BackgroundCommunities living in developing countries as well as populations affected by natural or man-made disasters can be left at great risk from water related diseases, especially those spread through the faecal-oral route. Conventional water treatments such as boiling and chlorination can be effective but may prove costly for impoverished communities. Solar water disinfection (SODIS) has been shown to be a cheap and effective way for communities to treat their water. The exposure to sunlight is typically carried out in small volume plastic beverage bottles (up to 2 l). Given the water requirements of consumption and basic personal hygiene, this may not always meet the needs of communities. Recent work has shown 19-L plastic water dispenser containers to be effective SODIS reactors, comparable in efficacy to PET bottles. In this paper we outline the need for studying SODIS in large volumes and discuss 4 main associated challenges.DiscussionApart from clean water needed for consumption, access to adequate water is essential for sanitation and hygiene. Contamination of treated water through unwashed hands or vessels contributes heavily to the spread of water borne pathogens in communities. Traditional water treatments such as boiling and chlorination can be effective but may prove financially burdensome for low income communities. SODIS in large vessels could be used as a simple method to meet water requirements in low income and disaster affected populations. However, there have been some concerns associated with the conventional SODIS method; we identify the main ones to be: (1) cold or cloudy weather; (2) the fear of leaching in plastic bottles; (3) water turbidity, and; (4) community acceptance.SummaryThe application of SODIS in large bottles like WDCs has the potential to be an efficient and cost effective method of disinfecting water, either for consumption until more rigorous water treatments can be put in place, or for sanitation and hygiene to curb the spread of fecal contamination. Further research is needed that can address some of the limitations and challenges associated with the use of large bottles for SODIS.
Sigma-1 and sigma-2 receptors are emerging therapeutic targets. Although the molecular identity of the sigma-2 receptor has recently been determined, receptor quantitation has used, and continues to use, the sigma-1 selective agents (+) pentazocine or dextrallorphan to mask the sigma-1 receptor in radioligand binding assays. Here, we have assessed the suitability of currently established saturation and competition binding isotherm assays that are used to quantify parameters of the sigma-2 receptor. We show that whilst the sigma-1 receptor mask (+) pentazocine has low affinity for the sigma-2 receptor (K i 406 nM), it can effectively compete at this site with [³H] di-O-tolyl guanidine (DTG) at the concentrations frequently used to mask the sigma-1 receptor (100 nM and 1 μM). This competition influences the apparent affinity of DTG and other ligands tested in this system. A more troublesome issue is that DTG can displace (+) pentazocine from the sigma-1 receptor, rendering it partly unmasked. Indeed, commonly used concentrations of (+) pentazocine, 100 nM and 1 μM, allowed 37 and 11% respectively of sigma-1 receptors to be bound by DTG (300 nM), which could result in an overestimation of sigma-2 receptor numbers in assays where sigma-1 receptors are also present. Similarly, modelled data for 1 μM dextrallorphan show that only 71-86% of sigma-1 receptors would be masked in the presence of 300 nM DTG. Therefore, the use of dextrallorphan as a masking agent would also lead to the overestimation of sigma-2 receptors in systems where sigma-1 receptors are present. These data highlight the dangers of using masking agents in radioligand binding studies and we strongly recommend that currently used masking protocols are not used in the study of sigma-2 receptors. In order to overcome these problems, we recommend the use of a cell line apparently devoid of sigma-1 receptors [e.g., MCF7 (ATCC HTB-22)] in the absence of any masking agent when determining the affinity of agents for the sigma-2 receptor. In addition, assessing the relative levels of sigma-1 and sigma-2 receptors can be achieved using [³H] DTG saturation binding followed by two-site analysis of (+) pentazocine competition binding with [³H] DTG.
Introduction
Sigma receptors (SRs) are regularly overexpressed in cancer however their functions remain unknown. Certain Sigma1-receptor (Sig1R) ligands trigger death in breast cancer (BCa) cells but not in non-cancerous breast cells (NCB). In stressed cells, Sig1R is vital to the pro-survival unfolded protein response (UPR). Cancer cells depend on UPR signalling for survival, investigating Sig1R mediated mechanisms in BCa vs. NCB might uncover novel and targetable weaknesses in cancer.
Method
UPR activation by Sig1R antagonist IPAG was examined in BCa cells by Western blotting. Sig1R and UPR marker localizations were examined by immunofluorescence. SR gene expression between 141 matched breast tumour tissue and tumour adjacent normal samples was compared using RNAseq data from The Cancer Genome Atlas (TCGA). Merged microarray datasets were used to compare SR expression in 399 primary breast tumours with relapse (BCaR) vs. 352 without relapse (BCaNR).
Result
Relative to non-cancerous human mammary epithelial cells, Sig1R expression was lowest in MCF7s and highest in MDA-MB-468s. IPAG induced differential temporal activation of all three branches of the UPR in MCF7 and tamoxifen-resistant, low Sig1R expressing cell line LY2. TCGA RNAseq data highlighted SR overexpression in BCa particularly in the basal subtype. Microarray data showed both oestrogen receptor (ER)+ and ER- BCaR primaries had elevated SIGMAR1 compared to BCaNR primaries of the same respective ER status.
Conclusion
BCa cells are dependent on Sig1R mediated signalling. Sig1R expression might indicate the propensity of breast tumours to relapse. Thus, Sig1R represents a potential target in BCa, particularly for aggressive subtypes.
Take-home message
The Sigma-1 receptor (Sig1R) has a vital but unknown pro-survival function in cancer; Sig1R ligands cause death in cancer cells while sparing non-cancerous ones. Characterizing Sig1R mediated signalling may reveal novel, selective therapeutic targets in cancer.
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