Plant lignans and their microbial metabolites, e.g., enterolactone (ENL), may affect bile acid (BA) metabolism through interaction with hepatic receptors. We evaluated the effects of a flaxseed lignan extract (50 mg/day secoisolariciresinol diglucoside) compared to a placebo for 60 days each on plasma BA concentrations in 46 healthy men and women (20–45 years) using samples from a completed randomized, crossover intervention. Twenty BA species were measured in fasting plasma using LC-MS. ENL was measured in 24-h urines by GC-MS. We tested for (a) effects of the intervention on BA concentrations overall and stratified by ENL excretion; and (b) cross-sectional associations between plasma BA and ENL. We also explored the overlap in bacterial metabolism at the genus level and conducted in vitro anaerobic incubations of stool with lignan substrate to identify genes that are enriched in response to lignan metabolism. There were no intervention effects, overall or stratified by ENL at FDR < 0.05. In the cross-sectional analysis, irrespective of treatment, five secondary BAs were associated with ENL excretion (FDR < 0.05). In vitro analyses showed positive associations between ENL production and bacterial gene expression of the bile acid-inducible gene cluster and hydroxysteroid dehydrogenases. These data suggest overlap in community bacterial metabolism of secondary BA and ENL.

In this paper, we consider an inverse problem of determining two space dependent ionic parameters of a strongly coupled parabolic-elliptic reaction-diffusion system arising in cardiac electrophysiology modeling when simulating drugs action with multi-electrode array/human induced pluripotent stem cells-cardiomyocytes (MEA/hiPSC-CM) assays. We use the bidomain model coupled to an ordinary differential equation (ODE) and we consider the classical phenomenological model in cardiac electrophysiology of FitzHugh-Nagumo to describe the ionic exchanges at the microscopic level. Our main result is the uniqueness and a Lipschitz stability estimate for two ionic parameters pk, γq of the model using sub-boundary observations over an interval of time. The key ingredients are a global Carleman-type estimates with a suitable observations acting on a part of the boundary.

Purpose: Fusobacterium nucleatum (Fn) has been associated with colorectal cancer (CRC) etiology and outcomes. However, these relationships may differ by tumor attributes. We examined whether Fn enrichment and presence in CRC was associated with tumor attributes and survival. Experimental Design: We measured the abundance of Fn via droplet digital PCR in patient-matched CRC tumor and normal tissue samples from a subset of participants in the Puget Sound CRC Cohort (n=526). Fn enrichment was defined as the continuous difference in Fn abundance (normalized to counts of a host housekeeping gene) between patient-matched tumor and normal tissue samples. Fn presence in tumor was classified categorically as negative, low (Fn abundance &gt;0 but &lt;median level among those positive for Fn), or high (abundance ≥median). Fn enrichment and presence variables were examined in relation to tumor attributes (site, stage, microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutation status), molecular subtypes, and CRC survival. Molecular subtypes were defined as: type 1 (MSI-high, CIMP-high, BRAF-mutated); type 2 (microsatellite stable [MSS]/MSI-low, CIMP-high, BRAF-mutated); type 3 (MSS/MSI-low, non-CIMP, KRAS-mutated); type 4 (MSS/MSI-low, non-CIMP, BRAF- and KRAS-wildtype); and type 5 (MSI-high, non-CIMP, BRAF- and KRAS-wildtype). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations of Fn enrichment and presence with tumor attributes, adjusted for age, sex, tumor site, and Fn abundance in normal tissue (Fn enrichment only). Cox regression was used to estimate hazard ratios (HR) and 95% CIs for the associations of Fn enrichment and presence with CRC survival, adjusted for age, sex, tumor site, tumor markers, and Fn abundance in normal tissue (Fn enrichment only). Results: High Fn presence was negatively associated with left-sided colon and rectal tumors. While Fn enrichment was only significantly associated with CIMP-high status (OR 1.2; 95% CI 1.0, 1.4; p=.03), high Fn presence was positively associated with MSI (OR 4.9; 95% CI 2.8, 8.4; p&lt;.001), CIMP-high (OR 3.2; 95% CI 1.8, 5.7; p&lt;.001), and BRAF-mutated status (OR 3.3; 95% CI 1.8, 6.1; p&lt;.001). Fn enrichment was associated with higher odds of type 2 tumor classification (OR 1.2 95% CI 1.0, 1.5; p=.03) and high Fn presence was associated with higher odds of type 1 (OR 5.8; 95% CI 2.3, 15.0; p&lt;.001) and type 5 tumor classification (OR 3.4; 95% CI 1.1, 10.4; p=.03). Continuous Fn enrichment was independently associated with lower survival (HR 1.1; 95% CI 1.0, 1.1; p=.006) but high Fn presence was not (HR 1.0; 95% CI 0.6, 1.6; p=.99). Conclusions: Our findings suggest that Fn enrichment and presence are associated with certain CRC tumor attributes and survival, but associations varied by how Fn status was defined. Citation Format: Courtney M. Hill, Meredith A. Hullar, Adriana Reedy, Rachel Malen, Hamza Ammar, Orsalem Kahsai, Ningxin Ma, Shuji Ogino, Timothy Randolph, Polly Newcomb, Amanda Phipps. Colorectal cancer attributes and outcomes according to Fusobacterium nucleatum enrichment and presence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5914.