Management of stream compensation for a large conjunctive use scheme,Shropshire, UK

The Shropshire Groundwater Scheme (SGS) is the largest conjunctive use scheme in the United Kingdom. The SGS operates in drought periods, pumping water from the Permo‐Triassic Sandstone aquifer in Shropshire, England to regulate flows in the River Severn, alongside releases from conventional surface water reservoirs. This regulation protects the environment and increases the security of supply of major public water supply abstractions downstream. An important operational consideration is the impact SGS groundwater abstraction has on small streams that rise on the Shropshire Permo‐Triassic Sandstone. Compensation boreholes have been installed to maintain flows during and after the operation of the SGS. This paper shows how a groundwater model of the East Shropshire Permo‐Triassic Sandstone has been used to estimate the required level of compensation flows for recent climatic conditions to optimise the use of the SGS. The catchment wide conditions are included in this analysis by using the results of a large‐scale surface water model of the River Severn.     

Review Essay

Book reviewed: Christopher C. Sellers, The Trials of Developing the ‘Social’ With the ‘Science’: A Review Essay of Hazards of the Job: From Industrial Disease to Environmental Health Science     

Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.     

EPLIN,a Putative Tumour Suppressor in Colorectal Cancer,Implications in Drug Resistance

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.     

The lantibiotic lacticin 3147 produced in a milk-based medium improves the efficacy of a bismuth-based teat seal in cattle deliberately infected with Staphylococcus aureus

A preparation of the bacteriocin lacticin 3147 (prepared from a demineralized whey protein fermentation liquor) was combined as a powder with a bismuth-based intramammary teat seal and evaluated for its potential as an antimicrobial in non-lactating cows. The lacticin/teat seal formulation enabled significant bacteriocin release from the seal without the requirement for a surfactant. Studies in vivo in lactating cows demonstrated that this formulation was effective in reducing bacterial recoveries (approximately 20-fold) from teats deliberately inoculated with Staphylococcus aureus after infusion. Moreover, this formulation also significantly reduced the numbers of Staph. aureus recovered from teats that were exposed to the challenge bacterium before the infusion of the teat seal preparation. The powdered preparation of lacticin 3147 did, however, cause some teat irritation as evidenced by associated rises in somatic cell count (SCC). However, this effect was short-lived and when the mean SCC readings pre-infusion and the final two readings post-infusion were compared, there was no significant difference in the immunological acceptance between treatments.     

Intramammary infusion of a live culture for treatment of bovine mastitis: effect of live lactococci on the mammary immune response

In the accompanying article, we demonstrated that a live culture of Lactococcus lactis compares favourably with antibiotics for treatment of bovine mastitis in two initial field trials. In an effort to explain the mechanism involved, this study investigated the effect of culture administration on the local immune response. In this respect we initially observed that infusion of the live culture Lactococcus lactis stimulated substantial recruitment of polymorphonucleocytes (PMN) and lymphocytes to the udder. For instance, in one assay, quarters infused with the probiotic experienced a dramatic increase (approximately 20,000-fold) in neutrophils over the first 48-h period from an average value of 83.6 cells/ml pre-treatment to 1.78 x 106 cells/ml 48 h post-infusion. Levels of the acute phase proteins haptaglobin and milk amyloid A were also elevated significantly in comparison with controls following infusion of the culture. The results of flow cytometric assays also demonstrated that while infusion of a live lactococcal culture led to an enhanced recruitment of PMN to the udder (from 1.85 x 104 cells/ml pre-infusion to 1.45 x 106 cells/ml 24 h post-infusion) cell-free supernatant from the same culture was not able to do so, indicating that live Lc. lactis can specifically trigger the mammary immune response to elicit PMN accumulation. These results suggest that the mechanism responsible for this probiotic treatment of mastitis is associated with stimulation of the host intramammary immune system.     

Characterisation of a uranium ore using multiple X-ray diffraction based methods

Uranium bearing ores are often a complex mixture of minerals and compounds, a number of which are not of economic importance and are commonly referred to as gangue materials. In order to improve the efficiency of the dissolution stage of the overall uranium extraction process, a greater understanding of the minerals and compounds present in the ore is required. A greater knowledge of the gangue materials present is important as they can influence various aspects of the dissolution process such as providing potential adsorption sites for aqueous uranium species and through influencing the equilibrium of reactions involving aqueous uranium species. In this study the mineralogy of a uranium ore was investigated using a range of X-ray diffraction (XRD) based methods including in situ high temperature XRD and XRD using a synchrotron beam line. The results obtained from standard XRD (Cu Kα), high temperature XRD and synchrotron XRD (16.534 keV) were compared and a number of minerals were identified. The improved spatial resolution and intensity of the synchrotron data allowed for superior phase identification of a variety of minerals where standard X-ray techniques gave inconclusive results.