Unique Features of Alarmone Metabolism in \u3ci\u3eClostridioides difficile\u3c/i\u3e

The “magic spot” alarmones (pp)pGpp, previously implicated in Clostridioides difficile antibiotic survival, are synthesized by the RelA-SpoT homolog (RSH) of C. difficile (RSHCd) and RelQCd. These enzymes are transcriptionally activated by diverse environmental stresses. RSHCd has previously been reported to synthesize ppGpp, but in this study, we found that both clostridial enzymes exclusively synthesize pGpp. While direct synthesis of pGpp from a GMP substrate, and (p)ppGpp hydrolysis into pGpp by NUDIX hydrolases, have previously been reported, there is no precedent for a bacterium synthesizing pGpp exclusively. Hydrolysis of the 5′ phosphate or pyrophosphate from GDP or GTP substrates is necessary for activity by the clostridial enzymes, neither of which can utilize GMP as a substrate. Both enzymes are remarkably insensitive to the size of their metal ion cofactor, tolerating a broad array of metals that do not allow activity in (pp)pGpp synthetases from other organisms. It is clear that while C. difficile utilizes alarmone signaling, its mechanisms of alarmone synthesis are not directly homologous to those in more completely characterized organisms

A design for cancer case–control studies using only incident cases: experience with the GEM study of melanoma

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology

A randomised controlled trial to determine the effect on response of including a lottery incentive in health surveys [ISRCTN32203485]

BACKGROUND: Postal questionnaires are an economical and simple method of data collection for research purposes but are subject to non-response bias. Several studies have explored the effect of monetary and non-monetary incentives on response. Recent meta-analyses conclude that financial incentives are an effective way of increasing response rates. However, large surveys rarely have the resources to reward individual participants. Three previous papers report on the effectiveness of lottery incentives with contradictory results. This study aimed to determine the effect of including a lottery-style incentive on response rates to a postal health survey. METHODS: Randomised controlled trial. Setting: North and West Birmingham. 8,645 patients aged 18 or over randomly selected from registers of eight general practices (family physician practices). Intervention: Inclusion of a flyer and letter with a health questionnaire informing patients that returned questionnaires would be entered into a lottery-style draw for £100 of gift vouchers. Control: Health questionnaire accompanied only by standard letter of explanation. Main outcome measures: Response rate and completion rate to questionnaire. RESULTS: 5,209 individuals responded with identical rates in both groups (62.1%). Practice, patient age, sex and Townsend score (a postcode based deprivation measure) were identified as predictive of response, with higher response related to older age, being female and living in an area with a lower Townsend score (less deprived). CONCLUSION: This RCT, using a large community based sample, found that the offer of entry into a lottery style draw for £100 of High Street vouchers has no effect on response rates to a postal health questionnaire

MC1R genotype may modify the effect of sun exposure on melanoma risk in the GEM study

We investigated whether MC1R genotype modifies the effect of sun exposure on melanoma risk in 1,018 cases with multiple melanomas (MPM) and 1,875 controls with one melanoma (SPM). There was some suggestion that MC1R genotype modified the effect of beach and water activities on MPM risk: ORs were 1.94 (95% CI 1.40–2.70) for any activities for no R variants and 1.39 (95% CI 1.05–1.84) with R variants (R151C, R160W, D294H, D84E) (p for interaction 0.08). MC1R modification of sun exposure effects appeared most evident for MPM of the head and neck: for early life ambient UV the OR was 4.23 (95% CI 1.76–10.20) with no R and 1.04 (95% CI 0.40–2.68) with R (p for interaction=0.01; p for three-way interaction=0.01). Phenotype modified the effect of sun exposure and MPM in a similar manner. We conclude that MC1R and pigmentary phenotype may modify the effects of sun exposure on melanoma risk on more continuously sun-exposed skin. Possible explanations include that risk may saturate with higher sun sensitivity for melanomas on continuously sun-exposed sites but continue to increase as sun exposure increases with lower sun sensitivity, or that sun sensitive people adapt their behaviour by increasing sun protection when exposed

Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study

Factors known to affect melanoma survival include age at presentation, sex and tumor characteristics. Polymorphisms also appear to modulate survival following diagnosis. Result from other studies suggest that vitamin D receptor (VDR) polymorphisms (SNPs) impact survival in patients with glioma, renal cell carcinoma, lung, breast, prostate and other cancers; however, a comprehensive study of VDR polymorphisms and melanoma-specific survival is lacking. We aimed to investigate whether VDR genetic variation influences survival in patients with cutaneous melanoma. The analysis involved 3566 incident single and multiple primary melanoma cases enrolled in the international population-based Genes, Environment, and Melanoma Study. Melanoma-specific survival outcomes were calculated for each of 38 VDR SNPs using a competing risk analysis after adjustment for covariates. There were 254 (7.1%) deaths due to melanoma during the median 7.6 years follow-up period. VDR SNPs rs7299460, rs3782905, rs2239182, rs12370156, rs2238140, rs7305032, rs1544410 (BsmI) and rs731236 (TaqI) each had a statistically significant (trend P values < 0.05) association with melanoma-specific survival in multivariate analysis. One functional SNP (rs2239182) remained significant after adjustment for multiple testing using the Monte Carlo method. None of the SNPs associated with survival were significantly associated with Breslow thickness, ulceration or mitosis. These results suggest that the VDR gene may influence survival from melanoma, although the mechanism by which VDR exerts its effect does not seem driven by tumor aggressiveness. Further investigations are needed to confirm our results and to understand the relationship between VDR and survival in the combined context of tumor and host characteristics

Major Radiodiagnostic Imaging in Pregnancy and the Risk of Childhood Malignancy: A Population-Based Cohort Study in Ontario

In a record-linkage study, Joel Ray and colleagues examine the association between diagnostic imaging during pregnancy and later childhood cancers

The economic pressures for biosimilar drug use in cancer medicine

The main rationale for using biosimilar drugs is for cost saving. The market development for biosimilar drugs will therefore depend on the degree to which cost saving measures are required by nations, medical insurers and individuals and the absolute savings that could be gained by switching from original drugs. This paper is designed to discover the degree to which financial constraints will drive future health spending and to discover if legal or safety issues could impact on any trend. A structured literature search was performed for papers and documents to 27 August 2011. Where multiple sources of data were available on a topic, data from papers and reports by multinational or national bodies were used in preference to data from regions or individual hospitals. Almost all health systems face current significant cost pressures. The twin driver of increasing cancer prevalence as populations age and cancer medicine costs rising faster than inflation places oncology as the most significant single cost problem. For some countries, this is predicted to make medicine unaffordable within a decade. Most developed countries have planned to embrace biosimilar use as a cost-control measure. Biosimilar introduction into the EU has already forced prices down, both the price of biosimilar drugs and competitive price reductions in originator drugs. Compound annual growth rates of use have been predicted at 65.8% per year. Most developed countries have planned to embrace biosimilar use as a major cost-control measure. Only legal blocks and safety concerns are likely to act against this trend. For centralised healthcare systems, and those with a strong tradition of generic medicine use, biosimilar use will clearly rise with predictions of more than 80% of prescriptions of some biologic drugs within 1 year of market entry in the USA. Delaying the implementation of such programmes however risks a real crisis in healthcare delivery for many countries and hospitals that few can now afford

Breast Cancer in Young Women: Poor Survival Despite Intensive Treatment

The general aim of the thesis was to gain increased insight into the long-term prognosis for young women with breast cancer. In a population-based cohort of 22,017 women with breast cancer, we studied prognosis by age. Women aged <35 (n=471), 35–39 (n=858) and 40–49 (n=4789) were compared with women aged 50–69. The cumulative 5-year relative survival ratio (RSR) and the relative excess risk (RER) of mortality were calculated. Women <35 years of age had a worse survival than middle-aged women, partly explained by a later stage at diagnosis. After correction for stage, tumor characteristics and treatment, young age remained an independent risk factor for death. The excess risk of death in young women was only present in stage I-II disease and was most pronounced in women with small tumors. For in-depth studies on a large subpopulation from the original cohort (all 471 women aged <35 and a random sample of 700 women aged 35–69), we collected detailed data from the medical records, re-evaluated slides and produced TMAs from tumor tissue. Breast cancer- specific survival (BCSS), distant disease-free survival (DDFS) and locoregional recurrence- free survival (LRFS) by age were analysed. In a multivariate analysis, age <35 and age 35– 39 years conferred a risk in LRFS but not in DDFS and BCSS. The age-related differences in prognosis were most pronounced in early stage luminal Her2-negative tumors, where low age was an independent prognostic factor also for DDFS (HR 1.87 (1.03–3.44)). To study the importance of proliferation markers for the long-term prognosis in young women, protein expression of Ki-67, cyclin A2, B1, D1 and E1 was analysed in 504 women aged <40 and in 383 women aged ≥40. The higher expression of proliferation markers in young women did not have a strong impact on the prognosis. Proliferation markers are less important in young women, and Ki-67 was prognostic only in young women with Luminal PR+ tumors. Age <40 years was an independent risk factor of DDFS exclusively in this subgroup (adjusted HR 2.35 (1.22-4.50)). The only cyclin adding prognostic value beyond subtype in young women was cyclin E1. In a cohort of 469 women aged <40 and 360 women aged ≥40 we examined whether Her2 status assessed by silver enhanced in situ hybridization (SISH) for all cases, would reveal a proportion of women undiagnosed by routine Her2 testing and whether this would affect their prognosis. With SISH testing for all women, the Her2-positive rate increased from 20.0% to 24.4% (p<0.001), and similarly for women aged <40 and ≥40 years. Young women had Her2+ breast cancer twice as often as middle-aged women. Her2 amplification was present in 4.6% of cases scored 0 with IHC, while the corresponding proportions for scores 1+, 2+ and 3+ were 36.0%, 83.7% and 96.8%, respectively. All Her2 amplified cases, both true positive and false negative, had a significantly worse BCSS than the true negative cases