Bi, Yan

Cardiovascular (CV) dysfunction is common in severe acute pancreatitis (AP) and contributes substantially to mortality. Although sex differences in CV diseases are well recognized, with males generally exhibiting higher risk and poorer outcomes, their influence on AP-associated CV responses remains poorly defined. Here, we examined sex-dependent alterations in vascular integrity and cardiac function using cerulein-induced mouse models of AP. Because obesity is associated with more severe forms of AP, cerulein was used to induce mild AP in lean wild-type C57BL/6J mice and a more severe phenotype in obese C57BL/6J mice. Across both models, pancreatic injury was comparable between sexes. A modest sex difference in vascular permeability was observed in the mild but not severe AP model. In mild AP, both males and females showed similar compensatory increases in cardiac systolic function; however, in severe AP, only female mice maintained this adaptive systolic augmentation. Circulating levels of free fatty acids, reflecting systemic tissue lipolysis, were lower in females. Impaired cardiac adaptation in males was accompanied by higher levels of seven different myocardial inflammatory cytokines, as well as elevated circulating levels of angiopoietin-2 (Angpt2). While Angpt2 levels correlated with the severity of cardiac dysfunction, Angpt2 neutralization did not improve, and indeed worsened cardiac function in males. Together, these findings delineate both sex-dependent and sex-independent CV responses in mild and severe AP and identify Angpt2 as a potential compensatory cardioprotective factor under obesity-associated severe AP.

INTRODUCTION: A deeper understanding of the factors influencing survival in patients with pancreatic ductal adenocarcinoma (PDAC) is essential for optimizing treatment strategies. This study investigates the independent association of body composition parameters with overall survival in patients with PDAC. METHODS: This retrospective multisite cohort study included patients diagnosed with PDAC. Diagnostic computed tomography scans were retrieved, and body composition was evaluated using a validated deep learning-based segmentation algorithm that measured tissue volume and density in a 20 cm vertical abdominal section. RESULTS: A total of 1,666 patients with PDAC were included, 938 male (56.3%) and median age 69 years (interquartile range 61–76). In the subgroup of patients who underwent surgical resection (n = 509), myosteatosis (intramuscular infiltration of adipose tissue; hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.16–2.11, P = 0.004), sarcopenic obesity (HR 1.75, 95% CI 1.06–2.91, P = 0.03), and less subcutaneous adipose tissue (HR 1.09, 95% CI 1.03–1.16, P = 0.002) were associated with higher mortality. In patients receiving palliative systemic therapy (n = 439), lower skeletal muscle density (HR 1.43, 95% CI 1.03–1.99, P = 0.03) was associated with higher mortality. In patients who did not undergo tumor-targeted treatment (n = 718), less visceral adipose tissue (HR 1.04, 95% CI 1.01–1.08, P = 0.02) was associated with higher mortality. DISCUSSION: Body composition parameters, derived from computed tomography scans at the time of PDAC diagnosis, particularly low skeletal muscle density, sarcopenic obesity, and low adipose tissue, are independently associated with overall survival in patients with PDAC. Evaluating body composition at diagnosis could enhance clinical decision-making and enable more personalized treatment strategies.

A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.

This study presents a streamlined, cost-effective genotyping workflow for clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) edited mouse models, focusing on trypsinogen genes. It simplifies initial F0 mouse screening using PCR and Sanger sequencing without needing exact sequences. For F1 mice, precise editing is identified through Sanger sequencing and algorithm decoding. The workflow includes a novel PCR strategy for distinguishing homozygous and heterozygous statuses in subsequent generations, effective for small deletions, multiple-gene knockouts, and knockins.

Background: Adequate response to moderate (conscious) sedation varies significantly between individuals. Polymorphisms in genes encoding drug metabolizing enzymes can lead to inter-individual variability in drug efficacy, potentially influencing sedation requirements during endoscopic procedures. Objectives: The aim of this study was to assess the potential role of inter-individual variation in inherited polymorphisms of drug-metabolizing enzymes, cytochrome P450 (CYP450), specifically CYP3A4 and CYP3A5, in sedation requirements for outpatient endoscopic procedures. Methods: A retrospective analysis of sedation requirements and pharmacogenomics data in 106 unique patients who received outpatient esophagogastroduodenoscopy (EGD), colonoscopy, or both between December 2011 and February 2019 was conducted. Patients were divided into two groups based on their sedation requirements during endoscopy (high vs. normal sedation). Results: Patients with reduced a CYP2C19 metabolism (poor + intermediate metabolizers) (odds ratio [OR] = 0.38, 95% confidence interval [CI]: 0.16–0.91, p = 0.03), poor CYP3A5 metabolism (OR = 0.25, 95% CI: 0.095–0.65, p = 0.0046), and poor UGT1A1 (OR = 2.76, 95% CI: 1.07–7.13, p = 0.08) had higher odds of requiring normal sedation compared to those with CYP2C19 increased metabolism, CYP3A5 intermediate metabolism, and UGT1A1 intermediate metabolism. Conclusion: Information about inter-individual variation in (CYP450) genes may be useful for determining the sedation requirements for outpatient endoscopic procedures. We found that patients with reduced CYP2C19 metabolism, poor CYP3A5 metabolism, and poor UGT1A1 metabolism were more likely to require normal sedation requirements during outpatient endoscopic procedures.