Biology subjects

Cornax, I.

Publications and source records attributed to Cornax, I..

6 recordsLinked to original sources

bioRxiv2026

Polystyrene Microplastics Accelerate Antibiotic Resistance Evolution and Exacerbate Pathogenicity in Acinetobacter Baumannii

Microplastics are pervasive environmental contaminants and are increasingly detected in contexts relevant to human health, yet their effects on antimicrobial resistance, host-pathogen interactions, and infection outcomes remain poorly understood. Here, we show that exposure to polystyrene microplastics alters both antibiotic resistance evolution and pathogenic behavior in Acinetobacter baumannii, a leading cause of multidrug-resistant hospital-acquired infections. Using experimental evolution under antibiotic selection, we demonstrate that microplastic exposure accelerates resistance emergence across multiple antibiotic classes. Although microplastic exposure did not uniformly enhance biofilm formation, it modestly impaired macrophage-mediated bacterial clearance, suggesting broader effects on bacterial adaptation and host interaction. In vivo, microplastic-associated infection resulted in more severe disease, characterized by increased lung tissue damage and reduced survival in a murine model of A. baumannii pneumonia. Together, these findings identify microplastics as ecological modifiers of bacterial adaptation, linking widespread plastic pollution to enhanced antimicrobial resistance and worsened infectious disease outcomes.

microbiology↗

bioRxiv2024

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK

Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in [~]180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.

genomics↗

bioRxiv2024

Tamm-Horsfall protein augments neutrophil NETosis during urinary tract infection

Urinary neutrophils are a hallmark of urinary tract infection (UTI), yet the mechanisms governing their activation, function, and efficacy in controlling infection remain incompletely understood. Tamm-Horsfall glycoprotein (THP), the most abundant protein in urine, uses terminal sialic acids to bind an inhibitory receptor and dampen neutrophil inflammatory responses. We hypothesized that neutrophil modulation is an integral part of THP-mediated host protection. In a UTI model, THP-deficient mice showed elevated urinary tract bacterial burdens, increased neutrophil recruitment, and more severe tissue histopathological changes compared to WT mice. Furthermore, THP-deficient mice displayed impaired urinary NETosis during UTI. To investigate the impact of THP on NETosis, we coupled in vitro fluorescence-based NET assays, proteomic analyses, and standard and imaging flow cytometry with peripheral human neutrophils. We found that THP increases proteins involved in respiratory chain, neutrophil granules, and chromatin remodeling pathways, enhances NETosis in an ROS-dependent manner, and drives NET-associated morphologic features including nuclear decondensation. These effects were observed only in the presence of a NETosis stimulus and could not be solely replicated with equivalent levels of sialic acid alone. We conclude that THP is a critical regulator of NETosis in the urinary tract, playing a key role in host defense against UTI.

immunology↗

bioRxiv2023

Oncolytic vesicular stomatitis virus is safe and provides a survival benefit for dogs with naturally occurring osteosarcoma

Osteosarcoma is a devastating bone cancer that disproportionally afflicts children, adolescents, and young adults. Standard therapy includes surgical tumor resection combined with multiagent chemotherapy, but many patients still suffer from metastatic disease progression. Neoadjuvant systemic oncolytic virus (OV) therapy has the potential to improve clinical outcomes by targeting primary and metastatic tumor sites and inducing durable antitumor immune responses. Here we described the first evaluation of neoadjuvant systemic therapy with a clinical-stage recombinant oncolytic Vesicular stomatitis virus (VSV), VSV-IFN{beta}-NIS, in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs. Canine osteosarcoma has a similar natural disease history as its human counterpart. VSV-IFN{beta}-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors. Treatment was well-tolerated and a "tail" of long-term survivors ([~]35%) was apparent in the VSV-treated group, a greater proportion than observed in two contemporary control cohorts. An increase in tumor inflammation was observed in VSV-treated tumors and RNAseq analysis showed that all the long-term responders had increased expression of a T-cell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFN{beta}-NIS is safe and may increase long-term survivorship in dogs with naturally occurring osteosarcoma, particularly those that exhibit pre-existing antitumor immunity.

cancer biology↗

bioRxiv2021

Transcriptional and Functional Activity of Canine Hemangiosarcoma to Support Hematopoiesis Demonstrate Bone Marrow Nurse Cell Ontogeny

Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. We did not uncover a definitive transmissible etiology, but our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, originate from stromal cells that are part of the bone marrow niche and that these cells may also support the growth of hematopoietic tumors. SignificanceWe demonstrate that molecular programs supporting expansion of immune and inflammatory cells in hemangiosarcoma resemble those of bone marrow niche cells, providing insights into the potential roles of these cells - whether physiological or pathological - in creating a permissive environment for the progression of hematopoietic malignancies.

cancer biology↗

bioRxiv2020

Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia

ABSTRACTStaphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗