Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes

Germline TP53 mutations result in cancer proneness syndromes known as Li-Fraumeni, Li-Fraumeni-like, and nonsyndromic predisposition with or without family history. To explore genotype/phenotype associations, we previously adopted a functional classification of all germline TP53 mutant alleles based on transactivation. Severe deficiency (SD) alleles were associated with more severe cancer proneness syndromes, and a larger number of tumors, compared with partial deficiency (PD) alleles. Because mutant p53 can exert dominant-negative (DN) effects, we addressed the relationship between DN and clinical manifestations. We reasoned that DN effects might be stronger in familial cancer cases associated with germline TP53 mutations, where mutant alleles coexist with the wild-type allele since conception. We examined 104 p53 mutant alleles with single amino acid substitutions described in the IARC germline database for (i) transactivation capability and (ii) capacity to reduce the activity of the wild-type allele (i.e., DN effect) using a quantitative yeast-based assay. The functional classifications of p53 alleles were then related to clinical variables. We confirmed that a classification based on transactivation alone can identify familial cancer cases with more severe clinical features. Classification based on DN effects allowed us to highlight similar associations but did not reveal distinct clinical subclasses of SD alleles, except for a correlation with tumor tissue prevalence. We conclude that in carriers of germline TP53 mutations transactivation-based classification of TP53 alleles appears more important for genotype/phenotype correlations than DN effects and that haplo-insufficiency of the TP53 gene is an important factor in cancer proneness in humans.     

Assessing the impact of misclassification error on an epidemiological association between two helminthic infections

Background

Polyparasitism can lead to severe disability in endemic populations. Yet, the association between soil-transmitted helminth (STH) and the cumulative incidence of Schistosoma japonicum infection has not been described. The aim of this work was to quantify the effect of misclassification error, which occurs when less than 100% accurate tests are used, in STH and S. japonicum infection status on the estimation of this association.

Methodology/Principal Findings

Longitudinal data from 2276 participants in 50 villages in Samar province, Philippines treated at baseline for S. japonicum infection and followed for one year, served as the basis for this analysis. Participants provided 1–3 stool samples at baseline and 12 months later (2004–2005) to detect infections with STH and S. japonicum using the Kato-Katz technique. Variation from day-to-day in the excretion of eggs in feces introduces individual variations in the sensitivity and specificity of the Kato-Katz to detect infection. Bayesian logit models were used to take this variation into account and to investigate the impact of misclassification error on the association between these infections. Uniform priors for sensitivity and specificity of the diagnostic test to detect the three STH and S. japonicum were used. All results were adjusted for age, sex, occupation, and village-level clustering. Without correction for misclassification error, the odds ratios (ORs) between hookworm, Ascaris lumbricoides, and Trichuris trichiura, and S. japonicum infections were 1.28 (95% Bayesian credible intervals: 0.93, 1.76), 0.91 (95% BCI: 0.66, 1.26), and 1.11 (95% BCI: 0.80, 1.55), respectively, and 2.13 (95% BCI: 1.16, 4.08), 0.74 (95% BCI: 0.43, 1.25), and 1.32 (95% BCI: 0.80, 2.27), respectively, after correction for misclassification error for both exposure and outcome.

Conclusions/Significance

The misclassification bias increased with decreasing test accuracy. Hookworm infection was found to be associated with increased 12-month cumulative incidence of S. japonicum infection after correction for misclassification error. Such important associations might be missed in analyses which do not adjust for misclassification errors.     

Out-of-field neutron and leakage photon exposures and the associated risk of second cancers in high-energy photon radiotherapy: current status

Determination and understanding of out-of-field neutron and photon doses in accelerator-based radiotherapy is an important issue since linear accelerators operating at high energies (>10 MV) produce secondary radiations that irradiate parts of the patient's anatomy distal to the target region, potentially resulting in detrimental health effects. This paper provides a compilation of data (technical and clinical) reported in the literature on the measurement and Monte Carlo simulations of peripheral neutron and photon doses produced from high-energy medical linear accelerators and the reported risk and/or incidence of second primary cancer of tissues distal to the target volume. Information in the tables facilitates easier identification of (1) the various methods and measurement techniques used to determine the out-of-field neutron and photon radiations, (2) reported linac-dependent out-of-field doses, and (3) the risk/incidence of second cancers after radiotherapy due to classic and modern treatment methods. Regardless of the measurement technique and type of accelerator, the neutron dose equivalent per unit photon dose ranges from as low as 0.1 mSv/Gy to as high as 20.4 mSv/Gy. This radiation dose potentially contributes to the induction of second primary cancer in normal tissues outside the treated area.     

Preclinical studies of porfiromycin as an adjunct to radiotherapy

The bioreductive alkylating agent porfiromycin (POR) is more toxic to EMT6 cells that are hypoxic at the time of treatment than to aerobic cells. The toxicity of POR to hypoxic EMT6 cells in vitro was similar to that of mitomycin C (MC): the aerobic toxicity of POR was considerably less than that of MC. Treatment of cells in vitro with POR before and during irradiation did not sensitize either hypoxic or aerobic cells to X rays; instead, only additive cytotoxicity was produced. In contrast, treatment of solid EMT6 tumors in vivo with POR plus radiation produced supra-additive cytotoxicity, as assessed by analyses of the complete dose-response curves for the killing of tumor cells by radiation alone or by POR alone. The supra-additivity of the combination regimens appeared to reflect the preferential killing by each agent of those tumor cells which were in an environment conferring resistance to the other agent. In contrast, combinations of POR and X rays produced only additive cytotoxicities to marrow CFU-GM. Supra-additive antineoplastic effects were obtained at doses of POR which produced little hematologic or other host toxicity. The complementary cytotoxicities of radiation and POR to cells in different microenvironments in solid tumors and the absence of a similar effect in normal tissue make optimized regimens combining radiotherapy and POR unusually promising for the treatment of solid tumors.     

Polyploid formation pathways have an impact on genetic rearrangements in resynthesized Brassica napus

? Polyploids can be produced by the union of unreduced gametes or through somatic doubling of F(1) interspecific hybrids. The first route is suspected to produce allopolyploid species under natural conditions, whereas experimental data have only been thoroughly gathered for the latter. ? We analyzed the meiotic behavior of an F(1) interspecific hybrid (by crossing Brassica oleracea and B.rapa, progenitors of B.napus) and the extent to which recombined homoeologous chromosomes were transmitted to its progeny. These results were then compared with results obtained for a plant generated by somatic doubling of this F? hybrid (CD.S?) and an amphidiploid (UG.S?) formed via a pathway involving unreduced gametes; we studied the impact of this method of polyploid formation on subsequent generations. ? This study revealed that meiosis of the F? interspecific hybrid generated more gametes with recombined chromosomes than did meiosis of the plant produced by somatic doubling, although the size of these translocations was smaller. In the progeny of the UG.S? plant, there was an unexpected increase in the frequency at which the C1 chromosome was replaced by the A1 chromosome. ? We conclude that polyploid formation pathways differ in their genetic outcome. Our study opens up perspectives for the understanding of polyploid origins.     

Optimal weekly scheduling in fractionated radiotherapy: effect of an upper bound on the dose fraction size

This work concerns the optimization of the dose fractionation for cancer radiotherapy schedules of the kind one fraction/day, five fractions/week, assuming a fixed overall treatment time. Constraints are set to limit the radiation damages to surrounding normal tissues, as well as the daily fraction size. The response to radiation of tumour and normal tissues is represented by the classical LQ model, including the exponential repopulation term. We provide a framework to analytically determine the optimal weekly scheme of radiation doses as a function of the tumour type, the fraction upper bound and the normal tissue parameters. For a comparison with the literature, we present some numerical examples of optimal treatment schedules for specific tumour types.     

Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma.

OBJECTIVE--To assess the risk of second brain tumour in patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. DESIGN--Long term follow up of a cohort of patients with pituitary adenoma and comparison of tumour occurrence with population incidence rates. SETTING--The Royal Marsden Hospital. SUBJECTS--334 patients with pituitary adenoma treated with conservative surgery and radiotherapy (median dose 45 Gy) and followed up for 3760 person years. MAIN OUTCOME MEASURES--Second intracranial tumour and systemic malignancy. RESULTS--Five patients developed a second brain tumour: two had astrocytoma, two meningioma, and one meningeal sarcoma. The cumulative risk of developing a second brain tumour over the first 10 years after treatment was 1.3% (95% confidence interval 0.4% to 3.9%) and over 20 years 1.9% (0.7% to 5.0%). The relative risk of a second brain tumour compared with the incidence in the normal population was 9.38 (3.05 to 21.89). There was no excess risk of any other type of second primary malignancy. CONCLUSIONS--There is an increased risk of second intracranial tumour in patients with pituitary adenoma treated with surgery and radiotherapy. Although radiation is likely to be the most important factor contributing to the excess risk, further study is required in a cohort of similar patients not receiving radiation.     

A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers

BACKGROUND: Nearly 20 types of cancer have been found to be inversely correlated with solar ultraviolet-B (UVB) levels determined geographically in ecologic studies, assuming that personal solar UVB irradiances were directly related to July solar UVB doses. This assumption has been questioned. METHODS: Rates of second cancer after diagnosis of nonmelanoma skin cancer (NMSC) from the literature were used in linear regression analyses. The risk modification of NMSC due to smoking was accounted for by comparing second cancer risk ratios (RRs) with lung cancer RRs in regression analysis for each cancer. RESULTS: For a diagnosis of squamous cell carcinoma, RRs for subsequent colon, gastric, and rectal cancers were significantly reduced, with that for renal cancer being marginally insignificant. For NMSC, RRs for cervical, esophageal, gastric, and rectal cancer were significantly reduced; those for colon and gallbladder cancer were marginally insignificant, while those for female breast, laryngeal, ovarian, renal, and uterine corpus cancers were insignificantly reduced; RRs for lip and salivary gland cancers and melanoma were significantly increased. Melanoma was inversely correlated with lung cancer. CONCLUSION: These results provide nearly direct evidence that solar UVB irradiance reduces the risk of many internal cancers. The likely mechanism is production of Vitamin D.     

Evaluating the epidemiological impact of national control programmes for helminths

During the past decade, there has been renewed commitment to programmes for helminth control, and several international initiatives have been launched. Scientific evaluation of large-scale interventions to reduce the incidence of infection and associated morbidity and mortality is vital, not only to demonstrate health benefits, but also to assess cost-effectiveness to show that monies from donor agencies have been used wisely. Using the example of schistosomiasis, this article outlines a framework for the evaluation of the impact of national control programmes, highlighting the important epidemiological and practical issues that must be addressed.     

Further studies on the month-of-birth effect on body size: Rural schoolchildren and an animal model

A previous study (Henneberg and Louw: Am. J. Hum. Biol. 2:227–233, 1990) showed that urban schoolchildren born between August and January were taller and heavier by 13 to 17% of the standard deviation (S) than those born in February to July. The study is now extended to 1,522 impoverished rural schoolchildren from the Little Karoo district of S. Africa and to 804 German Shepherd dogs kennelled at a breeding station in the Transvaal. The dogs provided a quasi-experimental model because for all of them nutrition and living conditions were practically identical throughout the year. The month-of-birth effect in the body weight of dogs was found to be stronger than that in urban children: dogs born between August and January were heavier by 22% of S than those born in February through July. In rural children the effect is present, but its magnitude is somewhat less and the peak is shifted by 2–3 months. Children born in May through October are 11% of S lighter than those born in November through April. It seems that living conditions characteristic of extreme poverty tend to diminish the effect. In both the animal model and rural children the month-of-birth effect decreases with advancing age and is more pronounced in males than in females. These findings are in agreement with previous observations in urban children from Cape Town. Since the living conditions of dogs and humans differ, as do the climatic conditions of Cape Town, Little Karoo and the Transvaal, it is surmised that the similarity of the effect may result from factors influencing the entire planet in a uniform way. © 1993 Wiley-Liss, Inc.     

Occupational epidemiological study of workers in an acrylonitrile using factory with particular attention to cancers and birth defects

An occupational epidemiological study was organised among workers in an acrylonitrile using factory in Hungary. Of the 888 workers, 783 were included in the study and three groups were differentiated: Group A (N = 452) with direct and continuous exposure, Group B (N = 171) with direct but occasional exposure and Group C (N = 160) without direct exposure, as referent. There were two main objectives: to determine the occurrence of cancer in workers and congenital abnormalities in their liveborn infants. The study did not indicate a higher occurrence of cancer among workers: only one lung cancer patient was found, prostate cancer did not occur. Among congenital abnormalities, the group of specified multiple congenital abnormalities showed a higher rate than expected but characteristic defect-pattern was not found among seven multimalformed babies, though five had cardiovascular malformations. In conclusion, our study did not indicate the carcinogenic, mutagenic and teratogenic effect of acrylonitrile among workers using this chemical in the factory.     

A cautionary comment on the generation of Berkson error in epidemiological studies

Exposure measurement error can be seen as one of the most important sources of uncertainty in studies in epidemiology. When the aim is to assess the effects of measurement error on statistical inference or to compare the performance of several methods for measurement error correction, it is indispensable to be able to generate different types of measurement error. This paper compares two approaches for the generation of Berkson error, which have recently been applied in radiation epidemiology, in their ability to generate exposure data that satisfy the properties of the Berkson model. In particular, it is shown that the use of one of the methods produces results that are not in accordance with two important properties of Berkson error.     

Penicillin: the medicine with the greatest impact on therapeutic outcomes

The principal point of this paper is that the discovery of penicillin and the development of the supporting technologies in microbiology and chemical engineering leading to its commercial scale production represent it as the medicine with the greatest impact on therapeutic outcomes. Our nomination of penicillin for the top therapeutic molecule rests on two lines of evidence concerning the impact of this event: (1) the magnitude of the therapeutic outcomes resulting from the clinical application of penicillin and the subsequent widespread use of antibiotics and (2) the technologies developed for production of penicillin, including both microbial strain selection and improvement plus chemical engineering methods responsible for successful submerged fermentation production. These became the basis for production of all subsequent antibiotics in use today. These same technologies became the model for the development and production of new types of bioproducts (i.e., anticancer agents, monoclonal antibodies, and industrial enzymes). The clinical impact of penicillin was large and immediate. By ushering in the widespread clinical use of antibiotics, penicillin was responsible for enabling the control of many infectious diseases that had previously burdened mankind, with subsequent impact on global population demographics. Moreover, the large cumulative public effect of the many new antibiotics and new bioproducts that were developed and commercialized on the basis of the science and technology after penicillin demonstrates that penicillin had the greatest therapeutic impact event of all times.     

Litter stoichiometric traits have stronger impact on humification than environment conditions in an alpine treeline ecotone

Plant and Soil - Litter humification is vital for carbon sequestration in terrestrial ecosystems. Probing the litter humification of treeline ecotone will be helpful to understand soil carbon...