MicroRNA-330-5p as a putative modulator of neoadjuvant chemoradiotherapy sensitivity in oesophageal adenocarcinoma

Oesophageal adenocarcinoma (OAC) is the sixth most common cause of cancer deaths worldwide, and the 5-year survival rate for patients diagnosed with the disease is approximately 17%. The standard of care for locally advanced disease is neoadjuvant chemotherapy or, more commonly, combined neoadjuvant chemoradiation therapy (neo-CRT) prior to surgery. Unfortunately, ~60-70% of patients will fail to respond to neo-CRT. Therefore, the identification of biomarkers indicative of patient response to treatment has significant clinical implications in the stratification of patient treatment. Furthermore, understanding the molecular mechanisms underpinning tumour response and resistance to neo-CRT will contribute towards the identification of novel therapeutic targets for enhancing OAC sensitivity to CRT. MicroRNAs (miRNA/miR) function to regulate gene and protein expression and play a causal role in cancer development and progression. MiRNAs have also been identified as modulators of key cellular pathways associated with resistance to CRT. Here, to identify miRNAs associated with resistance to CRT, pre-treatment diagnostic biopsy specimens from patients with OAC were analysed using miRNA-profiling arrays. In pre-treatment biopsies miR-330-5p was the most downregulated miRNA in patients who subsequently failed to respond to neo-CRT. The role of miR-330 as a potential modulator of tumour response and sensitivity to CRT in OAC was further investigated in vitro. Through vector-based overexpression the E2F1/p-AKT survival pathway, as previously described, was confirmed as a target of miR-330 regulation. However, miR-330-mediated alterations to the E2F1/p-AKT pathway were insufficient to significantly alter cellular sensitivity to chemotherapy (cisplatin and 5-flurouracil). In contrast, silencing of miR-330-5p enhanced, albeit subtly, cellular resistance to clinically relevant doses of radiation. This study highlights the need for further investigation into the potential of miR-330-5p as a predictive biomarker of patient sensitivity to neo-CRT and as a novel therapeutic target for manipulating cellular sensitivity to neo-CRT in patients with OAC

Increase in type A virus particles induced in BALB/c mouse epidermis during chemical carcinogenesis.

Electron microscopic observations of normal BALB/c mouse epidermis revealed the presence of isolated intracisternal A particles. Hyperplasia, papilloma and carcinoma formation induced by topical application of the carcinogenic polycyclic hydrocarbons benz(a)pyrene (B(a)P) and 3-methylcholanthrene (MC) is accompanied by an increase in the mumber of A particles. Topical application of a non-carcinogenic irritant alpha-pinene (alpha P) failed to provide comparable changes. Examination of the nuclei indicated occasional electron dense granules in the nucleoplasm which became more common throughout the progression of carcinogenesis

C-type and intracisternal A-type virus particles during epidermal carcinogenesis by tobacco smoke condensate in BALB/c mice.

Electron microscopic observations of sequential stages of skin carcinogenesis induced by tobacco smoke condensate (SC) and a cyclohexane fraction of tobacco smoke condensate (G) revealed an increase in incidence of intracisternal A particles within the epidermal cells. Tumours induced by SC also contained C-type particles, but these were not seen in G-induced tumours or after irritant or solvent treatment. There was no evidence of an increase in intracisternal A particles after irritant or solvent treatment. A direct relationship between the proliferation of A particles and neoplastic growth of BALB/c mouse epidermis appears likely. The data suggest possible activation of a latent C-type virus by SC

A downward revision to the distance of the 1806-20 cluster and associated magnetar from Gemini near-Infrared spectroscopy

We present H- and K-band spectroscopy of OB and Wolf-Rayet (WR) members of the Milky Way cluster 1806-20 (G10.0-0.3), to obtain a revised cluster distance of relevance to the 2004 giant flare from the SGR 1806-20 magnetar. From GNIRS spectroscopy obtained with Gemini South, four candidate OB stars are confirmed as late O/early B supergiants, while we support previous mid WN and late WC classifications for two WR stars. Based upon an absolute Ks-band magnitude calibration for B supergiants and WR stars, and near-IR photometry from NIRI at Gemini North plus archival VLT/ISAAC datasets, we obtain a cluster distance modulus of 14.7+/-0.35 mag. The known stellar content of the 1806-20 cluster suggests an age of 3-5 Myr, from which theoretical isochrone fits infer a distance modulus of 14.7+/-0.7 mag. Together, our results favour a distance modulus of 14.7+/-0.4 mag (8.7^+1.8_-1.5 kpc) to the 1806-20 cluster, which is significantly lower than the nominal 15 kpc distance to the magnetar. For our preferred distance, the peak luminosity of the December 2004 giant flare is reduced by a factor of three to 7 X 10^46 erg/s, such that the contamination of BATSE short gamma ray bursts (GRB's) from giant flares of extragalactic magnetars is reduced to a few percent. We infer a magnetar progenitor mass of ~48^+20_-8 Msun, in close agreement with that obtained recently for the magnetar in Westerlund 1.Comment: 6 pages, 4 figures, accepted for MNRAS Letter

'I would rather die': reasons given by 16-year-olds for not continuing their study of mathematics

Improving participation rates in specialist mathematics after the subject ceases to be compulsory at age 16 is part of government policy in England. This article provides independent and recent support for earlier findings concerning reasons for non- participation, based on free response and closed items in a questionnaire with a sample of over 1500 students in 17 schools, close to the moment of choice. The analysis supports findings that perceived difficulty and lack of confidence are important reasons for students not continuing with mathematics, and that perceived dislike and boredom, and lack of relevance, are also factors. There is a close relationship between reasons for non-participation and predicted grade, and a weaker relation to gender. An analysis of the effects of schools, demonstrates that enjoyment is the main factor differentiating schools with high and low participation indices. Building on discussion of these findings, ways of improving participation are briefly suggested

Robotic automation in computer controlled polishing

We first present a Case Study – the manufacture of 1.4 m prototype mirror-segments for the European Extremely Large Telescope, undertaken by the National Facility for Ultra Precision Surfaces, at the OpTIC facility operated by Glyndwr University. Scale-up to serial-manufacture demands delivery of a 1.4 m off-axis aspheric hexagonal segment with surface precision < 10 nm RMS every four days, compared with a typical year or more for an one-off part. This requires a radically-new approach to large optics fabrication, which will inevitably propagate into wider industrial optics. We report on how these ambitious requirements have stimulated an investigation into the synergy between robots and computer numerically controlled (‘CNC’) polishing machines for optical fabrication. The objective was not to assess which is superior. Rather, it was to understand for the first time their complementary properties, leading us to operate them together as a unit, integrated in hardware and software. Three key areas are reported. First is the novel use of robots to automate currently-manual operations on CNC polishing machines, to improve work-throughput, mitigate risk of damage to parts, and reduce dependence on highly-skilled staff. Second is the use of robots to pre-process surfaces prior to CNC polishing, to reduce total process time. The third draws the threads together, describing our vision of the automated manufacturing cell, where the operator interacts at cell rather than machine level. This promises to deliver a step-change in end-to-end manufacturing times and costs, compared with either platform used on its own or, indeed, the state-of-the-art used elsewhere

The role of robotics in computer controlled polishing of large and small optics

Following formal acceptance by ESO of three 1.4m hexagonal off-axis prototype mirror segments, one circular segment, and certification of our optical test facility, we turn our attention to the challenge of segment mass-production. In this paper, we focus on the role of industrial robots, highlighting complementarity with Zeeko CNC polishing machines, and presenting results using robots to provide intermediate processing between CNC grinding and polishing. We also describe the marriage of robots and Zeeko machines to automate currently manual operations; steps towards our ultimate vision of fully autonomous manufacturing cells, with impact throughout the optical manufacturing community and beyond

Effect of magnetic state on the γ−α\gamma -\alpha transition in iron: First-principle calculations of the Bain transformation path

Energetics of the fcc ($\gamma$) - bcc ($\alpha$) lattice transformation by the Bain tetragonal deformation is calculated for both magnetically ordered and paramagnetic (disordered local moment) states of iron. The first-principle computational results manifest a relevance of the magnetic order in a scenario of the $\gamma$ - $\alpha$ transition and reveal a special role of the Curie temperature of $\alpha$-Fe, $T_C$, where a character of the transformation is changed. At a cooling down to the temperatures $T < T_C$ one can expect that the transformation is developed as a lattice instability whereas for $T > T_C$ it follows a standard mechanism of creation and growth of an embryo of the new phase. It explains a closeness of $T_C$ to the temperature of start of the martensitic transformation, $M_s$.Comment: 4 pages, 3 figures, submitted in Phys. Rev. Letter

Contacting the spirits of the dead: paranormal belief and the teenage worldview

A number of previous studies have examined both the overall level of belief expressed by young people in the paranormal and the major demographic predictors of such belief. Building on this research tradition, the present study examines how one specific paranormal belief concerning contact with the spirits of the dead integrates with the wider teenage worldview. Data provided by 33,982 pupils age 13 to 15 years throughout England and Wales demonstrated that almost one in three young people (31%) believed that it is possible to contact the spirits of the dead. Compared with young people who did not share this belief, the young people who believed in the possibility of contacting the spirits of the dead displayed lower psychological wellbeing, higher anxiety, greater isolation, greater alienation, less positive social attitudes, and less socially conforming lifestyles. Overall, paranormal beliefs seem to be associated with a less healthy worldview, in both personal and social terms