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Background: In estimating radiation-associated cancer risks a fixed period for the minimum latency is often assumed. Two empirical latency functions have been used to model latency, continuously increasing from 0. A stochastic biologically-based approach yields a still more plausible way of describing latency and can be directly estimated from clinical data., Methods: We derived the parameters for a stochastic biologically-based model from tumour growth data for various cancers, and least-squares fitted the two types of empirical latency function to the stochastic model-predicted cumulative probability., Results: There is wide variation in growth rates among tumours, particularly slow for prostate and thyroid cancer and particularly fast for leukaemia. The slow growth rate for prostate and thyroid tumours implies that the number of tumour cells required for clinical detection cannot greatly exceed 10 6 . For all tumours, both empirical latency functions closely approximated the predicted biological model cumulative probability., Conclusions: Our results, illustrating use of a stochastic biologically-based model using clinical data not tied to any particular carcinogen, have implications for estimating latency associated with any mutagen. They apply to tumour growth in general, and may be useful for example, in planning screenings for cancer using imaging techniques., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

12-0-tetradecanoylphorbol-13-acetate (TPA) stimulates protein kinase C (PKC) which mediates apoptosis in androgen-sensitive LNCaP human prostate cancer cells. The downstream signals of PKC that mediate TPA-induced apoptosis in LNCaP cells are unclear. In this study, we found that TPA activates the c-Jun NH2-terminal kinase (JNK)/c-Jun/AP-1 pathway. To explore the possible role that the JNK/c-Jun/AP-1 signal pathway has on TPA-induced apoptosis in LNCaP cells, we stably transfected the scaffold protein, JNK interacting protein 1 (JIP-1), which binds to JNK inhibiting its ability to phosphorylate c-Jun. TPA (10(-9)-10(-7) mol l(-1)) caused phosphorylation of JNK in both wild-type and JIP-1-transfected (LNCaP-JIP-1) cells. It resulted in phosphorylation and upregulation of expression of c-Jun protein in the wild-type LNCaP cells, but not in the JIP-1-transfected LNCaP cells. In addition, upregulation of AP-1 reporter activity by TPA (10(-9) mol l(-1)) occurred in LNCaP cells but was abrogated in LNCaP-JIP-1 cells. Thus, TPA stimulated c-Jun through JNK, and JIP-1 effectively blocked JNK. TPA (10(-12)-10(-8) mol l(-1)) treatment of LNCaP cells caused their growth inhibition, cell cycle arrest, upregulation of p53 and p21waf1, and induction of apoptosis. All of these effects were significantly attenuated when LNCaP-JIP-1 cells were similarly treated with TPA. A previous study showed that c-Jun/AP-1 blocked androgen receptor (AR) signaling by inhibiting AR binding to AR response elements (AREs) of target genes including prostate-specific antigen (PSA). Therefore, we hypothesised that TPA would not be able to disrupt the AR signal pathway in LNCaP-JIP-1 cells. Contrary to expectation, TPA (10(-9)-10(-8) mol l(-1)) inhibited DHT-induced AREs reporter activity and decreased levels of PSA in the LNCaP-JIP-1 cells. Taken together, TPA, probably by stimulation of PKC, phosphorylates JNK, which phosphorylates and increases expression of c-Jun leading to AP-1 activity. Growth control of prostate cancer cells can be mediated through the JNK/c-Jun pathway, but androgen responsiveness of these cells can be independent of this pathway, suggesting that androgen independence in progressive prostate cancer may not occur through activation of this pathway.

Background: Work-related cancer is an important public health issue with a large financial impact on society. The key European legislative instrument is the Carcinogens and Mutagens Directive (2004/37/EC). In preparation for updating the Directive, the European Commission commissioned a study to provide a socioeconomic, health and environmental impact assessment.Methods: The evaluation was undertaken for 25 preselected hazardous substances or mixtures. Estimates were made of the number of cases of cancer attributable to workplace exposure, both currently and in the future, with and without any regulatory interventions, and these data were used to estimate the financial health costs and benefits.Results: It was estimated that if no action is taken there will be >700 000 attributable cancer deaths over the next 60 years for the substances assessed. However, there are only seven substances where the data suggest a clear benefit in terms of avoided cancer cases from introducing a binding limit at the levels considered. Overall, the costs of the proposed interventions were very high (up to [euro ]34 000 million) and the associated monetised health benefits were mostly less than the compliance costs.Conclusions: The strongest cases for the introduction of a limit value are for: respirable crystalline silica, hexavalent chromium, and hardwood dust. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers in the western world and is characterised by deregulation of the Wnt signalling pathway. Mutation of the adenomatous polyposis coli (APC) tumour suppressor gene, which encodes a protein that negatively regulates this pathway, occurs in almost 80% of CRC cases. The progression of this cancer from an early adenoma to carcinoma is accompanied by a well-characterised set of mutations including KRAS, SMAD4 and TP53. Using elegant genetic models the current paradigm is that the intestinal stem cell is the origin of CRC. However, human histology and recent studies, showing marked plasticity within the intestinal epithelium, may point to other cells of origin. Here we will review these latest studies and place these in context to provide an up-to-date view of the cell of origin of CRC. [ABSTRACT FROM AUTHOR]

Background:Interleukin-22 (IL-22) has been recently highlighted owing to its biological significance in the modulation of tissue responses during inflammation. However, the role of IL-22 in carcinogenesis has remained unclear. Here, we investigated the pathophysiological significance of IL-22 expression in gastric cancer tissues and examined the mechanism by which IL-22 promotes gastric cancer cell invasion.Methods:Human gastric cancer specimens were analysed by immunohistochemistry for expression of IL-22 and IL-22 receptor 1 (IL-22R1). The effects of IL-22-induced STAT3 and ERK signalling on invasive ability of gastric cancer cells were examined using a small-interfering RNA system and specific inhibitors. AGS cells were co-cultured with cancer-associated fibroblasts (CAFs) from human gastric cancer tissues and assessed by invasion assay.Results:Interleukin-22 and its receptor were expressed in α-smooth muscle actin-positive stromal cells and tumour cells at the invasive front of gastric cancer tissues, respectively. The expression of IL-22 and IL-22R1 was significantly related to lymphatic invasion. Interleukin-22 treatment promoted the invasive ability of gastric cancer cells through STAT3 and ERK activation. The invasive ability of gastric cancer cells was significantly enhanced by co-culture with IL-22-expressing CAFs.Conclusions:Interleukin-22 produced by CAFs promotes gastric cancer cell invasion via STAT3 and ERK signalling. [ABSTRACT FROM AUTHOR]

Background:Many studies have indicated an important implication of radiation-induced bystander effects (RIBEs) in cancer radiotherapy, but the detailed signalling remains unclear.Methods:The roles of tumour growth factor-beta1 (TGF-β1) and miR-21 in medium-mediated RIBEs in H1299 non-small-cell lung cancer cells were investigated using DNA damage, changes in proliferation and levels of reactive oxygen species (ROS) as end points. SB431542, a specific inhibitor of TGF-β type 1 receptor kinases, was used to inhibit TGF-β1 pathways in irradiated and bystander cells. Exogenous miR-21 regulation was achieved through inhibitor or mimic transfection.Results:Compared with relative sham-radiation-conditioned medium, radiation-conditioned medium (RCM) from irradiated cells 1 h post radiation (1-h RCM) caused an increase in ROS levels and DNA damage in bystander cells, while 18-h RCM induced cell cycle delay and proliferation inhibition. All these effects were eliminated by TGF-βR1 inhibition. One-hour RCM upregulated miR-21 expression in bystander cells, and miR-21 inhibitor abolished bystander oxidative stress and DNA damage. Eighteen-hour RCM downregulated miR-21 of bystander cells, and miR-21 mimic eliminated bystander proliferation inhibition. Furthermore, the dysregulation of miR-21 was attenuated by TGF-βR1 inhibition.Conclusions:The TGF-β1-miR-21-ROS pathway of bystander cells has an important mediating role in RIBEs in H1299 cells. [ABSTRACT FROM AUTHOR]

Background:To compare different ultrasound-based international ovarian tumour analysis (IOTA) strategies and risk of malignancy index (RMI) for ovarian cancer diagnosis using a meta-analysis approach of centre-specific data from IOTA3.Methods:This prospective multicentre diagnostic accuracy study included 2403 patients with 1423 benign and 980 malignant adnexal masses from 2009 until 2012. All patients underwent standardised transvaginal ultrasonography. Test performance of RMI, subjective assessment (SA) of ultrasound findings, two IOTA risk models (LR1 and LR2), and strategies involving combinations of IOTA simple rules (SRs), simple descriptors (SDs) and LR2 with and without SA was estimated using a meta-analysis approach. Reference standard was histology after surgery.Results:The areas under the receiver operator characteristic curves of LR1, LR2, SA and RMI were 0.930 (0.917-0.942), 0.918 (0.905-0.930), 0.914 (0.886-0.936) and 0.875 (0.853-0.894). Diagnostic one-step and two-step strategies using LR1, LR2, SR and SD achieved summary estimates for sensitivity 90-96%, specificity 74-79% and diagnostic odds ratio (DOR) 32.8-50.5. Adding SA when IOTA methods yielded equivocal results improved performance (DOR 57.6-75.7). Risk of Malignancy Index had sensitivity 67%, specificity 91% and DOR 17.5.Conclusions:This study shows all IOTA strategies had excellent diagnostic performance in comparison with RMI. The IOTA strategy chosen may be determined by clinical preference. [ABSTRACT FROM AUTHOR]

Background:Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is a functional long non-coding RNA (lncRNA), which is highly expressed in several tumours, including colorectal cancer (CRC). Its biological function and mechanism in the prognosis of human CRC is still largely under investigation.Methods:This study aimed to investigate the new effect mechanism of MALAT1 on the proliferation and migration of CRC cells in vitro and in vivo, and detect the expression of MALAT1, SFPQ (also known as PSF (PTB-associated splicing factor)), and PTBP2 (also known as PTB (polypyrimidine-tract-binding protein)) in CRC tumour tissues, followed by correlated analysis with clinicopathological parameters.Results:We found that overexpression of MALAT1 could promote cell proliferation and migration in vitro, and promote tumour growth and metastasis in nude mice. The underlying mechanism was associated with tumour suppressor gene SFPQ and proto-oncogene PTBP2. In CRC, MALAT1 could bind to SFPQ, thus releasing PTBP2 from the SFPQ/PTBP2 complex. In turn, the increased SFPQ-detached PTBP2 promoted cell proliferation and migration. SFPQ critically mediated the regulatory effects of MALAT1. Moreover, in CRC tissues, MALAT1 and PTBP2 were overexpressed, both of which were associated closely with the invasion and metastasis of CRC. However, the SFPQ showed unchanged expression either in CRC tissues or adjacent normal tissues.Conclusions:Our findings implied that MALAT1 might be a potential predictor for tumour metastasis and prognosis. Furthermore, the interaction between MALAT1 and SFPQ could be a novel therapeutic target for CRC. [ABSTRACT FROM AUTHOR]

Background:Nitrate and nitrite are present in many foods and are precursors of N-nitroso compounds, known animal carcinogens and potential human carcinogens. We prospectively investigated the association between nitrate and nitrite intake from dietary sources and risk of renal cell carcinoma (RCC) overall and clear cell and papillary histological subtypes in the NIH-AARP Diet and Health Study.Methods:Nitrate and nitrite intakes were estimated from a 124-item food frequency questionnaire. Over a mean follow-up of 9 years, we identified 1816 RCC cases (n=498, clear cell; n=115, papillary cell) among 491 841 participants. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).Results:Individuals in the highest quintile of nitrite intake from animal sources compared with those in the lowest quintile, had an increased risk of total RCC and clear cell subtype (HR=1.28, 95% CI, 1.10-1.49 and HR=1.68, 95% CI, 1.25-2.27, respectively). Nitrite from processed meats and other animal sources were associated with increased clear cell adenocarcinoma risk (HR=1.33, 95% CI, 1.01-1.76 and HR=1.78, 95% CI, 1.34-2.36, respectively). We found no association for nitrite intake from plant sources or nitrate intake overall.Conclusion:Our findings suggest that nitrite from animal sources may increase the risk of RCC, particularly clear cell adenocarcinomas. [ABSTRACT FROM AUTHOR]

Background:Experimental data convincingly propose the toxic metal cadmium as a prostate carcinogen. Cadmium is widely dispersed into the environment and, consequently, food is contaminated.Methods:A population-based cohort of 41 089 Swedish men aged 45-79 years was followed prospectively from 1998 through 2009 to assess the association between food frequency questionnaire-based estimates of dietary cadmium exposure (at baseline, 1998) and incidence of prostate cancer (3085 cases, of which 894 were localised and 794 advanced) and through 2008 for prostate cancer mortality (326 fatal cases).Results:Mean dietary cadmium exposure was 19 μg per day±s.d. 3.7. Multivariable-adjusted dietary cadmium exposure was positively associated with overall prostate cancer, comparing extreme tertiles; rate ratio (RR) 1.13 (95% confidence interval (CI): 1.03-1.24). For subtypes of prostate cancer, the RR was 1.29 (95% CI: 1.08-1.53) for localised, 1.05 (95% CI: 0.87-1.25) for advanced, and 1.14 (95% CI: 0.86-1.51) for fatal cases. No statistically significant difference was observed in the multivariable-adjusted risk estimates between tumour subtypes (Pheterogeneity=0.27). For localised prostate cancer, RR was 1.55 (1.16-2.08) among men with a small waist circumference and RR 1.45 (1.15, 1.83) among ever smokers.Conclusion:Our findings provide support that dietary cadmium exposure may have a role in prostate cancer development. [ABSTRACT FROM AUTHOR]

A sound knowledge base is required to target resources to reduce workplace exposure to carcinogens. This project aimed to provide an objective estimate of the burden of cancer in Britain due to occupation. This volume presents extensive analyses for all carcinogens and occupational circumstances defined as definite or probable human occupational carcinogens by the International Agency for Research on Cancer. This article outlines the structure of the supplement - two methodological papers (statistical approach and exposure assessment), eight papers presenting the cancer-specific results grouped by broad anatomical site, a paper giving industry sector results and one discussing work-related cancer-prevention strategies. A brief summary of the methods and an overview of the updated overall results are given in this introductory paper. A general discussion of the overall strengths and limitations of the study is also presented. Overall, 8010 (5.3%) total cancer deaths in Britain and 13, 598 cancer registrations were attributable to occupation in 2005 and 2004, respectively. The importance of cancer sites such as mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma and stomach cancers are highlighted, as are carcinogens such as asbestos, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists, as well as occupational circumstances such as shift work and occupation as a painter or welder. The methods developed for this project are being adapted by other countries and extended to include social and economic impact evaluation. [ABSTRACT FROM AUTHOR]

The article reports on the occupational cancer in Great Britain that affects the respiratory cancer sites including larynx, lung and mesothelioma. It states that laryngeal cancers are squamous in origin and it originates in the glottis. Lung cancer is a common malignant neoplasm which is prevalent in men as compared to the female population. Mesothelioma is described as a form of cancer that develops from the mesothelium. A table containing information on carcinogenic agents is presented.

The article discusses the occupational cancers in Great Britain which includes liver, esophagus and stomach. It states that these cancers arise due to exposure to carcinogenic agents including asbestos, mineral oils, solar radiation and silica. It is estimated that mortality due to occupational disease in Great Britain accounts to four percents.

Although only a relatively small proportion of cancer is attributable to occupational exposure to carcinogenic agents, the estimated number of deaths due to occupational cancer is high when compared to other deaths due to work-related ill health and injury. However, risk from occupational exposure to carcinogens can be minimised through proportionate but effective risk management. The Health and Safety Executive (HSE) is the regulator of workplace health and safety in Great Britain. As part of its aim to reduce ill health arising from failures to control properly exposure to hazards at work, HSE commissioned the research presented elsewhere in this supplement to enable it to identify priorities for preventing occupational cancer. The research has shown that occupational cancer remains a key health issue and that low-level exposure of a large number of workers to carcinogens is important. The finding that a small number of carcinogens have been responsible for the majority of the burden of occupational cancer provides key evidence in the development of priorities for significant reduction of occupational cancer. Although the research presented in this supplement reflects the consequences of past exposures to carcinogens, occupational cancer remains a problem. The potential for exposure to the agents considered in this research is still present in the workplace and the findings are relevant to prevention of future disease. In this article, the principle approaches for risk reduction are described. It provides supporting information on some of the initiatives already being undertaken, or those being put in place, to reduce occupational cancer in Great Britain. The need also for systematic collection of exposure information and the importance of raising awareness and changing behaviours are discussed. [ABSTRACT FROM AUTHOR]

The article discusses occupational nasopharengeal and sinonasal cancers in Great Britain. Causal factors for these cancers include Epstein-Barr virus infection, consumption of preserved food and respiratory tract infections. Formaldehyde, wood dusts, leather dust and nickel are considered as carcinogens.

To estimate the current occupational cancer burden due to past exposures in Britain, estimates of the number of exposed workers at different levels are required, as well as risk estimates of cancer due to the exposures. This paper describes the methods and results for estimating the historical exposures. All occupational carcinogens or exposure circumstances classified by the International Agency for Research on Cancer as definite or probable human carcinogens and potentially to be found in British workplaces over the past 20-40 years were included in this study. Estimates of the number of people exposed by industrial sector were based predominantly on two sources of data, the CARcinogen EXposure (CAREX) database and the UK Labour Force Survey. Where possible, multiple and overlapping exposures were taken into account. Dose-response risk estimates were generally not available in the epidemiological literature for the cancer-exposure pairs in this study, and none of the sources available for obtaining the numbers exposed provided data by different levels of exposure. Industrial sectors were therefore assigned using expert judgement to 'higher'- and 'lower'-exposure groups based on the similarity of exposure to the population in the key epidemiological studies from which risk estimates had been selected. Estimates of historical exposure prevalence were obtained for 41 carcinogens or occupational circumstances. These include exposures to chemicals and metals, combustion products, other mixtures or groups of chemicals, mineral and biological dusts, physical agents and work patterns, as well as occupations and industries that have been associated with increased risk of cancer, but for which the causative agents are unknown. There were more than half a million workers exposed to each of six carcinogens (radon, solar radiation, crystalline silica, mineral oils, non-arsenical insecticides and 2,3,7,8-tetrachlorodibenzo-p-dioxin); other agents to which a large number of workers are exposed included benzene, diesel engine exhaust and environmental tobacco smoke. The study has highlighted several industrial sectors with large proportions of workers potentially exposed to multiple carcinogens. The relevant available data have been used to generate estimates of the prevalence of past exposure to occupational carcinogens to enable the occupational cancer burden in Britain to be estimated. These data are considered adequate for the present purpose, but new data on the prevalence and intensity of current occupational exposure to carcinogens should be collected to ensure that future policy decisions be based on reliable evidence. [ABSTRACT FROM AUTHOR]

An approach using the attributable fraction (AF) has been developed to estimate the current burden of occupational cancer in Britain. The AF combines the relative risk (RR) associated with exposure with the proportion exposed. For each cancer-exposure pairing, the RR is selected from key epidemiological literature such as an industry, or population-based study, meta-analysis or review. The CARcinogen EXposure (CAREX) database provides point estimates for the number of workers exposed to a range of carcinogens; alternative sources are national surveys such as the Labour Force Survey and Census of Employment. The number of workers exposed are split between high and low exposure levels matched to appropriate RRs from the literature. The relevant period for cancer development during which exposure occurred is defined as the risk exposure period (REP). Estimation of the numbers ever exposed over the REP takes into account the changes in the number of people employed in primary and manufacturing industry and service sectors in Britain where appropriate, and adjustment is made for staff turnover over the period and for life expectancy. National estimates of the population ever of working age during the REP are used for the proportion denominator. Strategies have been developed to combine exposure AFs correctly while avoiding double counting and minimising bias. The AFs are applied to national cancer deaths and registrations to obtain occupation-attributable cancer numbers. The methods are adaptable for other diseases and other geographies, and are also adaptable to more sophisticated modelling if better exposure and dose-response data are available. [ABSTRACT FROM AUTHOR]

The AKT signalling pathway is a major regulator of protein synthesis that impinges on multiple cellular processes frequently altered in cancer, such as proliferation, cell growth, survival, and angiogenesis. AKT controls protein synthesis by regulating the multistep process of mRNA translation at every stage from ribosome biogenesis to translation initiation and elongation. Recent studies have highlighted the ability of oncogenic AKT to drive cellular transformation by altering gene expression at the translational level. Oncogenic AKT signalling leads to both global changes in protein synthesis as well as specific changes in the translation of select mRNAs. New and developing technologies are significantly advancing our ability to identify and functionally group these translationally controlled mRNAs into gene networks based on their modes of regulation. How oncogenic AKT activates ribosome biogenesis, translation initiation, and translational elongation to regulate these translational networks is an ongoing area of research. Currently, the majority of therapeutics targeting translational control are focused on blocking translation initiation through inhibition of eIF4E hyperactivity. However, it will be important to determine whether combined inhibition of ribosome biogenesis, translation initiation, and translation elongation can demonstrate improved therapeutic efficacy in tumours driven by oncogenic AKT. [ABSTRACT FROM AUTHOR]

Background: Occupational exposures to dusts have generally been examined in relation to cancers of the respiratory system and have rarely been examined in relation to other cancers, such as renal cell carcinoma (RCC). Although previous epidemiological studies, though few, have shown certain dusts, such as asbestos, to increase renal cancer risk, the potential for other occupational dust exposures to cause kidney damage and/or cancer may exist. We investigated whether asbestos, as well as 20 other occupational dust exposures, were associated with RCC risk in a large European, multi-center, hospital-based renal case-control study.Methods: General occupational histories and job-specific questionnaires were reviewed by occupational hygienists for subject-specific information. Odds ratios (ORs) and 95% confidence intervals (95% CIs) between RCC risk and exposures were calculated using unconditional logistic regression.Results: Among participants ever exposed to dusts, significant associations were observed for glass fibres (OR: 2.1; 95% CI: 1.1-3.9), mineral wool fibres (OR: 2.5; 95% CI: 1.2-5.1), and brick dust (OR: 1.5; 95% CI: 1.0-2.4). Significant trends were also observed with exposure duration and cumulative exposure. No association between RCC risk and asbestos exposure was observed.Conclusion: Results suggest that increased RCC risk may be associated with occupational exposure to specific types of dusts. Additional studies are needed to replicate and extend findings. [ABSTRACT FROM AUTHOR]

Background: It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT).Methods: In the Guernsey Breast Cancer Cohort Study, GGT was measured in sera from 1803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer.Results: After adjustment for age at entry, height, weight, age at menarche and first birth with nulliparity, there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile, the hazard ratio (HR) was 2.17 (95% confidence interval (CI): 1.19, 3.93). When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81 (95% CI: 1.37, 10.59). Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of 4.90 (95% CI: 1.86, 12.94).Conclusions: These results suggest that premenopausal women with high normal (above median) serum GGT or elevated levels (< or =40 IU l(-1)) are at increased risk of breast cancer and might benefit from close surveillance, possibly with breast magnetic resonance imaging scans. Serum GGT may mark previous exposure to carcinogens and lead to the identification of DNA adducts involved in mammary carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens.Methods: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed.Results: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer).Conclusion: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring. [ABSTRACT FROM AUTHOR]

We investigated stage at diagnosis in relation to socioeconomic status (SES) among 15 274 patients with colorectal adenocarcinoma diagnosed in 1996-2004 nationwide in Denmark. The effect of SES on the risk of being diagnosed with distant metastasis was analysed using logistic regression models. A reduction in the risk of being diagnosed with distant metastasis was seen in elderly rectal cancer patients with high income, living in owner-occupied housing and living with a partner. Among younger rectal cancer patients, a reduced risk was seen in those having long education. No social gradient was found among colon cancer patients. The social gradient found in rectal cancer patients was significantly different from the lack of association found among colon cancer patients. There are socioeconomic inequalities in the risk of being diagnosed with distant metastasis of a rectal, but not a colonic, cancer. The different risk profile of these two cancers may reflect differences in symptomatology. [ABSTRACT FROM AUTHOR]

Expression of profilin-1 (Pfn1) is downregulated in breast cancer cells, the functional significance of which is yet to be understood. To address this question, in this study we evaluated how perturbing Pfn1 affects motility and invasion of breast cancer cells. We show that loss of Pfn1 expression leads to enhanced motility and matrigel invasiveness of MDA-MB-231 breast cancer cells. Interestingly, silencing Pfn1 expression is associated with downregulation of both cell-cell and cell-matrix adhesions with concomitant increase in motility and dramatic scattering of normal human mammary epithelial cells. Thus, these data for the first time suggest that loss of Pfn1 expression may have significance in breast cancer progression. Consistent with these findings, even a moderate overexpression of Pfn1 induces actin stress-fibres, upregulates focal adhesion, and dramatically inhibits motility and matrigel invasiveness of MDA-MB-231 cells. Using mutants of Pfn1 that are defective in binding to either actin or proline-rich ligands, we further show that overexpressed Pfn1 must have a functional actin-binding site to suppress cell motility. Finally, animal experiments reveal that overexpression of Pfn1 suppresses orthotopic tumorigenicity and micro-metastasis of MDA-MB-231 cells in nude mice. These data imply that perturbing Pfn1 could be a good molecular strategy to limit the aggressiveness of breast cancer cells. [ABSTRACT FROM AUTHOR]

Id protein family consists of four members namely Id-1 to Id-4. Different from other basic helix-loop-helix transcription factors, they lack the DNA binding domain. Id proteins have been shown to be dysregulated in many different cancer types and their prognostic value has also been demonstrated. Recently, Id-1 has been shown to be upregulated in oesophageal squamous cell carcinoma (ESCC). However, the prognostic implications of Id proteins in ESCC have not been reported. We examined the expression of the Id proteins in ESCC cell lines and clinical ESCC specimens and found that Id protein expressions were dysregulated in both the ESCC cell lines and specimens. By correlating the expression levels of Id proteins and the clinicopathological data of our patient cohort, we found that M1 stage tumours had significantly higher nuclear Id-1 expression (P=0.012) while high nuclear Id-1 expression could predict development of distant metastasis within 1 year of oesophagectomy (P=0.005). In addition, high levels of Id-2 expression in both cytoplasmic and nuclear regions predicted longer patient survival (P=0.041). Multivariate analysis showed that high-level expression of Id-2 in both cytoplasmic and nuclear regions and lower level of nuclear Id-1 expression were independent favourable predictors of survival in our ESCC patients. Our results suggest that Id-1 may promote distant metastasis in ESCC, and both Id-1 and Id-2 may be used for prognostication for ESCC patients. [ABSTRACT FROM AUTHOR]

The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-beta for example in the intestine has been discussed as well as a preponderance or prolongation of growth factor stimulation. The experiments presented here demonstrated that COX-2 transfection of a TGF-beta-sensitive cell line abrogates the growth inhibitory effects of TGF-beta. However, analysis of the TGF-beta/Smad-signalling pathway clearly revealed that COX-2 overexpression did not interfere with that. Neither TGF-receptor expression nor Smad phosphorylation and signal transfer into the nucleus were influenced by COX-2 overexpression. In addition, a TGF-beta reporter assay revealed no difference between controls and COX-2-transfected cells. Thus, the proliferation inhibiting effects must have been well compensated by growth-inducing stimuli. Indications for this came from experiments showing an induction of TGF-alpha expression and secretion with a higher and prolonged stimulation of the ERK 1/2 (p42/44) pathway in COX-2 transfectants. This effect could have been triggered by direct prostaglandin receptor stimulation or changes in intracellular lipid mediators. An increase in PPAR signalling as proven by a reporter assay is indication for the latter. Therefore, inhibiting both COX-2 as well as the PPAR and TGF/EGF pathway could be effective in the inhibition of adenoma or even carcinoma development in the intestine. [ABSTRACT FROM AUTHOR]

Burnet proposed in the 1950's that the immune system is engaged in identifying and destroying abnormal cancerous cells. This process, termed immune surveillance, has been at the centre of intense debate for decades. Results using immunodeficient mice lend support to the immune surveillance hypothesis. We surmised that immune surveillance would be hampered by the inhibitory effect of naturally occurring FoxP3(+) regulatory T cells, a population of T cells shown to be present at an increased frequency in a variety of human tumours. The carcinogen, methylcholanthrene was injected subcutaneously into mice and the steady development of fibrosarcomas was observed over approximately 200 days. These fibrosarcomas were strikingly infiltrated with FoxP3(+) regulatory T cells implying that these cells impinge upon immune-mediated rejection of the tumour. This was confirmed by partial ablation of FoxP3(+) regulatory T-cell activity, which resulted in a marked reduction in tumour incidence. The reduction of tumour incidence was ablated in mice that lacked interferon gamma. These data offer strong support for the concept of immune surveillance and indicate that this process is limited by the inhibitory effect of FoxP3(+) regulatory T cells. [ABSTRACT FROM AUTHOR]

Using data from the Geneva Cancer Registry, we found that in 2002–2004, breast cancer incidence in women aged 25–39 years increased by 46.7% per year (95% CI: 7.1–74.0, P=0.015), which surveillance or detection bias may not fully explain.British Journal of Cancer (2007) 96, 1743–1746. doi:10.1038/sj.bjc.6603783 www.bjcancer.com Published online 29 May 2007 [ABSTRACT FROM AUTHOR]

Stage Ta/T1 urothelial carcinoma of the bladder (Ta/T1 BC) has a marked tendency to recur. Besides histopathology, markers such as CK20 expression and proliferation index (Ki67) have been shown to predict its clinical course. The replication-licensing factor minichromosome maintenance protein 2 (Mcm2) is a marker of proliferative potential shown to be a promising prognostic marker in various malignancies. The aim of the present study was to evaluate the prognostic value of Mcm2 in comparison to stage, grade, CK20 and Ki67. Initial sporadic Ta/T1 BC (n=71) were evaluated for their expression of CK20, Ki67 and Mcm2 by immunohistochemistry and tissue microarray technology. Prognostic power was analysed by univariate and multivariate Cox regression model for tumour recurrence rate. Median follow-up period was 39 months. A total of 35% patients experienced recurrence. While CK20 was not predictive, grade, Ki67 and Mcm2 were significantly related to recurrence rate in univariate Cox regression model. Only grade (HR 2.37; 95% CI 1.24–4.51; P=0.009) and Mcm2 expression with a cutoff 40% (HR 5.81; 95% CI 2.41–14.00; P<0.001) were independent predictors of recurrence rate in multivariate Cox regression analysis. In addition to grade, expression of Mcm2 is an independent predictor of recurrence in Ta/T1 BC.British Journal of Cancer (2007) 96, 1711–1715. doi:10.1038/sj.bjc.6603784 www.bjcancer.com Published online 15 May 2007 [ABSTRACT FROM AUTHOR]

Identification of an isolated tumour cell with metastatic ability is important for predicting the recurrence and prognosis of gastric cancer. A biological marker for evaluating the metastatic ability of gastric cancer cells has not yet been identified. We assessed vascular endothelial growth factor receptor-1 mRNA expression by quantitative real-time reverse transcriptase-polymerase chain reaction. Vascular endothelial growth factor receptor-1 mRNA in peripheral blood was more highly expressed in perioperative metastasis-positive and postoperative recurrence cases than in normal control cases, early cancer cases and nonmetastatic advanced cancer cases. The peripheral blood vascular endothelial growth factor receptor-1 mRNA-positive group was associated with advanced clinical stage, deep invasion beyond the muscularis propria, lymphatic involvement, vascular involvement, lymph node metastasis, positive peritoneal lavage cytology, preoperative metastasis and postoperative recurrence. Flow cytometry analysis disclosed that vascular endothelial growth factor receptor-1 expressing cells in the peripheral blood were more abundant in cancer cases with metastases than in cases without metastases. Our data suggest that the amount of positive cells may provide information on the clinical features of gastric cancer, especially in regard to gastric cancer metastasis.British Journal of Cancer (2007) 96, 1723–1728. doi:10.1038/sj.bjc.6603785 www.bjcancer.com Published online 8 May 2007 [ABSTRACT FROM AUTHOR]

Anthracyclines and platinum derivates are active drugs for advanced endometrial carcinoma (AEC), but new schedules with higher efficacy and better tolerability are needed. A phase II study was conducted to describe activity and tolerability of carboplatin (C)+pegylated liposomal doxorubicin (PLD) in patients with AEC. Patients with chemonaive AEC, PS 2, aged <75 years, with at least one measurable lesion were eligible. Treatment was C (area under curve 5)+PLD (40 mg m−2) on day 1 every 4 weeks, up to six cycles. Forty-two patients were needed in a single-stage design, with at least 13 objective responses to define the treatment active. Forty-two patients were enrolled. Median age was 64 years (31–74). A total of 64% of patients were recurrent while 36% were advanced. Three complete (7%) and 22 partial responses (52%) were observed, for an overall response rate of 59.5% (95% exact CI: 43.3–74.3). One death potentially related to treatment was recorded (death at home for unknown reasons after 6th cycle). Other relevant toxicities (% of patients) were grade 3/4 neutropaenia 33%/14%, febrile neutropaenia 5%, grade 3/4 thrombocytopaenia 17%/5%, grade 3/4 anaemia 31%/2%. Skin toxicity was mild: grade 1 14%, grade 2 10%, grade 3 5%. Hair loss: complete 5%, partial 12%. The combination of carboplatin and PLD shows good activity and favourable toxicity as first-line chemotherapy of patients with AEC, deserving further studies in this setting.British Journal of Cancer (2007) 96, 1639–1643. doi:10.1038/sj.bjc.6603787 www.bjcancer.com Published online 8 May 2007 [ABSTRACT FROM AUTHOR]

This study investigated the maximum tolerated dose of S-1 based on the frequency of its dose-limiting toxicities (DLT) with concurrent radiotherapy in patients with locally advanced pancreatic cancer. S-1 was administered orally at escalating doses from 50 to 80 mg m−2 b.i.d. on the day of irradiation during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Twenty-one patients (50 three; 60 five; 70 six; 80 mg m−2 seven patients) were enrolled in this trial. At a dose of 70 mg m−2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 haemorrhagic gastritis, whereas no patients at doses other than 70 mg m−2 demonstrated any sign of DLT. Among the 21 enrolled patients, four (19.0%) showed a partial response. The median progression-free survival time and median survival time for the patients overall were 8.9 and 11.0 months, respectively. The recommended dose of S-1 therapy with concurrent radiotherapy is 80 mg m−2 day−1. A multi-institutional phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway.British Journal of Cancer (2007) 96, 1650–1655. doi:10.1038/sj.bjc.6603788 www.bjcancer.com Published online 29 May 2007 [ABSTRACT FROM AUTHOR]

Data on 35 291 individuals with cancer, aged 13–24 years, in England from 1979 to 2001 were analysed by region and socio-economic deprivation of census ward of residence, as measured by the Townsend deprivation index. The incidence of leukaemia, lymphoma, central nervous system tumours, soft tissue sarcomas, gonadal germ cell tumours, melanoma and carcinomas varied by region (P<0.01, all groups) but bone tumour incidence did not. Lymphomas, central nervous system tumours and gonadal germ cell tumours all had higher incidence in less deprived census wards (P<0.01), while chronic myeloid leukaemia and carcinoma of the cervix had higher incidence in more deprived wards (P<0.01). In the least deprived wards, melanoma incidence was nearly twice that in the most deprived, but this trend varied between regions (P<0.001). These cancer incidence patterns differ from those seen in both children and older adults and have implications for aetiology and prevention.British Journal of Cancer (2007) 96, 1760–1766. doi:10.1038/sj.bjc.6603794 www.bjcancer.com Published online 15 May 2007 [ABSTRACT FROM AUTHOR]

We studied 12,450 cases of invasive melanoma diagnosed in Scotland in 1979-2003, by thickness, pathological type, and body site at ages under 40, 40-59, and 60 years and over. Melanoma incidence trebled in males from 3.57 to 10.93/10(5) per year, and increased 2.3-fold in females from 5.60 to 12.96/10(5) per year. The rate of increase fell in each successive 5-year period. The greatest increase was in males aged 60 years and over at diagnosis. Significant incidence increases were seen in melanomas < 1 mm in all three age groups, but those > 4 mm only increased significantly at ages 60 years and over. All histological types increased significantly at ages 60 years and over, and in this age group the greatest increase was seen on the head and neck. Five-year disease-free survival improved steadily. Survival figures for 1994-1998 ranged from 93.6% for males and 95.8% for females with tumours < 1 mm, to 52.4 and 48.3%, respectively, for those with tumours > 4 mm. Over the 25 years, melanoma mortality doubled in males from 1.1 to 2.4/10(5) per year, but was unchanged in females at 1.5/10(5) per year. Public education on melanoma is required both for primary prevention and earlier diagnosis, particularly for older males. [ABSTRACT FROM AUTHOR]

Chemical carcinogens from cigarette smoking and occupational exposure are risk factors for bladder transitional cell carcinoma (TCC). The Xeroderma Pigmentosum Group C (XPC) gene is essential for repair of bulky adducts from carcinogens. The Xeroderma Pigmentosum Group C gene polymorphisms may alter DNA repair capacity (DRC), thus giving rise to genetic predisposition to bladder cancer. Recent studies have demonstrated linkage disequilibrium between three polymorphisms in the XPC gene (polyAT, IVS11-6 and Lys939Gln) and these have been shown to influence the DRC, as well as to be associated with bladder cancer risk. We analysed all three XPC polymorphisms in 547 bladder TCC patients and 579 cancer-free controls to investigate the association between these polymorphisms and bladder cancer susceptibility, and we also attempted to assess gene–environmental interactions. We confirmed strong linkage disequilibrium among the polymorphisms (Lewontin's D′>0.99). Using logistic regression adjusting for smoking, occupational and family history, neither the heterozygote nor the homozygote variants of these polymorphisms were associated with increased bladder cancer risk (adjusted odds ratio[95% confidence interval] for heterozygote 0.82[0.63–1.07], 0.82[0.63–1.08] and 0.83[0.63–1.08] for PolyAT, IVS11-6 and Lys939Gln, respectively and homozygote variant, 0.98[0.68–1.42], 0.99[0.69–1.43] and 1.01[0.70–1.46]). Moreover, we did not find any significant interaction between these XPC polymorphisms and environmental exposure to cigarette smoking and occupational carcinogens.British Journal of Cancer (2005) 92, 2262–2265. doi:10.1038/sj.bjc.6602616 www.bjcancer.com Published online 10 May 2005 [ABSTRACT FROM AUTHOR]

A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95%of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20%of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.British Journal of Cancer (2005) 92, 784-790. doi:10.1038/sj.bjc.6602381 www.bjcancer.com Published online 8 February 2005 [ABSTRACT FROM AUTHOR]

Selective underascertainment of cases may bias estimates of cancer patient survival. We show that the magnitude of potential bias strongly depends on the time periods affected by underascertainment and on the type of survival analysis (cohort analysis vs period analysis). We outline strategies on how to minimise or overcome potential biases. [ABSTRACT FROM AUTHOR]

The British mesothelioma register contains all deaths from 1968 to 2001 where mesothelioma was mentioned on the death certificate. These data were used to predict the future burden of mesothelioma mortality in Great Britain. Poisson regression analysis was used to model male mesothelioma deaths from 1968 to 2001 as a function of the rise and fall of asbestos exposure during the 20th century, and hence to predict numbers of male deaths in the years 2002-2050. The annual number of mesothelioma deaths in Great Britain has risen increasingly rapidly from 153 deaths in 1968 to 1848 in 2001 and, using our preferred model, is predicted to peak at around 1950 to 2450 deaths per year between 2011 and 2015. Following this peak, the number of deaths is expected to decline rapidly. The eventual death rate will depend on the background level and any residual asbestos exposure. Between 1968 and 2050, there will have been approximately 90,000 deaths from mesothelioma in Great Britain, 65,000 of which will occur after 2001. [ABSTRACT FROM AUTHOR]

Minimum detection rates at screening are sometimes laid down as standards for breast cancer screening programmes, based on underlying incidence of the disease in the age group screened. Detection rates should also depend on desired sensitivity, mean sojourn time, interscreening interval and the screening round--that is, prevalent (first) or incident (second or subsequent). In this paper, we use these quantities to derive expected, minimum and maximum detection rates proportional to the underlying incidence as well as estimated underlying incidence rates from extrapolation of prescreening trends in England and Wales to derive alternative standard minimum, expected and maximum detection rates per 1000 women screened for the UK Breast Screening Programme, as follows: minimum detection rates should be 4.1 and 4.3 at prevalence screen and incidence screens, respectively; expected rates should be 6.9 and 4.8 and maximum rates of 9.6 and 5.5. These are consistent with observed detection rates in the UK programme. [ABSTRACT FROM AUTHOR]

The article focuses on the age distribution of cancer an multistage theory of carcinogenesis. However, two hypotheses about the mechanism of carcinogenesis have been put forward, which have been derived from analysis of cancer mortality statistics. Researchers used statistics from the U.S. for cancer of the stomach in women, and then classing all sites together, used statistics for cancer in men from various countries. They found that, within the age group 25-74 years, the logarithm of the death rate increased in direct proportion to the logarithm of the age, but about six times as rapidly; the death rate increased proportionally with the sixth power of the age. The concept of carcinogenesis as a multi-stage process also makes it easy to understand the mechanism of the latent period which occurs after exposure to a carcinogenic agent before the appearance of a tumor.

The WWOX (WW-domain containing oxidoreductase) is a candidate tumour suppressor gene spanning the same chromosome region, 16q23, as the second most common fragile site (FS), FRA16D. Deletions detected by comparative genomic hybridisation (CGH) and loss of heterozygosity at microsatellite markers on chromosome 16q are common in many human cancers including hepatocellular carcinoma (HCC). The development of human HCC is closely associated with exposure to oncogenic viruses and chemical carcinogens, agents known to frequently target common FS. We examined the status of WWOX genomic DNA, RNA and protein in 18 cell lines derived from human HCC and found recurrent alterations of the gene. Loss of DNA copy-number confined to band 16q23 was detected by CGH in several cell lines. Although homozygous deletions of the WWOX gene were not detected, WWOX mRNA expression was absent or lower in 60% of cell lines. The occurrence of aberrant WWOX reverse transcription-PCR products with deletion of exons 6-8 correlated significantly with altered WWOX expression. All of the cell lines showing mRNA downregulation had a decreased or undetectable level of WWOX protein as demonstrated by Western blotting with antibody to WWOX. Furthermore, 13 out of the 18 cell lines expressed decreased levels or no WWOX protein when compared with normal liver. These results show that WWOX gene is frequently altered in HCC and raise the possibility that this gene is implicated in hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Microsomal epoxide hydrolase (mEH) plays a dual role in the detoxification and activation of tobacco procarcinogens. Two polymorphisms affecting enzyme activity have been described in the exons 3 and 4 of the mEH gene, which result in the substitution of amino acids histidine to tyrosine at residue 113, and arginine to histidine at residue 139, respectively. We performed a hospital-based case-control study consisting of 277 newly diagnosed lung cancer patients and 496 control subjects to investigate a possible association between these two polymorphisms and lung cancer risk. The polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism and TaqMan assay using DNA from peripheral white blood cells. Logistic regression was performed to calculate odds ratios (ORs), confidence limits (CL) and to control for possible confounders. The exon 3 polymorphism of the mEH gene was associated with a significantly decreased risk of lung cancer. The adjusted OR, calculated relative to subjects with the Tyr113/Tyr113 wild type, for the His113/His113 genotype was 0.38 (95% CL 0.20-0.75). An analysis according to histological subtypes revealed a statistically significant association for adenocarcinomas; the adjusted OR for the His113/His113 genotype was 0.40 (95% CL 0.17-0.94). In contrast, no relationship between the exon 4 polymorphism and lung cancer risk was found. The adjusted OR, calculated relative to the His139/His139 wild type, was for the Arg139/Arg139 genotype 1.83 (0.76-4.44). Our results support the hypothesis that genetically reduced mEH activity may be protective against lung cancer. [ABSTRACT FROM AUTHOR]

Hydroxymethyl glutaryl coenzyme A inhibitors ("statins") are carcinogenic in rodents and an increased incidence of breast cancer was reported among pravastatin users in one randomised trial. We conducted a case-control study in the General Practice Research Database to evaluate the risk of breast cancer among 50- to 79-year old women treated with statins for hyperlipidaemia. Case and control women were matched by age, general practice, duration of prescription history in the General Practice Research Database, and index date. Adjusting for history of benign breast disease, body mass index, and use of hormone replacement therapy, women currently treated with statins had an estimated relative risk for breast cancer of 1.0 (95% confidence interval 0.6-1.6) compared to women without hyperlipidaemia. Untreated hyperlipidaemia was associated with an increased risk of breast cancer (estimated relative risk 1.6; 95% confidence interval 1.1-2.5). The estimated relative risk among women currently receiving only non-statin lipid-lowering drugs was similar to that of women with untreated hyperlipidaemia (1.8; 95% confidence interval 0.9-3.4). We found no evidence for an increasing trend in breast cancer risk with increasing duration of statin use (median duration 1.8 years, maximum 8.6 years). [ABSTRACT FROM AUTHOR]

Therapy of selected human malignancies with interferon-alpha is widely accepted but often complicated by the emergence of interferon-alpha resistance. Interferon is a pleiotropic cytokine with antiproliferative, antitumour, antiviral and immunmodulatory effect; it signals through the Jak-STAT signal transduction pathway where signal transducer and activator of transcription 1 plays an important role. Here we report both, a lack of signal transducer and activator of transcription induction in interferon-alpha resistant renal cell carcinoma cells and signal transducer and activator of transcription 1 reinduction of phorbol 12-myristate 13-acetate-stimulated peripheral blood mononuclear cells supernatant. Preliminary experiments on the identification of the molecules that reinducing signal transducers and activators of transcription 1 indicate that interferon-gamma may be the responsible candidate cytokine, but several others may be involved as well. This work provides the basis for therapeutic strategies directed at the molecular modulation of interferon-alpha resistance in human neoplasms. [ABSTRACT FROM AUTHOR]

Consumption of the bracken fern Pteridium aquilinum by cattle has been shown to induce bladder and intestinal carcinomas in cattle and to cause a number of diseases in other farm animals. An unstable glucoside named ptaquiloside, containing a reactive cyclopropane ring, has been isolated from the fern and its potent carcinogenicity proven. Nineteen of 31 ferns tested by chemotaxonomic methods in Japan have been found to contain potentially carcinogenic ptaquilosides as have Cheilanthes sieberi and Pteridium esculentum. Hydrolysis of ptaquilosides leads to pterosins; under milder conditions a dienone which is believed to be the primary carcinogen is obtained. Hypacrone, a sesquiterpine containing a reactive cyclopropane ring, has been isolated from Hypolepis punctata and its structure proved by synthesis. Illudins, structurally similar to ptaquiloside, have been isolated from the basidiomycete Omphalotus illudens. These give anti-tumour activity and similar reactivity with nucleophiles to ptaquiloside. Compound CC-1065, a highly toxic antibiotic also containing a cyclopropane ring, has been isolated from Streptomyces zelensis. The mechanism of its reactivity with DNA has been compared to that of ptaquiloside and the small structural differences between carcinogenic and anti-tumour activity discussed. Both CC-1065 and adozelesin, a synthetic analogue with anti-tumour activity, have been shown to alkylate the N-3 atom of adenine in a certain sequence of DNA. The reactivity of cysteine with ptaquilosides and illudins is discussed, as is the role of cysteine alkylating agents in apoptosis. [ABSTRACT FROM AUTHOR]

The article examines the cell biology of apoptosis and shows the role played by corrupted apoptosis in genesis of cancer. Apoptosis is a distinctive character of death process in tissue homeostasis. Undead cells have a high mutation frequency which equips them as founder cells of tumors. Some tumors arise as a direct result of apoptosis failure with the resulting persistence of mutated cells.

The majority of pituitary tumours are monoclonal in origin and arise sporadically or occasionally as part of multiple endocrine neoplasia type 1 (MEN1). Whilst a multi-step aetiology involving both oncogenes and tumour suppressor genes has been proposed for their development, the target(s) of these changes are less clearly defined. Both familial and sporadic pituitary tumours have been shown to harbour allelic deletion on 11q13, which is the location of the recently cloned MEN1 gene. We investigated 23 sporadic pituitary tumours previously shown to harbour allelic deletion on 11q13 with the markerPYGM centromeric and within 50 kb of the MEN1 locus. In addition, the use of intragenic polymorphisms in exon 9 and at D11S4946, and of telomeric loci at D11S4940 andD11S4936, revealed that five of 20 tumours had loss of heterozygosity (LOH) telomeric to the menin gene. However, the overall pattern of loss in informative cases was indicative of non-contiguous deletion that brackets the menin gene. Sequence analysis of all MEN1 coding exons and flanking intronic sequence, in tumours and matched patient leucocyte DNA, did not reveal mutation(s) in any of the 23 tumours studied. A benign polymorphism in exon 9 was encountered at the expected frequency, and in seven patients heterozygous for the polymorphism the tumour showed retention of both copies of the menin gene. Reverse transcription polymerase chain reaction analysis of ten evaluable tumours and four normal pituitaries revealed the presence of the menin transcript. Whilst these findings suggest that gene silencing is unlikely to be mechanistic in sporadic pituitary tumorigenesis, they do not exclude changes in the level or stability of the transcript or translation to mature protein. Our study would support and extend very recent reports of a limited role for mutations in theMEN1 gene in sporadic pituitary tumours. Alternatively, these findings may point to an, as yet, unidentified tumour suppressor gene in this... [ABSTRACT FROM AUTHOR]

In a nested case-control study of 86 cases of gastric adenocarcinoma in relation to Helicobacter pylori infection in the Korean Multi-center Cancer Cohort, the H. pylori IgG seropositivity was 83.7% and that of the 344 matched controls was 80.8%, with a matched odds ratio for H. pylori infection of 1.06 (95% CI, 0.80-1.40). [ABSTRACT FROM AUTHOR]

The number of male deaths from pleural cancer in France, Germany and Italy increased from about 8750 in 1990-1994 to 9550 in 1995-1999, suggesting that mesothelioma deaths in males may be levelling off in most of Western Europe.British Journal of Cancer (2004) 90, 1022-1024. doi:10.1038/sj.bjc.6601638 www.bjcancer.com [ABSTRACT FROM AUTHOR]