Faculty Bibliography

RAGE and its intracellular effector molecule, the actin polymerase DIAPH1, mediate inflammation and the complications of diabetes. Using NMR spectroscopy and mass spectrometry, we built a structural model of the RAGE-DIAPH1 complex, revealing how binding of the cytoplasmic tail of RAGE (ctRAGE) to DIAPH1 stimulates its actin polymerization activity, which is inhibited by a small molecule antagonist of RAGE-DIAPH1 interaction, RAGE406R. The solution structure of the RAGE406R - ctRAGE suggests that RAGE406R prevents the formation of the RAGE-DIAPH1. FRET, actin polymerization assays, smooth muscle cell migration, and THP1 cell inflammation experiments, together with the in vivo interrogation of the effects of RAGE406R in mouse models of inflammation and diabetic wound healing, support this mode of RAGE-DIAPH1 antagonism. Finally, the treatment of macrophages differentiated from peripheral blood-derived mononuclear cells from humans with type 1 diabetes with RAGE406R reduces the mRNA expression of the chemokine CCL2, diminishing the expression of a key node in the inflammatory response.

IMPORTANCE/UNASSIGNED:The oral microbiota may be involved in the development of pancreatic cancer, yet current evidence is largely limited to bacterial 16S amplicon sequencing and small retrospective case-control studies. OBJECTIVE/UNASSIGNED:To test whether the oral bacterial and fungal microbiome is associated with the subsequent development of pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from 2 epidemiological cohorts: the American Cancer Society Cancer Prevention Study-II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Among cohort participants who provided oral samples, those who prospectively developed pancreatic cancer were identified during follow-up. Control participants who remained free of cancer were selected by 1:1 frequency matching on cohort, 5-year age band, sex, race and ethnicity, and time since oral sample collection. Data were collected from August 2023 to September 2024, and data were analyzed from August 2023 to January 2025. EXPOSURES/UNASSIGNED:The oral bacterial and fungal microbiome were characterized via whole-genome shotgun sequencing and internal transcribed spacer (ITS) sequencing, respectively. The association of periodontal pathogens of the red complex (Treponema denticola, Porphyromonas gingivalis, and Tannerella forsythia) and orange complex (Fusobacterium nucleatum, F periodonticum, Prevotella intermedia, P nigrescens, Parvimonas micra, Eubacterium nodatum, Campylobacter shower, and C gracilis) with pancreatic cancer was tested via logistic regression. The association of the microbiome-wide bacterial and fungal taxa with pancreatic cancer was assessed by Analysis of Compositions of Microbiomes With Bias Correction 2 (ANCOM-BC2). Microbial risk scores (MRS) for pancreatic cancer were calculated from the risk-associated bacterial and fungal species. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Pancreatic cancer incidence. RESULTS/UNASSIGNED:Of 122 000 cohort participants who provided samples, 445 developed pancreatic cancer over a median (IQR) follow-up of 8.8 (4.9-13.4) years and were matched with 445 controls. Of these 890 participants, 474 (53.3%) were male, and the mean (SD) age was 67.2 (7.5) years. Three oral bacterial periodontal pathogens-P gingivalis, E nodatum, and P micra-were associated with increased risk of pancreatic cancer. A bacteriome-wide scan revealed 8 oral bacteria associated with decreased and 13 oral bacteria associated with increased risk of pancreatic cancer (false discovery rate-adjusted Q statistic less than .05). Of the fungi, genus Candida was associated with increased risk of pancreatic cancer. The MRS, based on 27 oral species, was associated with an increase in pancreatic cancer risk (multivariate odds ratio per 1-SD increase in MRS, 3.44; 95% CI, 2.63-4.51). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, oral bacteria and fungi were significant risk factors for pancreatic cancer development. Oral microbiota hold promise as biomarkers to identify individuals at high risk of pancreatic cancer, potentially contributing to personalized prevention.

Variations in the airway microbiome are associated with inflammatory responses in the lung and pulmonary disease outcomes. Regional changes in microbiome composition could have spatial effects on the metabolic environment, contributing to differences in the host response. Here, we profiled the respiratory microbiome (metagenome/metatranscriptome) and metabolome of a patient cohort, uncovering topographical differences in microbial function, which were further delineated using isotope probing in mice. In humans, the functional activity of taxa varied across the respiratory tract and correlated with immunomodulatory metabolites such as glutamic acid/glutamate and methionine. Common oral commensals, such as Prevotella, Streptococcus, and Veillonella, were more functionally active in the lower airways. Inoculating mice with these commensals led to regional increases in several metabolites, notably methionine and tyrosine. Isotope labeling validated the contribution of Prevotella melaninogenica in generating specific metabolites. This functional characterization of microbial communities reveals topographical changes in the lung metabolome and potential impacts on host responses.

BACKGROUND:Minoritized populations face many barriers to accessing evidence-based diabetes intervention. OBJECTIVES/OBJECTIVE:To evaluate the feasibility, acceptability, and potential efficacy of a social media-based intervention to improve glycemic control among Chinese Americans with type 2 diabetes. DESIGN/METHODS:A pilot randomized controlled trial (RCT) with 3-month and 6-month follow-ups. PARTICIPANTS/METHODS:Chinese Americans (n = 60, mean age 54.3 years old) with limited education (70.0% with high school or less) and low income (50.0% with annual household income < $25,000), and 88.3% have limited English proficiency. INTERVENTION/METHODS:Culturally and linguistically tailored diabetes videos (two videos/week for 12 weeks) delivered via social media and support calls from community health workers. MAIN MEASURES/METHODS:Primary outcomes include feasibility (video watch rate, biweekly call completion rate, and retention rates), acceptability (patient satisfaction), and HbA1c. Secondary health-related outcomes include body weight, BMI, physical activity, and dietary intake. Video watch rate and biweekly call completion rate were assessed at baseline and 3 months, while others were measured at baseline, 3 months, and 6 months. RESULTS:We observed high feasibility and acceptability of the intervention, with retention rates over 87%, an 89% video watch rate, 80% biweekly phone call completion, and a satisfaction rating of 9 out of 10. The intervention group showed a significantly greater increase in fruit intake compared to the control group (0.15 cups vs. - 0.44 cups, adj_p = 0.023) at 3 months. While no significant differences in other outcomes were observed between the groups, the intervention group showed significant improvements in key outcomes, including reduced HbA1c levels (- 1.08%, adj_p < 0.001), weight loss (- 5.15 lbs, adj_p = 0.004), lower BMI (- 0.83, adj_p = 0.023), and reduced starchy food intake (- 0.33 cups, adj_p = 0.033) at 6 months. CONCLUSIONS:The observed high feasibility and acceptability suggest the intervention's feasibility. However, due to the limited sample size, a larger-scale RCT is warranted to test the efficacy of the intervention. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03557697; https://clinicaltrials.gov/ct2/show/NCT03557697.

The pancreas tumor microbiota may influence tumor microenvironment and influence survival in early-stage pancreatic ductal adenocarcinoma (PDAC); however, current studies are limited and small. We investigated the relationship of tumor microbiota to survival in 201 surgically resected patients with localized PDAC (Stages I-II), from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) cohorts. We characterized the tumor microbiome using RNA-sequencing data. We examined the association of the tumor microbiome with overall survival (OS), via meta-analysis with the Cox PH model. A microbial risk score (MRS) was calculated from the OS-associated microbiota. We further explored whether the OS-associated microbiota is related to host tumor immune infiltration. PDAC tumor microbiome α- and β-diversities were not associated with OS; however, 11 bacterial species, including species of Gammaproteobacteria, confirmed by extensive resampling, were significantly associated with OS (all Q < 0.05). The MRS summarizing these bacteria was related to a threefold change in OS (hazard ratio = 2.96 per standard deviation change in the MRS, 95% confidence interval = 2.26-3.86). This result was consistent across the two cohorts and in stratified analyses by adjuvant therapy (chemotherapy/radiation). Identified microbiota and the MRS also exhibited association with memory B cells and naïve CD4⁺ T cells, which may be related to the immune landscape through BCR and TCR signaling pathways. Our study shows that a unique tumor microbiome structure, potentially affecting the tumor immune microenvironment, is associated with poorer survival in resected early-stage PDAC. These findings suggest that microbial mechanisms may be involved in PDAC survival, potentially informing PDAC prognosis and guiding personalized treatment strategies.IMPORTANCEMuch of the available data on the PDAC tumor microbiome and survival are derived from relatively small and heterogeneous studies, including those involving patients with advanced stages of pancreatic cancer. There is a critical knowledge gap in terms of the tumor microbiome and survival in early-stage patients treated by surgical resection; we expect that advancements in survival may initially be best achieved in these patients who are treated with curative intent.

BACKGROUND & AIMS/UNASSIGNED:Metabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high-fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. METHODS/UNASSIGNED:standard chow for 16 weeks (n = 40 mice). At sacrifice, plasma and liver were retrieved, the latter for single-nucleus RNA sequencing. Publicly available data sets of human male and female MASH liver were probed. RESULTS/UNASSIGNED:0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the standard chow. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. CONCLUSIONS/UNASSIGNED:Molecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female individuals in MAFLD/MASH studies and clinical trials. IMPACT AND IMPLICATIONS/UNASSIGNED:male patients with MASH. These results highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.

BACKGROUND:Type 2 diabetes (T2D) contributes to significant morbidity and mortality for Chinese immigrants in the United States, exacerbated by social determinants of health (SDOH) barriers such as language barriers, limited access to healthy foods, and low health literacy. OBJECTIVE:The goal of the Integrating Cultural Aspects into Diabetes Education (INCLUDE) study is to test a social media-based intervention adapting the Diabetes Prevention Program (DPP) for Chinese immigrants alongside a culturally adapted, community-supported agriculture program. Here, we report the protocol for the INCLUDE study. METHODS:INCLUDE is a 3-year randomized controlled trial (n=150). Participants with prediabetes or at risk for T2D are enrolled and randomized into either the control or intervention group (n=75 each). Participants from the intervention group receive 2-3 culturally tailored, in-language DPP videos weekly for 12 weeks, as well as biweekly phone calls from bilingual study staff to review video content, support goal setting, and assess and address SDOH-related barriers such as food insecurity. Intervention participants will also be given produce for 10 weeks as part of the community-supported agriculture program. Weight (primary outcome), self-efficacy, diet, physical activity, and food insecurity (secondary outcomes) are measured at baseline, 3-month, and 6-month intervals. Splined linear mixed models will be used to examine group differences in longitudinal weight and other secondary outcomes. The INCLUDE study was approved by the Institutional Review Board at the NYU Grossman School of Medicine. RESULTS:Recruitment started in May 2023, with the first cohort of 75 participants enrolled and randomized into 2 groups in July 2023. The 3-month and 6-month assessment of the first-year cohort has been completed. We have recruited 75 participants for the second cohort as of July 2024. CONCLUSIONS:The INCLUDE study will serve as an innovative model for culturally adapted, multilevel interventions for underserved communities previously unable to access evidence-based diabetes prevention initiatives. Aligning with several national calls for multilevel interventions, the INCLUDE intervention will provide critical data that will inform how researchers and public health professionals address SDOH barriers faced by underserved populations and prevent diabetes. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT05492916; https://clinicaltrials.gov/study/NCT05492916. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)/UNASSIGNED:DERR1-10.2196/65455.