Efficacy of EGFR Inhibition Is Modulated by Model, Sex, Genetic Background and Diet: Implications for Preclinical Cancer Prevention and Therapy Trials

Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR) in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies. The efficacy of the small molecule EGFR inhibitor AG1478 was evaluated using two mouse models, ApcMin/+ and azoxymethane (AOM), both sexes on three genetic backgrounds, C57BL/6J (B6) and A/J (A) inbred strains and AB6F1 hybrids, and two diets, standard chow (STD) or Western-style diet (WD). AG1478 has significant anti-tumor activity in the B6-ApcMin/+ model with STD but only moderately on the WD and in the AOM model on an A background with a WD but not STD. On the F1 hybrid background AG1478 is effective in the ApcMin/+ model with either STD or WD, but has only moderate efficacy in the AOM model with either diet. Sex differences were also observed. Unexpectedly, the level of liver EGFR phosphorylation inhibition by AG1478 was not positively correlated with inhibition of tumor growth in the AOM model. Model-dependent interactions between genetic background and diet can dramatically impact preclinical results, and indicate that low predictive values of preclinical studies can be attributed to study designs that do not account for the heterogeneous patient population or the diets they consume. Better-designed preclinical studies should lead to more accurate predictions of therapeutic response in the clinic

Factors affecting innovation and imitation of ICT in the agrifood sector

Diffusion of innovations has gained a lot of attention and concerns different scientific fields. Many studies, which examine the determining factors of technological innovations in the agricultural and agrifood sector, have been conducted using the widely used Technology Accepted Model, for a random sample of farmers or firms engaged in agricultural sector. In the present study, a holistic examination of the determining factors that affect the propensity of firms to innovate or imitate, is conducted. The diffusion of ICT tools of firms which are engaged in the NACE 02/03 as well as in the NACE 10/11 classifications for 49 heterogeneous national markets is examined, using the Bass model. The innovation parameter is positively associated with rural income, female employment, export activity and education of farmers, while the imitation parameter is increased in countries whose societies are characterized by uncertainty avoidance

The GenoChip: A New Tool for Genetic Anthropology

The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project’s new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. TheGenoChip includes ancestry informativemarkers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all knownY-chromosome andmtDNAhaplogroups. The chip was carefully vetted to avoid inclusion ofmedically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highestmean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPswithout any known health,medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics

Using visual methods to understand physical activity maintenance following cardiac rehabilitation

© 2015 Hardcastle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Few studies have explored the factors associated with long-term maintenance of exercise following cardiac rehabilitation. The present study used auto-photography and interviews to explore the factors that influence motivation and continued participation in physical activity among post cardiac rehabilitation patients. Twenty-three semi-structured interviews were conducted alongside participant-selected photographs or drawings with participants that had continued participation in physical activity for at least two years following the cardiac rehabilitation programme. Participants were recruited from circuit training classes in East Sussex in the UK. Thematic content analysis revealed seven main themes: fear of death and ill health avoidance, critical incidents, overcoming aging, social influences, being able to enjoy life, provision of routine and structure, enjoyment and psychological well-being. Fear of death, illness avoidance, overcoming aging, and being able to enjoy life were powerful motives for continued participation in exercise. The social nature of the exercise class was also identified as a key facilitator of continued participation. Group-based exercise suited those that continued exercise participation post cardiac rehabilitation and fostered adherence

Combined circular external fixation and open reduction internal fixation with pro-syndesmotic screws for repair of a diabetic ankle fracture

The surgical management of ankle fractures among the diabetic population is associated with higher complication rates compared to the general population. Efforts toward development of better methods in prevention and treatment are continuously evolving for these injuries. The presence of peripheral neuropathy and the possible development of Charcot neuroarthropathy in this high risk patient population have stimulated much surgical interest to create more stable osseous constructs when open reduction of an ankle fracture/dislocation is required. The utilization of multiple syndesmotic screws (pro-syndesmotic screws) to further stabilize the ankle mortise has been reported by many foot and ankle surgeons. In addition, transarticular Steinmann pins have been described as an adjunct to traditional open reduction with internal fixation (ORIF) of the ankle to better stabilize the talus, thus minimizing risk of further displacement, malunion, and Charcot neuroarthropathy. The authors present a unique technique of ORIF with pro-syndesmotic screws and the application of a multi-plane circular external fixator for management of a neglected diabetic ankle fracture that prevented further deformity while allowing a weight-bearing status. This technique may be utilized for the management of complex diabetic ankle fractures that are prone to future complications and possible limb loss

Rare retinal haemorrhages in translational accidental head trauma in children

PURPOSE: The characteristic findings in accidental head injury consist of linear skull fracture, epidural haematoma, localized subdural haematoma, or cortical contusion because of a linear or translational impact force. Retinal haemorrhages have been found, although uncommon, in accidental head trauma. METHODS: We performed a retrospective study of 24 consecutive cases of children with severe head injuries caused by falls. Inclusion criteria were skull fractures and/or intracranial haemorrhages documented by computerized tomography. All patients underwent a careful ophthalmic examination including dilated indirect fundoscopy within the first 48 h following admission. RESULTS: No retinal haemorrhages could be found in patients whose accidents were plausible and physical and imaging findings were compatible with reported histories. Excessive bilateral retinal haemorrhages were found in only three children with the typical signs of shaken baby syndrome. In eight children, trauma had led to orbital roof fractures. CONCLUSIONS: Retinal haemorrhages were not found in any of the patients with accidental trauma despite the severity of their head injuries. Hence, we add more evidence that there are strong differences between the ocular involvement in accidental translational trauma and those in victims of non-accidental trauma. Fall-related injuries carry a very low risk of retinal haemorrhages