Sphingosine Kinase 1 Promotes Malignant Progression in Colon Cancer and Independently Predicts Survival of Patients With Colon Cancer by Competing Risk Approach in South Asian Population

OBJECTIVES: Sphingosine kinase 1 (SphK1) phosphorylates the membrane sphingolipid, sphingosine, to sphingosine-1-phosphate (S1P), an oncogenic mediator, which drives tumor cell growth and survival. Although SphK1 has gained increasing prominence as an oncogenic determinant in several cancers, its potential as a therapeutic target in colon cancer remains uncertain. We investigated the clinical relevance of SphK1 expression in colon cancer as well as its inhibitory effects in vitro.

METHODS: SphK1 expression in human colon tumor tissues was determined by immunohistochemistry and its clinicopathological significance was ascertained in 303 colon cancer cases. The effects of SphK1 inhibition on colon cancer cell viability and the phosphoinositide 3-kinase (PI3K)/Akt cell survival pathway were investigated using a SphK1-selective inhibitor-compound 5c (5c). The cytotoxicity of a novel combination using SphK1 inhibition with the chemotherapeutic drug, 5-fluorouracil (5-FU), was also determined.

RESULTS: High SphK1 expression correlated with advanced tumor stages (AJCC classification). Using a competing risk analysis model to take into account disease recurrence, we found that SphK1 is a significant independent predictor for mortality in colon cancer patients. In vitro, the inhibition of SphK1 induced cell death in colon cancer cell lines and attenuated the serum-dependent PI3K/Akt signaling. Inhibition of SphK1 also enhanced the sensitivity of colon cancer cells to 5-FU.

CONCLUSION: Our findings highlight the impact of SphK1 in colon cancer progression and patient survival, and provide evidence supportive of further development in combination strategies that incorporate SphK1 inhibition with current chemotherapeutic agents to improve colon cancer outcomes.

'O daughter ... forget your people and your father's house': Early Modern Women Writers and the Spanish Imaginary

‘O daughter … forget your people and your father’s house’: Early Modern Women Writers and the Spanish ImaginaryAnne Holloway and Ramona WrayHolloway and Wray consider the perspectives offered by two very different seventeenth-century women (Mary Bonaventure Browne, or Mother Browne (b.1615- and Lady Ann Fanshawe (b.1625) both of whom exchanged Ireland for Spain, and both of whom record journeys both ‘real’ and imagined in their writings. Browne’s deployment of hagiographical tropes in her History of the Poor Clares may reveal the potential impact of Iberian conventual culture; her allusions to the markers of sanctity insistent on the immutability of the body, whilst accepting and anticipating spectral presence in the form of bilocation. Fanshawe’s Memoirs are considered alongside the material legacy of her ‘Booke of Receipts of Physickes, Salues, Waters, Cordialls, Preserues and Cookery.’ Her impressions both in transit and within the domus are similarly marked by receptivity and sensitivity to the host culture. Amidst a backdrop of religious persecution and political uncertainty, in both cases Spain emerges as a potentially enabling context for creativity and self-expression.Keywords: Memoir; Franciscan; Poor Clares; Fanshawe; Mary Bonaventure Browne; hagiography; life-writing; autobiography, women writers

Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

The Climate of War: Violence, Warfare and Climatic Reductionism

National security agencies and other interested parties now often regard conflict as the inevitable consequence of climate change. This inclination to reduce war to the vicissitudes of climate is not new however. Here I examine some of the earlier ways in which violence was attributed to climatic conditions, particularly in the United States, and trace links between these older advocates of climatic determinism and the recent writings of those insisting that climate change will usher in a grim world of chronic warfare. It ends by drawing attention to the writings of some critics who are troubled by the ease with which climatic reductionism is capturing the public imagination.

Analysing Web-Orchestrations Under Stress Using Uncertainty Profiles

An orchestration is a multi-threaded computation that invokes a number of remote services. In practice, the responsiveness of a web-service fluctuates with demand; during surges in activity service responsiveness may be degraded, perhaps even to the point of failure. An uncertainty profile formalizes a user's perception of the effects of stress on an orchestration of web-services; it describes a strategic situation, modelled by a zero-sum angel–daemon game. Stressed web-service scenarios are analysed, using game theory, in a realistic way, lying between over-optimism (services are entirely reliable) and over-pessimism (all services are broken). The ‘resilience’ of an uncertainty profile can be assessed using the valuation of its associated zero-sum game. In order to demonstrate the validity of the approach, we consider two measures of resilience and a number of different stress models. It is shown how (i) uncertainty profiles can be ordered by risk (as measured by game valuations) and (ii) the structural properties of risk partial orders can be analysed.

Plasmid DNA damage following exposure to atmospheric pressure non-thermal plasma: kinetics and influence of oxygen admixture

The nature and kinetics of plasmid DNA damage after DNA exposure to a kHz-driven atmospheric pressure nonthermal plasma jet has been investigated. Both single-strand break (SSB) and double-strand break (DSB) processes are reported here. While SSB had a higher rate constant, DSB is recognized to be more significant in living systems, often resulting in loss of viability. In a helium-operated plasma jet, adding oxygen to the feed gas resulted in higher rates of DNA DSB, which increased linearly with increasing oxygen content, up to an optimum level of 0.75% oxygen, after which the DSB rate decreased slightly, indicating an essential role for reactive oxygen species in the rapid degradation of DNA.

EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients

BACKGROUND: Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation.

METHODS: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response).

RESULTS: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P < 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS.

CONCLUSION: This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer.

Navigating the Borderlands: Brian McGilloway as Contemporary Cartographer of the Liminal in the Ulster Landscape

Set in the borderlands between Letterkenny and Derry-Londonderry, a landscape scarred by geological fold, river and cartographer’s pen, the Ulster crime novelist Brian McGilloway chronicles the hopes and fears of a contemporary society unable to escape a complicated history, redolent and entwined with the voices of its ‘ghosts of its past.’ Through his choice of chief protagonist, An Garda Síochána officer Benedict Devlin, McGilloway turns detective to critically investigate the both the seemingly straightforward and the unseen dwelling in the rural Ulster landscape. Following in the footsteps of Nordic and Tartan Noir in making commentary on current societ,y McGilloway recognises the importance of the past in trying to reach an understanding of the present. His critique however goes beyond criminal behaviour motivated primarily by politics or religion, allowing a deeper and more meaningful diagnosis of the ‘state of the nation’. Place, name and event become especially important in contextualising the liminality of McGilloway’s real rural border settings. In doing so, McGilloway continues in the rich tradition of Ulster poet such as Heaney, MacNiece, Muldoon and Hewitt in trying to rationalise the man-made amidst the elemental in the land of both the ‘Planter & The Gael.’ History, language, tradition and the sacral are all instruments of investigation in helping McGilloway present a revealing pathology and atlas of our times to his readers. Turning literary investigator, the author contends that there is much to learn from this physiography, not just for the borderlands region, but for the wider countryside and society beyond. Keywords Cultural Atlas, Crime Fiction, Place, Poetry, Rural.

Biomass-derived oxymethylene ethers as diesel additives: A techno-economic assessment

Conversion of agricultural biomass such as wood chips, wheat straw and forest residue for the production of fuels can help in reducing GHG emissions since they are considered as nearly carbon neutral. Around the world there is a significant amount of forest and agricultural-biomass available which could be used for the production of liquid fuels that can be blended with the petroleum-based diesel. Oxymethylene ethers (OMEs) can be derived from biomass via gasification, water-gas shift reaction and methanol production. The addition of OMEs to conventional diesel fuel has great potential to reduce soot formation during the combustion in diesel engines. Unlike methanol and dimethyl ether (DMM) which can also reduce soot formation, the physical properties of OMEs allow the use in modern diesel engines without significant change of the engines infrastructure. In this study, a detailed and data intensive process simulation model was developed to simulate all the unit operations involved in the production of OMEs from biomass. The unit operation considered include biomass drying, gasification, gas cleaning, water gas shift reaction, methanol production and OMEs synthesis. The simulation results were then utilized to conduct a detailed techno-economic assessment study of the whole biomass conversion chain to determine the most attractive pathways for OMEs production. Our recent study shows that the key parameters affecting the OMEs production are equivalence ratio, H2/CO ratio and optimal air flow. Overall, the cost of production ($/liter) of OMEs from different biomass feedstock in Alberta will be determined