Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed

Protocol for a multicentre randomised feasibility trial evaluating early Surgery Alone In LOw Rectal cancer (SAILOR)

Introduction There are 11,500 rectal cancers diagnosed annually in the UK. Although surgery remains the primary treatment there is evidence that preoperative radiotherapy (RT) improves local recurrence rates. High quality surgery in rectal cancer is equally important in minimising local recurrence. Advances in magnetic resonance imaging (MRI)-guided prediction of resection margin status and improvements in abdominoperineal excision of the rectum (APER) technique supports a reassessment of the contribution of preoperative RT. A more selective approach to RT may be appropriate given the associated toxicity. Methods and analysis This trial will explore the feasibility of a definitive trial evaluating the omission of RT in resectable low rectal cancer requiring APER. It will test the feasibility of randomising patients to i) standard care (neoadjuvant long course radiotherapy +/- chemotherapy and APER, or ii) APER surgery alone for cT2/T3ab N0/1 low rectal cancer with clear predicted resection margins on MRI. Radiotherapy schedule will be 45Gy over 5 weeks as current standard, with restaging and surgery after 8-12 weeks. Recruitment will be for 24 months with a minimum 12 month follow up. Objectives include testing the ability to recruit, consent and retain patients, to quantify the number of patients eligible for a definitive trial and to test feasibility of outcomes measures. These include locoregional recurrence rates, distance to circumferential resection margin, toxicity and surgical complications including perineal wound healing, quality of life and economic analysis. The quality of MRI staging, radiotherapy delivery and surgical specimen quality will be closely monitored. Ethics and dissemination The trial is approved by the regional ethics committee and Health Research Authority (HRA) or equivalent. Written informed consent will be obtained. Serious adverse events will be reported to Swansea Trials Unit (STU), the ethics committee and trial sites. Trial results will be submitted for peer review publication and to trial participants. Strengths and limitations of this study • A unique interventional study specific to low rectal cancer • Will explore the contribution of the modern abdominoperineal excision operation to cancer outcomes • Strict quality assurance processes for imaging, radiotherapy, surgery and pathology • Will establish if a future trial minimising radiotherapy use in low rectal cancer is feasible • Study is limited by short follow up perio

Simulation of greenhouse gases following land-use change to bioenergy crops using the ECOSSE model. A comparison between site measurements and model predictions

This article evaluates the suitability of the ECOSSE model to estimate soil greenhouse gas (GHG) fluxes from short rotation coppice willow (SRC-Willow), short rotation forestry (SRF-Scots Pine) and Miscanthus after landuse change from conventional systems (grassland and arable). We simulate heterotrophic respiration (Rh), nitrous oxide (N2O) and methane (CH4) fluxes at four paired sites in the UK and compare them to estimates of Rh derived from the ecosystem respiration estimated from eddy covariance (EC) and Rh estimated from chamber (IRGA) measurements, as well as direct measurements of N2O and CH4 fluxes. Significant association between modelled and EC-derived Rh was found under Miscanthus, with correlation coefficient (r) ranging between 0.54 and 0.70. Association between IRGA-derived Rh and modelled outputs was statistically significant at the Aberystwyth site (r = 0.64), but not significant at the Lincolnshire site (r = 0.29). At all SRC-Willow sites, significant association was found between modelled and measurement-derived Rh (0.44 ≤ r ≤ 0.77); significant error was found only for the EC-derived Rh at the Lincolnshire site. Significant association and no significant error were also found for SRF-Scots Pine and perennial grass. For the arable fields, the modelled CO2 correlated well just with the IRGA-derived Rh at one site (r = 0.75). No bias in the model was found at any site, regardless of the measurement type used for the model evaluation. Across all land uses, fluxes of CH4 and N2O were shown to represent a small proportion of the total GHG balance; these fluxes have been modelled adequately on a monthly time-step. This study provides confidence in using ECOSSE for predicting the impacts of future land use on GHG balance, at site level as well as at national level

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Capsular profiling of the Cronobacter genus and the association of specific Cronobacter sakazakii and C. malonaticus capsule types with neonatal meningitis and necrotizing enterocolitis

Background: Cronobacter sakazakii and C. malonaticus can cause serious diseases especially in infants where they are associated with rare but fatal neonatal infections such as meningitis and necrotising enterocolitis. Methods: This study used 104 whole genome sequenced strains, covering all seven species in the genus, to analyse capsule associated clusters of genes involved in the biosynthesis of the O-antigen, colanic acid, bacterial cellulose, enterobacterial common antigen (ECA), and a previously uncharacterised K-antigen. Results: Phylogeny of the gnd and galF genes flanking the O-antigen region enabled the defining of 38 subgroups which are potential serotypes. Two variants of the colanic acid synthesis gene cluster (CA1 and CA2) were found which differed with the absence of galE in CA2. Cellulose (bcs genes) were present in all species, but were absent in C. sakazakii sequence type (ST) 13 and clonal complex (CC) 100 strains. The ECA locus was found in all strains. The K-antigen capsular polysaccharide Region 1 (kpsEDCS) and Region 3 (kpsMT) genes were found in all Cronobacter strains. The highly variable Region 2 genes were assigned to 2 homology groups (K1 and K2). C. sakazakii and C. malonaticus isolates with capsular type [K2:CA2:Cell+] were associated with neonatal meningitis and necrotizing enterocolitis. Other capsular types were less associated with clinical infections. Conclusion: This study proposes a new capsular typing scheme which identifies a possible important virulence trait associated with severe neonatal infections. The various capsular polysaccharide structures warrant further investigation as they could be relevant to macrophage survival, desiccation resistance, environmental survival, and biofilm formation in the hospital environment, including neonatal enteral feeding tubes

Genetic analysis of a major international collection of cultivated apple varieties reveals previously unknown historic heteroploid and inbred relationships

Domesticated apple (Malus x domestica Borkh.) is a major global crop and the genetic diversity held within the pool of cultivated varieties is important for the development of future cultivars. The aim of this study was to investigate the diversity held within the domesticated form, through the analysis of a major international germplasm collection of cultivated varieties, the UK National Fruit Collection, consisting of over 2,000 selections of named cultivars and seedling varieties. We utilised Diversity Array Technology (DArT) markers to assess the genetic diversity within the collection. Clustering attempts, using the software STRUCTURE revealed that the accessions formed a complex and historically admixed group for which clear clustering was challenging. Comparison of accessions using the Jaccard similarity coefficient allowed us to identify clonal and duplicate material as well as revealing pairs and groups that appeared more closely related than a standard parent-offspring or full-sibling relations. From further investigation, we were able to propose a number of new pedigrees, which revealed that some historically important cultivars were more closely related than previously documented and that some of them were partially inbred. We were also able to elucidate a number of parent-offspring relationships that had resulted in a number of important polyploid cultivars. This included reuniting polyploid cultivars that in some cases dated as far back as the 18th century, with diploid parents that potentially date back as far as the 13th century

Potential climatic transitions with profound impact on Europe

We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

The impacts avoided with a 1.5 °C climate target: a global and regional assessment

The 2015 Paris Agreement commits countries to pursue efforts to limit the increase in global mean temperature to 1.5 °C above pre-industrial levels. We assess the consequences of achieving this target in 2100 for the impacts that are avoided, using several indicators of impact (exposure to drought, river flooding, heat waves and demands for heating and cooling energy). The proportion of impacts that are avoided is not simply equal to the proportional reduction in temperature. At the global scale, the median proportion of projected impacts avoided by the 1.5 °C target relative to a rise of 4 °C ranges between 62 and 95% across sectors: the greatest reduction is for heat wave impacts. The 1.5 °C target results in impacts that would be between 27 and 62% lower than with the 2 °C target. For each indicator, there are differences in the proportions of impacts avoided between regions depending on exposure and the regional changes in climate (particularly precipitation). Uncertainty in the proportion of impacts that are avoided for a specific sector depends on the range in the shape of the relationship between global temperature change and impact, and this varies between sectors