Biology subjects

Scott, M. C.

Publications and source records attributed to Scott, M. C..

3 recordsLinked to original sources

bioRxiv2026

Microbial-associated acylated putrescines as immunomodulatory molecules in inflammatory bowel diseases

The gut microbiota regulates intestinal immunity through metabolite production, yet most disease-associated metabolites remain functionally uncharacterized. In inflammatory bowel diseases (IBD), where the microbial metabolome is profoundly altered, we identify N-acyl putrescines as microbiome-associated metabolites enriched across two independent cohorts. N-oleoylputrescine (NOP) emerges as the primary immunomodulatory candidate, inducing robust transcriptional responses in dendritic cells and colonic organoids. Enterocloster species harboring nonribosomal peptide synthetase gene clusters synthesize NOP, confirmed by isotope-tracing in vitro and germ-free mouse colonization in vivo. NOP suppresses core IBD inflammatory pathways in mouse dendritic cells and human monocytes, reducing signatures of histologic inflammation and therapy non-response. NOP dampens inflammation in four colitis models, decreases myeloid cell NF-{kappa}B activation, and suppresses type 1 immune responses through a T cell-intrinsic mechanism. That NOP accumulates in IBD despite its anti-inflammatory properties reveals a holobiont defense strategy: the gut microbiota deploys immunomodulatory metabolites as a compensatory response to restore homeostasis.

immunology↗

bioRxiv2021

Development of an exosomal biomarker signature to detect minimal residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal mRNAs. The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by qRT-PCR, while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups ("healthy", "osteosarcoma", "other bone tumor", or "non-neoplastic disease"). Pre-treatment samples from osteosarcoma cases were used as the training set and a validation set from post-treatment samples was used for testing, classifying as "osteosarcoma-detected" or "osteosarcoma-NOT detected". Dogs in a validation set whose post-treatment samples were classified as "osteosarcoma-NOT detected" had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof-of-concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/429432v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1b612c4org.highwire.dtl.DTLVardef@8a1847org.highwire.dtl.DTLVardef@3ffd64org.highwire.dtl.DTLVardef@114df8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2019

Genomic analysis reveals shared genes and pathways in human and canine angiosarcoma

Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with high fatality and few effective treatment options. It is both rare and heterogenous, making large, well powered genomic studies nearly impossible. In dogs, angiosarcoma is common, with breeds like the golden retriever carrying heritable genetic factors that put them at very high risk. If the clinical similarity of canine and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine angiosarcoma via whole exome sequencing (47 golden retriever angiosarcomas) and RNA sequencing (74 angiosarcomas from multiple breeds). The predominant mutational signature was the age-associated deamination of cytosine to thymine, and somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). We compared the canine data to human data recently released by The Angiosarcoma Project, and found the same genes and many of the same pathways significantly enriched for somatic mutations, most notably protein kinases, glycoproteins, fibronectin Type III domains, EGF-like domains, and cell adhesion proteins such as cadherins. As in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. Canine angiosarcoma closely models human angiosarcoma on a genomic level, and is a powerful tool for investigating the pathogenesis of this devastating disease.

genomics↗