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- Bacalini, MG, et al.
(author)
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Association of rs3027178 polymorphism in the circadian clock gene PER1 with susceptibility to Alzheimer's disease and longevity in an Italian population
- 2022
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In: GeroScience. - : Springer Science and Business Media LLC. - 2509-2723 .- 2509-2715. ; 44:2, s. 881-896
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Journal article (peer-reviewed)abstract
- Many physiological processes in the human body follow a 24-h circadian rhythm controlled by the circadian clock system. Light, sensed by retina, is the predominant “zeitgeber” able to synchronize the circadian rhythms to the light-dark cycles. Circadian rhythm dysfunction and sleep disorders have been associated with aging and neurodegenerative diseases including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). In the present study, we aimed at investigating the genetic variability of clock genes in AD patients compared to healthy controls from Italy. We also included a group of Italian centenarians, considered as super-controls in association studies given their extreme phenotype of successful aging. We analyzed the exon sequences of eighty-four genes related to circadian rhythms, and the most significant variants identified in this first discovery phase were further assessed in a larger independent cohort of AD patients by matrix assisted laser desorption/ionization-time of flight mass spectrometry. The results identified a significant association between the rs3027178 polymorphism in the PER1 circadian gene with AD, the G allele being protective for AD. Interestingly, rs3027178 showed similar genotypic frequencies among AD patients and centenarians. These results collectively underline the relevance of circadian dysfunction in the predisposition to AD and contribute to the discussion on the role of the relationship between the genetics of age-related diseases and of longevity.
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- Witjes, J. Alfred, et al.
(author)
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EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer – An International Collaborative Multistakeholder Effort : Under the Auspices of the EAU-ESMO Guidelines Committees
- 2020
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In: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 77:2, s. 223-250
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Journal article (peer-reviewed)abstract
- BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SETTING: Online Delphi survey and consensus conference.PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.
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- 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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- 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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- Takahashi, M., et al.
(author)
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Reconciling Flux Experiments for Quantitative Modeling of Normal and Malignant Hematopoietic Stem/Progenitor Dynamics
- 2021
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In: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 16:4, s. 741-753
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Journal article (peer-reviewed)abstract
- Hematopoiesis serves as a paradigm for how homeostasis is maintained within hierarchically organized cell populations. However, important questions remain as to the contribution of hematopoietic stem cells (HSCs) toward maintaining steady state hematopoiesis. A number of in vivo lineage labeling and propagation studies have given rise to contradictory interpretations, leaving key properties of stem cell function unresolved. Using processed flow cytometry data coupled with a biology-driven modeling approach, we show that in vivo flux experiments that come from different laboratories can all be reconciled into a single unifying model, even though they had previously been interpreted as being contradictory. We infer from comparative analysis that different transgenic models display distinct labeling efficiencies across a heterogeneous HSC pool, which we validate by marker gene expression associated with HSC function. Finally, we show how the unified model of HSC differentiation can be used to simulate clonal expansion in the early stages of leukemogenesis. © 2021 The Authors
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- Aghajani, Moji, et al.
(author)
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Neural processing of socioemotional content in conduct-disordered offenders with limited prosocial emotions
- 2021
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In: Progress in Neuro-psychopharmacology and Biological Psychiatry. - : Elsevier. - 0278-5846 .- 1878-4216. ; 105
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Journal article (peer-reviewed)abstract
- BACKGROUND: Reflecting evidence on Callous-Unemotional (CU) traits (e.g., lack of empathy and guilt, shallow affect), the DSM-5 added a categorical CU-based specifier for Conduct Disorder (CD), labeled 'with Limited Prosocial Emotions' (LPE). Theory and prior work suggest that CD youths with and without LPE will likely differ in neural processing of negative socioemotional content. This proposition, however, is mainly derived from studies employing related, yet distinct, operationalizations of CU traits (e.g., dimensional measure/median split/top quartile), thus precluding direct examination of LPE-specific neurocognitive deficits.METHODS: Employing a DSM-5 informed LPE proxy, neural processing of recognizing and resonating negative socioemotional content (angry and fearful faces) was therefore examined here among CD offenders with LPE (CD/LPE+; N = 19), relative to CD offenders without LPE (CD/LPE-; N = 31) and healthy controls (HC; N = 31).RESULTS: Relative to HC and CD/LPE- youths and according to a linearly increasing trend (CD/LPE- < HC < CD/LPE+), CD/LPE+ youths exhibited hyperactivity within dorsolateral, dorsomedial, and ventromedial prefrontal regions during both emotion recognition and resonance. During emotion resonance, CD/LPE+ youths additionally showed increased activity within the posterior cingulate and precuneal cortices in comparison to HC and CD/LPE- youths, which again followed a linearly increasing trend (CD/LPE- < HC < CD/LPE+). These effects moreover seemed specific to the LPE specifier, when compared to a commonly employed method for CU-based grouping in CD (i.e., median split on CU scores).CONCLUSIONS: These data cautiously suggest that CD/LPE+ youths may exhibit an over-reliance on cortical neurocognitive systems when explicitly processing negative socioemotional information, which could have adverse downstream effects on relevant socioemotional functions. The findings thus seem to provide novel, yet preliminary, clues on the neurocognitive profile of CD/LPE+, and additionally highlight the potential scientific utility of the LPE specifier.
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