The real war on cancer: the evolutionary dynamics of cancer suppression.

Cancer is a disease of multicellular animals caused by unregulated cell division. The prevailing model of cancer (multistage carcinogenesis) is based on the view that cancer results after a series of (generally somatic) mutations that knock out the genetic mechanisms suppressing unregulated cell growth. The chance of these mutations occurring increases with size and longevity, leading to Peto's paradox: why don't large animals have a higher lifetime incidence of cancer than small animals? The solution to this paradox is evolution. From an evolutionary perspective, an increasing frequency of prereproductive cancer deaths results in natural selection for enhanced cancer suppression. The expected result is a prereproductive risk of cancer across species that is independent of life history. However, within species, we still expect cancer risk to increase with size and longevity. Here, I review the evolutionary model of cancer suppression and some recent empirical evidence supporting it. Data from humans and domestic dogs confirm the expected intraspecific association between size and cancer risk, while results from interspecific comparisons between rodents provide the best evidence to date of the predicted recruitment of additional cancer suppression mechanisms as species become larger or longer lived

The expression of tumour suppressors and proto-oncogenes in tissues susceptible to their hereditary cancers.

BackgroundStudies of familial cancers have found that only a small subset of tissues are affected by inherited mutations in a given tumour suppressor gene (TSG) or proto-oncogene (POG), even though the mutation is present in all tissues. Previous tests have shown that tissue specificity is not due to the presence vs absence of gene expression, as TSGs and POGs are expressed in nearly every type of normal human tissue. Using published microarray expression data we tested the related hypothesis that tissue-specific expression of a TSG or POG is highest in tissue where it is of oncogenic importance.MethodsWe tested this hypothesis by examining whether individual TSGs and POGs had higher expression in the normal (noncancerous) tissues where they are implicated in familial cancers relative to those tissues where they are not. We examined data for 15 TSGs and 8 POGs implicated in familial cancer across 12 human tissue types.ResultsWe found a significant difference between expression levels in susceptible vs nonsusceptible tissues. It was found that 9 (60%, P<0.001) of the TSGs and 5 (63%, P<0.001) of the POGs had their highest expression level in the tissue type susceptible to their oncogenic effect.ConclusionsThis highly significant association supports the hypothesis that mutation of a specific TSG or POG is likely to be most oncogenic in the tissue where the gene has its highest level of expression. This suggests that high expression in normal tissues is a potential marker for linking cancer-related genes with their susceptible tissues

Host and symbiont genetic contributions to fitness in a Trichogramma-Wolbachia symbiosis.

The fitness effects associated with Wolbachia infection have wide-ranging ecological and evolutionary consequences for host species. How these effects are modulated by the relative influence of host and Wolbachia genomes has been described as a balancing act of genomic cooperation and conflict. For vertically transmitted symbionts, like cytoplasmic Wolbachia, concordant host-symbiont fitness interests would seem to select for genomic cooperation. However, Wolbachia's ability to manipulate host reproductive systems and distort offspring sex ratios presents an evolutionary conflict of interest with infected hosts. In the parthenogenesis-inducing (PI) form of Wolbachia found in many haplodiploid insects, Wolbachia fitness is realized through females and is enhanced by their feminization of male embryos and subsequent parthenogenetic reproduction. In contrast, as long as Wolbachia is not fixed in a population and sexual reproduction persists, fitness for the host species is realized through both male and female offspring production. How these cooperating and competing interests interact and the relative influence of host and Wolbachia genomes were investigated in the egg parasitoid Trichogramma kaykai, where Wolbachia infection has remained at a low frequency in the field. A factorial design in which laboratory cultures of Wolbachia-infected T. kaykai were cured and re-infected with alternative Wolbachia strains was used to determine the relative influence of host and Wolbachia genomes on host fitness values. Our results suggest fitness variation is largely a function of host genetic background, except in the case of offspring sex ratio where a significant interaction between host and Wolbachia genomes was found. We also find a significant effect associated with the horizontal transfer of Wolbachia strains, which we discuss in terms of the potential for coadaptation in PI-Wolbachia symbioses

How do the attitudes and beliefs of healthcare professionals and older people impact on the appropriate use of multi-compartment compliance aids by older people living at home

Compliance with medication regimes is a widely researched topic within the field of healthcare. Older people are considered to be a greater risk of non-compliance due to multiple morbidities. Multi-compartment compliance aids are frequently issued to older people in an attempt to improve their medicines management. This thesis aims to determine whether the attitudes and beliefs of both the older people who use MCAs and the healthcare professionals who request their use, influence the use of such devices by older people living in the community. A preliminary study which investigated the use of MCAs in primary care is described. The findings suggested that over 100,00 people in the UK may be issued with a MCA despite little evidence for their efficacy. The literature review undertaken for this thesis concludes that very few studies have been undertaken in this area and those which have are mainly of poor quality. The results from these studies failed to conclusively support the use of these devices and further rigorous conducted studies are needed. The main study comprises qualitative, in-depth semi-structured interviews with older people, who are using a MCA and healthcare professionals. The interviews were analysed using a grounded theory approach. The study revealed that older people find MCAs easy to use and convenient although a minority of the participants did experience difficulties using the device. Maintaining independence and remaining in control was important for all the older people and this influenced their attitudes towards using their MCA. The healthcare professionals concurred with the observation that MCAs were convenient to use and despite a minority stating that MCAs assisted older people to remember to take their medication, the majority acknowledged that this was not the case. The healthcare professionals agreed that the decision to issue a MCA could be seen as paternalistic however there remained a belief that the issue of a MCA would assist the older person take their medication correctly. The thesis concludes by providing details of a proposed method for undertaking a holistic, patient-centred, multi-disciplinary assessment of older people's medicines management abilities

Adherence to UK national guidance for discharge information: an audit in primary care

Aims: Poor communication of clinical information between healthcare settings is associated with patient harm. In 2008, the UK National Prescribing Centre (NPC) issued guidance regarding the minimum information to be communicated upon hospital discharge. This study evaluates the extent of adherence to this guidance and identifies predictors of adherence. Methods: This was an audit of discharge summaries received by medical practices in one UK primary care trust of patients hospitalized for 24 h or longer. Each discharge summary was scored against the applicable NPC criteria which were organized into: ‘patient, admission and discharge’, ‘medicine’ and ‘therapy change’ information. Results: Of 3444 discharge summaries audited, 2421 (70.3%) were from two teaching hospitals and 906 (26.3%) from three district hospitals. Unplanned admissions accounted for 2168 (63.0%) of the audit sample and 74.6% (2570) of discharge summaries were electronic. Mean (95% CI) adherence to the total NPC minimum dataset was 71.7% [70.2, 73.2]. Adherence to patient, admission and discharge information was 77.3% (95% CI 77.0, 77.7), 67.2% (95% CI 66.3, 68.2) for medicine information and 48.9% (95% CI 47.5, 50.3) for therapy change information. Allergy status, co-morbidities, medication history and rationale for therapy change were the most frequent omissions. Predictors of adherence included quality of the discharge template, electronic discharge summaries and smaller numbers of prescribed medicines. Conclusions: Despite clear guidance regarding the content of discharge information, omissions are frequent. Adherence to the NPC minimum dataset might be improved by using comprehensive electronic discharge templates and implementation of effective medicines reconciliation at both sides of the health interface

Predictors of outcomes in diabetic foot osteomyelitis treated initially with conservative (nonsurgical) medical management: A retrospective study

The optimal way to manage diabetic foot osteomyelitis remains uncertain, with debate in the literature as to whether it should be managed conservatively (ie, nonsurgically) or surgically. We aimed to identify clinical variables that influence outcomes of nonsurgical management in diabetic foot osteomyelitis. We conducted a retrospective study of consecutive patients with diabetes presenting to a tertiary center between 2007 and 2011 with foot osteomyelitis initially treated with nonsurgical management. Remission was defined as wound healing with no clinical or radiological signs of osteomyelitis at the initial or contiguous sites 12 months after clinical and/or radiological resolution. Nine demographic and clinical variables including osteomyelitis site and presence of foot pulses were analyzed. We identified 100 cases, of which 85 fulfilled the criteria for analysis. After a 12-month follow-up period, 54 (63.5%) had achieved remission with nonsurgical management alone with a median (interquartile range) duration of antibiotic treatment of 10.8 (10.1) weeks. Of these, 14 (26%) were admitted for intravenous antibiotics. The absence of pedal pulses in the affected foot (n = 34) was associated with a significantly longer duration of antibiotic therapy to achieve remission, 8.7 (7.1) versus 15.9 (13.3) weeks (P = .003). Osteomyelitis affecting the metatarsal was more likely to be amputated than other sites of the foot (P = .016). In line with previous data, we have shown that almost two thirds of patients presenting with osteomyelitis healed without undergoing surgical bone resection

Factors determining the risk of diabetes foot amputations - a retrospective analysis of a tertiary diabetes foot care service

Aims: To identify which factors predict the need for minor or major amputation in patients attending a multidisciplinary diabetic foot clinic. Methods: A retrospective analysis of patients who attended over a 27 month period were included. Patients had to have attended ≥3 consecutive consultant led clinic appointments within 6 months. Data was collected on HbA1c, clinic attendance, blood pressure, peripheral arterial disease (PAD), and co-morbidities. Patients were followed up for 1 year. Results: 165 patients met the inclusion criteria. 121 were male. 33 patients had amputations. There was an association between poor glycaemic control at baseline and risk of amputation when adjusted for other factors, with those patients having HbA1c ≤58 at less risk of amputation with an odds of 0.14 (0.04 to 0.53) of amputation(p = 0.0036). Other statistically significant factors predictive of amputation were: missing clinic appointments (p = 0.0079); a high Charlson index (p = 0.03314); hypertension (p = 0.0216). No previous revascularisation was protective against amputation (p = 0.0035). However PAD was not seen to be statistically significant, although our results indicated a lower risk of amputation with no PAD. Overall, 34.9% (n = 58) of patients had good glycaemic control (HbA1c <58 mmol/mol) at baseline & 81.3% (n = 135) had improved their glycaemic control at their last follow up appointment. Conclusions: In this cohort poor glycaemic control, poor attendance, previous revascularisation & hypertension were associated with higher risk of amputation, with PAD showing a trend. Moreover, we demonstrated benefits in glycaemic control achieved by attending this DFC, which is likely to translate to longer term diabetes related health benefits