Showing papers by "International Agency for Research on Cancer published in 1995"
TL;DR: The results confirm the role of genitalHPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide and suggest that most genital HPVs are associated with cancer, at least occasionally.
Abstract: Background Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation Purpose Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types Methods More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity Results HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5% HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common There was significant geographic variation in the prevalence of some less common virus types A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors) Conclusions Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide They also suggest that most genital HPVs are associated with cancer, at least occasionally Implication The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs
3,272 citations
TL;DR: Investigation of the effect of various non-steroidal anti-inflammatory agents and related compounds on the induction of NO synthase (NOS) in macrophages activated with lipopolysaccharide and interferon-gamma found significantly reduced levels of the mRNA and 130-kDa protein of inducible NOS were expressed in Macrophage activated with curcumin, compared to those withoutCurcumin.
501 citations
TL;DR: Estimates of cancer risk associated with low-dose protracted exposures obtained are compatible with a range of possibilities, from a reduction of risk at low doses, to risks twice those on which current radiation protection recommendations are based.
Abstract: Studies of the mortality among nuclear industry workforces have been carried out, and nationally combined analyses performed, in the U.S., the UK and Canada. This paper presents the results of internationally combined analyses of mortality data on 95,673 workers (85.4% men) monitored for external exposure to ionizing radiation and employed for 6 months or longer in the nuclear industry of one of the three countries. These analyses were undertaken to obtain a more precise direct assessment of the carcinogenic effects of protracted low-level exposure to external, predominantly gamma, radiation. The combination of the data from the various studies increases the power to study associations between radiation and specific cancers. The combined analyses covered a total of 2,124,526 person-years (PY) at risk and 15,825 deaths, 3,976 of which were due to cancer. There was no evidence of an association between radiation dose and mortality from all causes or from all cancers. Mortality from leukemia, excluding chronic lymphocytic leukemia (CLL)--the cause of death most strongly and consistently related to radiation dose in studies of atomic bomb survivors and other populations exposed at high dose rates--was significantly associated with cumulative external radiation dose (one-sided P value = 0.046; 119 deaths). Among the 31 other specific types of cancer studied, a significant association was observed only for multiple myeloma (one-sided P value = 0.037; 44 deaths), and this was attributable primarily to the associations reported previously between this disease and radiation dose in the Hanford (U.S.) and Sellafield (UK) cohorts. The excess relative risk (ERR) estimates for all cancers excluding leukemia, and leukemia excluding CLL, the two main groupings of causes of death for which risk estimates have been derived from studies of atomic bomb survivors, were -0.07 per Sv [90% confidence interval (CI): -0.4, 0.3] and 2.18 per Sv (90% CI: 0.1, 5.7), respectively. These values correspond to a relative risk of 0.99 for all cancers excluding leukemia and 1.22 for leukemia excluding CLL for a cumulative protracted dose of 100 mSv compared to 0 mSv. These estimates, which did not differ significantly across cohorts or between men and women, are the most comprehensive and precise direct estimates of cancer risk associated with low-dose protracted exposures obtained to date. Although they are lower than the linear estimates obtained from studies of atomic bomb survivors, they are compatible with a range of possibilities, from a reduction of risk at low doses, to risks twice those on which current radiation protection recommendations are based.(ABSTRACT TRUNCATED AT 400 WORDS)
499 citations
TL;DR: Risk of BCC increased substantially with increasing intermittency in poor tanners but not at all in good tanners, and a particular amount of sun exposure delivered in infrequent, probably intense increments will increase risk of BCC more than a similar dose delivered more continuously over the same total period of time.
Abstract: Our report deals with the relationship of pattern and timing of sun exposure to basal cell carcinoma (BCC) in a population-based case-control study conducted in Western Australia in 1988. The main measure of intermittent exposure was based on the amount of exposure on non-working days relative to that over the whole week. Outdoor recreational activities, holidays and sunburn were also considered to be markers of intermittent exposure. We observed a statistically significant increase in risk of BCC with increasing proportion of weekly sun exposure obtained at the weekend, especially in late teenage (OR = 3.9, 95% CI 1.9-7.8 for maximum intermittency of exposure), exposure of the site of skin cancer during holidays (OR = 1.9, 95% CI 1.1-3.1 for the highest exposure quarter) and sunburn to the site (ORs of 1.8 for 3-10 and 1.5 for 11+ sunburns in a lifetime). Risk of BCC increased substantially with increasing intermittency in poor tanners but not at all in good tanners. Our data suggest that a particular amount of sun exposure delivered in infrequent, probably intense increments will increase risk of BCC more than a similar dose delivered more continuously over the same total period of time.
429 citations
TL;DR: Recent studies sugeest that the occurrence of mixed glomas is not indicative of a polyclonal orgin but rather reflects altered gene exprssion leading to a charge in the balance of growth factors influencing glioma defferentiation.
Abstract: Neoplastic transformation occurs in all glial cell types of the human nervous system, producing a wide variety of clinico-pathological entities and morphological variants. Astrocytomas are most common and span an unusually wide spectrum, ranging from the slowly growing juvenile pilocytic astrocytoma to the highly malignant glioblastoma multiforme. Diffusely infiltrating astrocytomas of the cerebral hemispheres show an inherent tendency for progression towards a more malignant phenotype. This change is morphologically categorized in histologic grading schemes (e.g., WHO Grade II to IV) and is associated with the sequential acquisition of genetic alterations, including mutations in the p53 and homozygous deletions of the p16 tumour suppressor genes. Loss of heterozygosity on chromosomes 10 and 19q as well as amplification of the EGF receptor are largely restricted to malignant gliomas and thus considered late events in astrocytoma progression. Gliomas often show phenotypic expression of different glial cell lineages (e.g., oligoastrocytoma). Recent studies suggest that the occurrence of mixed gliomas is not indicative of a polyclonal origin but rather reflects altered gene expression, leading to a change in the balance of growth factors influencing glioma differentiation.
339 citations
TL;DR: It is demonstrated that 8‐nitroguanine is formed dose‐dependently in calf thymus DNA incubated with low concentrations of peroxynitrite in vitro, a strong oxidant formed by reaction of nitric oxide with superoxide in inflamed tissues.
332 citations
311 citations
TL;DR: 8-Nitroguanine could act as a specific marker for DNA damage induced by peroxynitrite in inflamed tissues, contributing to the multistage carcinogenesis process.
Abstract: Nitric oxide and superoxide anion, both formed in inflamed tissues, react rapidly to form the peroxynitrite anion (ONOO-), a strong oxidant which can initiate reactions characteristic of hydroxyl radical (HO.), nitronium ion (NO2+) and nitrogen dioxide radical (NO2.). Peroxynitrite, therefore, may cause DNA or tissue damage, contributing to the multistage carcinogenesis process. We have studied reactions of various bases, nucleosides or deoxynucleosides with peroxynitrite in vitro. Guanine reacted rapidly with peroxynitrite under physiological conditions and formed several substances, two of which were yellow, a characteristic of nitro and nitroso compounds. On the basis of chromatographic and spectral evidence we identified the major compound (which accounts for approximately 80% of all compounds formed) as 8-nitroguanine. Its formation was maximal at approximately pH 8 and increased dose-dependently with peroxynitrite concentration, but was not dependent on guanine concentration. The presence of ferric ions, which has been shown to catalyse nitration of tyrosine, did not affect nitration of guanine. 8-Nitroguanine could act as a specific marker for DNA damage induced by peroxynitrite in inflamed tissues.Nitric oxide and superoxide anion, both formed in inflamed tissues, react rapidly to form the peroxynitrite anion (ONOO-), a strong oxidant which can initiate reactions characteristic of hydroxyl radical (HO.), nitronium ion (NO2+) and nitrogen dioxide radical (NO2.). Peroxynitrite, therefore, may cause DNA or tissue damage, contributing to the multistage carcinogenesis process. We have studied reactions of various bases, nucleosides or deoxynucleosides with peroxynitrite in vitro. Guanine reacted rapidly with peroxynitrite under physiological conditions and formed several substances, two of which were yellow, a characteristic of nitro and nitroso compounds. On the basis of chromatographic and spectral evidence we identified the major compound (which accounts for approximately 80% of all compounds formed) as 8-nitroguanine. Its formation was maximal at approximately pH 8 and increased dose-dependently with peroxynitrite concentration, but was not dependent on guanine concentration. The presence of ferric ions, which has been shown to catalyse nitration of tyrosine, did not affect nitration of guanine. 8-Nitroguanine could act as a specific marker for DNA damage induced by peroxynitrite in inflamed tissues.
299 citations
TL;DR: It is indicated that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype and individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1.
Abstract: Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.
268 citations
Journal Article•
TL;DR: The results suggest that all of the connexin genes examined could induce recovery of GJIC of HeLa cells, but only the cx 26 gene exerts strong negative growth control on He La cells; thus, thisConnexin gene may have different functions from other connexIn genes.
Abstract: In order to examine whether different connexin gene species exert different degrees of tumor-suppressing activity, we characterized growth characteristics of a gap junction-deficient human cancer cell line, HeLa cells, before and after transfection with cDNA for three different connexins, connexin (cx) 26, cx 40, and cx 43. All transfected cell lines (3 clones transfected with the cx 26 gene, 2 clones with cx 40, and 1 with cx 43) showed establishment of gap junctional intercellular communication (GJIC). Two of the cx 26-transfected clones showed significantly slower growth compared with the parental HeLa cells. When transfectants were grown in soft agar, the three cx 26-transfected clones grew much less than the other transfectants and parent HeLa cells. When injected into nude mice, the two cx 26 clones which exhibited the highest amount of cx 26 transcript induced almost no tumors, whereas other transfectants, including the cx 26 clone which exhibited the lowest amount of cx 26 transcript, were tumorigenic. Among transfectants of various connexin genes, there was no good inverse correlation between their GJIC and tumorigenicity. GJIC levels were significantly higher in tumors induced in nude mice by clone cx 26 A and E transfectants. These results suggest that all of the connexin genes examined could induce recovery of GJIC of HeLa cells, but only the cx 26 gene exerts strong negative growth control on HeLa cells; thus, this connexin gene may have different functions from other connexin genes.
266 citations
TL;DR: The formation of etheno adducts may be markers of DNA damage associated with LPO, as demonstrated by reaction of LPO products with nucleic acid bases.
Abstract: Lipid peroxidation (LPO) products are known to interact with DNA, yielding several types of adduct with nucleobases. In this study, we demonstrate the formation of two ethenobase adducts, 1,N6-ethenoadenine and 3,N4-ethenocytosine, by reaction of LPO products with nucleic acid bases. Rat liver microsomes were incubated at 37 degrees C for 30 min in the presence of inducers of LPO [Fe(II) or cumene hydroperoxide] and adenine or cytosine nucleotides or nucleosides, followed by further heating at 80 degrees C for 30 min to complete the reactions. The etheno adducts detected after immunoaffinity chromatography were 1,N6-etheno-cAMP and 1,N6-etheno-2'-deoxyadenosine (HPLC/fluorimetry), 3,N4-etheno-2'-deoxycytidine (competitive radioimmunoassay), and 1,N6-etheno-2'-deoxyadenosine 3'-monophosphate and 3,N4-etheno-2'-deoxycytidine 3'-monophosphate (32P-postlabeling). Incubation of arachidonic acid supplemented with Fe(II) also led to the formation of the 1,N6-etheno adduct from cAMP. LPO intermediates that may be involved are discussed. These data suggest that etheno adducts may be markers of DNA damage associated with LPO.
TL;DR: In vitro studies indicated that these promutagenic DNA lesions could arise from endogenously formed lipid peroxidation products.
Abstract: The etheno-bridged exocyclic DNA adducts 1,N6-ethenodeoxyadenosine (epsilon dA) and 3,N4-ethenodeoxycytine (epsilon dC) can be formed by several structurally diverse carcinogens and mutagens that include vinyl chloride and urethane In order to investigate the occurrence and persistence of these adducts in rodents exposed to such DNA-damaging agents, an ultra-sensitive detection method has been developed It is based on immunoaffinity purification of the etheno adducts and subsequent 32P-postlabelling followed by separation as 5'-monophosphates on polyethyleneimine-cellulose-coated thin-layer plates Normal nucleotides in the DNA samples were quantitated by HPLC Optimal conditions for enzymatic hydrolysis of DNA are described: deoxyuridine 3'-monophosphate was used as internal standard to correct for labelling efficiency of the etheno adducts The method had a detection limit of 25 amol of epsilon dA and epsilon dC for a 50 micrograms DNA sample Using this technique, analysis of liver DNA from humans with unknown exposure revealed the presence of epsilon dA and epsilon dC residues in the range of 0-27 adducts per 10(9) parent bases Liver DNA obtained from untreated mice and rats was also shown to contain similar low but variable levels of these etheno adducts In vitro studies indicated that these promutagenic DNA lesions could arise from endogenously formed lipid peroxidation products
TL;DR: The hypothesis that p53 mutations can give rise to loss of tumor suppressor functions as well as to gain of oncogenic transformation capabilities is proposed.
Abstract: Mutation of the p53 gene is among the most common lesions in a variety of human tumors, including those of the central nervous system. In most instances, mutation of one p53 allele is followed by loss of the remaining wild-type allele, resulting in cells with a complete absence of functional wild-type p53 protein. However, in some situations, such as at initiation of spontaneously arising gliomas or as the germline configuration of patients with the Li-Fraumeni syndrome, cells clearly carry both wild-type and mutant p53 alleles. These observations lead to the hypothesis that p53 mutations can give rise to loss of tumor suppressor functions as well as to gain of oncogenic transformation capabilities. In this review, we define the types of mutations that occur in the p53 gene in various glial tumors, contrast that with the spectra described in other human tumor types, and discuss the biochemistry and physiology of the p53 protein and its ability to regulate and be regulated by other gene products. We use this information to propose roles for p53 in the initiation and progression of human gliomas.
TL;DR: This combined analysis of data from three large case-control studies of oral cancer confirms the important effect of tobacco in the aetiology of the disease and indicates decreases in risk for everyone could be achieved by encouraging high fruit and vegetable consumption.
Abstract: This combined analysis of data from three large case-control studies of oral cancer confirms the important effect of tobacco in the aetiology of the disease. The studies have been conducted in the United States, Italy and China and results for risks associated with tobacco smoking were generally consistent across centres, while those for alcohol were not; increased risks amongst alcohol drinkers were evident in two centres but not in the study conducted in Turin, Italy. In addition, the combined analysis had large enough numbers to analyse the risk of tobacco consumption in non-drinkers. In females these showed increased risks while in males the effect of tobacco alone was weaker. Given the popularity of tobacco smoking, and its consequent high attributable risk in terms of oral cancer it is reassuring, in terms of public health, that cessation will result in a substantial reduction in risk; a 30% reduction in risk for those stopping smoking between 1 and 9 years, and a 50% reduction for those stopping more than 9 years. Although encouraging smokers to stop should be the principal aim, decreases in risk for everyone could be achieved by encouraging high fruit and vegetable consumption.
TL;DR: Lifetime accumulated sun exposure of the whole body showed no appreciable association with BCC either in total or for working days only, which is consistent with other observations which indicate that beyond a certain level of sun exposure risk of BCC does not increase further.
Abstract: A population-based case-control study of sun exposure and basal cell carcinoma (BCC) was conducted in Western Australia in 1988. Its aim was to examine the relationship between risk of BCC and the amount and pattern of sun exposure. This report deals with amount of exposure. The odds ratios (ORs) for BCC on the head and neck and limbs decreased with increasing total exposure, whereas the opposite was observed for BCC on the less heavily exposed trunk, with the highest OR in those with the greatest exposure. In an analysis of all body sites together in which the total hours of exposure to the specific site was treated as a continuous variable, an initial rise in risk of BCC was seen with a peak OR of 1.4 at about 35,000 hr of exposure, followed by a fall. In contrast to these site-specific patterns, lifetime accumulated sun exposure of the whole body showed no appreciable association with BCC either in total or for working days only. Risk of BCC was positively associated with lifetime exposure on non-working days, however, with an OR for higher than baseline categories of around 1.7. There was a significant interaction between ability to tan and total and occupational sun exposure. Risk increased with increasing exposure in those who tanned well but not in those who tanned poorly. This pattern is consistent with other observations which indicate that beyond a certain level of sun exposure risk of BCC does not increase further.
TL;DR: The data support the idea that in smokers who lack the GSTM1 gene, activation of carcinogens in tobacco smoke is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTm1-1 enzyme and low expression of GSTM3-3 enzyme) and quantitatively (low overall GST activity).
Abstract: The relationships between smoking and the expression of glutathione S-transferase (GST*) isozymes GSTM1-1, GSTM3-3, GSTP1-1 and GSTA1-1/2-2 (GSTA1/2), or between smoking and activities of epoxide hydrolase (EH) and aryl hydrocarbon hydroxylase (AHH) were investigated in lung samples from 27 patients with lung cancer and 11 control patients by immunoblot analysis and enzyme assays. Determination of genotypes in blood leucocyte DNA showed that possession of the mu-class GSTM1 gene was closely related to the expression of GSTM1-1 and GSTM3-3 enzymes in lung cytosol: patients with the GSTM1 null genotype had no detectable GSTM1 protein and less GSTM3 protein than patients with the GSTM1 gene (P < 0.001). Absence of the GSTM1 gene did not affect the content of phi-class GSTP1-1 or alpha-class GSTA1/2. GST activity towards 1-chloro-2,4-dinitrobenzene was lower (P < 0.01) in patients lacking the GSTM1 gene than in those expressing GSTM1; in general, patients with a low GSTM3-3, GSTP1-1 or GSTA1/2 content also had significantly less overall GST activity. The pulmonary content of GSTP1-1 was greater in cancer than in non-cancer patients (P < 0.05). Smoking did not influence the levels of GST isozymes or the EH activity. In contrast, the AHH activity was significantly (P < 0.01) increased by smoking. Neither AHH nor EH showed a correlation with GSTM1 polymorphism. Our data support the idea that in smokers who lack the GSTM1 gene, activation of carcinogens in tobacco smoke (e.g. benzo[alpha]pyrene) is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTM1-1 enzyme and low expression of GSTM3-3 enzyme) and quantitatively (low overall GST activity). This imbalance in the metabolism of carcinogens may explain the increased susceptibility to lung cancer reported in smokers with the GSTM1 null genotype.
TL;DR: This is the first human study evaluating the chemopreventive potential of Spirulina fusiformis and it was found that supplementation with SF did not result in increased serum concentration of retinol or beta-carotene, nor was it associated with toxicity.
Abstract: The blue-green microalgae Spirulina, used in daily diets of natives in Africa and America, have been found to be a rich natural source of proteins, carotenoids, and other micronutrients. Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina algae on oral carcinogenesis. Studies among preschool children in India have demonstrated Spirulina fusiformis (SF) to be an effective source of dietary vitamin A. We evaluated the chemopreventive activity of SF (1 g/day for 12 mos) in reversing oral leukoplakia in pan tobacco chewers in Kerala, India. Complete regression of lesions was observed in 20 of 44 (45%) evaluable subjects supplemented with SF, as opposed to 3 of 43 (7%) in the placebo arm (p < 0.0001). When stratified by type of leukoplakia, the response was more pronounced in homogeneous lesions: complete regression was seen in 16 of 28 (57%) subjects with homogeneous leukoplakia, 2 of 8 with erythroplakia, 2 of 4 with verrucous leukoplakia, and 0 of 4 with ulcerated and nodular lesions. Within one year of discontinuing supplements, 9 of 20 (45%) complete responders with SF developed recurrent lesions. Supplementation with SF did not result in increased serum concentration of retinol or beta-carotene, nor was it associated with toxicity. This is the first human study evaluating the chemopreventive potential of SF. More studies in different settings and different populations are needed for further evaluation.
TL;DR: The reproductive histories of 333 North American women found by haplotype analysis to carry BRCAI mutations were studied and it was found that an increased risk for breast cancer was associated with low parity and with recent birth cohort.
Abstract: The majority of, but not all, women with mutations in the BRCAI gene will be affected with breast or ovarian cancer by the age of 70. To establish whether known risk factors modify susceptibility to cancer in these women, we have studied the reproductive histories of 333 North American women who were found by haplotype analysis to carry BRCAI mutations. An increased risk for breast cancer was associated with low parity and with recent birth cohort. The risk of ovarian cancer decreased with increasing age at last childbirth; however, in contrast to the case for sporadic cancer, the risk of ovarian cancer in BRCAI carriers was found to increase significantly with increasing parity. © 1995 Wiley-Liss, Inc.
TL;DR: Findings indicate that workers exposed to phenoxy herbicides and their contaminants are at a higher risk of soft tissue sarcoma.
Abstract: We examined the effect of exposure to chemicals present in the production and spraying of phenoxy herbicides or chlorophenols in two nested case-control studies of soft tissue sarcoma and non-Hodgkin's lymphoma. Eleven sarcoma and 32 lymphoma cases occurring within an international cohort were matched for age, sex, and country of residence with 55 and 158 controls, respectively. Exposures to 21 chemicals or mixtures were estimated by three industrial hygienists who were blind to the subject's case-control status. Excess risk of soft tissue sarcoma was associated with exposure to any phenoxy herbicide [odds ratio (OR) = 10.3; 95% confidence interval (CI) = 1.2-91] and to each of the three major classes of phenoxy herbicides (2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, and 4-chloro-2-methylphenoxyacetic acid), to any polychlorinated dibenzodioxin or furan (OR = 5.6; 95% CI = 1.1-28), and to 2,3,7,8-tetrachlorodibenzo-p-dioxin (OR = 5.2; 95% CI = 0.85-32). Sarcoma risk was not associated with exposure to raw materials or other process chemicals. In the non-Hodgkin's lymphoma study, associations were generally weaker than those found in the study on sarcoma. These findings indicate that workers exposed to phenoxy herbicides and their contaminants are at a higher risk of soft tissue sarcoma.
TL;DR: Evidence is provided to support the hypothesis of an association between stomach and lung cancer and exposure to lead, and the main limitation of the present analysis is that the excess risks do not take account of potential confounders.
Abstract: OBJECTIVES--To review and summarise the epidemiological evidence on the carcinogenicity of occupational exposure to inorganic lead. METHODS--Case-control and cohort studies were reviewed and combined for meta-analysis. Fixed and random effect methods were used to estimate the summary effects. RESULTS--The combined results show a significant excess risk of overall cancer, stomach cancer, lung cancer, and bladder cancer, with relative risk ratios (RRs) and 95% confidence intervals (95% CIs) in the meta-analysis of 1.11 (1.05-1.17), 1.33 (1.18-1.49), 1.29 (1.10-1.50), and 1.41 (1.16-1.71) respectively. The RR (95% CI) for kidney cancer was also high, but did not reach significance (1.19 (0.96-1.48)). A separate analysis of studies of heavily exposed workers provided slightly increased RRs for cancers of the stomach (1.50) and lung (1.42). CONCLUSIONS--The findings from the workers with heavy exposure to lead provided some evidence to support the hypothesis of an association between stomach and lung cancer and exposure to lead. The main limitation of the present analysis is that the excess risks do not take account of potential confounders, because little information was available for other occupational exposures, smoking, and dietary habits. To some extent, the risk of lung cancer might be explained by confounders such as tobacco smoking and exposure to other occupational carcinogens. The excess risk of stomach cancer may also be explained, at least in part, by non-occupational factors. For bladder and kidney cancers, the excess risks are only suggestive of a true effect because of possible publication bias.
TL;DR: The results suggest that aberrant connexin localization is rather common in cancer cells and that possible molecular mechanisms include aberrant phosphorylation of Connexin proteins and lack of cell adhesion molecules.
Abstract: Two types of intercellular communication (humoral and cell contact-mediated) are involved in control of cellular function in multicellular organisms, both of them mediated by membrane-embedded proteins. Involvement of aberrant humoral communication in carcinogenesis has been well documented and genes coding for some growth factors and their receptors have been classified as oncogenes. More recently, cell contact-mediated communication has been found to have an important role in carcinogenesis, and some genes coding for proteins involved in this type of communication appear to form a family of tumor-suppressor genes. Both homologous (among normal or (pre-)cancerous cells) as well as heterologous (between normal and (pre)cancerous cells) communications appear to play important roles in cell growth control. Gap junctional intercellular communication (GJIC) is the only means by which multicellular organisms can exchange low molecular weight signals directly from within one cell to the interior of neighboring cells. GJIC is altered by many tumor-promoting agents and in many human and rodent tumors. We have recently shown that liver tumor-promoting agents inhibit GJIC in the rat liver in vivo. Molecular mechanisms which could lead to aberrant GJIC include: (1) mutation of connexin genes; (2) reduced and/or aberrant expression of connexin mRNA; (3) aberrant localization of connexin proteins, i.e., intracytoplasmic rather than in the cytoplasmic membrane; and (4) modulation of connexin functions by other proteins, such as those involved in extracellular matrix and cell adhesion. Whilst mutations of the cx 32 gene appear to be rare in tumors, cx 37 gene mutations have been reported in a mouse lung tumor cell line. Our results suggest that aberrant connexin localization is rather common in cancer cells and that possible molecular mechanisms include aberrant phosphorylation of connexin proteins and lack of cell adhesion molecules. Studies on transfection of connexin genes into tumor cells suggest that certain connexin genes (e.g., cx 26, cx 43 and cx 32) act as tumor-suppressor genes.
TL;DR: The photograph method is recommended for the assessment of portion sizes, provided that great care is taken to suggest the volume of the food portions in the photographs and in selecting a range of portions which encompasses the range of amounts of food actually consumed in the diet.
Abstract: Photographs are valuable aids in the estimation of food portion sizes and are easy to use in dietary surveys. As with other methods, employing photographs to estimate portion sizes consumed produces errors due to the method itself and errors from other sources such as poor recall of amounts actually eaten. This study was aimed at the first type of error and investigated errors due to the visual perception of food portions from food photographs in the absence of recall biases. Two hundred and seventy women were presented with various amounts of foods and asked to indicate the portion sizes using appropriate sets of photographs. The photographs showed three portion sizes (small, medium, large) for each of 45 foods commonly found in the French diet. The portions of real food estimated by subjects were prepared to the same weights as the portions photographed. Estimates of portion sizes were compared to the weighed amounts. They were found to be accurate within 25% in most cases. Except for three foods, errors on estimates were seen for one or more portions per food. Two patterns of errors were identified. For 22 foods, the small portion sizes were overestimated and the large portion sizes underestimated, but no error occurred with the medium portion. For 20 other foods, the three portion sizes were either all underestimated or all overestimated. The first pattern of error may be due to a general tendency to avoid extreme response categories, while the second pattern of error may be related to biased visual perception. In general, there was no obvious way to link the patterns of errors with the type or physical appearance of the foods. In conclusion, the photograph method is recommended for the assessment of portion sizes, provided that great care is taken to suggest the volume of the food portions in the photographs and in selecting a range of portions which encompasses the range of amounts of food actually consumed in the diet.
TL;DR: Findings suggest a common origin of the two cellular components from neoplastic glial cells, as well as an early event in the development of gliomas.
Abstract: Gliosarcomas are morphologically heterogeneous tumors of the central nervous system composed of gliomatous and sarcomatous components. The histogenesis of the latter is still a matter of debate. As mutations of the p53 tumor suppressor gene represent an early event in the development of gliomas, we attempted to determine whether both components of gliosarcomas share identical alterations of the p53 gene. Using single-strand conformation analysis (SSCA) and direct DNA sequencing of the p53 gene, we analyzed dissected gliomatous and sarcomatous parts of 12 formalin-fixed, paraffin-embedded gliosarcomas. The two tumors that contained a p53 alteration were found to carry the identical mutation (exon 5; codon 151, CCC-->TCC; codon 173, GTG-->GTA) in the gliomatous and the sarcomatous components. These findings suggest a common origin of the two cellular components from neoplastic glial cells.
Journal Article•
TL;DR: The results demonstrate that different types of liver tumor-promoting agents inhibit dye-coupling in rat liver in vivo, and may be due to aberrant localization of the major liver gap junction protein cx 32, rather than its transcriptional or translational disregulation.
TL;DR: This is the first report of microcapsules or microspheres containing biologically active material (DNA) being passed through the gastrointestinal tract, with the potential for substantial recovery.
Abstract: Calf thymus DNA was microencapsulated within crosslinked chitosan membranes, or immobilized within chitosan-coated alginate microspheres. Microcapsules were prepared by interfacial polymerization of chitosan, and alginate microspheres formed by emulsification/ internal gelation. Diameters ranged from 20 to 500 Μm, depending on the formulation conditions. Encapsulated DNA was quantifiedin situ by direct spectrophotometry (260 nm) and ethidium bromide fluorimetry, and compared to DNA measurements on the fractions following disruption and dissolution of the microspheres. Approximately 84% of the DNA was released upon core dissolution and membrane disruption, with 12% membrane bound. The yield of encapsulation was 96%. Leakage of DNA from intact microspheres/capsules was not observed. DNA microcapsules and microspheres were recovered intact from rat feces following gavage and gastrointestinal transit. Higher recoveries (60%) and reduced shrinkage during transit were obtained with the alginate microspheres. DNA was recovered and purified from the microcapsules and microspheres by chromatography and differential precipitation with ethanol. This is the first report of microcapsules or microspheres containing biologically active material (DNA) being passed through the gastrointestinal tract, with the potential for substantial recovery.
TL;DR: The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and thatAstrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p 53 mutations are capable of initiating neoplastic transformation in astroCytes of the human nervous system.
Abstract: Diffusely infiltrating low-grade astrocytomas (WHO grade II) have an intrinsic tendency for progression to anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV). This change is due to the sequential acquisition of genetic alterations, several of which have recently been identified. In low-grade astrocytomas, p53 mutations with or without loss of heterozygosity on chromosome 17p are the principal detectable change. Anaplastic astrocytomas contain p53 mutations at an overall incidence of 34% and, in addition, loss of heterozygosity on chromosome 19q and frequent homozygous deletion of the p16 tumor suppressor (MTS-1) gene. The most malignant astrocytic neoplasms, the glioblastoma, further shows loss of chromosome 10 and amplification of the epidermal growth factor receptor (EGF-R) gene at overall incidences of 66% and 34%, respectively. The type and distribution of p53 mutations in astrocytic brain tumours are not suggestive of specific environmental carcinogens operative in their aetiology. Analysis of 91 families with p53 germline mutations reported to date show that tumours of the nervous system account to 12% of all neoplasms. Of a total of 57 brain tumours reported, 30 were classified histologically and of these, 73% were of astrocytic origin. The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and that astrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p53 mutations are capable of initiating neoplastic transformation in astrocytes of the human nervous system.
International Agency for Research on Cancer1, University of British Columbia2, University of Minnesota3, French Institute of Health and Medical Research4, Université de Montréal5, University of Siena6, Istituto Superiore di Sanità7, National Institutes of Health8, University of Turin9, University of Florence10, University of Southern California11, University of Verona12, Fred Hutchinson Cancer Research Center13
TL;DR: Support is provided to the association between exposure to wood dust in a variety of occupations and the risk of sino-nasal adenocarcinoma and are consistent with the results of individual participating studies, although the magnitude of the excess risk varied.
Abstract: In order to examine the relationship between wood dust and sino-nasal cancer, data from 12 case-control studies conducted in seven countries were pooled and reanalyzed. The relative risks associated with wood-related jobs and with exposure to wood dust, measured using a job exposure matrix based on occupation and industry titles, were examined using logistic regression. The combined data set consisted of 680 male cases, 2,349 male controls, 250 female cases, and 787 female controls. A high risk of adenocarcinoma among men was associated with employment in wood-related occupations (odds ratio [OR] = 13.5, 95% confidence interval [CI] = 9.0-20.0) and the risk was greatest among men who had been employed in jobs with the highest wood dust exposure (OR = 45.5, 95% CI = 28.3-72.9) and increased with duration of exposure. The risk of adenocarcinoma also appeared elevated among women employed in wood-related jobs (OR = 2.5, 95% CI = 0.5-12.3), but the small number of exposed cases precluded detailed analysis. Women in wood dust-exposed jobs appeared to have an excess of squamous cell carcinoma (OR = 2.1, 95% CI = 0.8-5.5) which increased with duration of exposure. An increased risk of squamous cell carcinoma in men was seen only among those employed for 30 or more years in jobs with exposure to fresh wood (OR = 2.4, 95% CI = 1.1-5.0). The results of this analysis provide strong support to the association between exposure to wood dust in a variety of occupations and the risk of sino-nasal adenocarcinoma and are consistent with the results of individual participating studies, although the magnitude of the excess risk varied. The evidence in regard to squamous cell carcinomas was ambiguous and there was a great deal of heterogeneity observed in individual study results. This may be due to differences in risk associated with exposure to hardwoods and softwoods or with other, as yet to be identified, aspects of exposure.
TL;DR: The authors conclude that when relative risks are estimated for scaled, absolute intake differences rather than for quantile categories, a "calibration" study based on only a single day's food intake record can provide sufficient reference information to meet objectives 1 and 2.
Abstract: To evaluate the accuracy of dietary intake measurements in prospective cohort studies on diet, it is generally proposed that substudies be conducted to 1) correct relative risk estimates for biases due to measurement error, and 2) account for statistical power losses when estimating the sample size requirements of the cohort. Usually the substudy takes the form of a "validity" study, based on a small group of volunteers and using repeated daily food consumption records as reference measurements. In this methodological review, the authors conclude that when relative risks are estimated for scaled, absolute intake differences rather than for quantile categories, a "calibration" study based on only a single day's food intake record (but generally on a larger number of subjects) can provide sufficient reference information to meet objectives 1 and 2. A major advantage of calibration studies based on this single-day-per-subject design is that they can be conducted on a representative sample of cohort participants more easily than validity studies in which reference measurements are repeated.
TL;DR: A screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE) and efficiently screens 95% of the coding sequence and 90% of intron/exon junctions.
Abstract: Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ-line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5' half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C-terminal end of the protein.
TL;DR: The results suggest that plakoglobin might represent a putative tumor suppressor gene for breast and ovarian cancers, and a low-frequency polymorphism in the plakoxide coding sequence results in an arginine to histidine substitution at amino acid position 142 of the protein.
Abstract: The gene encoding human plakoglobin was mapped to chromosome 17q12-q22. An intragenic restriction fragment length polymorphism was used to localize the plakoglobin gene distal to locus KRT10 and proximal to the marker D17S858. The plakoglobin gene colocalizes with the polymorphic 17q21 marker UM8 on the same cosmid insert. This subregion of chromosome 17 is known to be particularly subjected to genetic alterations in sporadic breast and ovarian tumors. We show loss of heterozygosity of the plakoglobin gene in breast and ovarian tumors. We have identified a low-frequency polymorphism in the plakoglobin coding sequence which results in an arginine to histidine substitution at amino acid position 142 of the protein, as well as a silent mutation at nucleotide position 332 of the coding sequence. This polymorphism allowed us to demonstrate an allelic association of plakoglobin with predisposition to familial breast and ovarian cancers. Our results, together with the present knowledge about the biological function of plakoglobin, suggest that plakoglobin might represent a putative tumor suppressor gene for breast and ovarian cancers.