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Recurrent glioblastoma (GBM) remains a therapeutic challenge with poor prognosis and limited treatment options. This phase I, open-label, dose-escalation trial investigates the safety and tolerability of combining sulfasalazine, a cystine/glutamate antiporter-inhibitor, with gamma knife radiosurgery (GKRS) for patients with recurrent GBM. Sulfasalazine is hypothesized to potentiate radiotherapy by depleting tumor cells of glutathione (GSH), thereby enhancing susceptibility to reactive oxygen species generated during irradiation. The study aims to establish the maximum tolerated dose (MTD) of sulfasalazine in combination with GKRS and explore preliminary efficacy signals through imaging and clinical endpoints.•Primary objective: Determine the MTD of sulfasalazine combined with GKRS and recommend a dose for future•phase II trials using the common toxicity criteria for adverse events v4.0.•Secondary objectives: Assess changes in intratumoral GSH via GSH‑edited Magnetic Resonance Spectroscopy, tumor response by Response Assessment in Neuro‑Oncology criteria, metabolic response on Carbon-11 methionine positron emission tomography, quality of life, progression free and overall survival.•Design: Open-label, dose-escalation study enrolling 12-24 patients with recurrent GBM eligible for GKRS.Patients receive sulfasalazine for 3 days prior to GKRS, followed by 12 months of monitoring for adverse events, imaging biomarkers, radiological and survival outcomes. This trial will provide safety data and inform the potential of sulfasalazine as a radiosensitizer in GBM treatment.
Mount Kilimanjaro, with its steep elevational gradient (770-5886 m a.s.l.) and pronounced land-use heterogeneity, supports high biodiversity and diverse nature's contributions to people (NCP), but it is underrepresented in global spatial assessments. We address this gap by mapping NCP supply across 12 ecosystem types on the southern slopes identifying hotspots and coldspots and quantifying synergies and trade-offs among NCP categories. We use 25 context-specific NCP categories that integrate local and scientific knowledge with field measurements and remote-sensing-derived proxies. Combining long-term field data with remote sensing and machine learning, we upscaled plot-scale indicators into standardized supply maps. Total NCP supply is strongly concentrated in mid-elevation ecosystems: the 1100-2200 m band alone accounted for similar to 59% of total supply compared with similar to 18% in the lowlands (700-1100 m), and the 1100-2800 m belts together provide similar to 73%, whereas high-elevation zones (2800-4600 m) contribute <9%. Hotspots clustered in lower montane forest, Ocotea forest and homegardens at mid-elevations, while coldspots occur in Erica forest and Helichrysum vegetation at high elevations and in maize fields and savanna at low elevations. We detected moderate (r = 0.55) to strong synergies (r = 0.83) among the three NCP groups (material, regulating, non-material). After accounting for climatic co-variation, the correlations among NCP groups weakened (r = 0.23-0.44), underscoring the critical role of climate for NCP supply. Our study maps NCP hotspots and coldspots across Mt. Kilimanjaro and provides a decision-support layer for conservation, restoration and agroforestry management, as well as a blueprint for spatially-explicit NCP mapping and analyses.
Functional accounts of mind, brain, and behavior have profoundly shaped thinking across many disciplines. Despite this common lens, the processes driving adaptive outcomes are often studied in isolation, leading to narrow and localized explanations. This paper brings together perspectives across fields by identifying six dynamics that enable agents to behave adaptively. These dynamics span multiple timescales and systems, including individual-level processes—thinking, learning, and development—and population-level processes—market selection, cultural evolution, and genetic evolution. We examine the reasons behind functional explanations of cognition and behavior, the conditions that foster rationality, and the interactions between adaptive processes. Our goal is to bring the cognitive, social, biological, and computer sciences into closer conversation by exposing researchers to a wide range of perspectives on adaptive decision-making.
The high rate of student dropout, especially due to failure in the first months of training, remains an urgent problem of modern education, posing both economic and personnel risks. This fact served as the basis for considering in this study the possibility of creating a system of predicting the success of students based on mathematical statistical methods. The purpose of the work is empirical confirmation of the relationship between the activity of attending lectures and the success of students as a basis for the development of a digital assistant. With the help of correlation-regression analysis, a statistically significant positive relationship between the considered indicators was established. The obtained results allow us to conclude that attendance is one of the main predictors of good student performance. The developed model allows predicting the risk of failure at an early stage, timely informing students and the university administration, which contributes to improving the quality of the educational process and reducing the probability of student dropout.
Glioblastoma radioresistance is linked to glutathione, a key antioxidant protecting against oxidative stress. Sulfasalazine inhibits the xCT antiporter mediating cystine uptake required for glutathione synthesis in glioma, potentiating radiotherapy in preclinical studies. This trial evaluated safety and therapeutic potential of combining sulfasalazine with stereotactic radiosurgery (SRS) for recurrent glioblastoma. Adults with recurrences were enrolled in a 3 + 3 dose-escalation trial receiving 1.5, 3.0, 4.5, or 6.0 g sulfasalazine orally for 3 days before SRS. Primary endpoint was safety. Secondary endpoints included changes in quality of life (QOL), tumor glutathione-levels, metabolism, and volumes assessed via Functional-Assessment-of-Cancer-Therapy-Brain-questionnaire, glutathione-edited-MR-spectroscopy,11C-Methionine-PET, and MRI. Eleven eligible patients treated with GKRS only due to closed research facilities served as concurrent controls for time to local tumor progression, progression-free survival (PFS), and overall survival (OS). Twelve patients were enrolled and followed until death or consent withdrawal (n = 1). Of 20 adverse events, two were grade 3 (transient lymphocytopenia), four grade 2, and fourteen grade 1. QOL remained stable for 6 months (p = 0.292). Tumor glutathione-levels and metabolic activity were reduced on day 3 (p = 0.010) and 1 month (p = 0.052), respectively. Best RANO-responses were objective (5/11), stable (5/11) or progressive (1/11) for participants vs. stable (2/11) or progressive (9/11) for controls, p = 0.001. Participants had longer local tumor control (median difference: 5.3 months, 95% CI: 1.0-9.6, p < 0.001) and PFS (1.7 months, 95% CI: 0.3-3.0, p = 0.009), with equivalent OS (p = 0.915). In conclusion sulfasalazine and SRS were well tolerated, reducing intratumoral glutathione-levels and associated with more durable local control than SRS alone supporting phase II investigation. TRIAL REGISTRATION: NCT04205357.
