Publications by Year: 2025

AIM: Kidney transplantation remains the most effective treatment for end-stage kidney disease. Still, the development of de novo donor-specific antibodies (dnDSA) increases the risk of rejection and allograft failure. While molecular matching algorithms assess B-cell and T-cell epitope mismatches, no single method fully captures rejection risk across immune pathways. This study combines the HLA Epitope Registry (Epregistry), PIRCHE-T2, and PIRCHE-B scores to enhance risk stratification, allowing for early intervention in high-risk recipients and improving long-term outcomes.

METHODS: A retrospective study of 594 kidney transplant recipients in Saskatchewan (1981-2021), Canada, was conducted, tracking de novo donor-specific antibodies (dnDSA) development until January 2024. Epitope mismatch scores were calculated using Epregistry, PIRCHE-T2, and PIRCHE-B, and receiver operating characteristic (ROC) curve analysis determined the optimal cutoff values for predicting dnDSA formation. Patients were categorized into high-risk (all scores > cutoff), intermediate-risk (one algorithm > cutoff), and low-risk (all scores < cutoff) groups. Kaplan-Meier survival analysis evaluated dnDSA-free survival across risk categories.

RESULTS: Among 594 recipients, 104 individuals (17.5%) developed de novo DSA; of these, 29 patients developed more than one, resulting in a total of 146 dnDSA events. The most frequently targeted locus was HLA-DQ (72/146, 49.3%), followed by HLA-DR (25/146, 17.1%) and HLA-A (24/146, 16.4%). The optimal cutoff values for predicting dnDSA were 22.5 (Epregistry), 30.5 (PIRCHE-T2), and 5.5 (PIRCHE-B) for Class I, and 15.5 (Epregistry), 17.5 (PIRCHE-T2), and 5.5 (PIRCHE-B) for Class II (all p < 0.05). Across all molecular mismatch load metrics, Kaplan-Meier analysis demonstrated significantly lower dnDSA-free and antibody-mediated rejection (ABMR)-free survival among high-risk recipients compared with low-risk recipients (log-rank p < 0.001). In addition, both the PIRCHE-T2 score at HLA Class I loci and the overall PIRCHE-T2 score were significantly associated with T-cell mediated rejection (TCMR) (p < 0.01).

CONCLUSION: Integrating Epregistry, PIRCHE-T2, and PIRCHE-B enhances risk stratification for kidney transplant recipients. Epregistry and PIRCHE-B evaluate HLA antibody epitope mismatches, and PIRCHE-T2 focuses on T-cell mismatches. Applied in conjunction, the methods show improved predictive accuracy, making this multi-algorithm approach more effective in identifying high-risk patients. By enabling earlier interventions and personalized immunosuppressive strategies, this model has the potential to improve long-term transplant success.

This study investigated the effectiveness of melatonin in improving sleep quality among hospitalized patients. Researchers assessed sleep parameters, including duration, latency (time to fall asleep), awakenings, and subjective quality, before and after melatonin administration. Results showed significant improvement after melatonin across all measures, with increased sleep duration, faster sleep onset, fewer awakenings, and better reported sleep quality. These findings suggest melatonin supplementation as a potential strategy to enhance sleep in hospitalized patients.

Women with inflammatory bowel disease (IBD) experience distinct physiologic and clinical challenges across their lifespan. In childhood and adolescence, early exposure to corticosteroids, chronic inflammation, and malnutrition may impair pubertal development, disrupt hormonal regulation, and reduce peak bone mass accrual. During puberty, fluctuating levels of estrogen and progesterone can exacerbate gastrointestinal symptoms and IBD activity. In adult women, gynecologic comorbidities such as endometriosis and uterine fibroids may mimic or worsen IBD-related symptoms, contributing to diagnostic complexity, pelvic pain, and sexual dysfunction. As women transition into menopause, declining estrogen can further affect gastrointestinal motility and immune regulation, confounding IBD symptoms. Postmenopausal women with IBD are also at an increased risk for osteoporosis and may face elevated cardiovascular risk owing to systemic inflammation and hormonal changes. This article focuses on women with IBD beyond the years of pregnancy and lactation, emphasizing the impact of hormonal transitions, dysmenorrhea, sexual health concerns, and menopause.

Background: Rheumatoid arthritis (RA) is a systemic chronic inflammatory autoimmune disease causing progressive joint destruction, resulting in significant morbidity and increased mortality. Despite advances in treatment, current pharmacological options, including NSAIDs, DMARDs, and biological agents, have limitations in tissue repair and can lead to severe side effects. Objectives: This study aims to explore drug repurposing as a viable approach to identify novel therapeutic agents for RA by utilizing existing FDA-approved drugs. Methods: We applied an integrated computational strategy that uniquely combines network pharmacology with molecular docking and dynamics simulations. The process began with the construction of a protein-protein interaction (PPI) network from 2723 RA-associated genes, which identified five central targets: TNF-α, IL-6, IL-1β, STAT3, and AKT1. We then built protein-drug interaction (PDI) networks by screening 2637 FDA-approved drugs against these targets. Critically, the top candidates from this network analysis were not just docked but were further validated using 100 ns molecular dynamics simulations to thoroughly evaluate binding affinity, complex stability, and interaction dynamics. Results: This multi-tiered computational workflow identified Rifampicin, Telmisartan, Danazol, and Pimozide as the most promising repurposing candidates. They demonstrated strong binding affinities and, importantly, formed stable complexes with TNF-α, IL-6, IL-1β, and STAT3, respectively, in dynamic simulations. The key innovation of this study is this sequential funnel approach, which integrates large-scale network data with atomic-level simulation to prioritize high-confidence drug candidates for RA. Conclusions: In conclusion, this study highlights the potential of repurposing FDA-approved drugs to target key proteins involved in RA, offering a cost-effective and time-efficient strategy to discover new therapies.

PURPOSE: Pericytes, cells crucially important to maintain a healthy microvasculature, make direct connections with vascular endothelial cells, yet the functional significance of these contacts remains largely unexplored. This study aims to investigate the ultrastructural morphological changes that occur in the interactions between pericytes and endothelial cells in mice lacking the Notch3 receptor and in diabetic retinopathy.

METHODS: Serial section transmission electron microscopy (ssTEM) was used to image mouse retinal ganglion cell layer capillaries in wild type (WT; 19 vessels), Notch3 knockout (KO; 16 vessels), conditional Notch3 KO (23 vessels), and diabetic mice (18 vessels). Over 2,000 images were manually segmented to trace the boundaries of the basement membrane, endothelial cells, mural cells, and peg-and-socket connections. Automated image analysis was used to measure contact lengths between pericytes and endothelial cells and peg-and-socket features.

RESULTS: While the vessels analyzed in each group were of similar diameter and pericyte coverage, Notch3 KO vessels had deeper pegs and increased connectivity between pericytes and endothelial cells. In both Notch3 KO and diabetic conditions, there was also an increase in the size of pericyte pegs.

CONCLUSIONS: As the Notch3 receptor plays an important role in cell signaling between pericytes and endothelial cells, and diabetes is also known to disrupt Notch3 signaling, our hypothesis for the enlarged peg phenotype is that the pericytes and endothelial cells actively increase their contact surface to compensate for loss of Notch3 signaling.

OBJECTIVES: In the wake of the COVID-19 pandemic and upheaval in the global supply chain, the healthcare sector has grappled with acute shortages of essential resources. Such shortages, while intensified recently in scale and frequency, are not new, as disasters have posed recurrent challenges. An illustrative example is the impact of Hurricane Maria, which severely disrupted the production of normal saline (0.9% NaCl fluid bags) from Puerto Rico-the location of about half of the production of saline for the entire United States. Hospitals relying on "just in time" delivery models found themselves in a precarious situation, prompting a need for innovative solutions to sustain care delivery. The occurrence underscores the vulnerability of healthcare infrastructure to external disruptions and emphasizes the need for adaptive strategies to ensure the resilience of individuals and the system in the face of unforeseen challenges.

METHODS: Our study investigates the impact of Hurricane Maria on saline supplies at the University of Pittsburgh Medical Center (UPMC) and efforts toward building an adaptable model in anesthesia services among providers as well as on a broader, system-wide scale. The study occurred over an 18-month study period, using mixed methods to analyze intravenous (IV) fluid demand and usage patterns before, during, and after the hurricane, integrating qualitative data from 3 months of "participant observation" and survey data.

KEY FINDINGS AND CONCLUSION: System-level adaptation occurred through operating room scheduling, pharmacy-driven standardization, and alternative fluid adoption, while at the individual level, healthcare providers performed drug substitutions, changed mixing practices, and increased reliance on alternative crystalloids. These adaptive measures undertaken at UPMC offer insights for future crises at both the organizational and individual levels within the healthcare system.

Although there are no effective therapies to block or reverse Alzheimer's disease (AD) progression at present, a promising therapeutic strategy is to reduce levels of amyloid-β (Aβ) proteins, which drive the formation of amyloid plaque, a primary hallmark in AD brains. Herein, we report that amphiphilic lipid-DNA molecules (LD) were designed by incorporating a long alkyl chain into the nucleotide base. It significantly down-regulated Alzheimer's Aβ levels in vivo and in vitro. In contrast to small-molecule chemical drugs and antibody therapies, the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier (BBB) and accumulate in the brain, increasing the therapeutic effects. Notably, lipid-DNA downregulated the levels of Aβ peptides significantly in vitro. AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement, which was associated with brain engagement of LD and reduced Aβ levels. Thus, the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides. This work might provide a promising DNA engineering strategy for AD treatment.

Much akin to ubiquitylation, neddylation is catalyzed by a cascade of three enzymes: E1 NEDD8-activating enzyme, E2 NEDD8-conjugating enzyme (UBE2M or UBE2F), and E3 NEDD8 ligases. The best-known neddylation substrates are the members of cullin family, leading to the activation of Cullin-RING ligases, which regulate a variety of downstream biological processes largely via promoting ubiquitylation and subsequent proteasomal degradation of many key signaling proteins. Notably, neddylation enzymes and components of the Cullin-RING ligases are frequently altered in many human cancers and have been validated as promising cancer targets. As such, drug discovery efforts are underway to target neddylation-Cullin-RING ligases with a few selective small molecule inhibitors being advanced into various phases of clinical trials. This review firstly provides a brief introduction to neddylation, then focuses on lung cancer, and summarizes a wealth of current data showing how neddylation-Cullin-RING ligases are altered and affect the growth and survival of lung cancer cells, lung tumorigenesis, lung tumor microenvironment, and inflammatory response. A few reported small molecule inhibitors of neddylation enzymes as well as their activity against lung cancer cells are also summarized, and future perspectives with an ultimate goal of discovering effective treatment of lung cancer via targeting neddylation-Cullin-RING ligases are proposed.