Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations.

Increases in platinum group element (PGE) concentrations in ambient air and dust since the introduction of automotive catalytic converters in 1988 is a cause of concern. Until now, data derived from engine-test bench experiments have provided the basis for the assessment of human health risks associated with PGE exposure. Such experiments have provided valuable information regarding emission data that has been used to estimate ambient exposure concentrations. However, these data are not necessarily representative of typical environmental PGE exposure levels and conditions. Data on measured environmental concentrations is needed to provide a more adequate basis for the assessment of exposure and related risks. Twenty air and airborne-dust samples were provided by the Umweltbundesamt (Federal Environmental Agency, Germany) in the years 1988, 1989, 1992, 1997, and 1998. The samples were collected in Frankfurt/Main and the adjacent city of Offenbach. For this, 11 to 80 m3 of air were filtered over a 24-72 h period using a vacuum. Glass-fiber filters were used to collect samples. Sample platinum and rhodium concentrations were determined using adsorptive voltammetry. Although the number of samples collected in different years is limited, the results indicate a trend toward continuous increases in ambient concentrations of these metals between 1988 and 1998. Specifically, there were 46- and 27-fold increases in Pt and Rh concentrations, respectively. Despite these observed increases, the Pt concentrations measured (i.e., 147 pg/m3 on average, with a maximum of 246 pg/m3 in 1998) fell far below 15,000 pg/m3, which has been suggested as a guidance value (i.e., exposure at this level would be expected to be without appreciable health risk). The results of a particle-size distribution analysis of one sample (8-step impactor) that was collected 150 m away from a street show that approximately 75% of Pt and 95% of Rh occurs in association with large particulate matter of > 2 microns, with concentrations reaching a maximum in particles of 4.7 to 5.8 microns. The remaining 25% of Pt and 5% of Rh is present in fine particulate matter of < 2 microns. An approximate 10% of Pt and < 38% of Rh in airborne particles was found to be soluble in 0.1 molar HCl. Further, the results indicate that most of the emitted PGE particles from automotive catalytic converters, particularly those bound to fine particulate matter, are capable of being airborne. As a result, PGEs are not only present in areas close to emissions (e.g., roads), but can be transported over longer distances.

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