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Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Aerobic glycolysis, featured with elevated glucose consumption and lactate production, confers selective advantages on GBM by utilizing nutrients to support rapid cell proliferation and tumor growth. Pyruvate kinase 2 (PKM2), the last rate-limiting enzyme of glycolysis, is known to regulate aerobic glycolysis, and considered as a novel cancer therapeutic target. Herein, we aim to describe the cellular functions and mechanisms of a small molecular compound dimethylaminomicheliolide (DMAMCL), which has been used in clinical trials for recurrent GBM in Australia. Our results demonstrate that DMAMCL is effective on the inhibition of GBM cell proliferation and colony formation. MCL, the active metabolic form of DMAMCL, selectively binding to monomeric PKM2 and promoting its tetramerization, was also found to improve the pyruvate kinase activity of PKM2 in GBM cells. In addition, non-targeting metabolomics analysis reveals multiple metabolites involved in glycolysis, including lactate and glucose-6-phosphate, are decreased with DMAMCL treatment. The inhibitory effects of DMAMCL are observed to decrease in GBM cells upon PKM2 depletion, further confirming the importance of PKM2 in DMAMCL sensitivity. In conclusion, the activation of PKM2 by DMAMCL results in the rewiring aerobic glycolysis, which consequently suppresses the proliferation of GBM cells. Hence, DMAMCL represents a potential PKM2-targeted therapeutic agent against GBM. [ABSTRACT FROM AUTHOR]

Purpose: Caregivers of patients living longer with high-grade malignant glioma (HGG) have the unique challenge of caring for a person who may have cognitive impairment, along with cancer-related issues over a prolonged period of time. This study aims to detail the psychosocial profile of long-term caregivers, to describe their perceptions of the patient's quality of life and to examine predictors of their psychological distress.Methods: Sixty-nine caregivers (48%) of eligible patients with HGG surviving over 2 years were recruited from two Australian metropolitan tertiary hospitals. Caregivers completed cross-sectional measures of psychological distress (GHQ-12), caregiver impact (FACQ-PC) and patient functional well-being (FACT-Br TOI). Correlational analyses identified factors related to caregiver psychological distress. Those of significance (p ≤ .01) were examined using multiple regression models to determine their predictive value.Results: Caregivers were mostly female (73%), spouses (67%), cohabiting (78%) and were caring for patients surviving a median of 5.9 years since diagnosis. Whilst caregivers overall reported minimal psychological distress, 28% endorsed moderate to severe psychological distress, warranting clinical attention. Caregiver strain and low patient functional well-being both significantly predicted caregiver psychological distress (adjusted R(2) = .35, F(4, 60) = 17.7, p < .001), accounting for a moderate amount (35%) of variance. Other typical factors such as duration of caregiving, performance status, symptom burden and disease or demographic related factors were not predictive.Conclusions: Psychological distress affects a significant proportion of caregivers of patients living longer with HGG. The presence of caregiver strain and low patient functional well-being are the most important predictors of psychological distress among this cohort of caregivers. [ABSTRACT FROM AUTHOR]