Faculty Bibliography

BACKGROUND:mice) translates into restrained CC and increased survival in tumour-bearing mice. RAGE, which is not expressed in adult healthy myofibres, is re-expressed in atrophying myofibres in cancer conditions. However, the specific contribution of muscular RAGE to CC was unknown. METHODS:mice were subcutaneously injected with Lewis lung carcinoma (LLC) cells, and body changes and survival were monitored until 25 dpi, when histological, molecular and proteomic analyses were performed in tumour-bearing and control mice. Muscle samples of pre-cachectic and cachectic pancreatic cancer patients were analysed to validate the results. RESULTS:muscles showed increased amounts of several enzymes involved in glycolysis and glucose catabolism, typical of Warburg metabolism. Noteworthy, muscles of pre-cachectic and cachectic cancer patients showed ~3-fold increase (p < 0.05) in RAGE amounts and reduced Akt-GSK-3β-PGC-1α pathway, compared with healthy control subjects. CONCLUSIONS:Our data provide evidence that RAGE engagement at myofibre level drives loss of body and muscle weights and inflammation in cancer conditions. RAGE ablation in muscles confers resistance to CC through myofibre remodeling and glycolytic reprogramming. On the clinical side, the overexpression of RAGE is an early event in muscles of cancer patients, suggesting a role for RAGE in the onset of the cachectic syndrome. Thus, the molecular targeting of RAGE might be useful to counteract cachexia and prolong survival in cancer patients.

MOTIVATION/BACKGROUND:Large-scale prospective cohort studies collect longitudinal biospecimens alongside time-to-event outcomes to investigate biomarker dynamics in relation to disease risk. The nested case-control (NCC) design provides a cost-effective alternative to full cohort biomarker studies while preserving statistical efficiency. Despite advances in joint modeling for longitudinal and time-to-event outcomes, few approaches address the unique challenges posed by NCC sampling, non-normally distributed biomarkers, and competing survival outcomes. RESULTS:Motivated by the TEDDY study, we propose "JM-NCC", a joint modeling framework designed for NCC studies with competing events. It integrates a generalized linear mixed-effects model for potentially non-normally distributed biomarkers with a cause-specific hazard model for competing risks. Two estimation methods are developed. fJM-NCC leverages NCC sub-cohort longitudinal biomarker data and full cohort survival and clinical metadata, while wJM-NCC uses only NCC sub-cohort data. Both simulation studies and an application to TEDDY microbiome dataset demonstrate the robustness and efficiency of the proposed methods. AVAILABILITY/BACKGROUND:Software is available at https://github.com/Zhaoyn-oss/JMNCC and archived on Zenodo at https://zenodo.org/records/18199759 (DOI: 10.5281/zenodo.18199759). SUPPLEMENTARY INFORMATION/BACKGROUND:Supplementary data are available at Bioinformatics online.

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.

OBJECTIVE:This study examined racial and ethnic differences in percent total weight loss (%TWL) and glycemic improvement following sleeve gastrectomy (SG) and explored the role of socioeconomic and psychosocial factors in postsurgical outcomes. METHODS:This longitudinal study included patients who underwent SG between 2017 and 2020, with follow-up visits over 24 months. RESULTS:Non-Hispanic Black (NHB) participants had lower %TWL at 3, 12, and 24 months compared with Hispanic (H) and non-Hispanic White (NHW) participants. Fat mass index was initially lower in NHB, with smaller reductions over time and significant group differences persisting at 24 months. NHB participants had higher baseline fat-free mass index values; by 24 months, fat-free mass index values were lower in H participants. Hemoglobin A1c decreased across all groups but remained consistently higher in NHB and H compared with NHW at 24 months. NHB participants reported higher perceived discrimination, sleep disturbance, and perceived stress than H and NHW participants at all time points. Employment status predicted %TWL at 12 months. There was a significant interaction between race and ethnicity and employment status observed at 12 and 24 months, suggesting that employment-related disparities could impact surgical outcomes. CONCLUSIONS:NHB participants experienced less favorable outcomes following SG, emphasizing the need for tailored interventions addressing socioeconomic and psychosocial disparities.

DIAPH1 is a member of the family of Diaphanous Related Formins (DRFs) implicated in cell migration and cytokinesis. DRFs are maintained in an autoinhibited state by the intramolecular association between diaphanous inhibitory (DID) and diaphanous autoregulatory (DAD) domains. Actin polymerization requires the binding of activated RhoA to the GTPase binding domain (GBD) of DIAPH1 and the dissociation of DAD. In the presence of excess RhoA, actin polymerization is only partially activated. Using monomeric domain constructs of DIAPH1, the sequential binding affinities of RhoA and DAD to GBD-DID were characterized. Binding of RhoA and DAD were negatively cooperative requiring a 100-fold greater concentration of DAD to achieve saturation when RhoA binding site was occupied. The unimolecular architecture of full length DIAPH1 establishes an effective concentration of DAD in the micromolar range, which is 100-fold larger than the intrinsic affinity of DAD for DID. The effective concentration is large enough to maintain DIAPH1 autoinhibition, yet small enough to permit partial activation of DIAPH1 after RhoA binding. By exploiting negative cooperativity, DIAPH1 maintains a reserve of inactivated molecules enabling gradual responses to cellular processes that require prolonged and sustained regulation. The proposed mechanism is extended to other DIAPH1 activating ligands and broadly applicable to all DRFs.

Diabetes is a major risk factor for cardiovascular diseases. Patients with diabetes are at greater risk for morbidity and mortality post myocardial infarction. As the epidemic of diabetes continues at an alarming pace, identification of specific therapeutic interventions to protect diabetic patients from the devastating consequences of myocardial infarction is an urgent need. Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the diabetic circulation and heart. The interaction of AGEs with its key receptor, receptor for AGE or RAGE, contributes to cardiac injury and dysfunction. The discovery that intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, unveiled the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of pathological RAGE signaling during myocardial infarction. This review delves into intrinsic mechanisms by which AGE-RAGE axis via RAGE-DIAPH1 driven DIAPH1-Mitofusin2 (MFN2) interaction modulates pathogenic inter-organelle communications and opens opportunities for intensive studies to uncover the comprehensive mechanisms that drive injury-provoking actions from the intracellular space. This review illustrates the potential therapeutic cardioprotective benefits of antagonism of RAGE-DIAPH1interactions in the diabetic heart.

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.

The advanced glycation end products (AGEs) Webinar was co-hosted by Diabetes Technology Society and Kitalys Institute on August 8, 2024, with the goal of reviewing progress made in the measurement and use of AGEs in clinical practice. Meeting topics included (1) AGEs as predictors of diabetic nephropathy (DKD), (2) hemoglobin glycation index (HGI) and the glycation gap (GG), (3) formation and structure of AGEs, (4) AGEs as a risk factor of cardiovascular disease (CVD), and (5) approaches to limit or prevent AGE formation.