Biology subjects

Gorman, M.

Publications and source records attributed to Gorman, M..

4 recordsLinked to original sources

bioRxiv2026

A Patient-derived Organoid Platform for Uterine Carcinosarcoma that Emulates Disease Characteristics

Uterine carcinosarcoma (UCS) is a rare but extremely lethal endometrial cancer that metastasizes early and resists current treatment modalities. It is biphasic, built from malignant epithelial and mesenchymal cells. Genomic studies indicate that these tumors are clonal, and that the mesenchymal cells arise from the epithelial cells through cancer cell plasticity. This biology has been hard to study, because faithful patient-derived models are scarce. The gap is widened by inequity. Women of African ancestry carry the greatest burden of UCS, yet are underrepresented in existing models. To address this, we established patient-derived organoids (PDOs) from an ancestrally inclusive UCS cohort, alongside matched normal endometrial PDOs. The organoids reproduced the biphasic histology of the original tumors. Across four sequencing platforms, they retained the tumor mutation and copy-number landscape, remained stable across passages, and expanded for up to 28 months. At single-cell resolution, UCS PDOs captured both malignant compartments and traced continuous transcriptional trajectories along the epithelial-to-mesenchymal axis, capturing patient-specific cancer cell plasticity. The models also nominated candidate vulnerabilities in proof-of-concept therapeutic testing. UCS PDOs were enriched for CREB-family transcriptional programs, and CREB inhibition reduced their viability. Combined FGFR and YAP inhibition outperformed either agent alone. Together, this work delivers a histologically, genomically, and transcriptionally faithful, ancestrally inclusive, and lineage-resolved UCS organoid platform for studying cancer cell plasticity and its vulnerabilities in an aggressive and inequitably burdened cancer.

cancer biology↗

bioRxiv2026

The effects of dietary iron supplementation on bacterial infections in Manduca sexta larval hemolymph

Iron is an essential nutrient for all types of organisms, including insects and the microbes that infect them. We predicted that insects fed an iron-supplemented diet would accumulate more iron in their hemolymph, and, because infectious microbes acquire iron from their hosts, that this extra iron would increase the severity of bacterial infections. To test this hypothesis, we studied the effects of dietary iron supplementation on infection outcomes in Manduca sexta (tobacco hornworm). Larvae were fed an artificial diet, with or without antibiotics, or the same diets supplemented with 10 mM iron. Control and iron-treated larvae were inoculated with non-pathogenic Escherichia coli or the entomopathogenic Enterococcus faecalis, and bacterial load and larval survival were measured. We found that dietary iron supplementation increased the iron content of hemolymph by approximately 20 fold; however, contrary to our prediction, this increase in iron did not result in an increase in the bacterial load of either E. coli or E. faecalis. The effect of iron supplementation on survival was more complicated. As expected, for larvae inoculated with nonpathogenic E. coli, iron supplementation had no effect. For larvae inoculated with E. faecalis, the effect of iron supplementation depended on whether antibiotics were present in the diet. Without antibiotics, iron supplementation prolonged larval survival; with antibiotics, iron supplementation decreased larval survival. The results of this study do not support the hypothesis that dietary iron supplementation increases infection severity in M. sexta. Instead, the results support the viewpoint that the relationship between dietary iron and infection outcome is complex.

physiology↗

bioRxiv2022

Leptospira enrichment culture followed by ONT Nanopore sequencing allows better detection of Leptospira presence and diversity in water and soil samples.

BackgroundLeptospirosis, a life-threatening disease in humans and animals, is one of the most widespread global zoonosis. Contaminated soil and water are the major transmission sources in humans and animals. Clusters of disease outbreaks are common during rainy seasons. Methodology/Principal FindingsIn this study, to detect the presence of Leptospira, we applied PCR, direct metagenomic sequencing, and enrichment culture followed by metagenomic sequencing on water and soil samples. Direct sequencing and enrichment cultures followed by PCR or sequencing effectively detected pathogenic and nonpathogenic Leptospira compared to direct PCR and 16S amplification-based metagenomic sequencing in soil or water samples. Among multiple culture media evaluated, Ellinghausen-McCullough-Johnson-Harris (EMJH) media containing antimicrobial agents was superior in recovering and detecting Leptospira from the environmental samples. Our results show that enrichment culture followed by PCR can be used to confirm the presence of pathogenic Leptospira in environmental samples. Metagenomic sequencing on enrichment cultures effectively detects the abundance and diversity of Leptospira spp from environmental samples. Conclusions/SignificanceThe selection of methodology is critical when testing environmental samples for the presence of Leptospira. Selective enrichment culture improves Leptospira detection efficacy by PCR or metagenomic sequencing and can be used successfully to understand the presence and diversity of pathogenic Leptospira during environmental surveillance. Author SummaryLeptospirosis, a life-threatening disease in humans and animals, is one of the most widespread global zoonosis. Contaminated soil and water are major sources of transmission in humans and animals. For this reason, clusters of disease outbreaks are common during the rainy season. In this study, Leptospira enrichment cultures followed by PCR and sequencing detected pathogenic and nonpathogenic Leptospira in soil and water samples. The pathogenic and intermediate groups of Leptospira were more prevalent in soil samples tested. Metagenomic sequencing on enrichment culture is effective in detecting the abundance and diversity of various Leptospira spp. in environmental samples. Soil samples in proximity to water may be an ideal niche for Leptospira growth and survival and may be an appropriate sample of choice for testing.

microbiology↗

bioRxiv2019

Serological and metagenomic interrogation of cerebrospinal fluid implicates enteroviruses in pediatric acute flaccid myelitis

BackgroundSince 2014, the United States has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF) and only inconsistently identified from the respiratory tract, serum, or stool.\n\nMethodsWe interrogated CSF from children with AFM (n=42) and pediatric controls with other neurologic diseases (OND) (n=58). Samples were incubated with T7 bacteriophage expressing 481,966 sixty-two amino acid peptides with a fourteen amino acid overlap tiled across all known vertebrate virus and arbovirus genomes, an adaption of the VirScan method. Antibody-bound phage were deep sequenced to quantify enriched peptides with normalized counts expressed as reads per hundred thousand (rpK). EV antibody findings were confirmed with ELISA using whole viral protein 1 (VP1) from contemporary enterovirus (EV) A71 and D68 strains. Separately, metagenomic next-generation sequencing (mNGS) of CSF RNA, both unbiased and with targeted enrichment for EVs, was performed.\n\nResultsThe most significantly enriched viral family by VirScan of CSF in AFM versus OND controls was Picornaviridae (mean rpK 11,266 versus mean rpK 950, p-adjusted < 0.001, Wilcoxon signed-rank test with Bonferroni adjustment). Enriched Picornaviridae peptides belonged almost entirely to the genus Enterovirus. The mean EV VP1 ELISA signal in AFM (mean OD 0.51) was significantly higher than OND controls (mean OD 0.08, p-value < 0.001, Mann-Whitney test). mNGS did not detect additional enterovirus RNA in CSF.\n\nConclusionDespite the rare detection of EV RNA in the CNS of patients with AFM, a pan-viral serologic assay identified high levels of CSF EV antibodies in AFM CSF compared to CSF from OND controls. These results provide further evidence for a causal role of non-polio enteroviruses in AFM.

microbiology↗