Biology subjects

Centeno, D.

Publications and source records attributed to Centeno, D..

6 recordsLinked to original sources

bioRxiv2025

A benchmarking workflow for assessing the reliability of batch correction methods

One of the most pervasive challenges in large-scale untargeted metabolomics is short and long-term analytical variability introducing the necessity of batch effect correction. In this context, several strategies and methods have been developed to limit those effects, either by monitoring the data generation process to maximize reproducibility or by applying post-analysis data correction. Different evaluation frameworks, either assessing the degree of bias in the data through visual tools or quantitative indicators, or evaluating the prediction performance of known biomarkers, were also proposed. However, there is currently no clear consensus on how to evaluate batch correction methods. This work offers a strategy to assess multiple dimensions of batch correction efficiency within a comprehensive and reliable framework, designed to assess the effectiveness and reliability of batch correction methods. Based on Mahalanobis Conformity Index (MCI), it provides a multivariate and covariance-aware metric to quantify within- and between-batch variability. Additionally, it combines visualization techniques (Principal Component Analysis (PCA) and Multivariate INTegrative (MINT) PCA) with numerical indicators (batch dispersion, Coefficient of Variation), supporting both multidimensional and metabolite-specific evaluations. Lastly, this novel approach integrates statistical tools alongside chemistry-based metrics for method overfitting and overcorrection assessment. Applied within a use case for comparing LOESS-based and ComBat correction methods, the present workflow provided a structured approach to systematically assess the reliability of batch corrections, ensuring both data intercomparability and biological relevance in metabolomics studies. Author summaryThe assessment of batch correction is a challenge in metabolomics, where there is no consensus for a define strategy, making it a complex task. However, knowing the impact of batch correction on the datasets and consecutive possible impact on downstream statistical analyses, providing a reliable framework for its assessment is a cornerstone for reproducible results. The objective of the present work was to provide a framework and a set of interpretation tools combining numerical indicators, as well as diagnostic plots, for assessing the reliability of batch correction methods. We introduced a robust evaluation framework centered on the Mahalanobis Conformity Index, providing a multivariate and covariance-aware metric to quantify within- and between-batch variability. By coupling this index with visual tools (based on Principal Component Analysis (PCA) and Multivariate INTegrative (MINT) PCA), as well as compound-level diagnostics, we enabled a fine-grained and interpretable comparison of correction strategies, highlighting their strengths and potential pitfalls.

bioinformatics↗

bioRxiv2025

Suppression of Ovarian Cancer Cell Proliferation is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin.

The role of extracellular matrix adhesion components in modulation of the treatment sensitivity of ovarian cancer (OC) cells is not well understood. Analysis of ovarian cancer TCGA gene expression data sets revealed an inverse correlation between genes involved in cell-cycle progression and extracellular matrix interactions including laminin-binding receptor integrin {beta}4, a major component of extracellular matrix adhesion. Gene ontology analysis also showed that in patient populations with low integrin {beta}4 expression, cell cycle-related programs were activated, while in populations with high expression of integrin {beta}4, the activation of these cell cycle programs was lower. Suppression of proliferation with CDK4/6 inhibitor Palbociclib stimulated integrin {beta}4 expression and induced protection against cisplatin in cells naturally expressing low levels of integrin {beta}4. Additionally, ovarian cancer patient-derived organoids showed reduced cisplatin sensitivity when pretreated with Palbociclib. Our data also showed that integrin {beta}4 overexpression decreased ovarian cancer cell proliferation and at the same time, attenuated cisplatin response. Our investigations reveal that expression of integrin {beta}4 inversely correlates with cell cycle progression programs, whether observed in expression data of OC patient samples or in various OC cell lines. Consistently with these results, the overexpression of ITGB4 gene in ovarian cancer cell lines correlated with reduced cell proliferation rates and diminished sensitivity to cisplatin, supporting the idea that integrin {beta}4 and likely its matrix ligands play critical roles in the regulation of cellular growth and chemoresistance of ovarian cancer cells.

cancer biology↗

bioRxiv2025

Mutant p53R175H-Associated Protection of Ovarian Cancer Precursor Cells from Cisplatin Requires Expression of SLC6A6 Taurine Transporter

Tumor suppressor gene TP53 is ubiquitously mutated in ovarian cancer precursor lesions that undergo pervasive accumulation of DNA damage. Prior literature provides evidence that the expression of mutant p53 protein in epithelial cells is associated with increased survival in response to DNA-damaging treatments. Hence, identification and understanding of the mechanisms that, in response to DNA damage accumulation, support survival of ovarian cancer precursor cells carrying p53 mutations might provide important information about the evolution of the disease. Here we used a combination of OC precursor cell models, biochemistry, microscopy, and flow cytometry to provide evidence that the taurine transporter, the SLC6A6 molecule, contributes to cell protection from DNA-damaging (cisplatin) treatment. We found that expression of mutant p53R175H in OC precursor cells, the fallopian tube non-ciliated epithelial (FNE) cells, induced resistance to the DNA-damaging agent cisplatin. Most importantly, shRNA-mediated targeting of SLC6A6 transcript re-sensitized FNE cells expressing mutant p53R175H to cisplatin treatment. Our studies are consistent with the model that the loss of SLC6A6 alters mechanisms involved in the regulation of cell survival in response to DNA damage.

cancer biology↗

bioRxiv2023

The Dietary Supplement Taurine Suppresses Ovarian Cancer Growth

Taurine, a non-proteogenic amino acid, and commonly used nutritional supplement can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We have found that OC ascites-derived cells contained significantly more intracellular taurine than cell cultures modeling OC. In culture, elevation of intracellular taurine concentration to OC ascites-cells-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant- or wild-type p53 binding to DNA, and activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurines suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurines ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurines cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth, metabolism, and activate cell protective mechanisms involving mTOR and DNA damage sensing signal transduction.

cancer biology↗

bioRxiv2022

Extracellular Matrix Levels Modulate Outgrowths Dynamics in Ovarian Cancer.

Ovarian carcinoma (OC) forms outgrowths that extend from the outer surface of an afflicted organ into the peritoneum. OC outgrowth formation is poorly understood because there is limited availability of OC cell culture models to examine the behavior of cell assemblies that form outgrowths. Prompted by immunochemical evaluation of extracellular matrix (ECM) components, laminin {gamma}1 and collagens, in human tissues representing untreated and chemotherapy-recovered OC, we developed laminin- and collagen-rich ECM-reconstituted cell culture models amenable to studies of cell clusters that can form outgrowths. We demonstrate that ECM promotes outgrowth formation in fallopian tube non-ciliated epithelial cells (FNE) expressing mutant p53-R175H and various OC cell lines. Outgrowths were initiated by cells that had undergone outward translocation and, upon mechanical detachment, could intercalate into mesothelial cell monolayers. Electron microscopy, optical coherence tomography (OCT), and small amplitude oscillatory shear experiments revealed that high ECM concentration increased ECM fibrous network thickness and led to high shear elasticity in the ECM environment. These physical characteristics were associated with the suppression of outgrowths. A culture environment with low ECM concentration mimicked viscoelasticity of malignant peritoneal fluids (ascites) and supported cell proliferation, cell translocation, and outgrowth formation. These results highlight the importance of ECM microenvironments in modulating OC growth and could provide an additional explanation of why primary and recurrent ovarian tumors form outgrowths that protrude into the peritoneal cavity.

cancer biology↗

bioRxiv2018

The role of climate change education on individual lifetime carbon emissions

Strategies to mitigate climate change often center on clean technologies such as electric vehicles and solar panels, while the mitigation potential of a quality educational experience is rarely discussed. In this paper, we investigate the long-term impact that an intensive one-year university course had on individual carbon emissions by surveying students at least five years after having taken the course. A majority of course graduates reported pro-environmental decisions (i.e., type of car to buy, food choices) that can be attributed to experiences gained in the course. Furthermore, our carbon footprint analysis demonstrates that for the average course graduate, these decisions reduced their individual carbon emissions by 2.86 tons of CO2 per year. Focus group interviews identify that course graduates have developed a strong personal connection to climate change solutions, and this is realized in their daily behaviors and through their professional careers. The paper discusses in more detail the specific components of the course that are believed to be most impactful, and it shares preliminary outcomes from similar curriculum designs that are being used with K-12 students. Our analysis also demonstrates that if similar education programs were applied at scale, the potential reductions in carbon emissions would be of similar magnitude to other large-scale mitigation strategies such as rooftop solar or electric vehicles.

scientific communication and education↗