Residential segregation and health in Northern Ireland

Patterns of residential segregation in Northern Ireland reflect historic sectarian conflict as well as current animosities. A number of indices of segregation are examined in this paper and their relative merits in capturing localised societal divisions are discussed.The implications of such divisions on health as mediated through conflict-related stress are then considered. Costed datasets of hospital, community and anxiety/depression prescribing data havebeen assembled and attributed to local geographies.The association between geographical variations in these costs and levels of segregation was modelled using regression analysis.It was found that the level of segregation does not help to explain variations in costed utilisation of acute and elderly services but does explain variations in the costs of prescribing for anxiety and depression with controls for socio-economic deprivation included. Results in this paper would indicate that strategies to promote good relations in Northern Ireland have positive implications for mental health.

Relative metabolomic flux: Predicting changes in the environmental metabolome from the metagenome

Background: The world's oceans are home to a diverse array of microbial life whose metabolic activity helps to drive the earth's biogeochemical cycles. Metagenomic analysis has revolutionized our access to these communities, providing a system-scale perspective of microbial community interactions. However, while metagenome sequencing can provide useful estimates of the relative change in abundance of specific genes and taxa between environments or over time, this does not investigate the relative changes in the production or consumption of different metabolites.
Results: We propose a methodology, Predicted Relative Metabolic Turnover (PRMT) that defines and enables exploration of metabolite-space inferred from the metagenome. Our analysis of metagenomic data from a time-series study in the Western English Channel demonstrated considerable correlations between predicted relative metabolic turnover and seasonal changes in abundance of measured environmental parameters as well as with observed seasonal changes in bacterial population structure.
Conclusions: The PRMT method was successfully applied to metagenomic data to explore the Western English Channel microbial metabalome to generate specific, biologically testable hypotheses. Generated hypotheses linked organic phosphate utilization to Gammaproteobactaria, Plantcomycetes, and Betaproteobacteria, chitin degradation to Actinomycetes, and potential small molecule biosynthesis pathways for Lentisphaerae, Chlamydiae, and Crenarchaeota. The PRMT method can be applied as a general tool for the analysis of additional metagenomic or transcriptomic datasets.

Interaction strength, food web topology and the relative importance of species in food webs

P>1. We established complex marine communities, consisting of over 100 species, in large subtidal experimental mesocosms. We measured the strength of direct interactions and the net strength of direct and indirect interactions between the species in those communities, using a combination of theoretical and empirical approaches.

A novel reversible relative-humidity indicator ink based on methylene blue and urea

A new relative-humidity sensitive ink based on methylene blue and urea is described which can utilise the deliquescent nature of urea.

Evaluation of c-FLIP in castrate-resistant prostate cancer antagonizes therapeutic response to androgen receptor-targeted therapy

Purpose: To characterize the importance of cellular Fas-associated death domain (FADD)–like interleukin 1ß-converting enzyme (FLICE) inhibitory protein (c-FLIP), a key regulator of caspase-8 (FLICE)–promoted apoptosis, in modulating the response of prostate cancer cells to androgen receptor (AR)–targeted therapy.

Experimental Design: c-FLIP expression was characterized by immunohistochemical analysis of prostatectomy tissue. The functional importance of c-FLIP to survival and modulating response to bicalutamide was studied by molecular and pharmacologic interventions.

Results: c-FLIP expression was increased in high-grade prostatic intraepithelial neoplasia and prostate cancer tissue relative to normal prostate epithelium (P < 0.001). Maximal c-FLIP expression was detected in castrate-resistant prostate cancer (CRPC; P < 0.001). In vitro, silencing of c-FLIP induced spontaneous apoptosis and increased 22Rv1 and LNCaP cell sensitivity to bicalutamide, determined by flow cytometry, PARP cleavage, and caspase activity assays. The histone deacetylase inhibitors (HDACi), droxinostat and SAHA, also downregulated c-FLIP expression, induced caspase-8- and caspase-3/7–mediated apoptosis, and increased apoptosis in bicalutamide-treated cells. Conversely, the elevated expression of c-FLIP detected in the CRPC cell line VCaP underpinned their insensitivity to bicalutamide and SAHA in vitro. However, knockdown of c-FLIP induced spontaneous apoptosis in VCaP cells, indicating its relevance to cell survival and therapeutic resistance.

Conclusion: c-FLIP reduces the efficacy of AR-targeted therapy and maintains the viability of prostate cancer cells. A combination of HDACi with androgen deprivation therapy may be effective in early-stage disease, using c-FLIP expression as a predictive biomarker of sensitivity. Direct targeting of c-FLIP, however, may be relevant to enhance the response of existing and novel therapeutics in CRPC. Clin Cancer Res; 18(14); 3822–33.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours; informed scheduling of the bioreductive drug AQ4N improves treatment response

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment hypoxia is known to drive malignant progression. This study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold chambers (DSF) were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide and vehicle-only treated tumours were re-established in vitro and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2mg/kg/day) decreased tumour oxygenation by 45% within 24h, reaching a nadir of 0.09% oxygen (0.67±0.06 mmHg) by day 7; this persisted until day 14 when it increased up to day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at days 7 and 14 with revascularization occurring by day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50mg/kg; single dose) caused greater tumour growth delay than bicalutamide alone. This study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit.