Triazoles

Cat-transmitted sporotrichosis caused by Sporothrix brasiliensis is an emerging zoonosis in Latin America. Because treatment of feline sporotrichosis is often not effective, we sought to determine whether treatment failure results from S. brasiliensis strains that have existing elevated MICs for itraconazole, the primary treatment for this disease. During 2021-2023 at the triple border region of Brazil, Paraguay, and Argentina, 108 S. brasiliensis strains were isolated from felines before antifungal treatment. The main clinical manifestation was cutaneous disseminated sporotrichosis (61%), which was the only form resulting in sporotrichosis-induced deaths (61%). We conducted antifungal susceptibility testing for 9 antifungal compounds, evaluating for both mycelial and yeast phases. MIC levels were low for most antifungal agents but were higher in the mycelial phase than in the yeast phase, especially for voriconazole and isavuconazole. We conclude that the varying clinical manifestations of sporotrichosis and large differences in mortality rates were not caused by elevated itraconazole MICs.

ImportanceThird-generation aromatase inhibitors (AIs)-anastrozole, letrozole, and exemestane-are standard adjuvant endocrine therapy for women with postmenopausal hormone receptor (HR)-positive early-stage breast cancer. However, little is known about their comparative effectiveness in clinical settings.ObjectiveTo compare adjuvant anastrozole, letrozole, and exemestane in terms of disease-free survival (DFS) and overall survival (OS) in women with postmenopausal HR-positive early-stage breast cancer.Design, setting, and participantsThis comparative effectiveness study conducted in France emulated a target trial using national medicoadministrative data. The patient cohort was derived from the updated French Early Breast Cancer Cohort and consisted of women aged 50 to 75 years with early-stage breast cancer who were diagnosed between January 1, 2011, and December 31, 2020, and followed up through December 31, 2021. All women initiated adjuvant AI therapy without ovarian suppression. Data analysis was performed from November 2024 to May 2025.ExposuresUpfront adjuvant anastrozole, letrozole, and exemestane, evaluated under natural persistence and under a hypothetical intervention ensuring perfect persistence for 5 years.Main outcomes and measuresThe primary end points were DFS and OS. Both DFS and OS were estimated using adjusted Kaplan-Meier curves.ResultsAmong 148 436 women (median [IQR] age, 64 [59-69] years) included in the analyses, 38.5% initiated anastrozole, 52.9% initiated letrozole, and 8.5% initiated exemestane. After a median (IQR) follow-up of 63 (34-94) months, the 8-year DFS under natural persistence was estimated to be lower for the exemestane group (79.1%; 95% CI, 78.1%-80.0%) compared with the anastrozole (81.0%; 95% CI, 80.6%-81.5%) and letrozole (81.1%; 95% CI, 80.7%-81.5%) groups. Similarly, the 8-year OS was 88.8% (95% CI, 88.0%-89.6%) for the exemestane group compared with 90.5% (95% CI, 90.2%-90.8%) for the anastrozole group and 89.9% (95% CI, 89.6%-90.2%) for the letrozole group. Patients who initiated exemestane were also more likely to discontinue treatment within 5 years of therapy than their counterparts taking the other AIs (39.3% [95% CI, 38.3%-40.3%] in the exemestane group vs 35.1% [95% CI, 34.7%-35.6%] in the anastrozole group and 35.0% [95% CI, 34.6%-35.4%] in the letrozole group). However, the lower DFS and OS observed for exemestane compared with letrozole and anastrozole persisted under perfect persistence.Conclusions and relevanceThe findings of this comparative effectiveness study using a target trial emulation framework suggest that adjuvant endocrine therapy with exemestane may result in slightly lower DFS and OS compared with anastrozole and letrozole in patients with postmenopausal HR-positive early-stage breast cancer. The findings favor anastrozole or letrozole as initial treatment and highlight the need for future studies to inform AI selection.

Glaucoma is a neurodegenerative disease characterized by progressive degeneration of optic nerve axons and loss of retinal ganglion cells (RGCs). Although elevated intraocular pressure (IOP) is a major risk factor, many patients develop glaucoma with normal IOP, highlighting the need for neuroprotective therapies. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has shown beneficial effects in diabetes-induced retinal neurodegeneration. This study aimed to evaluate whether sitagliptin eye drops, previously effective in diabetes-induced retinal neurodegeneration, could prevent corticosteroid-induced glaucoma. Glaucoma was induced in mice by periocular injection of dexamethasone (DEX) once weekly for five weeks. Sitagliptin or vehicle eye drops were administered from day 14 to 35. Untreated mice served as controls. DEX treatment caused significant loss of RGC bodies and optic nerve axons compared to controls, which was prevented by sitagliptin eye drops (p p < 0.001), key mediators of inflammation and apoptosis. Sitagliptin eye drops exert a potent neuroprotective effect against corticosteroid-induced glaucoma, supporting their potential as a novel therapeutic strategy for glaucoma.

The proteostatic decline in Alzheimer's disease is well established, and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer's disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.