Mortality Burden of Heatwaves in Sydney, Australia Is Exacerbated by the Urban Heat Island and Climate Change: Can Tree Cover Help Mitigate the Health Impacts?

Heatwaves are associated with increased mortality and are exacerbated by the urban heat island (UHI) effect. Thus, to inform climate change mitigation and adaptation, we quantified the mortality burden of historical heatwave days in Sydney, Australia, assessed the contribution of the UHI effect and used climate change projection data to estimate future health impacts. We also assessed the potential for tree cover to mitigate against the UHI effect. Mortality (2006–2018) records were linked with census population data, weather observations (1997–2016) and climate change projections to 2100. Heatwave-attributable excess deaths were calculated based on risk estimates from a published heatwave study of Sydney. High resolution satellite observations of UHI air temperature excesses and green cover were used to determine associated effects on heat-related mortality. These data show that >90% of heatwave days would not breach heatwave thresholds in Sydney if there were no UHI effect and that numbers of heatwave days could increase fourfold under the most extreme climate change scenario. We found that tree canopy reduces urban heat, and that widespread tree planting could offset the increases in heat-attributable deaths as climate warming progresses

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling

Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages. HuH7 hepcidin mRNA expression was determined using quantitative polymerase chain reaction (Q-PCR). Hepcidin promoter activity was measured using luciferase reporter constructs containing a 0.9 kb fragment of the wild-type human hepcidin promoter, and constructs containing mutations in bone morphogenetic protein (BMP)/SMAD4, signal transducer and activator of transcription 3 (STAT3), CCAAT/enhancer-binding protein (C/EBP), and E-box-responsive elements. Hepatic expression of bone morphogenetic proteins BMP2 and BMP6 and the BMP inhibitor noggin was determined using Q-PCR, and the protein expression of hemojuvelin (HJV), pSMAD 1/5/8, and SMAD4 was determined by western blotting. Following exposure to hypoxia or H2O2, hepcidin mRNA expression and promoter activity increased in HuH7 cells monocultures but were decreased in HuH7 cells cocultured with THP-1 macrophages. This repression was attenuated by mutation of the BMP/SMAD4-response element, suggesting that modulation of SMAD signaling mediated the response to hypoxia. No changes in hepatocyte BMP2, BMP6 or noggin mRNA, or protein expression of HJV or pSMAD 1/5/8 were detected. However, treatment with hypoxia caused a marked decrease in nuclear and cytosolic SMAD4 protein and SMAD4 mRNA expression in cocultured HuH7 cells. Together these data indicate that hypoxia represses hepcidin expression through inhibition of BMP/SMAD signaling

Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition

Selective targeting of elevated copper (Cu) in cancer cells by chelators to induce tumor-toxic reactive oxygen species (ROS) may be a promising approach in the treatment of glioblastoma multiforme (GBM). Previously, the Cu chelator di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) attracted much interest due to its potent anti-tumor activity mediated by the formation of a highly redox-active Cu-Dp44mT complex. However, its translational potential was limited by the development of toxicity in murine models of cancer reflecting poor selectivity. Here, we overcame the limitations of Dp44mT by incorporating it in new biomimetic nanoparticles (NPs) optimized for GBM therapy. Biomimetic design elements enhancing selectivity included angiopeptide-2 functionalized red blood cell membrane (Ang-M) camouflaging of the NPs carrier. Co-loading Dp44mT with regadenoson (Reg), that transiently opens the blood-brain-barrier (BBB), yielded biomimetic Ang-MNPs@(Dp44mT/Reg) NPs that actively targeted and traversed the BBB delivering Dp44mT specifically to GBM cells. To further improve selectivity, we innovatively pre-loaded GBM tumors with Cu. Oral dosing of U87MG-Luc tumor bearing mice with diacetyl-bis(4-methylthiosemicarbazonato)-copperII (Cu(II)-ATSM), significantly enhanced Cu-level in GBM tumor. Subsequent treatment of mice bearing Cu-enriched orthotopic U87MG-Luc GBM with Ang-MNPs@(Dp44mT/Reg) substantially prevented orthotopic GBM growth and led to maximal increases in median survival time. These results highlighted the importance of both angiopeptide-2 functionalization and tumor Cu-loading required for greater selective cytotoxicity. Targeting Ang-MNPs@(Dp44mT/Reg) NPs also down-regulated antiapoptotic Bcl-2, but up-regulated pro-apoptotic Bax and cleaved-caspase-3, demonstrating the involvement of the apoptotic pathway in GBM suppression. Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorder

Biomimetic Dp44mT-nanoparticles selectively induce apoptosis in Cu-loaded glioblastoma resulting in potent growth inhibition

Selective targeting of elevated copper (Cu) in cancer cells by chelators to induce tumor-toxic reactive oxygen species (ROS) may be a promising approach in the treatment of glioblastoma multiforme (GBM). Previously, the Cu chelator di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) attracted much interest due to its potent anti-tumor activity mediated by the formation of a highly redox-active Cu-Dp44mT complex. However, its translational potential was limited by the development of toxicity in murine models of cancer reflecting poor selectivity. Here, we overcame the limitations of Dp44mT by incorporating it in new biomimetic nanoparticles (NPs) optimized for GBM therapy. Biomimetic design elements enhancing selectivity included angiopeptide-2 functionalized red blood cell membrane (Ang-M) camouflaging of the NPs carrier. Co-loading Dp44mT with regadenoson (Reg), that transiently opens the blood-brain-barrier (BBB), yielded biomimetic Ang-MNPs@(Dp44mT/Reg) NPs that actively targeted and traversed the BBB delivering Dp44mT specifically to GBM cells. To further improve selectivity, we innovatively pre-loaded GBM tumors with Cu. Oral dosing of U87MG-Luc tumor bearing mice with diacetyl-bis(4-methylthiosemicarbazonato)-copperII (Cu(II)-ATSM), significantly enhanced Cu-level in GBM tumor. Subsequent treatment of mice bearing Cu-enriched orthotopic U87MG-Luc GBM with Ang-MNPs@(Dp44mT/Reg) substantially prevented orthotopic GBM growth and led to maximal increases in median survival time. These results highlighted the importance of both angiopeptide-2 functionalization and tumor Cu-loading required for greater selective cytotoxicity. Targeting Ang-MNPs@(Dp44mT/Reg) NPs also down-regulated antiapoptotic Bcl-2, but up-regulated pro-apoptotic Bax and cleaved-caspase-3, demonstrating the involvement of the apoptotic pathway in GBM suppression. Notably, Ang-MNPs@(Dp44mT/Reg) showed negligible systemic drug toxicity in mice, further indicating therapeutic potential that could be adapted for other central nervous system disorders

Mortality burden attributable to exceptional PM2.5 air pollution events in Australian cities: A health impact assessment

Background: People living in Australian cities face increased mortality risks from exposure to extreme air pollution events due to bushfires and dust storms. However, the burden of mortality attributable to exceptional PM2.5 levels has not been well characterised. We assessed the burden of mortality due to PM2.5 pollution events in Australian capital cities between 2001 and 2020. Methods: For this health impact assessment, we obtained data on daily counts of deaths for all non-accidental causes and ages from the Australian National Vital Statistics Register. Daily concentrations of PM2.5 were estimated at a 5 km grid cell, using a Random Forest statistical model of data from air pollution monitoring sites combined with a range of satellite and land use-related data. We calculated the exceptional PM2.5 levels for each extreme pollution exposure day using the deviation from a seasonal and trend loess decomposition model. The burden of mortality was examined using a relative risk concentration-response function suggested in the literature. Findings: Over the 20-year study period, we estimated 1454 (95 % CI 987, 1920) deaths in the major Australian cities attributable to exceptional PM2.5 exposure levels. The mortality burden due to PM2.5 exposure on extreme pollution days was considerable. Variations were observed across Australia. Despite relatively low daily PM2.5 levels compared to global averages, all Australian cities have extreme pollution exposure days, with PM2.5 concentrations exceeding the World Health Organisation Air Quality Guideline standard for 24-h exposure. Our analysis results indicate that nearly one-third of deaths from extreme air pollution exposure can be prevented with a 5 % reduction in PM2.5 levels on days with exceptional pollution. Interpretation: Exposure to exceptional PM2.5 events was associated with an increased mortality burden in Australia's cities. Policies and coordinated action are needed to manage the health risks of extreme air pollution events due to bushfires and dust storms under climate change

Avoidable Mortality Attributable to Anthropogenic Fine Particulate Matter (PM2.5) in Australia

Ambient fine particulate matter <2.5 _m(PM2.5) air pollution increases premature mortality globally. Some PM2.5 is natural, but anthropogenic PM2.5 is comparatively avoidable. We determined the impact of long-term exposures to the anthropogenic PM component on mortality in Australia. PM2.5-attributable deaths were calculated for all Australian Statistical Area 2 (SA2; n = 2310) regions. All-cause death rates from Australian mortality and population databases were combined with annual anthropogenic PM2.5 exposures for the years 2006–2016. Relative risk estimates were derived from the literature. Population-weighted average PM2.5 concentrations were estimated in each SA2 using a satellite and land use regression model for Australia. PM2.5-attributable mortality was calculated using a health-impact assessment methodology with life tables and all-cause death rates. The changes in life expectancy (LE) from birth, years of life lost (YLL), and economic cost of lost life years were calculated using the 2019 value of a statistical life. Nationally, long-term populationweighted average total and anthropogenic PM2.5 concentrations were 6.5 _g/m3 (min 1.2–max 14.2) and 3.2 _g/m3 (min 0–max 9.5), respectively. Annually, anthropogenic PM2.5-pollution is associated with 2616 (95% confidence intervals 1712, 3455) deaths, corresponding to a 0.2-year (95% CI 0.14, 0.28) reduction in LE for children aged 0–4 years, 38,962 (95%CI 25,391, 51,669) YLL and an average annual economic burden of $6.2 billion (95$4.0 billion, $8.1 billion). We conclude that the anthropogenic PM2.5-related costs of mortality in Australia are higher than community standards should allow, and reductions in emissions are recommended to achieve avoidable mortality