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Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors. [ABSTRACT FROM AUTHOR]

Objective: To examine levator veli palatini muscle composition in patients with nonsyndromic cleft palate and investigate the impact of Veau class. Design: Prospective cohort study. Setting: Tertiary care academic hospital. Patients/Participants: Thirteen patients with nonsyndromic cleft palate were recruited. Interventions: During primary palatoplasty, a sample of levator veli palatini muscle was excised and prepared for histological analysis. Main Outcome Measures: Fat and collagen content were determined utilizing Oil Red and Sirius red stains, respectively, while muscle fiber cross-sectional areas were calculated from H&E-stained samples, with analysis using histomorphometric methods. Immunofluorescent staining of myosin heavy chain isoforms was performed. Results: Patients underwent repair at 10.8 months of age (interquartile range [IQR] 10.2-12.9). Fat content of the levator veli palatini muscle was low in both groups, ranging from 0% to 5.2%. Collagen content ranged from 8.5% to 39.8%; neither fat nor collagen content showed an association with Veau classes. Mean muscle fiber cross-sectional area decreased with increasing Veau class, from 808 µm2 (range 692-995 µm2) in Veau II to 651 µm2 (range 232-750 µm2) in Veau III (P =.02). There was also a nonsignificant decrease in proportion of type I muscle fibers with increasing Veau class (44.3% [range 31.4%-84.4%] in Veau II vs 35.3% [range 17.4%-61.3%] in Veau III). Conclusions: Muscle fiber area in levator veli palatini muscles decreases in Veau III clefts in comparison to Veau II. The impact of these differences in velopharyngeal dysfunction requires further analysis of a larger cohort. [ABSTRACT FROM AUTHOR]

Opportunities exist to reduce nitrous oxide (N2O) emissions from nitrogen (N) fertilizers using enhanced efficiency fertilizers (EEFs) and managing application timing. This study examined (1) application timing (fall/spring) and (2) fertilizer N source on N2O emissions, yield, and N uptake of Canadian hard red spring wheat (Triticum aestivum L.) in Southern Manitoba. Fertilizer N sources included granular urea and four EEF products: (1) polymer‐coated urea (environmentally smart nitrogen [ESN]); (2) urea plus nitrification inhibitor (eNtrench); (3) urea plus urease inhibitor (Limus); and (4) urea plus nitrification and urease inhibitor (SuperU). Nitrification‐inhibited products most consistently reduced N2O emissions while maintaining productivity. Compared to urea alone, urea + eNtrench was most effective in reducing cumulative N2O emissions by 47%–64% at four of six site‐years. SuperU reduced N2O emissions by 37%–57% at three of six site‐years. ESN and urea + Limus did not affect emissions in most years. Wheat yield, protein, and N uptake were unaffected by N source in five of six site‐years. Compared to spring, fall application gave greater N2O emissions by 33%–67% at three of six site‐years due to spring‐thaw emissions. Fall was inferior to spring application in wetter site years with lower yield, protein, and N uptake. Overall, nitrification‐inhibited products—either alone or with a urease inhibitor—are a promising tool to reduce N2O emissions while maintaining wheat productivity in Manitoba. However, given that there were few consistent increases in yield or protein, the additional cost of the inhibitors will be a barrier to adoption. Core Ideas: EEF products with nitrification and nitrification/urease inhibitors consistently reduced N2O emissions.Controlled release urea and urease‐inhibited urea did not reduce N2O emissions.Fall application of urea increased N2O emissions in three site‐years compared to spring application.The nitrification inhibitors applied with urea in fall or spring were effective to reduce N2O emissions.Overall, fall application decreased yield, grain protein, and N uptake in relatively wet years. [ABSTRACT FROM AUTHOR]

Background: The frequency and significance of IDH mutations in glioma across age groups is incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes., Methods: Clinical, histologic, and sequencing data from patients with IDH-mutant, grade 2-4 gliomas, were collected from collaborating institutions between 2013-2019. Patients were categorized as pediatric (<19y), YA (19-39y) or older adult (≥40y). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine association of age and other covariates with overall (OS) and progression-free survival (PFS)., Results: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS., Conclusions: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approach varied significantly by patient age and warrant further study as addressable age-associated outcome drivers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To examine levator veli palatini muscle composition in patients with nonsyndromic cleft palate and investigate the impact of Veau class., Design: Prospective cohort study., Setting: Tertiary care academic hospital., Patients/participants: Thirteen patients with nonsyndromic cleft palate were recruited., Interventions: During primary palatoplasty, a sample of levator veli palatini muscle was excised and prepared for histological analysis., Main Outcome Measures: Fat and collagen content were determined utilizing Oil Red and Sirius red stains, respectively, while muscle fiber cross-sectional areas were calculated from H&E-stained samples, with analysis using histomorphometric methods. Immunofluorescent staining of myosin heavy chain isoforms was performed., Results: Patients underwent repair at 10.8 months of age (interquartile range [IQR] 10.2-12.9). Fat content of the levator veli palatini muscle was low in both groups, ranging from 0% to 5.2%. Collagen content ranged from 8.5% to 39.8%; neither fat nor collagen content showed an association with Veau classes. Mean muscle fiber cross-sectional area decreased with increasing Veau class, from 808 µm 2 (range 692-995 µm 2 ) in Veau II to 651 µm 2 (range 232-750 µm 2 ) in Veau III ( P  = .02). There was also a nonsignificant decrease in proportion of type I muscle fibers with increasing Veau class (44.3% [range 31.4%-84.4%] in Veau II vs 35.3% [range 17.4%-61.3%] in Veau III)., Conclusions: Muscle fiber area in levator veli palatini muscles decreases in Veau III clefts in comparison to Veau II. The impact of these differences in velopharyngeal dysfunction requires further analysis of a larger cohort., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KBP is a consultant for Stryker CMF.