Biology subjects

Casado-Pelaez, M.

Publications and source records attributed to Casado-Pelaez, M..

3 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↗

bioRxiv2024

Discovery and evaluation of novel biomarkers reveal dasatinib as a potential treatment for a specific subtype of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) represents the most heterogeneous and aggressive subtype of breast carcinomas, characterized by the absence of clinical biomarkers (ER, PR, and HER2) and the lack of targeted therapies. In this regard, several clinical trials have consistently failed to effectively stratify patients and identify specific treatments that elicit substantial responses. This study aims to pinpoint biomarkers expressed exclusively in the basal mammary epithelial compartment, facilitating a refined subclassification of this breast cancer subtype. Using computational analyses of single-cell RNA sequencing data, we have identified a list of genes associated with basal identity (BC-markers). Histological validation in 137 human samples has enabled us to categorize TNBC patients into BC-positive and BC-negative TNBC subtypes. Significantly, the presence of these markers correlates with a poorer prognosis in TNBC patients. Functional analyses have revealed a pivotal role for TAGLN in cell migration, likely influencing tumor aggressiveness. Further, we discovered that BC-marker expression is associated with the mesenchymal phenotype and increased sensitivity to the tyrosine kinase inhibitor dasatinib, particularly in BC-positive TNBC, suggesting novel therapeutic avenues. In our study, TAGLN emerged as a potential predictive biomarker for dasatinib responsiveness, offering new directions for personalized therapy for TNBC patients.

cancer biology↗

bioRxiv2022

IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid

Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-{kappa}B has been implicated in the development of HSCs. Here, we identify a chromatin binding function for I{kappa}B (also known as the inhibitor of NF-{kappa}B) that is Polycomb repression complex 2 (PRC2)-dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the I{kappa}B knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. I{kappa}B deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such as in vitro culture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the I{kappa}B - deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, I{kappa}B binding itself is found in the promoters of retinoic acid receptors rar in the AGM, and rar{gamma} in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of I{kappa}B-deficient AGMs leading to premature dormancy of LT-HSCs that persists in the FL LT-HSCs.

cell biology↗