Effects of aluminium chloride and aluminium chlorohydrate on DNA repair in MCF10A immortalised non-transformed human breast epithelial cells

Use of underarm aluminium (Al)-based antiperspirant salts may be a contributory factor in breast cancer development. At the 10th Keele meeting, Al was reported to cause anchorage-independent growth and double strand DNA breaks in MCF10A immortalised non-transformed human breast epithelial cells. We now report that exposure of MCF10A cells to Al chloride or Al chlorohydrate also compromised DNA repair systems. Longterm (19–21 weeks) exposure to Al chloride or Al chlorohydrate at a 10−4 M concentration resulted in reduced levels of BRCA1 mRNA as determined by real-time RT-PCR and BRCA1 protein as determined by Western immunoblotting. Reduced levels of mRNA for other DNA repair genes (BRCA2, CHK1, CHK2, Rad51, ATR) were also observed using real-time RT-PCR. Loss of BRCA1 or BRCA2 gene function has long been associated with inherited susceptibility to breast cancer but these results suggest that exposure to aluminium-based antiperspirant salts may also reduce levels of these key components of DNA repair in breast epithelial cells. If Al can not only damage DNA but also compromise DNA repair systems, then there is the potential for Al to impact on breast carcinogenesis.

Intercomparison of the Arctic sea ice cover in global ocean–sea ice reanalyses from the ORA-IP project

Ocean–sea ice reanalyses are crucial for assessing the variability and recent trends in the Arctic sea ice cover. This is especially true for sea ice volume, as long-term and large scale sea ice thickness observations are inexistent. Results from the Ocean ReAnalyses Intercomparison Project (ORA-IP) are presented, with a focus on Arctic sea ice fields reconstructed by state-of-the-art global ocean reanalyses. Differences between the various reanalyses are explored in terms of the effects of data assimilation, model physics and atmospheric forcing on properties of the sea ice cover, including concentration, thickness, velocity and snow. Amongst the 14 reanalyses studied here, 9 assimilate sea ice concentration, and none assimilate sea ice thickness data. The comparison reveals an overall agreement in the reconstructed concentration fields, mainly because of the constraints in surface temperature imposed by direct assimilation of ocean observations, prescribed or assimilated atmospheric forcing and assimilation of sea ice concentration. However, some spread still exists amongst the reanalyses, due to a variety of factors. In particular, a large spread in sea ice thickness is found within the ensemble of reanalyses, partially caused by the biases inherited from their sea ice model components. Biases are also affected by the assimilation of sea ice concentration and the treatment of sea ice thickness in the data assimilation process. An important outcome of this study is that the spatial distribution of ice volume varies widely between products, with no reanalysis standing out as clearly superior as compared to altimetry estimates. The ice thickness from systems without assimilation of sea ice concentration is not worse than that from systems constrained with sea ice observations. An evaluation of the sea ice velocity fields reveals that ice drifts too fast in most systems. As an ensemble, the ORA-IP reanalyses capture trends in Arctic sea ice area and extent relatively well. However, the ensemble can not be used to get a robust estimate of recent trends in the Arctic sea ice volume. Biases in the reanalyses certainly impact the simulated air–sea fluxes in the polar regions, and questions the suitability of current sea ice reanalyses to initialize seasonal forecasts.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease- causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15. Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson’s disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.