Faculty Bibliography

Variable clinical behavior is seen in oral leukoplakia, a potentially malignant illness of the mouth that may be caused by etiological factors including cigarette smoking. Therefore, it is of interest to compare the features of oral leukoplakia lesions and epithelial dysplasia in 100 individuals, all of whom were either smokers or non-smokers, using a clinico-histopathological approach. Histopathological analysis was used to ascertain the extent of epithelial dysplasia after a thorough clinical evaluation that included the location, size, shape and duration of the lesion. Smokers were more likely to have leukoplakia on the buccal mucosa, whereas non-smokers tended to have lesions on the gingiva and tongue. Regardless of smoking status, histopathological investigation showed that moderate to severe dysplasia occurred in a considerable number of patients, even though mild dysplasia predominated in both groups. Thus, we show the need of biopsy and routine monitoring of all leukoplakic lesions, even while smoking is a major etiological factor for leukoplakia formation; dysplastic alterations and possible malignant risk may occur in smokers and non-smokers alike.

Critical-sized bone defects remain a significant clinical challenge, and dipyridamole (DIPY)-coated 3D-tricalcium phosphate (β-TCP) scaffolds have shown promising osteogenic efficacy in preclinical models. However, the literature on the systematic physicochemical characterization of this scaffold system, including optimization of DIPY loading parameters, release kinetics, and surface properties, is lacking. This study addresses these gaps by characterizing DIPY-loaded 3D-printed β-TCP scaffolds across solid and porous architectures, three coating concentrations (10, 100, and 1000 µM), and three coating volumes (250, 500, and 1000 µL). Under static PBS conditions, drug release over 21 days was quantifiable only at 1000 µM, and release-kinetics modeling (zero-order, Higuchi, and Korsmeyer-Peppas) was therefore restricted to this highest concentration. At 1000 µM, both scaffold types showed biphasic release profiles, with standard empirical models reasonably approximating the overall kinetics, while not fully capturing the biphasic behavior over the entire duration. Porous scaffolds showed significant volume-dependent release (p = 0.002, η

INTRODUCTION/BACKGROUND:Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD. METHODS:We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls. RESULTS:mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons. DISCUSSION/CONCLUSIONS:These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.

OBJECTIVES/OBJECTIVE:Laser and light-based therapies are widely used in dermatology, yet patients with inflammatory dermatoses are often excluded from cosmetic procedures due to concerns for disease exacerbation. This systematic review evaluated the safety and efficacy of these modalities to inform their use. METHODS:A PRISMA-guided search of PubMed, Embase, ClinicalTrials.gov, and Scopus from inception through March 1, 2026 identified studies of adults with psoriasis, atopic dermatitis, lichen sclerosus, lichen planus pigmentosus, frontal fibrosing alopecia, or cutaneous sarcoidosis treated with laser or light-based therapies. Eligible studies reported clinical outcomes and adverse events; reviews and studies without attributable outcomes were excluded. Risk of bias was assessed qualitatively, and results were synthesized descriptively. RESULTS:Fifty-seven studies including over 900 patients were analyzed, with the strongest evidence in psoriasis and lichen sclerosus. Across conditions and device types, therapies consistently demonstrated clinical improvement and were generally well tolerated. Adverse effects were predominantly localized and transient, including erythema, edema, blistering, and pigmentary changes. Serious adverse events were rare, with only isolated cases of koebnerization or disease worsening reported. Limitations include heterogeneity and predominance of small or non-randomized studies. CONCLUSIONS:These findings suggest that, in appropriately selected patients, laser and light-based therapies are safe and do not consistently precipitate disease exacerbation.

PURPOSE/OBJECTIVE:Although the recombinant zoster vaccine (RZV) has demonstrated high efficacy in prevention of herpes zoster, there are concerns about its safety in patients with herpes zoster ophthalmicus with no clear evidence regarding the benefit of combining RZV with suppressive antiviral therapy. This secondary analysis of the Zoster Eye Disease Study outcomes by RZV vaccination status aims to assess potential benefit and risk of vaccination. METHODS:The Zoster Eye Disease Study was conducted at 95 sites from November 2017 to June 2024. RZV administration, both before and after enrollment, was recorded on electronic data entry forms. Five hundred twenty-seven participants were randomized to receive 12 months of double-masked daily valacyclovir 1000 mg or placebo and then followed for 18 months. In this analysis, we evaluated the impact on study outcomes within 3 months of RZV vaccination and at 12 and 18 months. RESULTS:Of the 527 participants, 122 (23.1%) received RZV, 37 (7.0%) pre-enrollment (15 on valacyclovir and 22 on placebo), and 85 (16.1%) postenrollment (41 on valacyclovir and 44 on placebo). Among participants who received RZV after enrollment, end points occurred within 3 months after the first shot in 5/85 (5.9%), including 0 (0/41, 0%) on valacyclovir and 5 (5/44, 11.4%) on placebo (P = 0.057), after the second shot in 2/50 (4.0%), including 2 (2/26, 7.7%) on valacyclovir and 0 on placebo (P = 0.491). Over the first 12 months, the time-dependent Cox regression analysis estimated a hazard ratio of 0.726 for end points comparing those with RZV vaccination with those without [95% confidence interval (CI) 0.39-1.34, P = 0.303]. Over 18 months, the HR comparing valacyclovir without RZV with placebo was 0.75 (95% CI 0.56-0.99, P = 0.046), and comparing valacyclovir with RZV with placebo was 0.51 (95% CI 0.27-0.98, P = 0.042). CONCLUSIONS:Participants who received suppressive valacyclovir treatment compared with placebo had a significantly lower likelihood of new or worsening ocular adverse events at 18 months; the effect of valacyclovir was similar regardless of administration of RZV.

In the contemporary era of minimally invasive surgery, injectable biomaterial scaffolds have demonstrated significant potential in bone tissue engineering (BTE). Completely injectable hydrogel substratum with microscale bone graft particulates delivered through a needle-shaped orifice shifts a new paradigm for surgical interventions in clinical settings. Despite growing interest in biopolymer-based BTE systems, clinically applicable delivery platforms and a mechanistic understanding of cell-material interactions remain limited. This study developed a dual-syringe auto-mix system capable of generating an in situ cross-linking hydrogel-mineral construct composed of gelatin-hydroxyphenyl propionic acid, hyaluronic acid-tyramine, horseradish peroxidase, hydrogen peroxide, and calcium phosphate particles of varying sizes. Material distribution, rheological and mechanical properties, and swelling were characterized. Goat bone marrow-derived mesenchymal stem cells served as the basis for examining how the composite affected cell viability, morphology, proliferation, contractility, osteogenic differentiation, mineralization, and chemotactic behavior. To determine whether these biological findings were supported mechanically, an ex vivo cone-beam computed tomography model was used to evaluate volumetric stability and resistance to deformation at the graft-host interface. Cross-linking established a stable internal microarchitecture while remaining compatible with cell viability and nutrient-dependent survival. Formation of the gelatin-hyaluronan (GH) network significantly increased the storage modulus relative to gelatin (G) alone, whereas subsequent calcium phosphate incorporation (GH-CP) preserved this mechanical competence while attenuating the volumetric expansion of GH. These physical characteristics were accompanied by more organized cell morphology, enhanced osteogenic differentiation, and mineral deposition throughout a larger portion of the matrix. Heterogeneous interpenetrating gap striation (HIGS) appeared in regions of cellular aggregation and matrix deposition, and a new conceptualization of the osteogenic phenomenon, termed cling osteogenesis, has been proposed. These outcomes support an intricate relationship between early mechanical stabilization, mechanotransduction, and osteogenesis in injectable hydrogel-mineral systems.

PURPOSE/OBJECTIVE:Treatment options for progression on first-line endocrine therapy (ET)+CDK4/6i for ER-positive/HER2-negative (ER+/HER2-) advanced breast cancer (ABC) include ET plus targeted agents (CDK4/6i or PI3K/AKT/mTOR-pathway inhibitors). Elacestrant is the first single-agent oral SERD that significantly improved progression-free survival (PFS) versus standard-of-care ET in ESR1-mutated and overall ER+/HER2- ABC populations. PATIENTS AND METHODS/METHODS:This phase 1b/2, umbrella trial enrolled patients with ER+/HER2- ABC who received 1-2 lines of ET+CDK4/6i (including prior fulvestrant and primary endocrine resistance) and no prior chemotherapy for ABC. Patients received elacestrant with everolimus, alpelisib, capivasertib, abemaciclib, ribociclib, or palbociclib. We evaluated PFS of elacestrant plus everolimus. RESULTS:In phase 1b (n=23), the optimal RP2D was determined as elacestrant 345 mg plus everolimus 7.5 mg. The phase 2 patient population (n=50) included: 100% prior CDK4/6i, 50% prior fulvestrant, 72% visceral metastasis, 20% primary endocrine resistance, 42% ESR1mut, 50% PIK3CAmut. Median PFS was 8.3 months (95% CI:4.0-10.2) in all patients; 8.3 months (95% CI:3.5-12.9) in ESR1mut, 9.0 months (95% CI:4.2-12.7) in ESR1wt, 8.3 months (95% CI:3.6-10.2) in PIK3CAmut, and 9.4 months (95% CI:4.0-NR) in PIK3CAwt. Adverse events (AEs) were consistent with known safety of everolimus plus SOC ET. Most common AEs were grade 1-2. Any AE leading to drug withdrawal or dose reduction was 6% and 2%, respectively. CONCLUSIONS:Elacestrant plus everolimus showed a clinically meaningful PFS benefit across clinical/genomic subgroups, irrespective of ESR1 or PIK3CA-mutation status. Elacestrant has the potential to become an ET backbone for combinations to inhibit the PI3K/AKT/mTOR-pathway with everolimus as a promising all-oral treatment.

Brain arteriovenous malformations (bAVMs) are vascular anomalies characterized by direct arterial to venous shunting without an intervening capillary bed, predisposing patients to intracranial hemorrhage and subsequent neurological morbidity and mortality. Evidence suggests that development and evolution of bAVMs are influenced by ongoing molecular and inflammatory processes. Chronic inflammation within the AVM microenvironment has emerged as a key driver of dysregulated angiogenesis, vascular instability, and hemorrhage risk. The objective of this review is to examine the molecular and cellular mechanisms through which inflammatory pathways contribute to AVM development, rupture, and treatment response. A comprehensive search of the Web of Science database was performed from database inception through September 2024. Following removal of duplicate articles, titles and abstracts were screened and full texts were reviewed for relevance. Experimental, translational, and clinical studies investigating inflammatory signaling pathways, immune cell involvement, molecular biomarkers, and therapeutic implications in AVMs were included. A total of 342 studies were included in the final review. Current evidence demonstrates that inflammatory signaling plays a central role in AVM pathobiology. Pro-inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α promote endothelial activation, leukocyte recruitment, and abnormal angiogenesis within the AVM nidus. Dysregulation of signaling pathways such as VEGF, TGF-β/BMP, NF-κB, Notch, and KRAS/MAPK-ERK contributes to extracellular matrix degradation, vascular remodeling, and vessel fragility. Infiltration by macrophages and neutrophils further amplifies inflammatory cascades through the release of matrix metalloproteinases and reactive oxygen species, increasing rupture risk. In addition to its pathogenic role, inflammation also contributes to success of AVM obliteration using stereotactic radiosurgery through radiation-induced endothelial injury, immune cell recruitment, and progressive vascular fibrosis. Inflammation is a fundamental component of AVM formation, progression, and therapeutic response. Targeting these pathways, in combination with surgical or radiosurgical interventions, may offer new opportunities for improving AVM management and improving approaches in cerebrovascular neurosurgery.

Peri-implantitis, characterized by inflammation of peri-implant tissues and progressive bone loss, remains a major biological complication affecting long-term implant success. Material composition, surface characteristics and biocompatibility influence microbial colonization, host immune response and implant durability. Therefore, it is of interest to investigate the relationship between different dental implant materials and the incidence of peri-implantitis among patients treated at a tertiary dental center. Clinical parameters including probing depth, bleeding on probing, radiographic bone loss, plaque index and type of implant material were recorded and analyzed. Data shows that surface roughness and alloy composition influence peri-implant tissue response, with implants exhibiting rougher surfaces and greater plaque accumulation showing higher inflammation levels. Thus, we show that appropriate material selection, optimized surface engineering and meticulous maintenance are essential strategies to minimize peri-implantitis risk and ensure long-term implant stability.

PURPOSE/OBJECTIVE:To evaluate interobserver agreement between 2 experienced corneal specialists in classifying eyes as normal (N), keratoconus-suspect (KCN-S), or keratoconic (KCN) using Scheimpflug tomography, and to assess the discriminatory performance of tomographic asymmetry indices. METHODS:A total of 206 eyes from 103 participants (15-25 years) underwent Scheimpflug corneal tomography. Two experienced corneal specialists independently classified each eye based solely on four-map displays, without access to quantitative tomographic indices (BAD-D, ISV, IHD, IVA). Interobserver agreement was assessed using Cohen κ statistic. Discriminatory performance was evaluated by receiver operating characteristic (ROC) analysis and area under the curve (AUC), with observer classifications retrospectively compared with BAD-D, ISV, IHD, and IVA. RESULTS:Interobserver agreement was moderate (κ = 0.40, P <0.01). Agreement between observer classifications and BAD-D was substantial for observer 1 (κ = 0.70, P <0.01) and fair for observer 2 (κ = 0.35, P <0.01). Among the evaluated indices, BAD-D demonstrated the highest discriminatory performance (AUC = 0.94 and 0.85 using observer 1 and observer 2 classifications, respectively). In expert consensus cases, BAD-D achieved an AUC of 0.97. A BAD-D threshold of 1.10 yielded 90% sensitivity and 90% specificity. CONCLUSIONS:Moderate interobserver agreement highlights the diagnostic uncertainty of identifying early keratoconus-suspect eyes and may contribute to variability in reported keratoconus prevalence. Among the evaluated tomographic indices, BAD-D showed the strongest agreement with expert classifications and the greatest discriminatory ability, supporting its use as an adjunctive tool for early screening in young individuals.