Kansas City VA Medical Center

Pancreatic DuctalAdenocarcinoma (PDAC) is one of the most lethalmalignancies, with limited treatment options. Altered lipid metabolism,including dysregulated eicosanoid pathways, plays a role in PDAC progressionand therapy resistance. In this study, we investigated the impactof a treatment with polymeric hydroxychloroquine (PCQ), a novel macromolecularderivative of hydroxychloroquine (HCQ), on tumor lipid metabolismin a syngeneic mouse model of PDAC. Using a validated LC-MS/MS method,we quantified 72 eicosanoids in tumors to assess the metabolic changesinduced by PCQ and HCQ treatment. Our findings revealed significantPCQ-mediated downregulation of multiple protumorigenic eicosanoids,including PGD2, PGJ2, LTE4, LTB4, and HETEs, and upregulation of antitumorresolvins. This was further confirmed by Partial Least Squares DiscriminantAnalysis (PLS-DA) and heatmap analysis. The parent compound HCQ showedminimal impact on eicosanoid concentrations in the tumors, with nosignificant alterations at 24-h and modulation of only six eicosanoidsdownregulated at 72-h post treatment. Overall, our data highlighta novel role of PCQ in modulating tumor lipid metabolism, suggestinga unique mechanism of action and its potential as an adjuvant agentin the therapy of PDAC.

The ideal resection strategy for rectal neoplasms extending to the dentate line (RNDLs) remains unclear. Transanal surgical approaches and endoscopic mucosal resection (EMR) have their limitations related to inadequate visualization, device maneuverability, and securing an adequate margin on the anal side. Endoscopic submucosal dissection (ESD) appears to overcome some of the limitations of transanal surgical and snare-based endoscopic techniques. Therefore, we evaluated the safety and efficacy of ESD for resection of distal rectal lesions within 2cm of the dentate line. This is a large-scale multicenter retrospective study of patients who underwent ESD for RNDLs between 2015 and 2023. The primary outcomes were the rates of R0 and en bloc resection. Secondary outcomes were immediate and delayed adverse events. A total of 255 patients across 20 institutions were included (mean age 63.60, women 52.20%). The median lesion size was 40mm (IQR: 30 to 55), and the median resection time was 110 minutes (IQR: 81 to 169). The en bloc resection rate was 93.70% (n=236), and the rate of R0 resection was 85.40% (n=216). The rate of overall adverse events was 8.70% (n=22, 95% CI: 5.22% to 12.17%), with 13 cases of bleeding (5.10%), 4 cases of full-thickness perforation, and 1 case of postprocedural pain requiring intervention. All AEs were managed conservatively without the need for subsequent surgical or endoscopic interventions. ESD is safe and effective for resecting RNDLs with high en bloc and R0 resection rates, offering the potential for complete resection with minimal morbidity. It offers advantages over TEN, TAMIS, and other forms of transanal surgery due to the anatomy being less conducive to the equipment required for these techniques, lower cost, and lower rates of complications. However, careful patient selection, meticulous procedural planning, and close follow-up are essential to ensure optimal outcomes and minimize the risk of complications. Long-term follow-up studies and additional prospective controlled trials are warranted.

Background:Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established.Methods:Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8–16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks.Results:We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function.Conclusions:KDM5B activation in hepatocytes drives pathogenic cell–cell communication, leading to alcohol-induced loss of liver function in ALD.

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide, including US Veterans. An initial response to chemotherapy, such as Gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, reflecting an urgent need for targeted therapies. PDAC cells are highly addicted to oncogenic K-RAS mutations for their growth, progression, immunosuppression, and drug resistance, but mutant K-RAS in PDAC is still tricky to target. A glycosylation inhibitor, Tunicamycin (TM), is a potent killer of PDAC cells. However, free-form TM is found to be very toxic in in vivo implication as a therapy. To repeal the limitation of TM, we have synthesized a pH/Hypoxic-responsive iRGD-tagged biodegradable nano-encapsulated TM (NPTM) that was found to inhibit PDAC cell growth parallel with blocking K-RASG12D expression and its downstream signaling pathways associated with desmoplasia, and program cell death ligand 1 (PD-L1) expression. Moreover, NPTM markedly reduced the xenograft tumor growth, increased intratumoral CD8+ T cells, and increased in overall survival of treated mice. Furthermore, NPTM treatment synergizes with GEM to further regress PDAC growth in a PDAC xenograft model. These studies provide insights into NPTM treatment with a potential clinical application. Citation Format: Axel H. Breier, Debasmita Dutta, Anjali Kambhampati, Inamul Haque, Archana De, Sunil P. Upadhyay, Sushanta K. Banerjee, Mohiuddin Quadir, Snigdha Banerjee. Therapeutic implication of pH/hypoxic responsive nanoencapsulated tunicamycin on pancreatic cancer by targeting K-RasG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1843.

The performance of a high quality esophagogastroduodenoscopy (EGD) is dependent on the mucosal cleanliness. Recently, the Polprep: Effective Assessment of Cleanliness in EGD (PEACE) scale was created to assess the degree of mucosal cleanliness during EGD. The aim of this study was to validate this scoring system in a cohort of international endoscopists. In total, 39 EGD videos, with different degrees of mucosal cleanliness were retrieved from a previously conducted prospective trial. All experts rated the cleanliness of the mucosa on each video using the PEACE scale. To evaluate agreement of all scores (0-3), intraclass correlation coefficient 2.1 was used. The agreement on adequate (scores 2 and 3) and inadequate (scores 0 and 1) cleanliness was assessed using kappa values. Videos evaluating esophagus, stomach, and duodenum cleanliness were reviewed by 16 endoscopists. The PEACE scores demonstrated good agreement (intraclass correlation coefficient 0.82, 95% CI 0.75-0.89), especially for esophagus (0.84; 95% CI 0.71-0.95) and stomach (0.81; 95% CI 0.69-0.91), while agreement was moderate for the duodenum (0.69; 95% CI 0.51-0.87). The agreement was similar between Eastern (0.86; 95% CI 0.79-0.92) and Western experts (0.80; 95% CI 0.72-0.88). Similarly, agreement regarding adequate cleanliness was comparable between Eastern (0.70; 95% CI 0.55-0.85) and Western (0.74; 95% CI 0.64-0.84) endoscopists being overall 0.75 (95% CI 0.65-0.85). The PEACE scoring system is a simple and reliable scale to assess the cleanliness during EGD. The score is now validated among international experts with high concordance, justifying its use in clinical practice.