Biology subjects

Carneiro, F. R. G.

Publications and source records attributed to Carneiro, F. R. G..

3 recordsLinked to original sources

bioRxiv2025

Identifying potential therapeutic targets for T-cell acute lymphoblastic leukemia using malignant networks and topological analysis

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous disease requiring new therapeutic targets. We identified overexpressed genes in T-ALL cell lines, built subnetworks using the IntAct interactome, and evaluated the topological role of each gene. An attack strategy, removing one gene at a time, was applied with eleven network measures and persistent homology. A positive control group of essential genes for T-ALL tumorigenesis was included. Clustering, largest connected component, and especially Betti 1 effectively distinguished control genes from others, showing that topological metrics are valuable for target identification. Notably, NPM1 emerged as a key gene for maintaining network integrity, promoting proliferation, and ensuring survival, highlighting its potential as a promising therapeutic target in T-ALL. Significance of the studyThis study proposes an innovative approach to finding therapeutic targets for T-ALL based on oncogenic protein-protein interaction networks and the identification of the most effective analysis metrics following network attacks. These findings can be broadly applied to any neoplasm, seeking more personalized and efficient therapy.

cancer biology↗

bioRxiv2023

Statistical characterization of the dynamics of Glioblastoma Multiforme subtypes through parameters estimation of the epigenetic landscape

Glioblastoma Multiforme (GBM), a brain tumor distinguished for its aggressive nature, presents heterogeneity that stems from multifaceted mechanisms, such as genetic mutations, epigenetic modifications, genomic instability, and selective pressures. We reason that the aggressiveness of GBM enables even a limited dataset to serve as a representative sample within the domain of cancer attractors, allowing our sample to reflect a representative trajectory within the attractors domain. Utilizing single-cell RNA sequencing data, we proceed with a detailed analysis of GBMs cellular landscape. Rooted in characteristics observed in stochastic systems, we considered factors like genomic instability to introduce a level of noise or unpredictability, thereby characterizing the cancer dynamics through stochastic fixed points. These fixed points, derived from centroids obtained through various clustering methods, were rigorously verified for method sensitivity. This methodological foundation, wherein sample and time averages are equivalent, assigns paramount interpretative value to the data cluster centroids, aiding both in parameter fitting and subsequent stochastic simulations. This scenario is supported by the compelling correlation found between centroids of experimental and simulated datasets. The use of stochastic modeling to compute the Waddington landscape enriched our analysis of GBMs cellular heterogeneity and provided a visual framework for validating the centroids and standard deviations as accurate characterizations of potential cancer attractors. Specifically, this approach allowed us to assess the compatibility between data dispersion and the corresponding basin of attraction, thereby bridging molecular-level variations and systems-level dynamics. We also examined the stability and transitions between these attractors, revealing a potential interplay between subtypes and potentially uncovering factors that drive cancer recurrence and progression. By connecting molecular mechanisms related to cancer heterogeneity with statistical properties of gene expression dynamics we expect to set the stage for the development of potential diagnostic tools and pave the way for personalized therapeutic interventions.

systems biology↗

bioRxiv2020

Downregulation of the essential Rrp44 ribonuclease causes extensive ultra-structure cell modifications in Trypanosoma brucei

Rrp44/Dis3 is an essential protein conserved in all eukaryotes that functions in the maturation of many different RNA precursors and RNA surveillance. The Trypanosoma brucei Rrp44/Dis3 homologue (TbRRP44) is required for maturation of pre-rRNA, spliced leader, and U3 snoRNA precursors. Its depletion leads to inhibition of cell proliferation and eventually to cell death. In this work, we showed that TbRRP44 depletion causes a massive expansion of acidic and lysosome-derived vacuoles, enlargement of cell and nuclei sizes without changes in DNA content, mitochondrial inactivation, and autophagy induction. Consistently, 3D reconstructions using cryo-soft X-ray tomography revealed extreme vacuolation of the cytoplasm and numerous cellular alterations, including an increase in size and number of calcium-containing vesicles and lipid droplets. These multiple defects indicate that a combination of alterations converge to induce lysosome expansion. With time, the cytoplasm is taken up by lysosome-derived vacuoles, which may be a final stage leading to the cell death triggered by TbRRP44 depletion. These studies provide the first evidence on the ultra-structure cell modifications caused by deficiency of this essential ribonuclease in T. brucei.

cell biology↗