a-translational-surgical-porcine-model-for-postoperative-intra

A Translational Surgical Porcine Model for Postoperative Intra-Abdominal Adhesion Formation

A porcine model of postoperative intra-abdominal adhesion formation was established using Yucatan mini pigs. The protocol combines midline laparotomy, ...

Stanford University School of Medicine

Describe the early impact of the COVID-19 pandemic on general surgery residency training nationwide.

Surgical Education in the Time of COVID: Understanding the Early Response of Surgical Training Programs to the Novel Coronavirus Pandemic.

Xanthogranulomatous inflammation (XGI) is an uncommon process involving an accumulation of inflammatory cells, commonly lipid-laden macrophages. XGI has been described to occur throughout the body but only rarely in the lower gastrointestinal tract. We describe a case of XGI contributing to chronic obstructive symptoms in the terminal ileum, in which the patient had an initial diagnostic laparoscopy, continued to have symptoms, then proceeded to have the definitive treatment. To our knowledge, this is the first report of XGI associated with a prior small bowel anastomosis.

Xanthogranulomatous inflammation requiring small bowel anastomosis revision: A case report.

Diabetes mellitus is an increasingly prevalent chronic metabolic disorder characterized by physiologic hyperglycemia that, when left uncontrolled, can lead to significant complications in multiple organs. Diabetic wounds are common in the general population, yet the underlying mechanism of impaired healing in such wounds remains unclear. Single-cell RNA-sequencing (scRNAseq) has recently emerged as a tool to study the gene expression of heterogeneous cell populations in skin wounds. Herein, we review the history of scRNAseq and its application to the study of diabetic wound healing, focusing on how innovations in single-cell sequencing have transformed strategies for fibroblast analysis. We summarize recent research on the role of fibroblasts in diabetic wound healing and describe the functional and cellular heterogeneity of skin fibroblasts. Moreover, we highlight future opportunities in diabetic wound fibroblast research, with a focus on characterizing distinct fibroblast subpopulations and their lineages. Leveraging single-cell technologies to explore fibroblast heterogeneity and the complex biology of diabetic wounds may reveal new therapeutic targets for improving wound healing and ultimately alleviate the clinical burden of chronic wounds.

Characterizing Fibroblast Heterogeneity in Diabetic Wounds Through Single-Cell RNA-Sequencing.

Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224-hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224-hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that  and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224-hydrogel. The JUN-inhibiting T-5224-hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.

Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models.

A significant complication of Crohn's disease (CD) is intestinal fibrosis, which narrows the bowel lumen to form a stricture. Creeping fat (CF) is the wrapping of mesenteric adipose tissue around diseased bowel, of which the role in CD stricture progression is unclear. By constructing a human single-cell CD fibroblast atlas, we identified CF-derived, CTHRC1+ fibroblasts enriched for Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signatures and localized to a fibrotic CF-bowel wall interface within the stricture. We further showed that analogous Cthrc1+ mouse fibroblasts derive from mesenteric adipose tissue stromal cells, infiltrate fibrotic bowel, and deposit extracellular matrix in a YAP/TAZ-dependent manner in a mouse model of intestinal fibrosis. Our findings identify CF as a key source of pro-fibrotic fibroblasts and raise the possibility of improving future clinical management of stricture progression by targeting not only the bowel but also CF.

Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn's disease strictures.

Pancreatic ductal adenocarcinoma (PDAC) continues to carry a dismal prognosis. The disease is characterized by a uniquely dense fibrotic matrix generated by cancer-associated fibroblasts (CAFs). We have previously demonstrated that fibroblast-driven chronic inflammation suppresses T cell function through a myeloid differentiation primary response protein 88 (MYD88)-dependent mechanism. While extensively studied in myeloid cells, the role of MYD88 signaling in CAFs and its effects on PDAC remain poorly understood. In this study, we identify a MYD88-driven inflammatory CAF population in PDAC using a combination of bulk, single-cell, and spatial transcriptomic studies. Using an innovative collagen gel implantation model, we demonstrate that loss of MYD88 in CAFs enhances T cell infiltration and suppresses tumor growth. Combining MYD88 inhibition with immune checkpoint blockade significantly reduces tumor size and enhances antitumor immune responses, underscoring its potential as a therapeutic target in PDAC.

Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma, low immunogenicity, and resistance to therapy. Cancer-associated fibroblasts (CAFs) are key stromal cells within the tumor microenvironment (TME) that drive tumor progression. Interleukin-1 (IL-1) promotes fibrosis, pathogenic inflammation, and poor prognosis in PDAC. Using a single-cell multi-omic approach, we investigate the IL-1 signaling axis in human and mouse models of PDAC, identifying nuclear factor of activated T cells (NFAT) transcription factors as key mediators. IL1R1 CAFs activate an inflammatory phenotype associated with elevated NFAT motif activity and gene expression. In vivo, NFAT inhibition in a mouse model of PDAC significantly reduces tumor weight and fibrosis, supporting its pro-tumorigenic role. Our findings suggest that NFAT mediates IL-1-induced inflammation in PDAC, highlighting its potential as a therapeutic target. This study demonstrates the power of multi-omic analyses to uncover therapeutic targets within the complex TME.

Article	Year
Surgical Education in the Time of COVID: Understanding the Early Response of Surgical Training Programs to the Novel Coronavirus Pandemic. Journal of surgical education\| PubMed ID: 32768380	2021
Xanthogranulomatous inflammation requiring small bowel anastomosis revision: A case report. World journal of gastrointestinal surgery\| PubMed ID: 37032803	2023
Characterizing Fibroblast Heterogeneity in Diabetic Wounds Through Single-Cell RNA-Sequencing. Biomedicines\| PubMed ID: 39595104	2024
Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models. Science translational medicine\| PubMed ID: 40073155	2025
Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn's disease strictures. Cell\| PubMed ID: 40967215	2025
Disruption of fibroblast MYD88 signaling promotes antitumor immunity in pancreatic ductal adenocarcinoma. Cell reports\| PubMed ID: 41004339	2025
NFAT mediates pro-tumorigenic inflammation in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cell reports\| PubMed ID: 41533513	2026

Maria Korah

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