Citations

ABSTRACT Background and Objectives Surgical management of ipsilateral breast tumor recurrence (IBTR) is often mastectomy. No guidelines specifically address contralateral prophylactic mastectomy (CPM) for this population. We assessed factors associated with CPM at the time of IBTR mastectomy. Methods Patients undergoing mastectomy for IBTR (10/2008‐5/2024) were identified. Demographics, tumor characteristics, and treatment details were assessed. Results Of the 381 eligible IBTR patients, 221 (58.0%) had a unilateral therapeutic mastectomy and 160 (42.0%) underwent mastectomy with CPM. CPM patients were younger ( p < 0.0001), with lower clinical T category tumors ( p < 0.001) and less HR + HER2‐ invasive disease ( p = 0.004). CPM patients were more likely to undergo germline genetic testing (63.1% vs 41.6%, p < 0.0001) and were twice as likely to have immediate breast reconstruction ( p < 0.0001). On multivariable analysis, younger age, HR‐HER2 + IBTR subtype, pathogenic variants known at the time of surgery (relative to negative testing and/or no genetic testing), immediate breast reconstruction, and prior radiation for index cancer were each associated with CPM (all p < 0.05). Conclusion In our series of 381 patients treated with mastectomy for IBTR, 42% also had a CPM. Multiple factors, including age, tumor stage and biology, immediate breast reconstruction, and genetic testing may impact CPM choice.

G protein-coupled receptors (GPCRs) are among the most common drug targets, with numerous agonists and antagonists approved for clinical use. More recently, it has been appreciated that drugs can also modulate the action of natural agonists of these receptors, thus providing unique clinical advantages. Here, we describe the identification and characterization of a small molecule positive allosteric modulator (PAM) of secretin action at the class B G protein-coupled secretin receptor. This phenyl(trifluoromethyl)-pyrimidine can occupy the secretin receptor without stimulating its internalization, yet priming it to enhance both the potency and efficacy of the action of natural secretin. This is also shown to exhibit its effects on cells expressing low numbers of these receptors, without enhancing the effects of other structurally related hormones acting at other class B GPCRs. The mechanism responsible for this PAM effect is the slowing of the off-rate of receptor-bound secretin. This compound can serve as a lead to the development of other drugs that enhance the action of natural endogenous secretin and can be utilized to explore the potential therapeutic utility of such compounds.

Background: Atezolizumab plus bevacizumab (A + B) and durvalumab plus tremelimumab (D + T) are approved first-line systemic therapy options for advanced hepatocellular carcinoma (HCC), with no head-to-head comparison. In this propensity-matched analysis, we compared the survival of patients with advanced HCC who received either A + B or D + T therapy. Methods: Patients with advanced HCC who received A + B or D + T treatment in the first-line setting were identified using the TriNetX platform, a health research network that provides access to electronic health record data from 112 healthcare organizations. Propensity-score-matched (PSM) analysis was conducted, and the median overall survival (OS) was estimated using the Kaplan–Meier method. Results: We identified 2819 patients with HCC who were treated with A + B or D + T: 2031 patients received A + B and 788 received D + T. Compared to patients in the A + B cohort, those who received D + T were more likely to be older (median age: 68.4 vs. 66.9 years), have lower platelet counts (186.8 vs. 201.3), higher prevalence of hypoalbuminemia with levels < 2.7 g/dL (35.2% vs. 28.4%), higher prevalence of bilirubin levels between 2.0 and 2.9 mg/dL (28.8% vs. 23.8%), and decreased INR with levels between 0.0 and 1.6 (92.1% vs. 86.3%). After PSM, 1536 patients were included in the survival analyses, with all variables adequately matched. There was no significant difference in the median OS between those receiving A + B or D + T [16.3 vs. 22.5 months, hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76–1.0]. Higher rates of immune-mediated colitis were noted in the D + T group. Conclusions: Similar survival rates were observed among patients with advanced HCC who received A + B and D + T in the first-line setting. Our study suggests that both A + B and D + T are valid treatment options, and that therapy can be tailored based on comorbidities, adverse effects, and patient preferences.

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.