Biology subjects

Sole, F.

Publications and source records attributed to Sole, F..

4 recordsLinked to original sources

bioRxiv2025

The Multiomics Blueprint of Extreme Human Lifespan

The indexed individual, from now on termed M116, was the worlds oldest verified living person from January 17th 2023 until her passing on August 19th 2024, reaching the age of 117 years and 168 days (https://www.supercentenarian.com/records.html). She was a Caucasian woman born on March 4th 1907 in San Francisco, USA, from Spanish parents and settled in Spain since she was 8. A timeline of her life events and her genealogical tree are shown in Supplementary Fig. 1a-b. Although centenarians are becoming more common in the demographics of human populations, the so-called supercentenarians (over 110 years old) are still a rarity. In Catalonia, the historic nation where M116 lived, the life-expectancy for women is 86 years, so she exceeded the average by more than 30 years (https://www.idescat.cat). In a similar manner to premature aging syndromes, such as Hutchinson-Gilford Progeria and Werner syndrome, which can provide relevant clues about the mechanisms of aging, the study of supercentenarians might also shed light on the pathways involved in lifespan. To unfold the biological properties exhibited by such a remarkable human being, we developed a comprehensive multiomics analysis of her genomic, transcriptomic, metabolomic, proteomic, microbiomic and epigenomic landscapes in different tissues, as depicted in Fig. 1a, comparing the results with those observed in non-supercentenarian populations. The picture that emerges from our study shows that extremely advanced age and poor health are not intrinsically linked and that both processes can be distinguished and dissected at the molecular level. O_FIG O_LINKSMALLFIG WIDTH=156 HEIGHT=200 SRC="FIGDIR/small/639740v1_fig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1705be6org.highwire.dtl.DTLVardef@1a16e4borg.highwire.dtl.DTLVardef@15005f1org.highwire.dtl.DTLVardef@b6297b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig. 1C_FLOATNO Chromosomes and genes.a, Schematic representation of all -omics studied in the supercentenarian. b, Telomeres marked with Cy3 (yellow) in nuclei stained with DAPI (blue) observed in HT-qFISH from M116 and younger womens PBMCs. Scale bars: 20 {micro}m. c, Telomere length (Kb) calculation (left) and percentage of extremely short telomeres (below the 20th percentile) (right) in M116 (orange) using standard curve from samples previously analyzed (black) and control women (blue) (Online Methods). d, Circos plot with chromosomal alterations detected through optical genome mapping in supercentenarian. e, Variants of interest (VOI)-harboring genes found in supercentenarians genomic DNA contributing to immune function, cardiovascular health, neuroprotection, metabolism, and DNA dynamics. f, Significantly enriched functions of VOI-harboring genes in the supercentenarian. g, VOI-harbouring genes significantly contributing to enriched functions. h, VOI-harboring genes found in supercentenarians genomic and mitochondrial DNA contributing to mitochondrial function. i, Mean fluorescence intensity of TMRE (a marker of mitochondrial membrane potential) and SOX (a marker of mitochondrial superoxide ion) in PBMCs from the supercentenarian (orange) and healthy controls across various ages (gray). Unpaired t-test was used to statistically compare M116 to the mean of all control women. *p < 0.05. C_FIG

genomics↗

bioRxiv2023

Single cell profiling of del(5q) MDS unveils its transcriptional landscape and the impact of lenalidomide

While del(5q) MDS patients comprise a well-defined hematological subgroup, the molecular basis underlying its origin, and the reason behind the relapse after lenalidomide remains unknown. Using scRNA-seq on CD34+ progenitor cells from patients with del(5q) MDS we were able to identify cells harboring the deletion, enabling us to deeply characterize the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. We found, across all patients, an enrichment of del(5q) cells in GMP and megakaryocyte-erythroid progenitors not described to date. Interestingly, both del(5q) and non-del(5q) cells presented similar transcriptional lesions when compared to progenitors from healthy individuals, indicating that all cells, and not only those harboring the deletion, are altered in these patients and may contribute to aberrant hematopoietic differentiation. However, GRN analysis revealed a group of regulons with aberrant activity in del(5q) cells that could be responsible for triggering altered hematopoiesis, pointing to a more prominent role of these cells in the phenotype of these patients. An analysis of del(5q) MDS patients achieving hematological response upon lenalidomide treatment showed that the drug reverted several transcriptional alterations in both del(5q) and non-del(5q) cells, but other lesions remained, which may be responsible for potential future relapses. Moreover, lack of hematological response was associated with the inability of lenalidomide to reverse transcriptional alterations. Collectively, this study provides a deep characterization of del(5q) and non-del(5q) cells at single-cell resolution, revealing previously unknown transcriptional alterations that could contribute to disease pathogenesis, or lack of responsiveness to lenalidomide. KEY POINTS- Del(5q) and non-del(5q) CD34+ cells share similar transcriptional alterations, with del(5q) cells presenting additional lesions. - Hematological response to lenalidomide is associated with the reversal of some transcriptional lesions in del(5q) and non-del(5q) cells

cancer biology↗

bioRxiv2023

MUTATIONAL PROFILE ENABLES THE IDENTIFICATION OF A HIGH RISK SUBGROUP IN MYELODYSPLASTIC SYNDROMES WITH ISOLATED TRISOMY 8

INTRODUCTION ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION CONTRIBUTIONS COMPETING INTERESTS FIGURE LEGENDS REFERENCES Myelodysplastic syndromes (MDS) are a group of clonal hematological disorders characterized by clinical heterogeneity and genetic diversity1,2. MDS display peripheral cytopenias due to ineffective hematopoiesis, morphologic dysplasia in one or more cell lineages and an increased risk of leukemia transformation. In fact, more than 30% of MDS patients progress to acute myeloid leukemia (AML). Approximately, 50% of patients show cytogenetic alterations and more than 90% have at least one genetic lesion at diagnosis2,3. ...

genetics↗

bioRxiv2019

Implications of TP53 Allelic State for Genome Stability, Clinical Presentation and Outcomes in Myelodysplastic Syndromes

TP53 mutations are associated with poor clinical outcomes and treatment resistance in myelodysplastic syndromes. However, the biological and clinical relevance of the underlying mono- or bi-allelic state of the mutations is unclear. We analyzed 3,324 MDS patients for TP53 mutations and allelic imbalances of the TP53 locus and found that 1 in 3 TP53-mutated patients had mono-allelic targeting of the gene whereas 2 in 3 had multiple hits consistent with bi-allelic targeting. The established associations for TP53 with complex karyotype, high-risk presentation, poor survival and rapid leukemic transformation were specific to patients with multi-hit state only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System, while mono-allelic patients did not differ from TP53 wild-type patients. The separation by allelic state was retained in therapy-related MDS. Findings were validated in a cohort of 1,120 patients. Ascertainment of TP53 allelic state is critical for diagnosis, risk estimation and prognostication precision in MDS, and future correlative studies of treatment response should consider TP53 allelic state.

genomics↗