Citations

Abstract Deep mutational scanning (DMS) has proven effective for mapping protein–protein interactions (PPIs), but it cannot provide complete coverage of the mutation landscape, particularly for multi‐mutant variants. To address this limitation, we trained machine‐learning (ML) models on previously generated DMS data for a stabilized amyloid precursor protein inhibitor (APPI) binding to either of two serine proteases, mesotrypsin and kallikrein‐6 (KLK6), which are implicated in various human disorders. We combined the models to accurately predict the binding selectivity of APPI variants, including double‐mutant variants, for the two serine proteases. We achieved a Pearson correlation of 0.937 between predicted log 2 selectivity enrichment ratios and DMS‐derived values. We further validated the predictions of our combined model by yeast‐surface‐display measurements and inhibition assays of purified APPI variants and revealed epistatic interactions that shape protease selectivity. Guided by binding selectivity predictions, we identified highly selective APPI variants, including the most selective mesotrypsin inhibitor reported to date. Together, these findings support the use of DMS and ML as a framework for predicting PPI selectivity and prioritizing selective therapeutic protein variants.

Abstract The mutation status of isocitrate dehydrogenase (IDH) in glioma patients has diagnostic and prognostic significance but is available only after surgery. Rapid and sensitive intraoperative molecular diagnosis is essential for distinguishing tumor from infiltrative and from normal brain tissue to maximize safe resection. IDH-mutant (mut)tumors produce high concentrations of 2-hydroxyglutarate (2HG), which serves as a surrogate marker of IDH mutation. Here, we use desorption electrospray ionization-multiple reaction monitoring (DESI-MRM), a form of mass spectrometry (MS), for rapid prediction of IDH mutation status. A set of 30 human brain smears was analyzed using DESI-MRM experiments to predict the mutation status of IDH and quantify 2HG in glioma samples within 2 min (endogenous reference molecule) or 7 min (external standard). Nanoelectrospray ionization (nESI) was employed as a validation method. An isotopically labeled surrogate internal standard allowed quantitative measurement of 2HG and clear separation between IDH-mut and IDH-wildtype (wt) samples, showing 100% agreement with clinical diagnosis. 2HG concentrations in IDH-mut samples ranged from 88 to 1445 ng mg–1, while IDH-wt samples exhibited 2HG concentrations of 9–15 ng mg–1. Calibration curves showed method accuracy within ≤15%. The quantitative results obtained using isotopically labeled standards showed a strong correlation between IDH mutation score and 2HG concentrations, as did an earlier semiquantitative (ratiometric, endogenous standard) method. These findings highlight the standalone capability of DESI-MRM for making measurements to justify assessments for intraoperative diagnosis and to support surgical decision-making to improve patient outcomes.

Abstract INTRODUCTION Although cerebrospinal fluid (CSF) biomarkers reflect neurodegeneration in Alzheimer's disease (AD), it remains unclear whether these biomarkers track neurodegeneration in early‐onset Alzheimer's disease (EOAD). METHODS In 80 EOAD patients, we examined correlations between eight CSF biomarker levels and cortical thickness decreases within the EOAD cortical atrophy signature. Significant correlations were then entered into a multiple regression analysis. We also examined contributions of EOAD atrophy and CSF biomarkers to cognitive impairment. RESULTS The levels of four CSF biomarkers correlated to EOAD signature atrophy. Stepwise regression analyses revealed that CSF neurofilament light chain (NfL) levels best predicted EOAD signature atrophy. Multiple regression showed EOAD signature atrophy combined with CSF NfL levels explained more variance in cognitive impairment than either factor alone. DISCUSSION Within EOAD patients, CSF NfL levels relate to the magnitude of cortical atrophy, and a combination of EOAD signature atrophy and CSF NfL levels most robustly predict cognitive impairment.

Background: Pulsatile tinnitus (PT) is frequently caused by venous sinus stenosis and may be associated with idiopathic intracranial hypertension (IIH). Venous sinus stenting (VSS) directly addresses venous outflow obstruction and has emerged as a therapeutic option; however, outcome data remain heterogeneous. We performed an updated systematic review and meta-analysis to evaluate the efficacy and durability of VSS for PT and to compare outcomes between IIH-associated and isolated PT. Methods: MEDLINE, Scopus, and Web of Science were searched from inception through December 2025 following PRISMA guidelines. Clinical studies reporting PT outcomes after VSS were included. Random-effects meta-analyses of proportions were conducted to estimate pooled rates of overall improvement, complete resolution, and recurrence. Prespecified subgroup analyses compared IIH versus isolated PT. Results: Thirty-two studies comprising 850 patients were included (641 with IIH; 209 with isolated PT). Venous sinus stenosis accounted for 90.3% of treated etiologies. The pooled rate of overall PT improvement was 89.8% (95% CI, 85.5-92.9). Complete resolution occurred in 87.1% (95% CI, 82.5-90.6). Recurrence at last follow-up was 10.9% (95% CI, 8.3-14.2). Improvement and complete resolution rates did not differ significantly between IIH and isolated PT. Recurrence was higher in IIH (12.0%) than in isolated PT (5.7%), without reaching statistical significance. Conclusions: VSS is associated with high rates of PT improvement and complete resolution with low recurrence. Recurrence trends appear higher in IIH, suggesting underlying pathophysiology may influence durability.

ABSTRACT Lupus nephritis requires long-term immunosuppressive therapy, which is often associated with severe systemic side effects. Therefore, new therapeutic strategies that maintain high efficacy while minimizing adverse effects is essential. Although nanomedicine has advanced systemic and kidney-targeted drug delivery, a reliable method for glomerulus-specific delivery is lacking. Collagen IV (Col4)-alpha 3, located in the glomerular basement membrane (GBM) at the blood–tissue interface through fenestrated capillary endothelium, represents an ideal target for glomeruli delivery. Herein, we developed a novel liposomal nanoparticle conjugated with a Col4-alpha 3 binding peptide (Col4-α3-NPs) for selective glomerular targeting. Prednisolone-loaded Col4-α3-NPs were administered to lupus-prone mice twice weekly for 8 weeks. Kidney injury and function were evaluated biweekly, and renal immune cell populations were analyzed by flow cytometry at study completion. The results show that rhodamine-labeled NPs predominantly accumulate in kidney glomeruli 48 hours after intravenous injection. The Col4-NP system demonstrated stable and prolonged release of the encapsulated drug for over 48 hours. Lupus-prone mice treated with prednisolone-loaded Col4-NPs showed significantly improved renal function and histology, including a 30% increase in glomerular filtration rate (GFR), a 56% reduction in proteinuria, and decreased IgG deposition and fibrosis. Notably, treatment also enhanced renal regulatory T cell (Treg) populations. These findings suggest that glomerulus-targeted Col4-α3-NPs hold significant translational promise. This platform may offer an effective, site-specific treatment for lupus nephritis while minimizing systemic side effects and could be adapted for other glomerular diseases requiring targeted therapy.

We previously reported 5-year results of 57 patients with major acetabular defects (Paprosky 2B through 3B) who underwent full (31) or half (26) cup-cage reconstructions. This study provides an update with 8.8-year mean follow-up. The 10-year cumulative incidence of and survivorship free from revision, reoperation, and complications were estimated. The 10-year cumulative incidence of revision was 14% for full and 12% for half constructs. The incidence of revision for aseptic loosening was 4.3% and 4.6%, respectively. The 10-year survivorship free from aseptic loosening for patients with pelvic discontinuity was 88.9% (95% confidence interval [CI], 70.6% to 100%) and 85.7% (95% CI, 61.8% to 100%), respectively; no patient without pelvic discontinuity required revision for aseptic loosening. The 10-year cumulative incidence of complications was 42% for all patients, including a 15% incidence of dislocation. Thus, both full and half cup-cage constructs provided durable fixation for complex acetabular bone loss at 10 years, although dislocation remains a concern. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Background: Although skin cancer survivors have an increased risk of future malignancies, many are unaware of this and may not undergo preventative screening. Objective: To evaluate skin cancer survivors’ prevalence of breast, colorectal, cervical, and lung cancer screening. Methods: This is a retrospective cross-sectional analysis of The Behavioral Risk Factor Surveillance System database from 2017 to 2021 comparing skin cancer, other cancer, and non-cancer controls. Multivariate analysis compared screening rates, controlled for socioeconomic, chronic disease, and behavioral factors. Results: Compared to non-cancer controls, skin cancer survivors had higher odds of undergoing screening for breast (odds ratios [OR]: 1.35, 95% confidence interval [CI] 1.20–1.51), colorectal (OR 1.53, 95% CI 1.40–1.66), and cervical cancer (OR 1.32, 95% CI 1.12–1.56). Lung cancer screening rates were low and similar between skin cancer survivors and non-cancer individuals (OR 1.21, 95% CI 0.84–1.74). In a subset analysis of skin cancer survivors, those who had melanoma were less likely to be screened for breast and colorectal cancer. Limitations: This study is based on anonymous, national survey data, relying on patient recall of their health information. Conclusion: Skin cancer survivors undergo cancer screenings for breast, colorectal, and cervical cancer at higher rates compared to non-cancer controls. Melanoma survivors have lower rates of breast and colorectal screening compared to non-melanoma skin cancer survivors. Skin cancer survivors should be reminded of preventive cancer screening, particularly for lung cancer.

Background: Alopecia is a burgeoning area of patient interest and dermatologic investigation. Alopecia following a solid organ transplant has been relatively unexplored, despite the potential for significant symptomatic and psychological impact on patients posttransplant. Objective: We set out to study alopecia in patients following solid organ transplants, including presentation, etiology, evaluation, and management. Methods: We performed a retrospective analysis of patients who underwent solid organ transplant without a preceding history of alopecia at a single center between January 1, 2011, and December 31, 2020, to record new alopecia diagnoses posttransplant. Demographic data, transplant type, immunosuppressive regimen, and type of alopecia were all collected. Results: Between 2011 and 2020, a total of 3,732 patients underwent a solid organ transplant with a median age of 58 (range: 18-82) years. Sixty-two percent were men, 72.5% were White, and 8.4% identified as Hispanic or Latino. Out of 3,732 patients who underwent a solid organ transplant, 39 (1%) subsequently developed alopecia. Risk of alopecia was higher in females (hazard ratio [HR] = 12.26, P < .001), Hispanics (HR = 2.49, P = .043), and pancreas transplant patients (HR = 24.26, P < .001). Limitations: This is a retrospective review. Conclusion: In this study, alopecia was rare after a solid organ transplant, but further investigation is needed to assess for potential underdiagnosis of alopecia following transplant and the higher risks reported in certain populations.