Biology subjects

Moro, C. F.

Publications and source records attributed to Moro, C. F..

3 recordsLinked to original sources

bioRxiv2025

The Role of N-acetylcysteine Amide in Acute Graft-versus-host Disease Mouse Model

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic hematopoietic cell transplantation (allo-HCT), resulting in reduced quality of life, morbidity, and mortality in transplanted patients. Clinical strategies to prevent GvHD are frequently associated with off-target effects and dose-related toxicity. Given that oxidative stress is elevated in allo-HCT recipients and contributes to the pathogenesis of GvHD, the current study aims to characterize the role of N-acetylcysteine amide (NACA), a novel antioxidant, as the prophylactic treatment for acute GvHD. Using a murine GvHD model, we found that oral administration of NACA significantly reduced GvHD severity, prolonged survival, and improved the clinical manifestations and integrity of target organs compared to saline or N-acetylcysteine (NAC) treatment. NACA modulated splenic T cells differentiation with an increase in the regulatory (Treg) subset and a decrease in the cytotoxic (CD8+) subset. Moreover, inflammatory mediators, such as ROS and pro-inflammatory cytokines were downregulated by NACA treatment. In addition, NACA hindered donor T-cell proliferation in the recipients, and restrained Th1 and Th17, but not Th2 polarization. Importantly, NACA did not influence full donor engraftment in bone marrow and spleen. Taken together, our findings provide a new candidate for GvHD prophylactic treatment by targeting oxidative stress that can be easily translated to clinical use. Key PointsO_LINACA provides superior prophylactic effect against aGvHD compared to NAC in an allogeneic transplantation mouse model. C_LIO_LINACA treatment neither showed systemic toxicity nor altered the engraftment of the donor cells. C_LI

pharmacology and toxicology↗

bioRxiv2024

Genderized Gut and Oral Microbiome Shifts: Uncovering Sex-Specific Dysbiosis in Pancreatic Cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, responsible for approximately 466,000 deaths globally in 2020. Its incidence increases by about 1% annually, with a higher occurrence in males than females. While differences in immune responses and tumor biology between sexes have been explored, the role of the microbiome in gender-specific PDAC progression is still unclear. Investigating these differences could offer crucial insights for personalized treatment strategies for males and females. MethodsThis study reanalyzed oral and gut microbiome data from BioProject: PRJNA832909, comprising 191 samples from PDAC patients and healthy controls. Using shotgun metagenomic sequencing, we examined gender-specific bacterial signatures. Alpha diversity (richness) and beta diversity (community composition) were analyzed. Differentially abundant bacterial taxa were identified via LEfSe, and gender-specific bacterial panels were validated using CombiROC. ResultsAlpha diversity analysis revealed significant differences in microbial richness, particularly between male and female PDAC patients and their healthy controls. Beta diversity demonstrated distinct microbial shifts between the PDAC and control groups across genders. LEfSe identified several pathogenic bacteria contributing to gender-specific dysbiosis, including Streptococcus, Fusobacterium, and Prevotella. Shared and sex-specific bacterial species in PDAC were highlighted through Venn diagram analysis. CombiROC validated the predictive ability of these bacterial markers, with AUC values exceeding 0.90 for both sexes. ConclusionThis study uncovered gender-specific microbial patterns in PDAC patients, potentially influenced by sex-specific immune responses. These findings provide important insights into the progression of PDAC and support sex-targeted diagnostic and therapeutic interventions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/616338v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@4b1d97org.highwire.dtl.DTLVardef@183c267org.highwire.dtl.DTLVardef@1500547org.highwire.dtl.DTLVardef@8a854c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype - basal or classical - similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.

cancer biology↗