.
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| 11. |
- Govaere, Olivier, et al.
(author)
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Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
- 2020
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In: Science Translational Medicine. - Washington, DC, United States : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:572
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Journal article (peer-reviewed)abstract
- The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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| 12. |
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| 13. |
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| 14. |
- Tesi, Tommaso, et al.
(author)
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Source, diagenesis, and fluxes of particulate organic carbon along the western Adriatic Sea (Mediterranean Sea)
- 2013
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In: Marine Geology. - : Elsevier BV. - 0025-3227 .- 1872-6151. ; 337, s. 156-170
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Journal article (peer-reviewed)abstract
- In this study, we investigated the modern organic carbon (OC) cycling along the clinoform-shaped deposit that developed after the attainment of the modern sea-level in the Adriatic Sea (similar to 5.5 kyr cal BP). Newly acquired data were combined with published results to characterize the (i) origin, (ii) diagenesis, and (iii) fluxes of OC along the Adriatic clinoform. delta C-13, Delta C-14, and lignin phenols were used to constrain the composition of CC accumulating in surface sediments. Sediment cores collected at different water depths were used to describe the early diagenesis during burial in different regions. In addition, on the basis of an extensive number of accumulation rates and CC data, we assessed the flux of CC to the seabed and its burial. Our results showed that terrigenous CC is the dominant CC source in the Po prodelta mainly in the form of pre-aged soil-derived CC and vascular plant fragments. Along the clinoform, both Delta 14C and the concentration of lignin-derived phenols decreased with increasing distance from the Po prodelta indicating the influence of an additional pool of aged CC that gradually becomes more important because of its selective preservation during the sediment transport. As a result, degradation rates (k) decreased along the clinoform as a function of the sediment oxidative history. The calculated half-life of reactive OC (t(1/2)) was similar to 14.6 yrs in the Po prodelta whereas topset/forest deposits south of this region exhibited higher values, similar to 100 yrs, indicating the presence of refractory material. In the distal bottomset region, the tip was particularly high ranging from similar to 255 to similar to 912 yrs. Because of the significant southward component of the sediment transport, the CC deposition in the southern surface sediments exceeded the local CC input via rivers (ratio deposition/input 12). Conversely, the northern Adriatic was characterized by a marked imbalance (ratio deposition/input 0.3-0.5). According to our calculations, the CC flux to the seabed along the clinoform was similar to 309 Gg of C per year whereas the OC burial was similar to 180 Gg of C per year, corresponding to an overall burial efficiency of similar to 59%.
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| 15. |
- Zabulica, M, et al.
(author)
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Gene Editing Correction of a Urea Cycle Defect in Organoid Stem Cell Derived Hepatocyte-like Cells
- 2021
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In: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 22:3
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Journal article (peer-reviewed)abstract
- Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.
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| 16. |
- Gensous, N, et al.
(author)
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Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver
- 2020
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In: Nutrients. - : MDPI AG. - 2072-6643. ; 12:2
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Journal article (peer-reviewed)abstract
- A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
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| 17. |
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| 18. |
- Pellegrini, C, et al.
(author)
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A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration
- 2021
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In: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13, s. 639428-
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Research review (other academic/artistic)abstract
- Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.
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