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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical and pathological data of ten patients with gliomatosis cerebri are compared with 48 well documented cases from the literature. The most striking clinical findings were behavioural and mental changes, seizures, motor weakness and headaches. Though diagnostic techniques have gained in sophistication, the clinical diagnosis of gliomatosis cerebri remains difficult. Laboratory and radiograph tests are mostly unconclusive. Expectations that computed tomography might lead to an accurate diagnosis were not fulfilled. Histological examination disclosed a diffuse proliferation of glial elements infiltrating normal nervous tissue with destruction of myelin sheaths, but only slight damage to neurons and axons. In two cases, areas typical of oligodendroglioma were also present. Glial fibrillary acidic protein staining showed in seven cases that most of the neoplastic cells were of astrocytic origin. In addition, GFAP negative neoplastic cells with the appearance of oligodendroglia and intermediate elements between astroglia and oligodendroglia and irregularly shaped naked nuclei of unidentified nature were found. On the basis of the two-stage theory of carcinogenesis, it is suggested that this disease might be the result of propagation of initiated glial elements which have not yet undergone the process of tumor conversion.
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PMID:Gliomatosis cerebri: clinical and histological findings. 405 56

The methodology of the 1982 Report of the Surgeon General is examined with special reference to smoking and lung cancer. Part II of the Report describes the five criteria for causality that have guided the judgment of committees since 1964. I show that not one of the criteria, plausibly interpreted, is satisfied by the epidemiologic evidence for lung cancer. A weakness underlying all the Reports is a prior failure to recognize all the logical possibilities inherent in an association between smoking and a disease. The five criteria and the subjective method of "judgment" are inappropriate to a scientific analysis; they should be replaced by the objective testing of hypotheses. Limitations in the evidence and in concepts about tobacco carcinogenesis preclude definitive conclusions. Nevertheless, the entire association between cigarette smoking and lung cancer--at least in male Caucasoid populations--is unlikely to be explained by causation.
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PMID:The surgeon general's "epidemiologic criteria for causality." A critique. 665 26

An acknowledged weakness of current testing programmes for genotoxic hazard has been the potential insensitivity of the established mouse bone marrow micronucleus test and rat liver unscheduled DNA synthesis (UDS) assays to direct-acting or short-lived mutagens, which may be consumed at the site of initial contact. In such cases, in vivo test systems sampling tissues such as the skin or the stomach would provide valuable data. To test these principles a stomach UDS assay was evaluated using the potent locally active mutagen 1-chloromethylpyrene (1-CMP). Contrary to expectations, no UDS response was observed 16 h following 1-CMP dosage by oral gavage. To confirm the integrity of the 1-CMP used for the stomach UDS assay, a sample of the stored chemical was re-evaluated in vitro and shown to be still strongly positive in the Ames assay and to have alkylating activity at least 15 min after incubation at stomach acid pH. No UDS response was observed when test dose levels were reduced or when earlier sampling times were used. Other genotoxic endpoints were examined in stomach. 32P-Postlabelling analysis revealed high levels of adduct formation in gastric DNA. An assay utilizing electrophoresis of DNA (the comet assay) showed the occurrence of DNA damage following dosing with 1-CMP in vivo. These positive results confirmed that 1-CMP should be regarded as a potential in vivo genotoxin. The failure to detect a UDS response to 1-CMP in stomach was investigated; a strong UDS response was observed in an in vitro hepatocyte UDS assay of 1-CMP indicating that the rat was capable of repairing 1-CMP-derived DNA adducts. Pretreatment of rats with hydroxyurea depressed the level of incorporation of thymidine into DNA both in negative and positive [methyl-N-nitrosoguanidine (MNNG)] controls. The results of these studies indicated that the protease digestion method employed did not selectively or efficiently sample those cells with any UDS response to 1-CMP or MNNG, and the activity seen for the latter was most likely due to the presence of S phase cells within the digests. As a result of the finding that UDS responses were not demonstrated for the potent direct-acting mutagens 1-CMP and MNNG, the protease digestion/scintillation method for stomach UDS does not appear to have general value in a screening programme for locally active genotoxic agents.
Carcinogenesis 1993 Apr
PMID:Genotoxic activity of 1-chloromethylpyrene in stomach epithelium in vivo: insensitivity of the stomach scintillation UDS assay. 847 27

Polychlorinated dibenzo-p-dioxins (PCDDs), commonly known as dioxins, form as unwanted impurities in the manufacturing of chlorophenol and its derivatives--pulp and paper--and in the combustion of municipal, sewage-sludge, hospital, and hazardous waste. Combustion, in presence of a chlorine donor, seems to be a major source of these compounds. High levels of dioxins are also emitted from metallurgical industries including copper smelters, electric furnaces in steel mills, and wire reclamation incinerators. Trace levels are detectable in emissions from motor vehicles using leaded gasoline or diesel fuel, in forest fires, and in residential wood burning. Extremely persistent and widely distributed in the environment, PCDDs have been detected in all three primary and many secondary media. Releases into the air occur mainly from combustor emissions. Atmospheric dispersion, deposition, and subsequent accumulation in the food chain seem to be the major pathways of exposure to the general population. Residues of these chemicals have been detected in soil, sediment, fish, meat, cow's milk, human adipose tissue, and mothers' milk. In general, these chemicals have high lipophilicity. The elimination half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans is approximately 7-11 years. Very little human toxicity data from exposure to PCDDs are available. Health-effect data obtained from occupational settings in humans are based on exposure to chemicals contaminated with TCDD. It produces a spectrum of toxic effects in animals and is one of the most toxic chemicals known. Most of the toxicity data available on TCDD are from high-dose oral exposures to animals. Very few percutaneous and no inhalation exposure data are available in the literature. There is a wide range of difference in sensitivity to PCDD lethality in animals. The signs and symptoms of poisoning with chemicals contaminated with TCDD in humans are analogous to those observed in animals. Dioxin exposures to humans are associated with increased risk of severe skin lesions such as chloracne and hyperpigmentation, altered liver function and lipid metabolism, general weakness associated with drastic weight loss, changes in activities of various liver enzymes, depression of the immune system, and endocrine- and nervous-system abnormalities. It is a potent teratogenic and fetotoxic chemical in animals. A very potent promoter in rat liver carcinogenesis, TCDD also causes cancers of the liver and other organs in animals. Populations occupationally or accidentally exposed to chemicals contaminated with dioxin have increased incidences of soft-tissue sarcoma and non-Hodgkin's lymphoma. No comprehensive studies have been conducted to determine any health impact to the general population from environmental exposure to PCDDs. This paper presents a brief review of relevant animal and human data for projecting any possible health effects from environmental exposures to PCDDs.
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PMID:Health impact of polychlorinated dibenzo-p-dioxins: a critical review. 951 23

Most gastroduodenal ulcer disease results from a weakness in the normal gastric mucous barrier against the penetration of acid secreted by the stomach. Based on meticulous and insightful research, the distinguished physiologist Franklin Hollander hypothesized that the stomach is protected against its own acid secretion by a dynamic two-component mucus-mucosal barrier. Hollander and his co-workers defined the physical and chemical characteristics of the mucus components of this barrier, as well as the defense provided by the surface epithelial cell layer, which he viewed as the second line of defense (the second component). Barrier investigators at Mount Sinai demonstrated the effects of impairment of barrier function with resultant increased back-diffusion of acid, and they defined the consequences of this acid penetration into the gastric epithelium. The contribution of these workers included important observations on the natural impermeability of the gastric corpus and fundus as well as the normally increased permeability of the antrum. They also presented evidence on the role of bile in duodenogastric reflux in gastric ulcer disease and the presence of impaired barrier function in patients with gastric ulcer and pernicious anemia. Further studies included demonstration that stress and carcinogens could disrupt the gastric mucosal barrier. Disruption of the barrier, in turn, was shown to allow carcinogenesis to occur by permitting the absorption of certain carcinogens which otherwise are warded off by the barrier. The Hollander two-component gastric mucosal barrier hypothesis has, in recent years, been increasingly validated by experimental data coming from other laboratories.
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PMID:The gastric mucosal barrier. 1067 82

Reactions to oral contraceptive therapy tend to be maximal during the first few months of use. They include nausea or epigastric discomfort, malaise, dizziness, nervousness, fatigue, weakness, leg cramps, headache, and depression. The estrogenic component is thought to be the cause. There may also be a psychogenic basis reflecting apprehension. Breast tenderness is an occasional complaint and intermenstrual spotting or breakthrough bleeding is often reported. Increasing dosage has reduced this symptom. Dysmenorrhea prior to treatment may be improved but occasionally it is aggravated. Drug-induced amenorrhea presents a double problem in that failure to resume medication 7 days after completion of a cycle results in a risk of conception. Episodes of severe uterine bleeding in patients discontinuing use after several months or years have been reported. Other side effects include a skin reaction resembling acne, pruritus, hirsutism, thinning of scalp hair, increased skin pigmentation, and weight gain or loss. Serious vascular complications and hepatic dysfunction have been shown and deviation of thyroid function may be shown by increase of serum protein-bound iodine (PBI). Clinical signs of hyperthyroidism have not been described. Oral contraception is associated with elevated plasma cortisol (hydrocortisone) levels and decreased urinary levels of 17-hydroxycorticosteroids (17-OCHS). Suppression of ovarian activity by oral contraceptives is rapidly reversible. Fear of carcinogenesis has caused much alarm but no proof as of the present time. Safety of long term use will require additional years of experience.
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PMID:Side-effects and possible complications of oral contraceptive drugs. 1225 41

DNA double-strand breaks constitute the most dangerous type of DNA damage induced by ionising radiation (IR). Accordingly, the resistance of cells to IR is modulated by three intimately related cellular processes: DNA repair, recombination, and replication. Significant discoveries in this field of research have been made over the last few years. A picture seems to be emerging in which perturbations of recombination in cancer cells are a more widespread cause of genomic instability than previously appreciated. Conversely, such cells may also be more sensitive to certain chemotherapeutic drugs and to IR. Thus, the alterations in recombination that promote carcinogenesis by causing genomic instability may also be the weakness of the tumours that arise in this setting, a concept which could hold great promise for the advancement of cancer treatment in the not too distant future.
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PMID:Repair of radiation damage to DNA. 1505 44

Interventions designed to delay or prevent the development of invasive colorectal adenocarcinoma might result in a profound impact on the incidence of and mortality from colorectal cancer. Current developmental efforts focus in two major directions: identification and testing of combination-targeted signal transduction pathway modulators and development of nutriceuticals. Both approaches recognize the heterogeneity of the carcinogenesis process. Combinations of agents (eg, aspirin or sulindac with DFMO, calcium with fiber), which have complementary or synergistic mechanisms or agents with broad spectrum anti-carcinogenic effects can potentially improve upon the effects of single agents and account for redundant signal transduction pathways involved in uncontrolled growth of clonal cells. Preliminary data in rodent systems suggest nutriceuticals or standardized foodstuffs, which contain multiple components, many of which are not identified have synergistic anticarcinogenesis effects. Diet modulation or supplementation with known standardized foodstuffs may be ideal in individuals at risk for colorectal cancer. Current clinical models for colorectal cancer prevention focus upon a pathologic-surrogate endpoint (reducing the recurrence or emergence of adenomas). This surrogate, generally accepted at a regulatory level, might not represent the true malignant progression from normal colonic mucosa to the malignant phenotype. Could the intervention simply prevent the emergence of adenomas that would not have progressed to invasive neoplasia in any event? Despite this major weakness, the adenoma remains the regulatory endpoint for efficacy because the cancer event remains rare, even among individuals selected as high-risk epidemiology but without known, highly pressured genetic-based stress. Over the next decade, the emergence of molecular and proteomic profiling tools have the potential of selecting adenomas that will progress to adenocarcinomas and will allow for investigation to be focused on individuals at increased risk.
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PMID:Strategies for prevention of colorectal cancer: pharmaceutical and nutritional interventions. 1534 79

Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
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PMID:Hypothesis: neoplasms in myotonic dystrophy. 1964 6

Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer.
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PMID:Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates. 2138 84


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