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Sample records for carcinogenesis molecular concepts

  1. Molecular mechanisms of carcinogenesis

    International Nuclear Information System (INIS)

    Hall, E.J.

    1997-01-01

    The possibility that chromosomal changes are responsible for neoplasia was proposed in the early years of this century. A combination of improved cytogenetics and the advent of recombinant technology has settled the issue. As recently as 20 years ago, however, the genetic and molecular basis of familiar predisposition to cancer were a mystery, and it is only in the last few years that light has been shed on a few specific types of malignancies. As the genetic basis of human cancer had been documented, a number of genes have been identified as functioning either as oncogenes which act in a dominant fashion to promote tumor growth when mutated, or as tumor suppressor genes which act in a recessive fashion

  2. Molecular mechanisms in radiation carcinogenesis: introduction

    International Nuclear Information System (INIS)

    Setlow, R.B.

    1975-01-01

    Molecular studies of radiation carcinogenesis are discussed in relation to theories for extrapolating from cellular and animal models to man. Skin cancer is emphasized because of sunlight-induced photochemical damage to DNA. It is emphasized that cellular and animal models are needed as well as molecular theories for quantitative evaluation of hazardous environmental agents. (U.S.)

  3. Diet, lifestyle, and molecular alterations that drive colorectal carcinogenesis

    NARCIS (Netherlands)

    Diergaarde, B.

    2004-01-01

    Environmental factors have been repeatedly implicated in the etiology of colorectal cancer, and much is known about the molecular events involved in colorectal carcinogenesis. The relationships between environmental risk factors and the molecular alterations that drive colorectal carcinogenesis are

  4. Carcinogenesis

    International Nuclear Information System (INIS)

    Anon.

    1976-01-01

    Progress is reported on studies at the molecular, biochemical, and immunological level of carcinogenesis induced in mice by viruses, radiation, or environmental chemicals alone or in combinations. Emphasis was placed on the identification and assessments of cocarcinogens and studies on their mechanisms of action. Data are included on mechanisms of carcinogenesis in the liver, thyroid, Harderian glands, skin, and lungs. The effects of the food additive butylated hydroxytoluene (BHT), phenobarbitol, DDT, uv irradiation, the herbicide 3-amino-1,2,4-triazole(AT), the pituitary hormone prolactin, topically applied 8-methoxypsoralen (8-MOP), and benzo(a) pyrene(BaP) on tumor induction or enhancement were studied

  5. Molecular epidemiology of radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Trosko, J.E.

    1996-01-01

    The role of ionizing radiation in carcinogenesis is discussed. Every cell contains proto-oncogenes, which if damaged may lead to cell transformation. Every cell also contains tumor suppressor genes, which guard against transformation. Thus, transformation would seem to require a double injury to the DNA in a cell. Ionizing radiation is known to be a relatively weak mutagen, but a good clastogen (inducer of chromosome breaks, deletions and rearrangements). Ionizing radiation may therefore be a 'promoter' of cancer, i.e. a stimulant of the clonal expansion of transformed cells, if it kills enough cells to induce compensatory hyperplasia - i.e. rapid growth of cells. Ionizing radiation may be a 'progressor', if it deactivates tumor suppressor genes tending to suppress the growth of existing clones of transformed cells resulting from any of numerous causes. It may therefore be an oversimplification to say that radiation causes cancer; rather, it seems to be a weak initiator, an indirect promoter, and a late-stage progressor. 2 figs

  6. Molecular oncology focus - Is carcinogenesis a 'mitochondriopathy'?

    Directory of Open Access Journals (Sweden)

    Ścińska Anna

    2010-04-01

    Full Text Available Abstract Mitochondria are sub-cellular organelles that produce adenosine triphosphate (ATP through oxidative phosphorylation (OXPHOS. As suggested over 70 years ago by Otto Warburg and recently confirmed with molecular techniques, alterations in respiratory activity and in mitochondrial DNA (mtDNA appear to be common features of malignant cells. Somatic mtDNA mutations have been reported in many types of cancer cells, and some reports document the prevalence of inherited mitochondrial DNA polymorphisms in cancer patients. Nevertheless, a careful reanalysis of methodological criteria and methodology applied in those reports has shown that numerous papers can't be used as relevant sources of data for systematic review, meta-analysis, or finally for establishment of clinically applicable markers. In this review technical and conceptual errors commonly occurring in the literature are summarized. In the first place we discuss, why many of the published papers cannot be used as a valid and clinically useful sources of evidence in the biomedical and healthcare contexts. The reasons for introduction of noise in data and in consequence - bias for the interpretation of the role of mitochondrial DNA in the complex process of tumorigenesis are listed. In the second part of the text practical aspects of mtDNA research and requirements necessary to fulfill in order to use mtDNA analysis in clinics are shown. Stringent methodological criteria of a case-controlled experiment in molecular medicine are indicated. In the third part we suggest, what lessons can be learned for the future and propose guidelines for mtDNA analysis in oncology. Finally we conclude that, although several conceptual and methodological difficulties hinder the research on mitochondrial patho-physiology in cancer cells, this area of molecular medicine should be considered of high importance for future clinical practice.

  7. Initiator of carcinogenesis selectively and stably inhibits stem cell differentiation: a concept that initiation of carcinogenesis involves multiple phases

    International Nuclear Information System (INIS)

    Scott, R.E.; Maercklein, P.B.

    1985-01-01

    A concept of carcinogenesis was recently devised in our laboratory that suggests the development of defects in the control of cell differentiation is associated with an early phase of carcinogenesis. To test this proposal directly, the effects of an initiator of carcinogenesis (i.e., UV irradiation) on proadipocyte stem cell differentiation and proliferation was assayed. In this regard, 3T3 T proadipocytes represent a nontransformed mesenchymal stem cell line that possesses the ability to regulate its differentiation at a distinct state in the G 1 phase of the cell cycle as well as the ability to regulate its proliferation at two additional G 1 states. The results establish that a slow dosage of 254 nm UV irradiation selectivity and stably inhibits the differentiation of a high percentage of proadipocyte stem cells without significantly altering their ability to regulate cellular proliferation in growth factor-deficient or nutrient-deficient culture conditions. Differentiation-defect proadipocyte stem cells are demonstrated not to be completely transformed but to show an increased spontaneous transformation rate, as evidenced by the formation of type III foci in high density cell cultures. These data support the role of defects in the control of differentiation in the inhibition of carcinogenesis. These observations support a concept that the initiation of carcinogenesis involves multiple phases

  8. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome.

    Science.gov (United States)

    Ahadova, Aysel; Gallon, Richard; Gebert, Johannes; Ballhausen, Alexej; Endris, Volker; Kirchner, Martina; Stenzinger, Albrecht; Burn, John; von Knebel Doeberitz, Magnus; Bläker, Hendrik; Kloor, Matthias

    2018-07-01

    Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. © 2018 UICC.

  9. Carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.

    1975-01-01

    The long-term aims are concerned with various aspects of the natural history and biology of cancer, the mechanism of induction and of the advancement of time of appearance of tumors, the development of systems suitable for the assay of oncogenesis and cocarcinogenesis, and the elucidation of some of the factors important to the problem of extrapolation of estimates of risk made in experimental systems to the estimate of risk in man. It is necessary to have a number of test systems in order to study the various factors related to cocarcinogenesis; some of these are clearly tissue specific. The liver tumor system is clearly useful for certain compounds, and the liver is an excellent tissue for the study of the mechanisms of cocarcinogenesis. This year we report on the relatively rapid induction of what appears histologically to be carcinoma of the thyroid by aminotriazole. In a collaborative study with the Neutron and Gamma-Ray Toxicity Group, we have established a new example of synergism in carcinogenesis, namely between radiation and pituitary hormone(s) in the production of Harderian gland tumors. Not only does a synergistic effect on incidence occur, but also on the degree of malignancy of the tumor induced. We thus have three different model systems for the study of various aspects of cocarcinogenesis: various chemicals, including nononcogenic polycyclic hydrocarbons, in liver tumorigenesis; ionizing radiation and aminotriazole in thyroid tumorigenesis; and in conjunction with the JANUS Program, the interaction of radiation and hormones in the production of Harderian gland, mammary gland, and other tumors

  10. Carcinogenesis

    International Nuclear Information System (INIS)

    Reilly, C.A. Jr.

    1979-01-01

    This section contains summaries of research in the following areas: use of liver for mechanistic studies of multistage hepatocarcinogenesis and for screening of environmental contaminants for tumor initiating and promoting activity; molecular properties of rat liver ornithine aminotransferase; regulation of gene expression in rat liver; methods of tumor detection; mechanisms of radiation and viral oncogenesis; biphenyl metabolism by rat liver microsomes; and studies on aryl hydrocarbon hydroxylase activity

  11. BRAFV600E: implications for carcinogenesis and molecular therapy.

    LENUS (Irish Health Repository)

    Cantwell-Dorris, Emma R

    2012-02-01

    The mitogen-activated protein kinase (MAPK)\\/extracellular signal-regulated kinase (ERK) pathway is frequently mutated in human cancer. This pathway consists of a small GTP protein of the RAS family that is activated in response to extracellular signaling to recruit a member of the RAF kinase family to the cell membrane. Active RAF signals through MAP\\/ERK kinase to activate ERK and its downstream effectors to regulate a wide range of biological activities including cell differentiation, proliferation, senescence, and survival. Mutations in the v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) isoform of the RAF kinase or KRAS isoform of the RAS protein are found as activating mutations in approximately 30% of all human cancers. The BRAF pathway has become a target of interest for molecular therapy, with promising results emerging from clinical trials. Here, the role of the most common BRAF mutation BRAF(V600E) in human carcinogenesis is investigated through a review of the literature, with specific focus on its role in melanoma, colorectal, and thyroid cancers and its potential as a therapeutic target.

  12. Recent Concepts of Ovarian Carcinogenesis: Type I and Type II

    Directory of Open Access Journals (Sweden)

    Masafumi Koshiyama

    2014-01-01

    Full Text Available Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas. The carcinogenesis of endometrioid and clear cell carcinoma (CCC arising from endometriotic cysts is significantly influenced by the free iron concentration, which is associated with cancer development through the induction of persistent oxidative stress. A subset of mucinous carcinomas develop in association with ovarian teratomas; however, the majority of these tumors do not harbor any teratomatous component. Other theories of their origin include mucinous metaplasia of surface epithelial inclusions, endometriosis, and Brenner tumors. Low grade serous carcinomas are thought to evolve in a stepwise fashion from benign serous cystadenoma to a serous borderline tumor (SBT. With regard to high grade serous carcinoma, the serous tubal intraepithelial carcinomas (STICs of the junction of the fallopian tube epithelium with the mesothelium of the tubal serosa, termed the “tubal peritoneal junction” (TPJ, undergo malignant transformation due to their location, and metastasize to the nearby ovary and surrounding pelvic peritoneum. Other theories of their origin include the ovarian hilum cells.

  13. Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Payne CM

    2011-05-01

    Full Text Available Claire M Payne, Cheray Crowley-Skillicorn, Carol Bernstein, Hana Holubec, Harris BernsteinDepartment of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USAAbstract: Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.Keywords: chromosome 1p, colon carcinogenesis, molecular pathways, cellular pathways

  14. Molecular profiles of finasteride effects on prostate carcinogenesis.

    Science.gov (United States)

    Li, Jin; Kim, Jeri

    2009-06-01

    Our inability to distinguish between low-grade prostate cancers that pose no threat and those that can kill compels newly diagnosed early prostate cancer patients to make decisions that may negatively affect their lives needlessly for years afterward. To reliably stratify patients into different risk categories and apply appropriate treatment, we need a better molecular understanding of prostate cancer progression. Androgen ablation therapy and 5-alpha reductase inhibitors reduce dihydrotestosterone levels and increase apoptosis. Because of the differing biological potentials of tumor cells, however, these treatments may, in some cases, worsen outcome by selecting for or inducing adaptation of stronger androgen receptor signaling pathways. Reduced dihydrotestosterone also may be associated with altered survival pathways. Complicating treatment effects further, molecular adaptation may be accelerated by interactions between epithelial and stromal cells. The hypothesis that early prostate cancer cells with differing biological potential may respond differently to finasteride treatment is worth testing. Ongoing studies using a systems biology approach in a preoperative prostate cancer setting are testing this hypothesis toward developing more-rational clinical interventions.

  15. Basic molecular biology in radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Rytoemaa, T.

    1992-01-01

    The tumour suppressor gene p53 is 'guardian of the genome'. If a DNA molecule (each chromosome has one DNA molecule) is damaged by an external factor, such as ionizing radiation, the protein product of the p53 gene stops the cell's proliferative activity until the damage is repaired. If the repair fails, the p53 gene product normally triggers programmed death of the cell. P53 gene itself is commonly damaged by radiation (or by another DNA-damaging factor). The altered gene product fails to control the integrity of the genome, and it also prevents the guardian action of the protein which is produced by the intact allele (each cell has two p53 genes). Under these circumstances any subsequent damage to DNA, induced e.g. by a chemical, is easily 'fixed'. Potentially critical sites for an additional DNA damage are the proto-oncogens (when damaged these genes are called oncogens), which commonly act as components of the regulatory network in a cell. Permanent malfunction of the signal network may then lead to uncontrolled cell growth, resulting in a malignant clone (=cancer). This simplified molecular model seems to be the common mechanism in many (or most) human cancers. (orig.)

  16. Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

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    Takeshi Toyoda

    2014-06-01

    Full Text Available Since the discovery of Helicobacter pylori (H. pylori, many efforts have been made to establish animal models for the investigation of the pathological features and molecular mechanisms of gastric carcinogenesis. Among the animal models, Mongolian gerbils and mice are particularly useful for the analysis of H. pylori-associated inflammatory reactions and gastric cancer development. Inhibitors of oxidative stress, cyclooxygenase-2 (COX-2 and nuclear factor-κB, exert preventive effects on chronic gastritis and the development of adenocarcinomas in H. pylori-infected gerbils. Genetically-modified mouse models, including transgenic and knockout mice, have also revealed the importance of p53, COX-2/prostaglandin, Wnt/β-catenin, proinflammatory cytokines, gastrin and type III mucin in the molecular mechanisms of gastric carcinogenesis. Microarray technology is available for comprehensive gene analysis in the gastric mucosa of mouse models, and epigenetics, such as DNA methylation, could be an alternative approach to correlate the observations in animal models with the etiology in humans.

  17. Genetic and Molecular Differences in Prostate Carcinogenesis between African American and Caucasian American Men

    Directory of Open Access Journals (Sweden)

    Shiv Srivastava

    2013-07-01

    Full Text Available Prostate cancer is the most common non-skin cancer and the second leading cause of cancer-related death for men in the United States. Prostate cancer incidence and associated mortality are highest in African American men in comparison to other races. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different pathways of prostate carcinogenesis between African American and Caucasian men. This review focuses on some of the recent molecular biology discoveries, which have been investigated in prostate carcinogenesis and their likely contribution to the known discrepancies across race and ethnicity. Key discussion points include the androgen receptor gene structure and function, genome-wide association studies and epigenetics. The new observations of the ethnic differences of the ERG oncogene, the most common prostate cancer gene, are providing new insights into ERG based stratification of prostate cancers in the context of ethnically diverse patient populations. This rapidly advancing knowledge has the likely potential to benefit clinical practice. Current and future work will improve the ability to sub-type prostate cancers by molecular alterations and lead to targeted therapy against this common malignancy.

  18. Protective molecular mechanisms of resveratrol in UVR-induced Skin carcinogenesis.

    Science.gov (United States)

    Aziz, Saba W; Aziz, Moammir H

    2018-01-01

    Skin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Borg, D.C.

    1984-01-01

    Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures. (ACR)

  20. Report of National Cancer Institute symposium: comparison of mechanisms of carcinogenesis by radiation and chemical agents. I. Common molecular mechanisms

    International Nuclear Information System (INIS)

    Borg, D.C.

    1984-01-01

    Some aspects of molecular mechanisms common to radiation and chemical carcinogenesis are discussed, particularly the DNA damage done by these agents. Emphasis is placed on epidemiological considerations and on dose-response models used in risk assessment to extrapolate from experimental data obtained at high doses to the effects from long-term, low-level exposures. 3 references, 6 figures

  1. Radiation carcinogenesis

    International Nuclear Information System (INIS)

    Adams, G.E.

    1987-01-01

    In this contribution about carcinogenesis induced by ionizing radiation some radiation dose-response relationships are discussed. Curves are shown of the relation between cell survival and resp. low and high LET radiation. The difference between both curves can be ascribed to endogenous repair mechanisms in the cell. The relation between single-gen mutation frequency and the surviving fractions of irradiated cells indicates that these repairing mechanisms are not error free. Some examples of reverse dose-response relationships are presented in which decreasing values of dose-rate (LET) correspond with increasing radiation induced cell transformation. Finally some molecular aspects of radiation carcinogenesis are discussed. (H.W.). 22 refs.; 4 figs

  2. New concepts for molecular magnets

    Science.gov (United States)

    Pilawa, Bernd

    1999-03-01

    Miller and Epstein (1994) define molecular magnets as magnetic materials which are prepared by the low-temperature methods of the preparative chemistry. This definition includes molecular crystals of neutral radicals, radical salts and charge transfer complexes as well as metal complexes and polymers with unpaired spins (Dormann 1995). The challenge of molecular magnets consists in tailoring magnetic properties by specific modifications of the molecular units. The combination of magnetism with mechanical or electrical properties of molecular compounds promise materials of high technical interest (Gatteschi 1994a and 1994b, Möhwald 1996) and both the chemical synthesis of new molecular materials with magnetic properties as well as the physical investigation and explanation of these properties is important, in order to achieve any progress. This work deals with the physical characterization of the magnetic properties of molecular materials. It is organized as follows. In the first part molecular crystals of neutral radicals are studied. After briefly discussing the general magnetic properties of these materials and after an overview over the physical principles of exchange interaction between organic radicals I focus on the interplay between the crystallographic structure and the magnetic properties of various derivatives of the verdazyl and nitronyl nitroxide radicals. The magnetic properties of metal complexes are the subject of the second part. After an overview over the experimental and theoretical tools which are used for the investigation of the magnetic properties I shortly discuss the exchange coupling of transition metal ions and the magnetic properties of complexes of two and three metal ions. Special emphasis is given to spin cluster compounds. Spin cluster denote complexes of many magnetic ions. They are attractive as building blocks of molecular magnets as well as magnetic model compounds for the study of spin frustration, molecular super

  3. Molecular markers of carcinogenesis for risk stratification of individuals with colorectal polyps: a case-control study.

    Science.gov (United States)

    Gupta, Samir; Sun, Han; Yi, Sang; Storm, Joy; Xiao, Guanghua; Balasubramanian, Bijal A; Zhang, Song; Ashfaq, Raheela; Rockey, Don C

    2014-10-01

    Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer. We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n = 216; 46% female) in which cases were patients with colorectal cancer and synchronous adenoma and controls were patients with adenoma but no colorectal cancer at baseline or within 5 years of follow-up. In phase I of analyses, we compared expression of molecular markers of carcinogenesis in case and control adenomas, blind to case status. In phase II of analyses, patients were randomly divided into independent training and validation groups to develop a model for predicting case status. We found that seven markers [p53, p21, Cox-2, β-catenin (BCAT), DNA-dependent protein kinase (DNApkcs), survivin, and O6-methylguanine-DNA methyltransferase (MGMT)] were significantly associated with case status on unadjusted analyses, as well as analyses adjusted for age and advanced adenoma status (P marker component). When applied to the validation set, a predictive model using these seven markers showed substantial accuracy for identifying cases [area under the receiver operation characteristic curve (AUC), 0.83; 95% confidence interval (CI), 0.74-0.92]. A parsimonious model using three markers performed similarly to the seven-marker model (AUC, 0.84). In summary, we found that molecular markers of carcinogenesis distinguished adenomas from patients with and without colorectal cancer. Furthermore, we speculate that prospective studies using molecular markers to identify individuals with polyps at risk for future neoplasia are warranted. ©2014 American Association for Cancer Research.

  4. Molecular concept in human oral cancer.

    Science.gov (United States)

    Krishna, Akhilesh; Singh, Shraddha; Kumar, Vijay; Pal, U S

    2015-01-01

    The incidence of oral cancer remains high in both Asian and Western countries. Several risk factors associated with development of oral cancer are now well-known, including tobacco chewing, smoking, and alcohol consumption. Cancerous risk factors may cause many genetic events through chromosomal alteration or mutations in genetic material and lead to progression and development of oral cancer through histological progress, carcinogenesis. Oral squamous carcinogenesis is a multistep process in which multiple genetic events occur that alter the normal functions of proto-oncogenes/oncogenes and tumor suppressor genes. Furthermore, these gene alterations can deregulate the normal activity such as increase in the production of growth factors (transforming growth factor-α [TGF-α], TGF-β, platelet-derived growth factor, etc.) or numbers of cell surface receptors (epidermal growth factor receptor, G-protein-coupled receptor, etc.), enhanced intracellular messenger signaling and mutated production of transcription factors (ras gene family, c-myc gene) which results disturb to tightly regulated signaling pathways of normal cell. Several oncogenes and tumor suppressor genes have been implicated in oral cancer especially cyclin family, ras, PRAD-1, cyclin-dependent kinase inhibitors, p53 and RB1. Viral infections, particularly with oncogenic human papilloma virus subtype (16 and 18) and Epstein-Barr virus have tumorigenic effect on oral epithelia. Worldwide, this is an urgent need to initiate oral cancer research programs at molecular and genetic level which investigates the causes of genetic and molecular defect, responsible for malignancy. This approach may lead to development of target dependent tumor-specific drugs and appropriate gene therapy.

  5. Studies on the repair of double strand break of DNA and cellular carcinogenesis, and consideration on the concept of extinction of nuclear power

    International Nuclear Information System (INIS)

    Teraoka, Hirobumi

    2013-01-01

    This paper describes the relationship between the repair of double strand break (DSB) of DNA and cellular carcinogenesis mainly on author's investigations, and his recent thought aiming at the extinction of nuclear power. The molecular repairing system is explained about DNA DSB induced by radiation and chemicals. When DSB occurs, nucleosome consisting from 4 core-histones participates to link the broken ends and then repair mechanisms of homologous recombination (HRR) and non-homologous end joining (NHEJ) begin to work. The latter is dominant in mammalians. Thus the genetic defect in these systems of DSB response and repair is a course of disorders such as ataxia telangiectasia (AT) (DSB sensor defect), genetic breast cancer (HRR defect), and radiosensitive-severe combined immunodeficiency (RS-SCID) (NHEJ defect), all of which result in cancer formation. NHEJ repair is known to be error-prone. Against multi-step carcinogenesis where accumulated gene mutations lead to the cancer formation, the author thinks chromosomal instability is one of important carcinogenic causes: the instability can be a trigger of producing cancer stem cells because the cells can be yielded from mouse embryonic stem cells where DSB is shown to participate in the process. Low dose radiation produces a small amount of DSB, to which the repair response is less sensitive at G2/M checkpoint, ultimately leading to genomic instability. Considering effects of the low dose radiation exposure above, and of the internal exposure to 3 H-thymidine beta ray in cells, of indoor Rn participating 16% of lung cancer incidence (Canadian epidemiological data) and so on, together with moral and social responsibility of scientist and technologist, the author says to have attained to the concept of the ''Extinction of Nuclear Power''. (T.T)

  6. Molecular Genetic Changes Associated With Colorectal Carcinogenesis Are Not Prognostic for Tumor Regression Following Preoperative Chemoradiation of Rectal Carcinoma

    International Nuclear Information System (INIS)

    Zauber, N. Peter; Marotta, Steven P.; Berman, Errol; Grann, Alison; Rao, Maithili; Komati, Naga; Ribiero, Kezia; Bishop, D. Timothy

    2009-01-01

    Purpose: Preoperative chemotherapy and radiation has become the standard of care for many patients with rectal cancer. The therapy may have toxicity and delays definitive surgery. It would therefore be desirable to identify those cancers that will not regress with preoperative therapy. We assessed a series of rectal cancers for the molecular changes of loss of heterozygosity of the APC and DCC genes, K-ras mutations, and microsatellite instability, changes that have clearly been associated with rectal carcinogenesis. Methods and Materials: Diagnostic colonoscopic biopsies from 53 patients who received preoperative chemotherapy and radiation were assayed using polymerase chain reaction techniques followed by single-stranded conformation polymorphism and DNA sequencing. Regression of the primary tumor was evaluated using the surgically removed specimen. Results: Twenty-three lesions (45%) were found to have a high degree of regression. None of the molecular changes were useful as indicators of regression. Conclusions: Recognized molecular changes critical for rectal carcinogenesis including APC and DCC loss of heterozygosity, K-ras mutations, and microsatellite instability are not useful as indicators of tumor regression following chemoradiation for rectal carcinoma.

  7. The molecular concept of law

    Directory of Open Access Journals (Sweden)

    Hendrik Gommer

    2011-04-01

    Full Text Available In his famous work The Concept of Law Hart asked himself the question 'what is law?' Hart makes a very strict distinction between rules and morals: morals are rooted in biology, rules source back to society. Hart's sociological truisms have proven to be untrue, because modern evolutionary biology is not about the survival of the individual (or even of a species but about the spreading of genes. This knowledge changes the fundamentals of Hart's theory and therefore his theory as a whole. In addition, my theory captures vital insights of Dworkin, legal realism, Posner and CLS, while at the same time forming a significant improvement upon them.In essence, the biological theory of law presented in this article is based on fractal patterns. Macroscale patterns recur in microscale patterns. The spreading of genes depends on important characteristics of genes: they are stable, they replicate, they need nutrients to replicate and they can cooperate. Superficially, genes, cells, organisms and groups may seem to act purposefully, but it is merely a pattern, with genes as generators, that brings structure to chaos. Human desires are in fact the needs of their genes. Thanks to language, morals can be put in words and become rules. To keep everyone working together, we need an ingenious device - like the law - to maintain that complex situations can continue to be judged on the basis of the simple principle of stability and reciprocity. To a degree, therefore, law itself can be derived from unconscious emotions and morals.

  8. Cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Waalkes, Michael P.

    2003-01-01

    Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis

  9. Cadmium carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Waalkes, Michael P

    2003-12-10

    Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.

  10. Molecular Phylogenetics: Concepts for a Newcomer.

    Science.gov (United States)

    Ajawatanawong, Pravech

    Molecular phylogenetics is the study of evolutionary relationships among organisms using molecular sequence data. The aim of this review is to introduce the important terminology and general concepts of tree reconstruction to biologists who lack a strong background in the field of molecular evolution. Some modern phylogenetic programs are easy to use because of their user-friendly interfaces, but understanding the phylogenetic algorithms and substitution models, which are based on advanced statistics, is still important for the analysis and interpretation without a guide. Briefly, there are five general steps in carrying out a phylogenetic analysis: (1) sequence data preparation, (2) sequence alignment, (3) choosing a phylogenetic reconstruction method, (4) identification of the best tree, and (5) evaluating the tree. Concepts in this review enable biologists to grasp the basic ideas behind phylogenetic analysis and also help provide a sound basis for discussions with expert phylogeneticists.

  11. Molecular concept in human oral cancer

    OpenAIRE

    Krishna, Akhilesh; Singh, Shraddha; Kumar, Vijay; Pal, U. S.

    2015-01-01

    The incidence of oral cancer remains high in both Asian and Western countries. Several risk factors associated with development of oral cancer are now well-known, including tobacco chewing, smoking, and alcohol consumption. Cancerous risk factors may cause many genetic events through chromosomal alteration or mutations in genetic material and lead to progression and development of oral cancer through histological progress, carcinogenesis. Oral squamous carcinogenesis is a multistep process in...

  12. Radiation carcinogenesis

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram deals with all aspects of radiation carcinogenesis. The term radiation here includes U-V radiation and the entire electromagnetic spectrum, electron and other charged particle beams, neutrons, and alpha and beta radiation from radioactive substances. Abstracts included concern relationships between radiation and carcinogenesis in humans, experimental induction of tumors in animals by irradiation, studies on the mechanism of radiation carcinogenesis at the cellular level, studies of RBE, dose response or dose threshold in relation to radiation carcinogenesis, and methods and policies for control of radiation exposure in the general population. In general, this Cancergram excludes abstracts on radio-therapy, radiologic diagnosis, radiation pathology, and radiation biology, where these articles have no bearing on radiation carcinogenesis

  13. Monitoring pancreatic carcinogenesis by the molecular imaging of cathepsin E in vivo using confocal laser endomicroscopy.

    Directory of Open Access Journals (Sweden)

    Hui Li

    Full Text Available The monitoring of pancreatic ductal adenocarcinoma (PDAC in high-risk populations is essential. Cathepsin E (CTSE is specifically and highly expressed in PDAC and pancreatic intraepithelial neoplasias (PanINs, and its expression gradually increases along with disease progression. In this study, we first established an in situ 7,12-dimethyl-1,2-benzanthracene (DMBA-induced rat model for PanINs and PDAC and then confirmed that tumorigenesis properties in this model were consistent with those of human PDAC in that CTSE expression gradually increased with tumor development using histology and immunohistochemistry. Then, using in vivo imaging of heterotopically implanted tumors generated from CTSE- overexpressing cells (PANC-1-CTSE in nude mice and in vitro imaging of PanINs and PDAC in DMBA-induced rats, the specificity of the synthesized CTSE-activatable probe was verified. Quantitative determination identified that the fluorescence signal ratio of pancreatic tumor to normal pancreas gradually increased in association with progressive pathological grades, with the exception of no significant difference between PanIN-II and PanIN-III grades. Finally, we monitored pancreatic carcinogenesis in vivo using confocal laser endomicroscopy (CLE in combination with the CTSE-activatable probe. A prospective double-blind control study was performed to evaluate the accuracy of this method in diagnosing PDAC and PanINs of all grades (>82.7%. This allowed us to establish effective diagnostic criteria for CLE in PDAC and PanINs to facilitate the monitoring of PDAC in high-risk populations.

  14. Curcumin Protects against UVB-Induced Skin Cancers in SKH-1 Hairless Mouse: Analysis of Early Molecular Markers in Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Kuen-Daw Tsai

    2012-01-01

    Full Text Available Curcumin (CUR has been shown to possess a preventive effect against various cancers and interfere with multiple-cell signaling pathways. We evaluated the protective effects of CUR in regression of UVB-induced skin tumor formation in SKH-1 hairless mice and its underlying early molecular biomarkers associated with carcinogenesis. Mice irradiated with UVB at 180 mJ/cm2 twice per week elicited 100% tumor incidence at 20 weeks. Topical application of CUR prior to UVB irradiation caused delay in tumor appearance, multiplicity, and size. Topical application of CUR prior to and immediately after a single UVB irradiation (180 mJ/cm2 resulted in a significant decrease in UVB-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells together with an increase in p53 and p21/Cip1-positive cell population in epidermis. Simultaneously, CUR also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2, prostaglandin E2 (PGE2, and nitric oxide (NO levels. The results suggest that the protective effect of CUR against photocarcinogenesis is accompanied by downregulation of cell proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-κB, and of inflammatory responses involving COX-2, PGE2, and NO, while upregulation of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair.

  15. The molecular biology of radiation-induced carcinogenesis: thymic lymphoma, myeloid leukaemia and osteosarcoma

    Energy Technology Data Exchange (ETDEWEB)

    Janowski, M [Centre d' Etude de l' Energie Nucleaire, Mol (Belgium); Cox, R [Medical Research Council, Harwell (UK). Radiobiological Research Unit; Strauss, P G [GSF, Neuherberg (Germany, F.R.). Abt. fuer Molekulare Zellpathologie

    1990-04-01

    In mice, external X- or {gamma}-irradiation may induce thymic lymphomas or myeloid leukaemias, while bone-seeking {alpha}-emitters may induce osteosarcomas, and to a lesser extent acute myeloid leukaemia. The paper reviews briefly some experimental data in respect to molecular mechanisms underlying these radio-carcinogenic processes. Thymic lymphomagenesis proceeds by an indirect mechanism in which recombinant proviruses could be involved. Myeloid leukaemogenesis is characterized by a very early putative initiating event, consisting of non-random rearrangements and/or deletions of chromosome 2. Osteosarcomagenesis in mice is often associated with the expression of proviruses, and the tumors often contain somatically acquired proviruses. (UK).

  16. Defining Molecular Sensors to Assess Long-Term Effects of Pesticides on Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Fanny L'Héritier

    2014-09-01

    Full Text Available The abundance of dioxins and dioxin-like pollutants has massively increased in the environment due to human activity. These chemicals are particularly persistent and accumulate in the food chain, which raises major concerns regarding long-term exposure to human health. Most dioxin-like pollutants activate the aryl hydrocarbon receptor (AhR transcription factor, which regulates xenobiotic metabolism enzymes that belong to the cytochrome P450 1A family (that includes CYP1A1 and CYP1B1. Importantly, a crosstalk exists between estrogen receptor α (ERα and AhR. More specifically, ERα represses the expression of the CYP1A1 gene, which encodes an enzyme that converts 17β-estradiol into 2-hydroxyestradiol. However, (ERα does not repress the CYP1B1 gene, which encodes an enzyme that converts 17β-estradiol into 4-hydroxyestradiol, one of the most genotoxic estrogen metabolites. In this review, we discuss how chronic exposure to xenobiotic chemicals, such as pesticides, might affect the expression of genes regulated by the AhR–ERα crosstalk. Here, we focus on recent advances in the understanding of molecular mechanisms that mediate this crosstalk repression, and particularly on how ERα represses the AhR target gene CYP1A1, and could subsequently promote breast cancer. Finally, we propose that genes implicated in this crosstalk could constitute important biomarkers to assess long-term effects of pesticides on human health.

  17. Molecular evolution of colorectal cancer: from multistep carcinogenesis to the big bang.

    Science.gov (United States)

    Amaro, Adriana; Chiara, Silvana; Pfeffer, Ulrich

    2016-03-01

    Colorectal cancer is characterized by exquisite genomic instability either in the form of microsatellite instability or chromosomal instability. Microsatellite instability is the result of mutation of mismatch repair genes or their silencing through promoter methylation as a consequence of the CpG island methylator phenotype. The molecular causes of chromosomal instability are less well characterized. Genomic instability and field cancerization lead to a high degree of intratumoral heterogeneity and determine the formation of cancer stem cells and epithelial-mesenchymal transition mediated by the TGF-β and APC pathways. Recent analyses using integrated genomics reveal different phases of colorectal cancer evolution. An initial phase of genomic instability that yields many clones with different mutations (big bang) is followed by an important, previously not detected phase of cancer evolution that consists in the stabilization of several clones and a relatively flat outgrowth. The big bang model can best explain the coexistence of several stable clones and is compatible with the fact that the analysis of the bulk of the primary tumor yields prognostic information.

  18. Theoretical Concepts in Molecular Photodissociation Dynamics

    DEFF Research Database (Denmark)

    Henriksen, Niels Engholm

    1995-01-01

    This chapter contains sections titled: Introduction Quantum Dynamics of Molecular Photofragmentation The Total Reaction Probability Final Product Distributions Time-Independent Approach, Stationary Scattering States Gaussian Wave Packet Dynamics Wigner Phase Space Representation The Diatomic...

  19. The Molecular Biology Capstone Assessment: A Concept Assessment for Upper-Division Molecular Biology Students

    Science.gov (United States)

    Couch, Brian A.; Wood, William B.; Knight, Jennifer K.

    2015-01-01

    Measuring students' conceptual understandings has become increasingly important to biology faculty members involved in evaluating and improving departmental programs. We developed the Molecular Biology Capstone Assessment (MBCA) to gauge comprehension of fundamental concepts in molecular and cell biology and the ability to apply these concepts in…

  20. Metabolic syndrome: clinical concept and molecular basis.

    Science.gov (United States)

    Funahashi, Tohru; Matsuzawa, Yuji

    2007-01-01

    The metabolic syndrome is a cluster of insulin resistance, elevated blood pressure, and atherogenic dyslipidemia and is a common basis of cardiovascular diseases (CVD). Although the precise mechanism remains to be elucidated, a practical definition is needed. A worldwide definition that considers increased waist circumference as an essential component has been settled. Visceral fat locates upstream of the liver. Free fatty acids and glycerol derived from visceral fat reach the liver and stimulate lipoprotein synthesis and gluconeogenesis, respectively. The adipose tissue produces a variety of bioactive substances conceptualized as 'adipocytokines'. Overproduction of plasminogen activator inhibitor-1 and tumor necrosis factor- seems to relate to the thrombotic and inflammatory tendency. On the other hand, adiponectin, which has antiatherogenic and antidiabetic activities, is reduced in subjects with metabolic syndrome. In Japan, the waist circumference criterion based on visceral fat accumulation has been adopted. The concept of this syndrome has been widely publicized, and health promotion programs based on the concept have commenced in various areas of the country. Such 'Adipo-Do-It' movement is an incentive to encourage physical exercise to reduce visceral fat and is a big challenge to prevent life-style-related diseases and CVD.

  1. Molecular concepts of water splitting. Nature's approach

    International Nuclear Information System (INIS)

    Cox, Nicholas; Lubitz, Wolfgang

    2013-01-01

    Based on studies of natural systems, much has also been learned concerning the design principles required for biomimetic catalysis of water splitting and hydrogen evolution. In summary, these include use of abundant and inexpensive metals, the effective protection of the active sites in functional environments, repair/replacement of active components in case of damage, and the optimization of reaction rates. Biomimetic chemistry aims to mimic all these features; many labs are working toward this goal by developing new approaches in the design and synthesis of such systems, encompassing not only the catalytic center, but also smart matrices and assembly via self-organization. More stable catalysts that do not require self-repair may be obtained from fully artificial (inorganic) catalytic systems that are totally different from the biological ones and only apply some basic principles learned from nature. Metals other than Mn/Ca, Fe, and Ni could be used (e.g. Co) in new ligand spheres and other matrices. For light harvesting, charge separation/stabilization, and the effective coupling of the oxidizing/reducing equivalents to the redox catalysts, different methods have been proposed - for example, covalently linked molecular donor-acceptor systems, photo-voltaic devices, semiconductor-based systems, and photoactive metal complexes. The aim of all these approaches is to develop catalytic systems that split water with sunlight into hydrogen and oxygen while displaying high efficiency and long-term stability. Such a system - either biological, biomimetic, or bioinspired - has the potential to be used on a large scale to produce 'solar fuels' (e.g. hydrogen or secondary products thereof). (orig.)

  2. Carcinogenesis. Genetics and circumstances

    International Nuclear Information System (INIS)

    Hino, Okio

    2005-01-01

    Described are the author's study and aspect concerning carcinogenesis and radiation carcinogenesis, where he thinks cancer is not automatic, has a process and takes time. For radiation carcinogenic studies, he has used a model of the rat with genetically determined kidney cancer which is highly radiosensitive. That is, mutation by the so-called 2nd-hit of the causal gene (tumor suppressing gene Tsc2) is studied in the animal where the 1st-hit has been done by retrotransposon insertion, with and without exposure to radiations (X-ray, heavy particle beam and cosmic ray) for elucidating the mutation spectrum of the causal gene, the carcinogenic target, for the ultimate aim to prevent human cancer. He discusses the drama-type molecular mechanisms leading to cancer, gene abnormality and disease crisis, discontinuity in continuity in cancer formation, and importance of the timely diagnosis and appropriate therapy, and concludes the present age is becoming such one as that the nature of cancer even if genetic can be controlled by circumstances like timely and appropriate intervention. (S.I.)

  3. Molecular-Scale Electronics: From Concept to Function.

    Science.gov (United States)

    Xiang, Dong; Wang, Xiaolong; Jia, Chuancheng; Lee, Takhee; Guo, Xuefeng

    2016-04-13

    Creating functional electrical circuits using individual or ensemble molecules, often termed as "molecular-scale electronics", not only meets the increasing technical demands of the miniaturization of traditional Si-based electronic devices, but also provides an ideal window of exploring the intrinsic properties of materials at the molecular level. This Review covers the major advances with the most general applicability and emphasizes new insights into the development of efficient platform methodologies for building reliable molecular electronic devices with desired functionalities through the combination of programmed bottom-up self-assembly and sophisticated top-down device fabrication. First, we summarize a number of different approaches of forming molecular-scale junctions and discuss various experimental techniques for examining these nanoscale circuits in details. We then give a full introduction of characterization techniques and theoretical simulations for molecular electronics. Third, we highlight the major contributions and new concepts of integrating molecular functionalities into electrical circuits. Finally, we provide a critical discussion of limitations and main challenges that still exist for the development of molecular electronics. These analyses should be valuable for deeply understanding charge transport through molecular junctions, the device fabrication process, and the roadmap for future practical molecular electronics.

  4. Molecular biology - Part I: Techniques, terminology, and concepts

    International Nuclear Information System (INIS)

    Brown, J. Martin

    1996-01-01

    Purpose/Objective: One of the barriers to understanding modern molecular biology is the lack of a clear understanding of the relevant terminology, techniques, and concepts. This refresher course is intended to address these deficiencies starting from a basic level. The lecture will cover many of the common uses of recombinant DNA, including gene cloning and manipulation. The goal is to enable the nonspecialist to increase his or her understanding of molecular biology in order to more fully enjoy reading current publications and/or listening seminars. Radiation biologists trying to understand a little more molecular biology should also benefit. The following concepts will be among those explained and illustrated: restriction endonucleases, gel electrophoresis, gene cloning, use of vectors such as plasmids, bacteriophage, cosmids and viruses, cDNA and genomic libraries, Southern, Northern, and Western blotting, fluorescent in situ hybridization, polymerase chain reaction (PCR), gel retardation, and reporter gene assays

  5. Molecular conservation of estrogen-response associated with cell cycle regulation, hormonal carcinogenesis and cancer in zebrafish and human cancer cell lines

    Directory of Open Access Journals (Sweden)

    Govindarajan Kunde R

    2011-05-01

    Full Text Available Abstract Background The zebrafish is recognized as a versatile cancer and drug screening model. However, it is not known whether the estrogen-responsive genes and signaling pathways that are involved in estrogen-dependent carcinogenesis and human cancer are operating in zebrafish. In order to determine the potential of zebrafish model for estrogen-related cancer research, we investigated the molecular conservation of estrogen responses operating in both zebrafish and human cancer cell lines. Methods Microarray experiment was performed on zebrafish exposed to estrogen (17β-estradiol; a classified carcinogen and an anti-estrogen (ICI 182,780. Zebrafish estrogen-responsive genes sensitive to both estrogen and anti-estrogen were identified and validated using real-time PCR. Human homolog mapping and knowledge-based data mining were performed on zebrafish estrogen responsive genes followed by estrogen receptor binding site analysis and comparative transcriptome analysis with estrogen-responsive human cancer cell lines (MCF7, T47D and Ishikawa. Results Our transcriptome analysis captured multiple estrogen-responsive genes and signaling pathways that increased cell proliferation, promoted DNA damage and genome instability, and decreased tumor suppressing effects, suggesting a common mechanism for estrogen-induced carcinogenesis. Comparative analysis revealed a core set of conserved estrogen-responsive genes that demonstrate enrichment of estrogen receptor binding sites and cell cycle signaling pathways. Knowledge-based and network analysis led us to propose that the mechanism involving estrogen-activated estrogen receptor mediated down-regulation of human homolog HES1 followed by up-regulation cell cycle-related genes (human homologs E2F4, CDK2, CCNA, CCNB, CCNE, is highly conserved, and this mechanism may involve novel crosstalk with basal AHR. We also identified mitotic roles of polo-like kinase as a conserved signaling pathway with multiple entry

  6. Understanding Carcinogenesis for Fighting Oral Cancer

    OpenAIRE

    Tanaka, Takuji; Ishigamori, Rikako

    2011-01-01

    Oral cancer is one of the major global threats to public health. Oral cancer development is a tobacco-related multistep and multifocal process involving field cancerization and carcinogenesis. The rationale for molecular-targeted prevention of oral cancer is promising. Biomarkers of genomic instability, including aneuploidy and allelic imbalance, are able to measure the cancer risk of oral premalignancies. Understanding of the biology of oral carcinogenesis will give us important advances for...

  7. Cellular Dichotomy Between Anchorage-Independent Growth Responses to bFGF and TA Reflects Molecular Switch in Commitment to Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Waters, Katrina M.; Tan, Ruimin; Opresko, Lee K.; Quesenberry, Ryan D.; Bandyopadhyay, Somnath; Chrisler, William B.; Weber, Thomas J.

    2009-11-01

    We have investigated gene expression patterns underlying reversible and irreversible anchorage-independent growth (AIG) phenotypes to identify more sensitive markers of cell transformation for studies directed at interrogating carcinogenesis responses. In JB6 mouse epidermal cells, basic fibroblast growth factor (bFGF) induces an unusually efficient and reversible AIG response, relative to 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced AIG which is irreversible. The reversible and irreversible AIG phenotypes are characterized by largely non-overlapping global gene expression profiles. However, a subset of differentially expressed genes were identified as common to reversible and irreversible AIG phenotypes, including genes regulated in a reciprocal fashion. Hepatic leukemia factor (HLF) and D-site albumin promoter-binding protein (DBP) were increased in both bFGF and TPA soft agar colonies and selected for functional validation. Ectopic expression of human HLF and DBP in JB6 cells resulted in a marked increase in TPA- and bFGF-regulated AIG responses. HLF and DBP expression were increased in soft agar colonies arising from JB6 cells exposed to gamma radiation and in a human basal cell carcinoma tumor tissue, relative to paired non-tumor tissue. Subsequent biological network analysis suggests that many of the differentially expressed genes that are common to bFGF- and TPA-dependent AIG are regulated by c-Myc, SP-1 and HNF-4 transcription factors. Collectively, we have identified a potential molecular switch that mediates the transition from reversible to irreversible AIG.

  8. Radiation and non-radiation damage to DNA. Onset of molecular instability and carcinogenesis. Theoretical explorations on DNA damage and repair

    International Nuclear Information System (INIS)

    Pinak, Miroslay; Bunta, J.K.

    2006-01-01

    The current work is focused on results of molecular dynamics simulations performed on two DNA damages: 8-oxoguanine as the most significant oxidative damage leading to transversion mutation cytosine-guanine→adenine-thymine', which is common mutation found in human cancer cells; and on the DNA strand break, the type of damage that is considered to be one of the most significant damage leading to genetic instability that may result in enhanced cell proliferation or carcinogenesis. Except the structural changes induced by these two lesions the role and importance of electrostatic energy in recognition process in which a respective repair enzyme recognizes damaged DNA site is also described. Among the significant results can be included the fact, that most of the damages on DNA alternate locally electronic state by modifying chemical and electron orbital configuration. This modified configuration may be represented outside DNA molecule as an enhanced electrostatic interaction with surrounding environment, that may signal the presence of the damaged site toward the repair enzyme. Work on the DNA strand break shows that open valences at broken strand ends are quickly filled by the electrons generated during radiolysis. Results of simulation indicate a local instability of hydrogen bonds between complementary bases. (author)

  9. Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats.

    Science.gov (United States)

    Zahran, Walid E; Elsonbaty, Sawsan M; Moawed, Fatma S M

    2017-08-01

    Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing γ radiation (γ-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy γ-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, β-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and β-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with γ-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level γ-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Experimental studies on lung carcinogenesis and their relationship to future research on radiation-induced lung cancer in humans

    International Nuclear Information System (INIS)

    Cross, F.T.

    1991-03-01

    The usefulness of experimental systems for studying human lung carcinogenesis lies in the ease of studying components of a total problem. As an example, the main thrust of attack on possible synergistic interactions between radiation, cigarette smoke, and other irritants must be by means of research on animals. Because animals can be serially sacrificed, a systematic search can be made for progressive lung changes, thereby improving our understanding of carcinogenesis. The mechanisms of radiation-induced carcinogenesis have not yet been delineated, but modern concepts of molecular and cellular biology and of radiation dosimetry are being increasingly applied to both in vivo and in vitro exposure to determine the mechanisms of radiation-induced carcinogenesis, to elucidate human data, and to aid in extrapolating experimental animal data to human exposures. In addition, biologically based mathematical models of carcinogenesis are being developed to describe the nature of the events leading to malignancy; they are also an essential part of a rational approach to quantitative cancer risk assessment. This paper summarizes recent experimental and modeling data on radon-induced lung cancer and includes the confounding effects of cigarette-smoke exposures. The applicability of these data to understanding human exposures is emphasized, and areas of future research on human radiation-induced carcinogenesis are discussed. 7 refs., 2 figs., 3 tabs

  11. Molecular Theory of the Living Cell Concepts, Molecular Mechanisms, and Biomedical Applications

    CERN Document Server

    Ji, Sungchul

    2012-01-01

    This book presents a comprehensive molecular theory of the living cell based on over thirty concepts, principles and laws imported from thermodynamics, statistical mechanics, quantum mechanics, chemical kinetics, informatics, computer science, linguistics, semiotics, and philosophy. The author formulates physically, chemically and enzymologically realistic molecular mechanisms to account for the basic living processes such as ligand-receptor interactions, protein folding, single-molecule enzymic catalysis, force-generating mechanisms in molecular motors, signal transduction, regulation of the genome-wide RNA metabolism, morphogenesis, the micro-macro coupling in coordination dynamics, the origin of life, and the mechanisms of biological evolution itself. Possible solutions to basic and practical problems facing contemporary biology and biomedical sciences have been suggested, including pharmacotheragnostics and personalized medicine.

  12. The molecular biology capstone assessment: a concept assessment for upper-division molecular biology students.

    Science.gov (United States)

    Couch, Brian A; Wood, William B; Knight, Jennifer K

    2015-03-02

    Measuring students' conceptual understandings has become increasingly important to biology faculty members involved in evaluating and improving departmental programs. We developed the Molecular Biology Capstone Assessment (MBCA) to gauge comprehension of fundamental concepts in molecular and cell biology and the ability to apply these concepts in novel scenarios. Targeted at graduating students, the MBCA consists of 18 multiple-true/false (T/F) questions. Each question consists of a narrative stem followed by four T/F statements, which allows a more detailed assessment of student understanding than the traditional multiple-choice format. Questions were iteratively developed with extensive faculty and student feedback, including validation through faculty reviews and response validation through student interviews. The final assessment was taken online by 504 students in upper-division courses at seven institutions. Data from this administration indicate that the MBCA has acceptable levels of internal reliability (α=0.80) and test-retest stability (r=0.93). Students achieved a wide range of scores with a 67% overall average. Performance results suggest that students have an incomplete understanding of many molecular biology concepts and continue to hold incorrect conceptions previously documented among introductory-level students. By pinpointing areas of conceptual difficulty, the MBCA can provide faculty members with guidance for improving undergraduate biology programs. © 2015 B. A. Couch et al. CBE—Life Sciences Education © 2015 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  13. Radiogenic cell transformation and carcinogenesis

    Science.gov (United States)

    Yang, T. C.; Georgy, K. A.; Mei, M.; Durante, M.; Craise, L. M.

    1995-01-01

    Radiation carcinogenesis is one of the major biological effects considered important in the risk assessment for space travel. Various biological model systems, including both cultured cells and animals, have been found useful for studying the carcinogenic effects of space radiations, which consist of energetic electrons, protons and heavy ions. The development of techniques for studying neoplastic cell transformation in culture has made it possible to examine the cellular and molecular mechanisms of radiation carcinogenesis. Cultured cell systems are thus complementary to animal models. Many investigators have determined the oncogenic effects of ionizing and nonionizing radiation in cultured mammalian cells. One of the cell systems used most often for radiation transformation studies is mouse embryonic cells (C3H10T1/2), which are easy to culture and give good quantitative dose-response curves. Relative biological effectiveness (RBE) for heavy ions with various energies and linear energy transfer (LET) have been obtained with this cell system. Similar RBE and LET relationship was observed by investigators for other cell systems. In addition to RBE measurements, fundamental questions on repair of sub- and potential oncogenic lesions, direct and indirect effect, primary target and lesion, the importance of cell-cell interaction and the role of oncogenes and tumor suppressor genes in radiogenic carcinogenesis have been studied, and interesting results have been found. Recently several human epithelial cell systems have been developed, and ionizing radiation have been shown to transform these cells. Oncogenic transformation of these cells, however, requires a long expression time and/or multiple radiation exposures. Limited experimental data indicate high-LET heavy ions can be more effective than low-LET radiation in inducing cell transformation. Cytogenetic and molecular analyses can be performed with cloned transformants to provide insights into basic genetic

  14. Mechanisms of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Bekkum, D.W. van

    1975-01-01

    This speculative review on radiation carcinogenesis deals mainly with its immunological aspects. It need not be emphasized that the role of immunology in carcinogenesis is not yet well understood. Immunological aspects of radiation carcinogenesis comprise a large number of different parameters on the part of the host as well as on the part of the tumor itself. Only two aspects, both related to radiation, will be discussed here. One is the way in which the carcinogenic exposure to ionizing radiation may affect the immune reactivity of the irradiated organism, thereby perhaps changing its responses against the malignant cells. The second aspect is the immunological properties of cells transformed by ionizing irradiation, which may provide the targets for a host-anti-tumor reaction

  15. Liver Development, Regeneration, and Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Janet W. C. Kung

    2010-01-01

    Full Text Available The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

  16. Bioresponsive probes for molecular imaging: concepts and in vivo applications

    NARCIS (Netherlands)

    Duijnhoven, S.M. van; Robillard, M.S.; Langereis, S.; Grull, H.

    2015-01-01

    Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo. In most molecular imaging approaches, probes are used to bind to disease-specific biomarkers highlighting disease target sites. In recent years, a new subset of

  17. Bioresponsive probes for molecular imaging : Concepts and in vivo applications

    NARCIS (Netherlands)

    van Duijnhoven, S.M.J.; Robillard, M.S.; Langereis, S.; Grüll, H.

    2015-01-01

    Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo. In most molecular imaging approaches, probes are used to bind to disease-specific biomarkers highlighting disease target sites. In recent years, a new subset of

  18. Introduction to Genetic Mechanisms of Carcinogenesis

    International Nuclear Information System (INIS)

    Yang, W.K.

    1983-01-01

    Recent technical advances in nucleic acid research and molecular biology have made it possible to explore the complicated genetic systems of eukaryotic cells. One of the fields showing rapid progress concerns genes and gene regulatory functions related to neoplastic processes. Thus, the 35th Annual Conference of the Biology Division of Oak Ridge National Laboratory, held at Gatlinburg, April 12-15, 1982, was organized with the intention to bring together investigators working on seemingly diverse fields of cancer research to discuss and exchange their views on the genetic mechanisms of carcinogenesis. The meeting was attended by workers from chemical, physical as well as biological carcinogenesis fields, by classical geneticists as well as by molecular biologists, and by researchers interested in experimental as well as in human cancers. Included in this volume are papers by the invited speakers of the symposium as well as by those presenting poster papers at the meeting

  19. Radiation carcinogenesis, laboratory studies

    International Nuclear Information System (INIS)

    Shellabarger, C.J.

    1974-01-01

    Laboratory studies on radioinduced carcinogenesis are reviewed. Some topics discussed are: radioinduced neoplasia in relation to life shortening; dose-response relationships; induction of skin tumors in rats by alpha particles and electrons; effects of hormones on tumor response; effects of low LET radiations delivered at low dose-rates; effects of fractionated neutron radiation; interaction of RBE and dose rate effects; and estimates of risks for humans from animal data. (U.S.)

  20. Oral Carcinogenesis and Oral Cancer Chemoprevention: A Review

    OpenAIRE

    Tanaka, Takuji; Tanaka, Mayu; Tanaka, Takahiro

    2011-01-01

    Oral cancer is one of the major global threats to public health. The development of oral cancer is a tobacco-related multistep and multifocal process involving field cancerization and carcinogenesis. The rationale for molecular-targeted prevention of oral cancer is promising. Biomarkers of genomic instability, including aneuploidy and allelic imbalance, are possible to measure the cancer risk of oral premalignancies. Understanding of the biology of oral carcinogenesis will yield important adv...

  1. Essential concepts and underlying theories from physics, chemistry, and mathematics for "biochemistry and molecular biology" majors.

    Science.gov (United States)

    Wright, Ann; Provost, Joseph; Roecklein-Canfield, Jennifer A; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members from around the country. The workshops have focused on developing lists of Core Principles or Foundational Concepts in Biochemistry and Molecular Biology, a list of foundational skills, and foundational concepts from Physics, Chemistry, and Mathematics that all Biochemistry or Molecular Biology majors must understand to complete their major coursework. The allied fields working group created a survey to validate foundational concepts from Physics, Chemistry, and Mathematics identified from participant feedback at various workshops. One-hundred twenty participants responded to the survey and 68% of the respondents answered yes to the question: "We have identified the following as the core concepts and underlying theories from Physics, Chemistry, and Mathematics that Biochemistry majors or Molecular Biology majors need to understand after they complete their major courses: 1) mechanical concepts from Physics, 2) energy and thermodynamic concepts from Physics, 3) critical concepts of structure from chemistry, 4) critical concepts of reactions from Chemistry, and 5) essential Mathematics. In your opinion, is the above list complete?" Respondents also delineated subcategories they felt should be included in these broad categories. From the results of the survey and this analysis the allied fields working group constructed a consensus list of allied fields concepts, which will help inform Biochemistry and Molecular Biology educators when considering the ASBMB recommended curriculum for Biochemistry or Molecular Biology majors and in the development of appropriate assessment tools to gauge student understanding of how these concepts relate to biochemistry and molecular biology. © 2013 by The International Union of Biochemistry and Molecular Biology.

  2. . Modern concepts on carcinogenesis: the value of insufficiency of malignant cell elimination mechanisms in the tumor progression in case of neoplasia at different localizations

    Directory of Open Access Journals (Sweden)

    Chesnokova N.P.

    2016-03-01

    Full Text Available The article presents the review of contemporary concepts of tumor induction mechanisms applicable for neoplastic transformation, promotion and proliferation. The paper also contains an in-depth analysis of results of authors' own observations and study of immunological protection mechanisms of a significant number of patients diagnosed with oncopathologies of mammary and thyroid glands as well as adenocarcinoma of ascending colon. We have established common development patterns of T-cell and B-cell immunodeficiencies that are not influenced by location and proliferation of neoplastic tumors; the progress of such immunodeficincies, however, depends on regional metastasis development. Thus, we can conclude that insufficiency of immunological defense mechanisms leading to disruption of maligned cell elimination process is the primary pathogenic factor for metastatic tumor development.

  3. Essential Concepts and Underlying Theories from Physics, Chemistry, and Mathematics for "Biochemistry and Molecular Biology" Majors

    Science.gov (United States)

    Wright, Ann; Provost, Joseph; Roecklein-Canfield, Jennifer A.; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members from around the country. The workshops have focused on developing lists of Core Principles or Foundational Concepts in Biochemistry and Molecular Biology, a list of foundational skills, and foundational concepts from Physics, Chemistry,…

  4. Tangible Models and Haptic Representations Aid Learning of Molecular Biology Concepts

    Science.gov (United States)

    Johannes, Kristen; Powers, Jacklyn; Couper, Lisa; Silberglitt, Matt; Davenport, Jodi

    2016-01-01

    Can novel 3D models help students develop a deeper understanding of core concepts in molecular biology? We adapted 3D molecular models, developed by scientists, for use in high school science classrooms. The models accurately represent the structural and functional properties of complex DNA and Virus molecules, and provide visual and haptic…

  5. Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats

    Directory of Open Access Journals (Sweden)

    Yi Zhao

    2016-01-01

    Full Text Available Dendrobium officinale (Tie Pi Shi Hu in Chinese has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg were orally administered to the rats of the gastric carcinogenesis model. Compared with the cancer model group, the high dose of Dendrobium officinale extracts significantly inhibited the rate of carcinogenesis. Further analysis revealed that Dendrobium officinale extracts could regulate the DNA damage, oxidative stress, and cytokines related with carcinogenesis and induce cell apoptosis in order to prevent gastric cancer.

  6. Radiation and multistage carcinogenesis

    International Nuclear Information System (INIS)

    Day, N.E.

    1984-01-01

    Epidemiological data are insufficient at present to define with much precision the shape of the dose-response curve for radiation carcinogenesis at low or moderate dose levels, for different organs. The available data have to be supplemented with theoretical models for the mode of action. These models, however, often seem not to take into account the complex nature of the process of carcinogenesis. They relate more to mutational events, rather than the long process of cancer induction. In addition, they ignore the fact that in the human situation radiation is one among a large number of exposures, and even the basic form of the dose response may be dependent on the presence or absence of other factors. Information on modes of action usually comes from experimental results, where the requisite combination of exposures can be chosen in advance. Epidemiology, however, also provides information on mechanisms. The purpose of this paper is to consider some of the information that epidemiology provides on the role of radiation in increasing cancer risk in humans

  7. Free radicals in chemical carcinogenesis.

    Science.gov (United States)

    Clemens, M R

    1991-12-15

    During the past decade, remarkable progress has been made in our understanding of cancer-causing agents, mechanisms of cancer formation and the behavior of cancer cells. Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, and lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). It has been estimated that about 75-80% of all human cancers are environmentally induced, 30-40% of them by diet. Only a small minority, possibly no more than 2% of all cases, result purely from inherent genetic changes. Several lines of evidence confirm that the fundamental molecular event or events that cause a cell to become malignant occur at the level of the DNA and a variety of studies indicate that the critical molecular event in chemical carcinogenesis is the interaction of the chemical agent with DNA. The demonstration that DNA isolated from tumor cells can transfect normal cells and render them neoplastic provides direct proof that an alteration of the DNA is responsible for cancer. The transforming genes, or oncogenes, have been identified by restriction endonuclease mapping. One of the characteristics of tumor cells generated by transformation with viruses, chemicals, or radiation is their reduced requirement for serum growth factors. A critical significance of electrophilic metabolites of carcinogenes in chemical carcinogenesis has been demonstrated. A number of "proximate" and "ultimate" metabolites, especially those of aromatic amines, were described. The "ultimate" forms of carcinogens actually interact with cellular constituents to cause neoplastic transformation and are the final metabolic products in most pathways. Recent evidence indicates that free radical derivatives of chemical carcinogens may be produced both metabolically and nonenzymatically during their metabolism. Free radicals carry no

  8. Atomic and molecular spectroscopy basic concepts and applications

    CERN Document Server

    Kakkar, Rita

    2015-01-01

    Spectroscopy is the study of electromagnetic radiation and its interaction with solid, liquid, gas and plasma. It is one of the widely used analytical techniques to study the structure of atoms and molecules. The technique is also employed to obtain information about atoms and molecules as a result of their distinctive spectra. The fast-spreading field of spectroscopic applications has made a noteworthy influence on many disciplines, including energy research, chemical processing, environmental protection and medicine. This book aims to introduce students to the topic of spectroscopy. The author has avoided the mathematical aspects of the subject as far as possible; they appear in the text only when inevitable. Including topics such as time-dependent perturbation theory, laser action and applications of Group Theory in interpretation of spectra, the book offers a detailed coverage of the basic concepts and applications of spectroscopy.

  9. [Precision Oncology and "Molecular Tumor Boards" - Concepts, Chances and Challenges].

    Science.gov (United States)

    Holch, Julian Walter; Westphalen, Christoph Benedikt; Hiddemann, Wolfgang; Heinemann, Volker; Jung, Andreas; Metzeler, Klaus Hans

    2017-11-01

    Recent developments in genomics allow a more and more comprehensive genetic analysis of human malignancies, and have sparked hopes that this will contribute to the development of novel targeted, effective and well-tolerated therapies.While targeted therapies have improved the prognosis of many cancer patients with certain tumor types, "precision oncology" also brings along new challenges. Highly personalized treatment strategies require new strategies for clinical trials and translation into routine clinical practice. We review the current technical approaches for "universal genetic testing" in cancer, and potential pitfalls in the interpretation of such data. We then provide an overview of the available evidence supporting treatment strategies based on extended genetic analysis. Based on the available data, we conclude that "precision oncology" approaches that go beyond the current standard of care should be pursued within the framework of an interdisciplinary "molecular tumor board", and preferably within clinical trials. © Georg Thieme Verlag KG Stuttgart · New York.

  10. External radiation carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.; Storer, J.B.

    1987-01-01

    There have been many reviews of the subject of radiation carcinogenesis in general and of specific radiation-induced cancers. The aim of this article is not to give an exhaustive, and perhaps exhausting, review of all that has been published since the thorough treatise of Walburg in volume 4 of this series but rather to concentrate on the questions that still remain of importance and recent contributions to the answers. In the years since 1974 a vast amount of information has been reported, and the authors assess what gain there has been in knowledge. For example, it is in the 13 years since the last review that the great majority of data for the carcinogenic effects of neutrons has appeared. It is over 50 years since the discovery of the neutron, and yet knowledge of the carcinogenic effects of neutrons is far from adequate

  11. A molecular concept of caste in insect societies.

    Science.gov (United States)

    Sumner, Seirian; Bell, Emily; Taylor, Daisy

    2018-02-01

    The term 'caste' is used to describe the division of reproductive labour that defines eusocial insect societies. The definition of 'caste' has been debated over the last 50 years, specifically with respect to the simplest insect societies; this raises the question of whether a simple categorisation of social behaviour by reproductive state alone is helpful. Gene-level analyses of behaviours of individuals in hymenopteran social insect societies now provide a new empirical base-line for defining caste and understanding the evolution and maintenance of a reproductive division of labour. We review this literature to identify a set of potential molecular signatures that, combined with behavioural, morphological and physiological data, help define caste more precisely; these signatures vary with the type of society, and are likely to be influenced by ecology, life-history, and stage in the colony cycle. We conclude that genomic approaches provide us with additional ways to help quantify and categorise caste, and behaviour in general. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Molecular concepts of water splitting. Nature's approach

    Energy Technology Data Exchange (ETDEWEB)

    Cox, Nicholas; Lubitz, Wolfgang [Max-Planck-Institut fuer Chemische Energiekonversion, Muelheim an der Ruhr (Germany)

    2013-07-01

    Based on studies of natural systems, much has also been learned concerning the design principles required for biomimetic catalysis of water splitting and hydrogen evolution. In summary, these include use of abundant and inexpensive metals, the effective protection of the active sites in functional environments, repair/replacement of active components in case of damage, and the optimization of reaction rates. Biomimetic chemistry aims to mimic all these features; many labs are working toward this goal by developing new approaches in the design and synthesis of such systems, encompassing not only the catalytic center, but also smart matrices and assembly via self-organization. More stable catalysts that do not require self-repair may be obtained from fully artificial (inorganic) catalytic systems that are totally different from the biological ones and only apply some basic principles learned from nature. Metals other than Mn/Ca, Fe, and Ni could be used (e.g. Co) in new ligand spheres and other matrices. For light harvesting, charge separation/stabilization, and the effective coupling of the oxidizing/reducing equivalents to the redox catalysts, different methods have been proposed - for example, covalently linked molecular donor-acceptor systems, photo-voltaic devices, semiconductor-based systems, and photoactive metal complexes. The aim of all these approaches is to develop catalytic systems that split water with sunlight into hydrogen and oxygen while displaying high efficiency and long-term stability. Such a system - either biological, biomimetic, or bioinspired - has the potential to be used on a large scale to produce 'solar fuels' (e.g. hydrogen or secondary products thereof). (orig.)

  13. Molecular analysis of primary gastric cancer, corresponding xenografts, and 2 novel gastric carcinoma cell lines reveals novel alterations in gastric carcinogenesis

    NARCIS (Netherlands)

    Milne, Anya N. A.; Sitarz, Robert; Carvalho, Ralph; Polak, Mirjam M.; Ligtenberg, Madolijn; Pauwels, Patrick; Offerhaus, G. Johan A.; Weterman, Marian A. J.

    2007-01-01

    We report the molecular characterization of 8 primary gastric carcinomas, corresponding xenografts, and 2 novel gastric carcinoma cell lines. We compared the tumors and cell lines, with respect to histology, immunohistochemistry, copy number, and hypermethylation of up to 38 genes using

  14. contribution to carcinogenesis

    Directory of Open Access Journals (Sweden)

    Aneta Białkowska

    2014-01-01

    Full Text Available The centrosomes are subcellular organelles composed of two centrioles surrounded by a pericentriolar material. In animal cells they are responsible for the organization of the interphase microtubule cytoskeleton including microtubule nucleation and elongation, their attachment and release. The centrosomes are also involved in the construction of the mitotic spindle and chromosome segregation. More than a century ago it was suggested that these structures might be involved in human diseases, including cancer. Cancer cells show a high frequency of centrosome aberrations, especially amplification. Centrosome defects may increase the incidence of multipolar mitoses that lead to chromosomal segregation abnormalities and aneuploidy, which is the predominant type of genomic instability found in human solid tumors. The number of these organelles in cells is strictly controlled and is dependent on the proper process of centrosome duplication. Multiple genes that are frequently found mutated in cancers encode proteins which participate in the regulation of centrosome duplication and the numeral integrity of centrosomes. In recent years there has been growing interest in the potential participation of centrosomes in the process of carcinogenesis, especially because centrosome abnormalities are observed in premalignant stages of cancer development. The common presence of abnormal centrosomes in cancer cells and the role these organelles play in the cells suggest that the factors controlling the number of centrosomes may be potential targets for cancer therapy.

  15. Gene amplification in carcinogenesis

    Directory of Open Access Journals (Sweden)

    Lucimari Bizari

    2006-01-01

    Full Text Available Gene amplification increases the number of genes in a genome and can give rise to karyotype abnormalities called double minutes (DM and homogeneously staining regions (HSR, both of which have been widely observed in human tumors but are also known to play a major role during embryonic development due to the fact that they are responsible for the programmed increase of gene expression. The etiology of gene amplification during carcinogenesis is not yet completely understood but can be considered a result of genetic instability. Gene amplification leads to an increase in protein expression and provides a selective advantage during cell growth. Oncogenes such as CCND1, c-MET, c-MYC, ERBB2, EGFR and MDM2 are amplified in human tumors and can be associated with increased expression of their respective proteins or not. In general, gene amplification is associated with more aggressive tumors, metastases, resistance to chemotherapy and a decrease in the period during which the patient stays free of the disease. This review discusses the major role of gene amplification in the progression of carcinomas, formation of genetic markers and as possible therapeutic targets for the development of drugs for the treatment of some types of tumors.

  16. Foundational Concepts and Underlying Theories for Majors in "Biochemistry and Molecular Biology"

    Science.gov (United States)

    Tansey, John T.; Baird, Teaster, Jr.; Cox, Michael M.; Fox, Kristin M.; Knight, Jennifer; Sears, Duane; Bell, Ellis

    2013-01-01

    Over the past two years, through an NSF RCN UBE grant, the ASBMB has held regional workshops for faculty members and science educators from around the country that focused on identifying: 1) core principles of biochemistry and molecular biology, 2) essential concepts and underlying theories from physics, chemistry, and mathematics, and 3)…

  17. Tensions and opportunities in convergence: Shifting concepts of disease in emerging molecular medicine.

    NARCIS (Netherlands)

    Boenink, Marianne

    2009-01-01

    The convergence of biomedical sciences with nanotechnology as well as ICT has created a new wave of biomedical technologies, resulting in visions of a ‘molecular medicine’. Since novel technologies tend to shift concepts of disease and health, this paper investigates how the emerging field of

  18. Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8

    Directory of Open Access Journals (Sweden)

    Abdulamir Ahmed S

    2010-09-01

    Full Text Available Abstract Background Colorectal cancer (CRC has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac and without history of bacteremia (CRC-wo/bac by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL-8, COX-2, IFN-γ, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. Results SGMB were found to be remarkably isolated in tumorous (TU and non-tumorous (NTU tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P 10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P Conclusions The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8.

  19. Radiation signatures in childhood thyroid cancers after the Chernobyl accident: Possible roles of radiation in carcinogenesis

    Science.gov (United States)

    Suzuki, Keiji; Mitsutake, Norisato; Saenko, Vladimir; Yamashita, Shunichi

    2015-01-01

    After the Tokyo Electric Power Company Fukushima Daiichi nuclear power plant accident, cancer risk from low-dose radiation exposure has been deeply concerning. The linear no-threshold model is applied for the purpose of radiation protection, but it is a model based on the concept that ionizing radiation induces stochastic oncogenic alterations in the target cells. As the elucidation of the mechanism of radiation-induced carcinogenesis is indispensable to justify the concept, studies aimed at the determination of molecular changes associated with thyroid cancers among children who suffered effects from the Chernobyl nuclear accident will be overviewed. We intend to discuss whether any radiation signatures are associated with radiation-induced childhood thyroid cancers. PMID:25483826

  20. Atom economy, molecular engeneering and biphasic organometallic catalysis: molecular concepts for the generation of "green" technologies

    OpenAIRE

    Dupont, Jairton

    2000-01-01

    For economical and ecological reasons, synthetic chemists are confronted with the increasing obligation of optimizing their synthetic methods. Maximizing efficiency and minimizing costs in the production of molecules and macromolecules constitutes, therefore, one of the most exciting challenges of synthetic chemistry. The ideal synthesis should produce the desired product in 100% yield and selectivity, in a safe and environmentally acceptable process. In this highlight the concepts of atom ec...

  1. Colorectal Carcinogenesis: Role of Oxidative Stress and Antioxidants.

    Science.gov (United States)

    Carini, Francesco; Mazzola, Margherita; Rappa, Francesca; Jurjus, Abdo; Geagea, Alice Gerges; Al Kattar, Sahar; Bou-Assi, Tarek; Jurjus, Rosalyn; Damiani, Provvidenza; Leone, Angelo; Tomasello, Giovanni

    2017-09-01

    One of the contributory causes of colon cancer is the negative effect of reactive oxygen species on DNA repair mechanisms. Currently, there is a growing support for the concept that oxidative stress may be an important etiological factor for carcinogenesis. The purpose of this review is to elucidate the role of oxidative stress in promoting colorectal carcinogenesis and to highlight the potential protective role of antioxidants. Several studies have documented the importance of antioxidants in countering oxidative stress and preventing colorectal carcinogenesis. However, there are conflicting data in the literature concerning its proper use in humans, since these studies did not yield definitive results and were performed mostly in vitro on cell populations, or in vivo in experimental animal models. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Materials learning from life: concepts for active, adaptive and autonomous molecular systems.

    Science.gov (United States)

    Merindol, Rémi; Walther, Andreas

    2017-09-18

    Bioinspired out-of-equilibrium systems will set the scene for the next generation of molecular materials with active, adaptive, autonomous, emergent and intelligent behavior. Indeed life provides the best demonstrations of complex and functional out-of-equilibrium systems: cells keep track of time, communicate, move, adapt, evolve and replicate continuously. Stirred by the understanding of biological principles, artificial out-of-equilibrium systems are emerging in many fields of soft matter science. Here we put in perspective the molecular mechanisms driving biological functions with the ones driving synthetic molecular systems. Focusing on principles that enable new levels of functionalities (temporal control, autonomous structures, motion and work generation, information processing) rather than on specific material classes, we outline key cross-disciplinary concepts that emerge in this challenging field. Ultimately, the goal is to inspire and support new generations of autonomous and adaptive molecular devices fueled by self-regulating chemistry.

  3. Effects of environmental stressors on histone modifications and their relevance to carcinogenesis: a systematic review.

    NARCIS (Netherlands)

    Dik, S.; Scheepers, P.T.J.; Godderis, L.

    2012-01-01

    Carcinogenesis is a complex process involving both genetic and epigenetic mechanisms. The cellular molecular epigenetic machinery, including histone modifications, is associated with changes in gene expression induced by exposure to environmental agents. In this paper, we systematically reviewed

  4. Experimental, statistical, and biological models of radon carcinogenesis

    International Nuclear Information System (INIS)

    Cross, F.T.

    1991-09-01

    Risk models developed for underground miners have not been consistently validated in studies of populations exposed to indoor radon. Imprecision in risk estimates results principally from differences between exposures in mines as compared to domestic environments and from uncertainties about the interaction between cigarette-smoking and exposure to radon decay products. Uncertainties in extrapolating miner data to domestic exposures can be reduced by means of a broad-based health effects research program that addresses the interrelated issues of exposure, respiratory tract dose, carcinogenesis (molecular/cellular and animal studies, plus developing biological and statistical models), and the relationship of radon to smoking and other copollutant exposures. This article reviews experimental animal data on radon carcinogenesis observed primarily in rats at Pacific Northwest Laboratory. Recent experimental and mechanistic carcinogenesis models of exposures to radon, uranium ore dust, and cigarette smoke are presented with statistical analyses of animal data. 20 refs., 1 fig

  5. Modeling Multiple Causes of Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Jones, T D

    1999-01-24

    An array of epidemiological results and databases on test animal indicate that risk of cancer and atherosclerosis can be up- or down-regulated by diet through a range of 200%. Other factors contribute incrementally and include the natural terrestrial environment and various human activities that jointly produce complex exposures to endotoxin-producing microorganisms, ionizing radiations, and chemicals. Ordinary personal habits and simple physical irritants have been demonstrated to affect the immune response and risk of disease. There tends to be poor statistical correlation of long-term risk with single agent exposures incurred throughout working careers. However, Agency recommendations for control of hazardous exposures to humans has been substance-specific instead of contextually realistic even though there is consistent evidence for common mechanisms of toxicological and carcinogenic action. That behavior seems to be best explained by molecular stresses from cellular oxygen metabolism and phagocytosis of antigenic invasion as well as breakdown of normal metabolic compounds associated with homeostatic- and injury-related renewal of cells. There is continually mounting evidence that marrow stroma, comprised largely of monocyte-macrophages and fibroblasts, is important to phagocytic and cytokinetic response, but the complex action of the immune process is difficult to infer from first-principle logic or biomarkers of toxic injury. The many diverse database studies all seem to implicate two important processes, i.e., the univalent reduction of molecular oxygen and breakdown of aginuine, an amino acid, by hydrolysis or digestion of protein which is attendant to normal antigen-antibody action. This behavior indicates that protection guidelines and risk coefficients should be context dependent to include reference considerations of the composite action of parameters that mediate oxygen metabolism. A logic of this type permits the realistic common-scale modeling of

  6. Epigenetic mechanism of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Niwa, Ohtsura

    1995-01-01

    Carcinogenic action of radiations has long been thought to be due to its mutagenic activity. Since DNA damage is induced and distributes in a stochastic fashion, radiation induction of cancers was also assumed to follow a stochastic kinetics. However, recent progress in radiation research has revealed that some features of radiation carcinogenesis are not explainable by the simple action of radiation as a DNA damaging and mutagenic agent. Firstly, frequencies of radiation-induced transformation in vitro and radiation-induced mammary cancers in rats are too high to be accounted for by the frequency of radiation-induced mutation. Secondly, trans-generation carcinogenesis among F1 mice born to irradiated parents occurs also much more frequently than to be predicted by the frequency of radiation induced germline mutation. Thirdly, multistage carcinogenesis theory predicts that carcinogens give hits to the target cells so as to shorten the latency of cancers. However, latencies of radiation induced solid cancers among atomic bomb survivors are similar to those of the control population. Fourthly, although radiation elevates the frequency of cancers, the induced cancers seem to share the same spectrum of cancer types as in the unirradiated control populations. This suggests that radiation induces cancer by enhancement of the spontaneous carcinogenesis process. These data suggest that the first step of radiation carcinogenesis may not be the direct induction of mutation. Radiation may induce genetic instability which increases the spontaneous mutation rate in the cells to produce carcinogenic mutations. Growth stimulatory effect of radiation may also contribute to the process. Thus, epigenetic, but not genetic effect of radiation might better contribute in the process of carcinogenesis. (author)

  7. Experimental radiation carcinogenesis is studies at NIRS

    International Nuclear Information System (INIS)

    Sado, Toshihiko

    1992-01-01

    Experimental radiation carcinogenesis studies conducted during the past decade at NIRS are briefly reviewed. They include the following: 1) Age dependency of susceptibility to radiation carcinogenesis. 2) Radiation-induced myeloid leukemia. 3) Mechanism of fractionated X-irradiation (FX) induced thymic lymphomas. 4) Significance of radiation-induced immunosuppression in radiation carcinogenesis in vivo. 5) Other ongoing studies. (author)

  8. DNA damage and carcinogenesis

    International Nuclear Information System (INIS)

    Stelow, R.B.

    1980-01-01

    Although cancer may arise as a result of many different types of molecular changes, there is little reason to doubt that changes to DNA are one of the more important ones in cancer initiation. Although DNA repair mechanisms seem able to eliminate a very large fraction of deleterious changes to DNA, we not only have little insight into the molecular mechanisms involved in such repair, but have a negligible amount of information to permit us to estimate the shape of dose response relations at low doses. The case of skin cancer is a special one, in that the average population is exposed to sufficient solar uv so that the effects of small increments in uv dose may be estimated. An approximate 85% reduction in DNA repair increases skin cancer incidence 10 4 fold

  9. Radiation carcinogenesis: radioprotectors and photosensitizers

    International Nuclear Information System (INIS)

    Fry, R.J.M.

    1982-01-01

    This paper outlines 1) some of the salient features of radiation carcinogenesis that are pertinent to the questions of how the carcinogenic effects might be influenced, 2) the effects of radioprotectors on ionizing radiation-induced cancer, and 3) the effect of photosensitizers on UVR-induced skin cancer

  10. Radiation carcinogenesis: radioprotectors and photosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1982-01-01

    This paper outlines 1) some of the salient features of radiation carcinogenesis that are pertinent to the questions of how the carcinogenic effects might be influenced, 2) the effects of radioprotectors on ionizing radiation-induced cancer, and 3) the effect of photosensitizers on UVR-induced skin cancer.

  11. Bacterionomics and vironomics in carcinogenesis

    Directory of Open Access Journals (Sweden)

    Pratiwi Sudarmono

    2017-02-01

    Full Text Available Virus and bacteria are microbes which are very common cause human infection. Most of the bacterial infection can be eradicated by antibiotics and infection symptoms disappear. But for virus infection, once infected, the virus will persistently stay in the host, even undergo not only a lytic cycle but also integrated into host genome. Nowadays, at least 6 virus type are consistently related to human cancer, such as EBV,HPV,HTLV,HBV,HCV,HKSV, and the new one Merkel Virus (MCV. Although not every infected people will get cancer, but around 20% of the whole cancer in human are caused by viral oncogene. Class one oncogenic bacterial is Helicobacter pylori. Infection with this bacteria can cause persistent gastro duodenal inflammation which cause some alteration in gastric cell growth into transformation. Expression of Cag gene and Vac gene and some expression of OMP protein usually link to gastric cancer. Molecular mechanisms of carcinogenesis for every virus which cause infection  is a very complex , which include several processes caused by cell transformation. Besides, other host and environmental factors are also play a significant role in cancer development. Some scientist put a Hallmark analysis as a model to quickly summarize what pathobiology process will happen and what gene or protein caused the process. The Hallmark analysis comprise of several process which may happen simultaneously because some of the Hallmark is caused by the same protein. The Hallmark consists of various virus strategies in oncogenesis such as promoting angiogenesis, avoiding immune destruction, genome instability and mutation, deregulating cellular energetic, resisting cell death, sustaining proliferative signaling, evading growth suppressors, enabling cellular immortality, promoting inflammation and activation metastasis. For example, infection by HPV, will cause low grade dysplasia which can continue to invasive cervical cancer. After host cell transformation, in

  12. Molecular and cellular mechanisms of cadmium carcinogenesis

    International Nuclear Information System (INIS)

    Waisberg, Michael; Joseph, Pius; Hale, Beverley; Beyersmann, Detmar

    2003-01-01

    Cadmium is a heavy metal, which is widely used in industry, affecting human health through occupational and environmental exposure. In mammals, it exerts multiple toxic effects and has been classified as a human carcinogen by the International Agency for Research on Cancer. Cadmium affects cell proliferation, differentiation, apoptosis and other cellular activities. Cd 2+ does not catalyze Fenton-type reactions because it does not accept or donate electrons under physiological conditions, and it is only weakly genotoxic. Hence, indirect mechanisms are implicated in the carcinogenicity of cadmium. In this review multiple mechanisms are discussed, such as modulation of gene expression and signal transduction, interference with enzymes of the cellular antioxidant system and generation of reactive oxygen species (ROS), inhibition of DNA repair and DNA methylation, role in apoptosis and disruption of E-cadherin-mediated cell-cell adhesion. Cadmium affects both gene transcription and translation. The major mechanisms of gene induction by cadmium known so far are modulation of cellular signal transduction pathways by enhancement of protein phosphorylation and activation of transcription and translation factors. Cadmium interferes with antioxidant defense mechanisms and stimulates the production of reactive oxygen species, which may act as signaling molecules in the induction of gene expression and apoptosis. The inhibition of DNA repair processes by cadmium represents a mechanism by which cadmium enhances the genotoxicity of other agents and may contribute to the tumor initiation by this metal. The disruption of E-cadherin-mediated cell-cell adhesion by cadmium probably further stimulates the development of tumors. It becomes clear that there exist multiple mechanisms which contribute to the carcinogenicity of cadmium, although the relative weights of these contributions are difficult to estimate

  13. Parasite Infection, Carcinogenesis and Human Malignancy

    Directory of Open Access Journals (Sweden)

    Hoang van Tong

    2017-02-01

    Full Text Available Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity.

  14. Development of the kinetic molecular theory of gases concept inventory: Preliminary results on university students’ misconceptions

    Directory of Open Access Journals (Sweden)

    Nataša Erceg

    2016-11-01

    Full Text Available In this study, we investigated students’ understanding of concepts related to the microscopic model of gas. We thoroughly reviewed the relevant literature and conducted think alouds with students by asking them to answer open-ended questions about the kinetic molecular theory of gases. Thereafter, we transformed the open-ended questions into multiple-choice questions, whereby distractors were based on the results of the think alouds. Thus, we obtained a set of 22 questions, which constitutes our current version of the kinetic molecular theory of gases concept inventory. The inventory has been administered to 250 students from different universities in Croatia, and its content validity has been investigated trough physics teacher surveys. The results of our study not only corroborate the existence of some already known student misconceptions, but also reveal new insights about a great spectrum of students’ misconceptions that had not been reported in earlier research (e.g., misconceptions about intermolecular potential energy and molecular velocity distribution. Moreover, we identified similar distribution of students’ responses across the surveyed student groups, despite the fact that they had been enrolled in different curricular environments.

  15. (Radiation carcinogenesis in the whole body system)

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1990-12-14

    The objectives of the trip were: to take part in and to give the summary of a Symposium on Radiation Carcinogenesis at Tokyo, and to give a talk at the National Institute of Radiological Sciences at Chiba. The breadth of the aspects considered at the conference was about as broad as is possible, from effects at the molecular level to human epidemiology, from the effects of tritium to cancer induction by heavy ions. The events induced by cancer that lead to cancer and the events that are secondary are beginning to come into better focus but much is still not known. Interest in suppressor genes is increasing rapidly in the studies of human tumors and many would predict that the three or four suppressor genes associated with cancer are only the first sighting of a much larger number.

  16. Carcinogenesis from ionizing radiation

    International Nuclear Information System (INIS)

    Merz, L.

    1992-01-01

    Additional cases of radiations-induced cancer resulting from an increase in the effective radiation dose to the public have become a matter of public interest after the Chernobyl 'disaster'. There has since been general concern in the minds of many people that they, their children and grandchildren would develop cancer after years or even decades because of the additional radiation exposure. An attempt has been made so settle this question for good by applying the 'dose-effect relationship', a principle generally accepted in radiation protection. This dose-effect relationship, which has been recommended by the International Commission on Radiological Protection and is used in radiation protection practice in Germany, implies the existence of a linear relationship between the added radiation dose and the relative rate of additional cases of cancer caused in the public. Any added dose, even the lowest dose, increases the rate of cancer in the public. There is no radiation dose threshold below which the cancer rate would not be increased. The new dose-effect relationship presented here, however, is not linear, contains a pronounced threshold level, but constitutes a better description of reality than the model used by the International Commission on Radiological Protection. The essence of the new concept is derived from principles of chaos theory. (orig.) [de

  17. Radiation carcinogenesis in scid mice

    Energy Technology Data Exchange (ETDEWEB)

    Ishii, Hiroko; Nishimura, Mayumi; Kobayashi, Shigeru; Tsuji, Hideo; Shimada, Yoshiya; Ogiu, Toshiaki [National Inst. of Radiological Sciences, Chiba (Japan); Suzuki, Fumio; Sado, Toshihiko

    1999-06-01

    Scid mice which have the defect of DNA-dependent protein kinase catalitic subunit, exhibit the limited activities of repair from DNA double strand breaks, and are sensitive to ionizing radiation. In order to study the relationship between repair capacity for DNA double strand breaks and carcinogenesis, the effects of ionizing radiation were studied using scid homozygotes (scid/scid), scid heterozygotes (scid/+) and CB-17 (+/+) mice. Both the Scid bone marrow cells and fibroblast cell lines from Scid embryos were highly sensitivity to acute effects of ionizing radiation. Carcinogenesis experiments showed the high incidence of thymic lymphomas (80 to 90%) in 1 to 3 Gy {sup 137}Cs-{gamma}-ray-irradiated Scid mice. (author)

  18. Ultraviolet radiation-induced carcinogenesis: mechanisms and experimental models

    International Nuclear Information System (INIS)

    Ramasamy, Karthikeyan; Shanmugam, Mohana; Balupillai, Agilan; Govindhasamy, Kanimozhi; Gunaseelan, Srithar; Muthusamy, Ganesan; Robert, Beualah Mary; Nagarajan, Rajendra Prasad

    2017-01-01

    Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis. (author)

  19. Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats

    OpenAIRE

    Zhao, Yi; Liu, Yan; Lan, Xi-Ming; Xu, Guo-Liang; Sun, You-Zhi; Li, Fei; Liu, Hong-Ning

    2016-01-01

    Dendrobium officinale (Tie Pi Shi Hu in Chinese) has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg) were orally adminis...

  20. Impact of Professional Learning on Teachers' Representational Strategies and Students' Cognitive Engagement with Molecular Genetics Concepts

    Science.gov (United States)

    Nichols, Kim

    2018-01-01

    A variety of practices and specialised representational systems are required to understand, communicate and construct molecular genetics knowledge. This study describes teachers' use of multimodal representations of molecular genetics concepts and how their strategies and choice of resources were interpreted, understood and used by students to…

  1. Biologically based modelling and simulation of carcinogenesis at low doses

    International Nuclear Information System (INIS)

    Ouchi, Noriyuki B.

    2003-01-01

    The process of the carcinogenesis is studied by computer simulation. In general, we need a large number of experimental samples to detect mutations at low doses, but in practice it is difficult to get such a large number of data. To satisfy the requirements of the situation at low doses, it is good to study the process of carcinogenesis using biologically based mathematical model. We have mainly studied it by using as known as 'multi-stage model'; the model seems to get complicated, as we adopt the recent new findings of molecular biological experiments. Moreover, the basic idea of the multi-stage model is based on the epidemiologic data of log-log variation of cancer incidence with age, it seems to be difficult to compare with experimental data of irradiated cell culture system, which has been increasing in recent years. Taking above into consideration, we concluded that we had better make new model with following features: 1) a unit of the target system is a cell, 2) the new information of the molecular biology can be easily introduced, 3) having spatial coordinates for checking a colony formation or tumorigenesis. In this presentation, we will show the detail of the model and some simulation results about the carcinogenesis. (author)

  2. Carcinogenesis

    International Nuclear Information System (INIS)

    Buess, E.M.; Cerny, E.A.; Chan, E.W.

    1977-01-01

    The first section deals with the assessment of carcinogens and cocarcinogens and the underlying mechanisms of their actions. The second concerns cancer induction by bone-seeking radionuclides and seeks to provide a firm foundation for estimating cancer risks to human populations in the event of accidental incorporation of radionuclides. The third is aimed at defining the role of oncornavirus activation in tumor induction by radiation and other environmental pollutants. The other two sections describe the new studies, one dealing with the development of an in vitro cell system (murine teratocarcinoma cells) to screen chemicals rapidly for carcinogenic and mutagenic capacity, and the other investigating the potential use of plasma isozymes as indicators of mutagenesis in mammals. Accomplishments and projections for each of these studies follow

  3. Alterations in mtDNA, gastric carcinogenesis and early diagnosis.

    Science.gov (United States)

    Rodrigues-Antunes, S; Borges, B N

    2018-05-26

    Gastric cancer remains one of the most prevalent cancers in the world. Due to this, efforts are being made to improve the diagnosis of this neoplasm and the search for molecular markers that may be involved in its genesis. Within this perspective, the mitochondrial DNA is considered as a potential candidate, since it has several well documented changes and is readily accessible. However, numerous alterations have been reported in mtDNA, not facilitating the visualization of which alterations and molecular markers are truly involved with gastric carcinogenesis. This review presents a compilation of the main known changes relating mtDNA to gastric cancer and their clinical significance.

  4. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  5. THE EVALUATION OF A TOOL FOR DISSEMINATION OF BIOTECHNOLOGY AND MOLECULAR BIOLOGY CONCEPTS IN FORMAL EDUCATION

    Directory of Open Access Journals (Sweden)

    F.M. Escanhoela

    2007-05-01

    Full Text Available Since 2003, the CBME Scientific Dissemination Coordination hasdeveloped a project related to the production and distribution of a scientificdissemination newspaper, called CBME InFORMAÇÃO, directed to high-schoolstudents and teachers. It is a quarterly publication and shows the concepts andadvances of studies in molecular biology and biotechnology. In order to evaluatethe newspaper, a research was accomplished in 2005. It involved 177 studentsfrom six high schools of São Carlos and region. In addition, opinions of fivescience teachers that worked with the newspaper in their classrooms, as well aseight Biology undergraduates were collected. The teachers received somequestionnaires that had to be answered by them and their students after a specifyactivity with the periodical – basically, the activities consisted of three stages:individual reading of the newspaper; formulation of questions by the teacher and,finally, group discussion on the chosen theme. The research confirmed theimportance of the use of the periodical as a tool in the formation of critical readersof facts related to the biotechnology and molecular biology, what should contributewith the citizenship development in the students. Moreover, it provided a possibilityto reorganize the periodical.

  6. Mutagenesis and carcinogenesis resulting from environment pollution

    International Nuclear Information System (INIS)

    Dimitrov, B.

    2001-01-01

    The paper reviews different ways of environmental contamination with natural and artificial harmful substances (chemical and radioactive) and their role in the processes of mutagenesis and carcinogenesis. The recent studies of the mechanism of mutagenesis and carcinogenesis due to environmental pollution are discussed

  7. Mutiple simultaneous event model for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Baum, J.W.

    1979-01-01

    Theoretical Radiobiology and Risk Estimates includes reports on: Multiple Simultaneous Event Model for Radiation Carcinogenesis; Cancer Risk Estimates and Neutron RBE Based on Human Exposures; A Rationale for Nonlinear Dose Response Functions of Power Greater or Less Than One; and Rationale for One Double Event in Model for Radiation Carcinogenesis

  8. Molecular Consortia—Various Structural and Synthetic Concepts for More Effective Therapeutics Synthesis

    Directory of Open Access Journals (Sweden)

    Anna Pawełczyk

    2018-04-01

    Full Text Available The design and discovery of novel drug candidates are the initial and most probably the crucial steps in the drug development process. One of the tasks of medicinal chemistry is to produce new molecules that have a desired biological effect. However, even today the search for new pharmaceuticals is a very complicated process that is hard to rationalize. Literature provides many scientific reports on future prospects of design of potentially useful drugs. Many trends have been proposed for the design of new drugs containing different structures (dimers, heterodimers, heteromers, adducts, associates, complexes, biooligomers, dendrimers, dual-, bivalent-, multifunction drugs and codrugs, identical or non-identical twin drugs, mixed or combo drugs, supramolecular particles and various nanoindividuals. Recently much attention has been paid to different strategies of molecular hybridization. In this paper, various molecular combinations were described e.g., drug–drug or drug-non-drug combinations which are expressed in a schematic multi-factor form called a molecular matrix, consisting of four factors: association mode, connection method, and the number of elements and linkers. One of the most popular trends is to create small–small molecule combinations such as different hybrids, codrugs, drug–drug conjugates (DDCs and small-large molecule combinations such as antibody-drug conjugates (ADCs, polymer-drug conjugates (PDCs or different prodrugs and macromolecular therapeutics. A review of the structural possibilities of active framework combinations indicates that a wide range of potentially effective novel-type compounds can be formed. What is particularly important is that new therapeutics can be obtained in fast, efficient, and selective methods using current trends in chemical synthesis and the design of drugs such as the “Lego” concept or rational green approach.

  9. Environmental carcinogenesis and genetic variability

    International Nuclear Information System (INIS)

    Knudsen, A.G. Jr

    1977-01-01

    It was found that carcinogenesis in man may involve the interaction of genetic and environmental forces, and that mutation, whether germinal or somatic, seems to be involved in the origin of many, perhaps all cancers. The cancers of man may be visualized as occurring in four groups of individuals according to whether (1) neither genetic nor environmental factors are dominant, i.e. 'background' or 'spontaneous' cancer, (2) heredity alone is dominant, (3) environment alone is important, or (4) both are operating (Knudsen, 1977). The last two groups together are widely thought to contribute 70-80% of cancer cases in the United States; the relative contribution of each group is a major question to be answered

  10. Time factors in radiation carcinogenesis

    International Nuclear Information System (INIS)

    Sasaki, Shunsaku

    1995-01-01

    Results of experiments using B6C3F 1 female mice were made subject of analysis on the time factors in radiation carcinogenesis. In the experiment for examination of influence of age at irradiation on the lifetime risk and on distribution of ages at death, mice were irradiated at day 12, 14 or 17 of the prenatal period, or day 0, 7, 35, 105, 240 or 365 of the postnatal period with doses ranging from 0.48 to 5.7 Gy gamma-rays from 137 Cs. In the experiment to examine the reduction factor for carcinogenic effect by multiple fractionation of gamma-rays dose 1.9 or 3.8 Gy was divided into 10 fractions, which were delivered once a week during period from 5 to 15 weeks of age. All mice were allowed to live out their life spans under a specific pathogen free condition. The cumulative relative risk for mortality from all causes except lymphoma and leukemia was shown to decrease with age when mice were irradiated at the fetal, neonatal, suckling, adolescent or young adult period, whereas, the decrease in the cumulative relative risk was very little when gamma-rays were given at the intermediate adult period. The lifetime risk for the increase in mortality and for the induction of solid tumors was highest in mice irradiated during neonatal, suckling or adolescent period. Age-dependence of susceptibility to radiation carcinogenesis was different for each type of neoplasm. However, the most susceptible period for induction of each type of neoplasm concentrated in the age from neonatal to adolescent period. Radiation-induced late effects were apparently reduced by multiple fractionation of radiation dose, but the reduction factor for the increase in the long-term mortality did not exceed 2.0. (author)

  11. Parasite Infection, Carcinogenesis and Human Malignancy.

    Science.gov (United States)

    van Tong, Hoang; Brindley, Paul J; Meyer, Christian G; Velavan, Thirumalaisamy P

    2017-02-01

    Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  12. Molecular Biology and Prevention of Endometrial Cancer

    National Research Council Canada - National Science Library

    Maxwell, George L

    2006-01-01

    To increase our understanding of the molecular aberrations associated with endometrial carcinogenesis and the biologic mechanisms underlying the protective effect of oral contraceptive (OC) therapy. 1...

  13. Molecular Biology and Prevention of Endometrial Cancer

    National Research Council Canada - National Science Library

    Maxwell, George

    2003-01-01

    To increase our understanding of the molecular aberrations associated with endometrial carcinogenesis and the biologic mechanisms underlying the protective effect of oral contraceptive therapy. Methods: 1...

  14. Molecular Biology and Prevention of Endometrial Cancer

    National Research Council Canada - National Science Library

    Maxwell, George L

    2004-01-01

    To increase our understanding of the molecular aberrations associated with endometrial carcinogenesis and the biologic mechanisms underlying the protective effect of oral contraceptive therapy. Methods: 1...

  15. Source-sink interaction: a century old concept under the light of modern molecular systems biology.

    Science.gov (United States)

    Chang, Tian-Gen; Zhu, Xin-Guang; Raines, Christine

    2017-07-20

    Many approaches to engineer source strength have been proposed to enhance crop yield potential. However, a well-co-ordinated source-sink relationship is required finally to realize the promised increase in crop yield potential in the farmer's field. Source-sink interaction has been intensively studied for decades, and a vast amount of knowledge about the interaction in different crops and under different environments has been accumulated. In this review, we first introduce the basic concepts of source, sink and their interactions, then summarize current understanding of how source and sink can be manipulated through both environmental control and genetic manipulations. We show that the source-sink interaction underlies the diverse responses of crops to the same perturbations and argue that development of a molecular systems model of source-sink interaction is required towards a rational manipulation of the source-sink relationship for increased yield. We finally discuss both bottom-up and top-down routes to develop such a model and emphasize that a community effort is needed for development of this model. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  16. Bioresponsive probes for molecular imaging:Concepts and in vivo applications

    OpenAIRE

    Duijnhoven, van, SMJ Sander; Robillard, MS Marc; Langereis, S Sander; Grüll, H Holger

    2015-01-01

    Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo. In most molecular imaging approaches, probes are used to bind to disease-specific biomarkers highlighting disease target sites. In recent years, a new subset of molecular imaging probes, known as bioresponsive molecular probes, has been developed. These probes generally benefit from signal enhancement at the site of interaction with its target. There are mainly ...

  17. Perspectives in the paradigm of radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Sugakhara, T.; Vatanabe, M.; Niva, O.; Nikajdo, O.

    1995-01-01

    Carcinogenesis is analysed as a multistage process consisting of initiation, promotion and progression. This model includes the mutation of oncogenes and the loss of hetrezygosity by tumor-suppressor genes. The threshold concept of radiation cancerogenesis is proposed, under which ionizing radiation can induce in somatic cell genetic effects a s result of DNA damage and epigenetic changes as well. The epigenetic changes (through DNA or cytoplasma) can be stabilized as mutations observed in many cancer cells and play a dominant role in radiation cancerogenesis induction. The ration of epigenetic and genetic effects largely depends on radiation doses

  18. Statistical modeling and extrapolation of carcinogenesis data

    International Nuclear Information System (INIS)

    Krewski, D.; Murdoch, D.; Dewanji, A.

    1986-01-01

    Mathematical models of carcinogenesis are reviewed, including pharmacokinetic models for metabolic activation of carcinogenic substances. Maximum likelihood procedures for fitting these models to epidemiological data are discussed, including situations where the time to tumor occurrence is unobservable. The plausibility of different possible shapes of the dose response curve at low doses is examined, and a robust method for linear extrapolation to low doses is proposed and applied to epidemiological data on radiation carcinogenesis

  19. Recent progress in nickel carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Sunderman, F.W. Jr.

    1984-01-01

    Positive bacterial mutagenesis tests have been obtained with Ni(II) in Corynybacterium, but not in E. coli, S. typhimurium, or B. subtilis. Transformation assays of several soluble and crystalline Ni compounds have been positive in Syrian hamster embryo cells. Ni(II) binds to DNA, RNA, and nucleoproteins, and becomes localized in nucleoli. Genotoxic effects of Ni include: (a) chromosomal aberrations, including sister-chromatid exchanges, (b) DNA strandbreaks and DNA-protein crosslinks, (c) inhibition of DNA and RNA synthesis, (d) infidelity of DNA transcription, and (e) mutations at the HGPRTase locus in Chinese hamster cells and the TK locus in mouse lymphoma cells. These findings are consistent with somatic mutation as the mechanism for initiation of nickel carcinogenesis. Ni compounds cause reversible transition of double-stranded poly(dG-dC) DNA from the right-handed B-helix to the left-handed Z-helix, suggesting a mechanism whereby nickel might modulate oncogene expression. 99 references, 4 tables.

  20. Implications of tyrosine phosphoproteomics in cervical carcinogenesis

    Directory of Open Access Journals (Sweden)

    DeFord James

    2008-01-01

    Full Text Available Abstract Background Worldwide cervical cancer remains a leading cause of mortality from gynecologic malignancies. The link between cervical cancer and persistent infection with HPV has been established. At a molecular level little is known about the transition from the precancerous state to invasive cancer. To elucidate this process, cervical biopsies from human specimens were obtained from precancerous state to stage III disease. Methods Cervical biopsies were obtained from patients with a diagnosis of cervical cancer undergoing definitive surgery or staging operation. Biopsies were obtained from patients with precancerous lesions at the time of their excisional procedure. Control samples were obtained from patients undergoing hysterectomy for benign conditions such as fibroids. Samples were subjected to proteomic profiling using two dimensional gel electrophoresis with subsequent trypsin digestion followed by MALDI-TOF protein identification. Candidate proteins were then further studied using western blotting, immunoprecipitation and immunohistochemistry. Results Annexin A1 and DNA-PKcs were found to be differentially expressed. Phosphorylated annexin A1 was up regulated in diseased states in comparison to control and its level was strongly detected in the serum of cervical cancer patients compared to controls. DNA-PKcs was noted to be hyperphosphorylated and fragmented in cancer when compared to controls. By immunohistochemistry annexin A1 was noted in the vascular environment in cancer and certain precancerous samples. Conclusion This study suggests a probable role for protein tyrosine phosphorylation in cervical carcinogenesis. Annexin A1 and DNA-PK cs may have synergistic effects with HPV infection. Precancerous lesions that may progress to cervical cancer may be differentiated from lesions that will not base on similar immunohistochemical profile to invasive squamous cell carcinoma.

  1. Overview of osseous tissue findings from the lifespan carcinogenesis studies: From whole animals to molecules

    International Nuclear Information System (INIS)

    Miller, S.C.; Jee, W.S.S.; Bruenger, F.B.; Lloyd, R.D.; Taylor, G.N.

    1991-01-01

    This summary presents some of the findings from the 226 Ra and 239 Pu lifespan carcinogenesis studies in Beagle dogs and discusses these findings relative to the tissue, cellular and molecular biology of osseous tissues. This report attempts to integrate some of the dosimetric and pathological findings with current understanding of the factors that may influence carcinogenesis (and non-carcinogenic pathologies) at the various levels of biological organization. Emphasis is placed on the findings from the 226 Ra study, as this study has recently been completely reviewed and verified

  2. Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

    Science.gov (United States)

    Tahara, Hideaki; Sato, Marimo; Thurin, Magdalena; Wang, Ena; Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Lee, Peter P; Khleif, Samir N; Wigginton, Jon M; Ambs, Stefan; Akutsu, Yasunori; Chaussabel, Damien; Doki, Yuichiro; Eremin, Oleg; Fridman, Wolf Hervé; Hirohashi, Yoshihiko; Imai, Kohzoh; Jacobson, James; Jinushi, Masahisa; Kanamoto, Akira; Kashani-Sabet, Mohammed; Kato, Kazunori; Kawakami, Yutaka; Kirkwood, John M; Kleen, Thomas O; Lehmann, Paul V; Liotta, Lance; Lotze, Michael T; Maio, Michele; Malyguine, Anatoli; Masucci, Giuseppe; Matsubara, Hisahiro; Mayrand-Chung, Shawmarie; Nakamura, Kiminori; Nishikawa, Hiroyoshi; Palucka, A Karolina; Petricoin, Emanuel F; Pos, Zoltan; Ribas, Antoni; Rivoltini, Licia; Sato, Noriyuki; Shiku, Hiroshi; Slingluff, Craig L; Streicher, Howard; Stroncek, David F; Takeuchi, Hiroya; Toyota, Minoru; Wada, Hisashi; Wu, Xifeng; Wulfkuhle, Julia; Yaguchi, Tomonori; Zeskind, Benjamin; Zhao, Yingdong; Zocca, Mai-Britt; Marincola, Francesco M

    2009-01-01

    Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that

  3. Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

    Directory of Open Access Journals (Sweden)

    Rivoltini Licia

    2009-06-01

    Full Text Available Abstract Supported by the Office of International Affairs, National Cancer Institute (NCI, the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc and the United States Food and Drug Administration (FDA to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers

  4. Role of bacteria in oral carcinogenesis

    Directory of Open Access Journals (Sweden)

    R Rajeev

    2012-01-01

    Full Text Available Oral cancer is the most common cancer diagnosed in Indian men and is the leading cause of cancer deaths. It is considered as a multistep and multifactorial disease. Besides accumulation of genetic mutations, numerous other carcinogens are involved. In this category, viral and chemical carcinogens are well studied and documented. However, in the oral cavity, the role of microbiota in carcinogenesis is not known. Microbial populations on mouth mucosa differ between healthy and malignant sites, and certain oral bacterial species have been linked with malignancies, but the evidence is still weak in this respect. Nevertheless, oral microorganisms inevitably up-regulate cytokines and other inflammatory mediators that affect the complex metabolic pathways, and may thus be involved in carcinogenesis. Poor oral health associates statistically with prevalence of many types of cancer such as pancreatic and gastrointestinal cancer. This review presents possible carcinogenesis pathway involved in bacterial carcinogenesis, commonly implicated bacteria in oral carcinogenesis, and their role in cancer therapeutics as well.

  5. Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

    International Nuclear Information System (INIS)

    Wheeler, D. L.; Verma, A. K.; Denning, M. F.

    2013-01-01

    The multistep model of mouse skin carcinogenesis has facilitated identification of irreversible genetic events of initiation and progression, and epigenetic events of tumor promotion. Mouse skin tumor initiation can be accomplished by a single exposure to a sufficiently small dose of a carcinogen, and this step is rapid and irreversible. However, promotion of skin tumor formation requires a repeated and prolonged exposure to a promoter, and that tumor promotion is reversible. Investigations focused on the mechanisms of mouse carcinogenesis have resulted in the identifications of potential molecular targets of cancer induction and progression useful in planning strategies for human cancer prevention trials. This special issue contains eight papers that focus on mouse models used to study individual proteins expressed in the mouse skin and the role they play in differentiation, tissue homeostasis, skin carcinogenesis, and chemo prevention of skin cancer.

  6. Transplacental arsenic carcinogenesis in mice

    International Nuclear Information System (INIS)

    Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

    2007-01-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans

  7. Clinical and molecular analyses of Beckwith-Wiedemann syndrome: Comparison between spontaneous conception and assisted reproduction techniques.

    Science.gov (United States)

    Tenorio, Jair; Romanelli, Valeria; Martin-Trujillo, Alex; Fernández, García-Moya; Segovia, Mabel; Perandones, Claudia; Pérez Jurado, Luis A; Esteller, Manel; Fraga, Mario; Arias, Pedro; Gordo, Gema; Dapía, Irene; Mena, Rocío; Palomares, María; Pérez de Nanclares, Guiomar; Nevado, Julián; García-Miñaur, Sixto; Santos-Simarro, Fernando; Martinez-Glez, Víctor; Vallespín, Elena; Monk, David; Lapunzina, Pablo

    2016-10-01

    Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by an excessive prenatal and postnatal growth, macrosomia, macroglossia, and hemihyperplasia. The molecular basis of this syndrome is complex and heterogeneous, involving genes located at 11p15.5. BWS is correlated with assisted reproductive techniques. BWS in individuals born following assisted reproductive techniques has been found to occur four to nine times higher compared to children with to BWS born after spontaneous conception. Here, we report a series of 187 patients with to BWS born either after assisted reproductive techniques or conceived naturally. Eighty-eight percent of BWS patients born via assisted reproductive techniques had hypomethylation of KCNQ1OT1:TSS-DMR in comparison with 49% for patients with BWS conceived naturally. None of the patients with BWS born via assisted reproductive techniques had hypermethylation of H19/IGF2:IG-DMR, neither CDKN1 C mutations nor patUPD11. We did not find differences in the frequency of multi-locus imprinting disturbances between groups. Patients with BWS born via assisted reproductive techniques had an increased frequency of advanced bone age, congenital heart disease, and decreased frequency of earlobe anomalies but these differences may be explained by the different molecular background compared to those with BWS and spontaneous fertilization. We conclude there is a correlation of the molecular etiology of BWS with the type of conception. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Molecular Biology and Prevention of Endometrial Cancer. Addendum

    National Research Council Canada - National Science Library

    Maxwell, George L

    2008-01-01

    Objective: To increase our understanding of the molecular aberrations associated with endometrial carcinogenesis and the biologic mechanisms underlying the protective effect of oral contraceptive (OC) therapy. Methods: 1...

  9. Operation of micro and molecular machines: a new concept with its origins in interface science.

    Science.gov (United States)

    Ariga, Katsuhiko; Ishihara, Shinsuke; Izawa, Hironori; Xia, Hong; Hill, Jonathan P

    2011-03-21

    A landmark accomplishment of nanotechnology would be successful fabrication of ultrasmall machines that can work like tweezers, motors, or even computing devices. Now we must consider how operation of micro- and molecular machines might be implemented for a wide range of applications. If these machines function only under limited conditions and/or require specialized apparatus then they are useless for practical applications. Therefore, it is important to carefully consider the access of functionality of the molecular or nanoscale systems by conventional stimuli at the macroscopic level. In this perspective, we will outline the position of micro- and molecular machines in current science and technology. Most of these machines are operated by light irradiation, application of electrical or magnetic fields, chemical reactions, and thermal fluctuations, which cannot always be applied in remote machine operation. We also propose strategies for molecular machine operation using the most conventional of stimuli, that of macroscopic mechanical force, achieved through mechanical operation of molecular machines located at an air-water interface. The crucial roles of the characteristics of an interfacial environment, i.e. connection between macroscopic dimension and nanoscopic function, and contact of media with different dielectric natures, are also described.

  10. Radiation carcinogenesis and related radiobiology. Special listing

    International Nuclear Information System (INIS)

    1980-01-01

    The special listing of Current Cancer Research Projects is a publication of the International Cancer Research Data Bank (ICRDB) Program of the National Cancer Institute. Each Listing contains descriptions of ongoing projects in one selected cancer research area. The research areas include: Human cancer and exposure to radiation; Experimental radiation carcinogenesis and radiation biology

  11. Experimental radiation carcinogenesis: what have we learned

    Energy Technology Data Exchange (ETDEWEB)

    Fry, R.J.M.

    1980-01-01

    The author reviews the need for animal experiments in development of a biological model for radioinduced carcinogenesis. He concludes they are vital for: (1) study of mechanisms; (2) establishment of generalizations; (3) elucidation of dose-response and time-dose relationships; and (4) determination of dose-distributions and their results, particularly for radionuclides. (PSB)

  12. Experimental radiation carcinogenesis: what have we learned

    International Nuclear Information System (INIS)

    Fry, R.J.M.

    1980-01-01

    The author reviews the need for animal experiments in development of a biological model for radioinduced carcinogenesis. He concludes they are vital for: (1) study of mechanisms; (2) establishment of generalizations; (3) elucidation of dose-response and time-dose relationships; and (4) determination of dose-distributions and their results, particularly for radionuclides

  13. In vitro studies of human lung carcinogenesis.

    Science.gov (United States)

    Harris, C C; Lechner, J F; Yoakum, G H; Amstad, P; Korba, B E; Gabrielson, E; Grafstrom, R; Shamsuddin, A; Trump, B F

    1985-01-01

    Advances in the methodology to culture normal human lung cells have provided opportunities to investigate fundamental problems in biomedical research, including the mechanism(s) of carcinogenesis. Using the strategy schematically shown in Figure 1, we have initiated studies of the effects of carcinogens on the normal progenitor cells of the human cancers caused by these carcinogens. Extended lifespans and aneuploidy were found after exposure of mesothelial cells to asbestos and bronchial epithelial cells to nickel sulfate. These abnormal cells may be considered to be preneoplastic and at an intermediate position in the multistage process of carcinogenesis. Human bronchial epithelial cells can also be employed to investigate the role of specific oncogenes in carcinogenesis and tumor progression. Using the protoplast fusion method for high frequency gene transfection, vHa-ras oncogene initiates a cascade of events in the normal human bronchial cells leading to their apparent immortality, aneuploidy, and tumorigenicity in athymic nude mice. These results suggest that oncogenes may play an important role in human carcinogenesis.

  14. Molecular biology of mycoplasmas: from the minimum cell concept to the artificial cell.

    Science.gov (United States)

    Cordova, Caio M M; Hoeltgebaum, Daniela L; Machado, Laís D P N; Santos, Larissa Dos

    2016-01-01

    Mycoplasmas are a large group of bacteria, sorted into different genera in the Mollicutes class, whose main characteristic in common, besides the small genome, is the absence of cell wall. They are considered cellular and molecular biology study models. We present an updated review of the molecular biology of these model microorganisms and the development of replicative vectors for the transformation of mycoplasmas. Synthetic biology studies inspired by these pioneering works became possible and won the attention of the mainstream media. For the first time, an artificial genome was synthesized (a minimal genome produced from consensus sequences obtained from mycoplasmas). For the first time, a functional artificial cell has been constructed by introducing a genome completely synthesized within a cell envelope of a mycoplasma obtained by transformation techniques. Therefore, this article offers an updated insight to the state of the art of these peculiar organisms' molecular biology.

  15. "Intelligent" design of molecular materials: Understanding the concepts of design in supramolecular synthesis of network solids

    Science.gov (United States)

    Moulton, Brian D.

    This work endeavors to delineate modern paradigms for crystal engineering, i.e. the design and supramolecular synthesis of functional molecular materials. Paradigms predicated on an understanding of the geometry of polygons and polyhedra are developed. The primary focus is on structural determination by single crystal X-ray crystallography, structural interpretation using a suite of graphical visualization and molecular modeling software, and on the importance of proper graphical representation in the presentation and explanation of crystal structures. A detailed analysis of a selected series of crystal structures is presented. The reduction of these molecular networks to schematic representations that illustrate their fundamental connectivity facilitates the understanding of otherwise complex supramolecular solids. Circuit symbols and Schlafli notation are used to describe the network topologies, which enables networks of different composition and metrics to be easily compared. This reveals that molecular orientations in the crystals and networks are commensurate with networks that can be derived from spherical close packed lattices. The development of a logical design strategy for a new class of materials based on our understanding of the chemical composition and topology of these networks is described. The synthesis and crystal structure of a series of new materials generated by exploitation of this design strategy is presented, in addition to a detailed analysis of the topology of these materials and their relationship to a 'parent' structure. In summary, this dissertation demonstrates that molecular polygons can self-assemble at their vertexes to produce molecular architectures and crystal structures that are consistent with long established geometric dogma. The design strategy represents a potentially broad ranging approach to the design of nanoporous structures from a wide range of chemical components that are based on molecular shape rather than chemical

  16. Biological Complexities in Radiation Carcinogenesis and Cancer Radiotherapy: Impact of New Biological Paradigms

    Directory of Open Access Journals (Sweden)

    Hossein Mozdarani

    2012-01-01

    Full Text Available Although radiation carcinogenesis has been shown both experimentally and epidemiologically, the use of ionizing radiation is also one of the major modalities in cancer treatment. Various known cellular and molecular events are involved in carcinogenesis. Apart from the known phenomena, there could be implications for carcinogenesis and cancer prevention due to other biological processes such as the bystander effect, the abscopal effect, intrinsic radiosensitivity and radioadaptation. Bystander effects have consequences for mutation initiated cancer paradigms of radiation carcinogenesis, which provide the mechanistic justification for low-dose risk estimates. The abscopal effect is potentially important for tumor control and is mediated through cytokines and/or the immune system (mainly cell-mediated immunity. It results from loss of growth and stimulatory and/or immunosuppressive factors from the tumor. Intrinsic radiosensitivity is a feature of some cancer prone chromosomal breakage syndromes such as ataxia telangectiasia. Radiosensitivity is manifested as higher chromosomal aberrations and DNA repair impairment is now known as a good biomarker for breast cancer screening and prediction of prognosis. However, it is not yet known whether this effect is good or bad for those receiving radiation or radiomimetic agents for treatment. Radiation hormesis is another major concern for carcinogenesis. This process which protects cells from higher doses of radiation or radio mimic chemicals, may lead to the escape of cells from mitotic death or apoptosis and put cells with a lower amount of damage into the process of cancer induction. Therefore, any of these biological phenomena could have impact on another process giving rise to genome instability of cells which are not in the field of radiation but still receiving a lower amount of radiation. For prevention of radiation induced carcinogenesis or risk assessment as well as for successful radiation

  17. Conception and synthesis of new molecular cages for xenon MRI applications

    International Nuclear Information System (INIS)

    Delacour, L.

    2011-01-01

    Non-invasive proton magnetic resonance imaging ( 1 H MRI) is a powerful clinical tool for the detection of numerous diseases. Although MRI contrast agents are often used to improve diagnostic specificity, this technique has limited applications in molecular imaging because of its inherently low sensitivity when compared to nuclear medicine or fluorescence imaging. Laser-polarized 129 Xe NMR spectroscopy is a promising tool to circumvent sensitivity limitations. Indeed, optical pumping increases the nuclear spin polarization of xenon by several orders of magnitude (10 4 to 10 5 ), thus small amounts of gas dissolved in biological tissues (blood, lungs...) can be rapidly detected with an excellent signal-to-noise ratio. In addition, the high polarizability of the xenon electron cloud, which induces a very high sensitivity to its environment, makes this nucleus very attractive for molecular imaging. Detection of biomolecules can be achieved by biosensors, which encapsulate xenon atoms in molecular cages that have been functionalized to bind the desired biological target. Cage molecules such as cryptophanes have high affinity for xenon and thus appear as ideal candidates for its encapsulation. During this PhD thesis we worked on the synthesis and the functionalization of new cryptophanes. (author) [fr

  18. Conception and synthesis of the new cryptophane for the applications in xenon NMR molecular imaging

    International Nuclear Information System (INIS)

    Gao, Bo

    2016-01-01

    Among all the imaging techniques, magnetic resonance imaging (MRI) offers several advantages owing to its low invasiveness, its harmlessness and its spatial in-depth resolution but suffers from poor sensitivity. To address this issue, different strategies were proposed, including the utilization of hyper-polarizable species such as "1"2"9Xe. Xenon is an inert gas with a polarizable electronic cloud which leads to an extreme sensitivity to its chemical environment. Its capacity of being hyper-polarized makes it possible to obtain a significant gain of sensitivity. Nevertheless, xenon has no specificity to any biological target therefore it needs to be encapsulated and vectorized. Different molecular cages were proposed and we are particularly interested in cryptophane which is one of the best candidates for xenon encapsulation. In this context, the objective of this thesis is to design new cryptophanes which can be used as molecular platforms to construct novel "1"2"9Xe MRI biosensors usable for in vivo imaging. To meet this demand, these cryptophanes should be mono-functionalizable and enough soluble in water. In this thesis, the polyethylene glycol (PEG) group is used to improve the poor solubility of the hydrophobic molecular cage. And there is a systematic discussion of how to break the symmetry of cryptophanes and different strategies were attempted to synthesize mono-functionalized cryptophanes. As a result, several PEGylated mono-functionalized cryptophanes were obtained and their properties for encapsulating xenon were tested [fr

  19. Electron ionization LC-MS with supersonic molecular beams--the new concept, benefits and applications.

    Science.gov (United States)

    Seemann, Boaz; Alon, Tal; Tsizin, Svetlana; Fialkov, Alexander B; Amirav, Aviv

    2015-11-01

    A new type of electron ionization LC-MS with supersonic molecular beams (EI-LC-MS with SMB) is described. This system and its operational methods are based on pneumatic spray formation of the LC liquid flow in a heated spray vaporization chamber, full sample thermal vaporization and subsequent electron ionization of vibrationally cold molecules in supersonic molecular beams. The vaporized sample compounds are transferred into a supersonic nozzle via a flow restrictor capillary. Consequently, while the pneumatic spray is formed and vaporized at above atmospheric pressure the supersonic nozzle backing pressure is about 0.15 Bar for the formation of supersonic molecular beams with vibrationally cold sample molecules without cluster formation with the solvent vapor. The sample compounds are ionized in a fly-though EI ion source as vibrationally cold molecules in the SMB, resulting in 'Cold EI' (EI of vibrationally cold molecules) mass spectra that exhibit the standard EI fragments combined with enhanced molecular ions. We evaluated the EI-LC-MS with SMB system and demonstrated its effectiveness in NIST library sample identification which is complemented with the availability of enhanced molecular ions. The EI-LC-MS with SMB system is characterized by linear response of five orders of magnitude and uniform compound independent response including for non-polar compounds. This feature improves sample quantitation that can be approximated without compound specific calibration. Cold EI, like EI, is free from ion suppression and/or enhancement effects (that plague ESI and/or APCI) which facilitate faster LC separation because full separation is not essential. The absence of ion suppression effects enables the exploration of fast flow injection MS-MS as an alternative to lengthy LC-MS analysis. These features are demonstrated in a few examples, and the analysis of the main ingredients of Cannabis on a few Cannabis flower extracts is demonstrated. Finally, the advantages of

  20. Science literacy and meaningful learning: status of public high school students from Rio de Janeiro face to molecular biology concepts

    Directory of Open Access Journals (Sweden)

    Daniel Alves Escodino

    2013-12-01

    Full Text Available In this work we aimed to determine the level of Molecular Biology (MB science literacy of students from two Brazilian public schools which do not consider the rogerian theory for class planning and from another institution, Cap UERJ, which favours this theory. We applied semiclosed questionnaires specific to the different groups of science literacy levels. Besides, we have asked them to perform conceptual maps with MB concepts in order to observe if they have experienced meaningful learning. Finally, we prepared MB classes for students of the three schools, considering their conceptual maps and tried to evaluate, through a second map execution, if the use of alternative didactics material, which consider meaningful learning process, would have any effect over the appropriation of new concepts. We observed that most students are placed at Functional literacy level. Nonetheless, several students from CAp were also settled at the higher Conceptual and Procedural levels. We found that most students have not experienced meaningful learning and that the employment of didactic material and implementation of proposals which consider the cognitive structure of the students had a significant effect on the appropriation of several concepts.

  1. Concept of a Cloud Service for Data Preparation and Computational Control on Custom HPC Systems in Application to Molecular Dynamics

    Science.gov (United States)

    Puzyrkov, Dmitry; Polyakov, Sergey; Podryga, Viktoriia; Markizov, Sergey

    2018-02-01

    At the present stage of computer technology development it is possible to study the properties and processes in complex systems at molecular and even atomic levels, for example, by means of molecular dynamics methods. The most interesting are problems related with the study of complex processes under real physical conditions. Solving such problems requires the use of high performance computing systems of various types, for example, GRID systems and HPC clusters. Considering the time consuming computational tasks, the need arises of software for automatic and unified monitoring of such computations. A complex computational task can be performed over different HPC systems. It requires output data synchronization between the storage chosen by a scientist and the HPC system used for computations. The design of the computational domain is also quite a problem. It requires complex software tools and algorithms for proper atomistic data generation on HPC systems. The paper describes the prototype of a cloud service, intended for design of atomistic systems of large volume for further detailed molecular dynamic calculations and computational management for this calculations, and presents the part of its concept aimed at initial data generation on the HPC systems.

  2. Proof of concept for molecular velcro based on the attractive interaction between porphyrin and pyridine containing copolymers

    Directory of Open Access Journals (Sweden)

    M. Sievers

    2018-06-01

    Full Text Available In this short communication, we investigated the synthesis and mixing of porphyrin and pyridine functionalized copolymers as a proof of concept for a velcro-like interaction. A functionalized porphyrin monomer with one polymerizable side chain was synthesized following a rational synthetic pathway. Subsequent copolymerization and careful removal of residual free porphyrin led to poly(n-butyl acrylate-co-5,10,15-triphenyl-20-(3-vinylphenylporphyrin. The immobilized porphyrin was transformed into the corresponding zinc(II complex, which is capable of the coordinative binding of one pyridine moiety. Complete metallation was proven by absorption spectroscopy. 4-Vinylpyridine was immobilized by copolymerization with n-butyl acrylate, too. Via controlled radical polymerization conditions, the molecular weight of poly(n-butyl acrylate-co-4-vinylpyridine was limited to one tenth of the molecular weight of the porphyrin containing copolymer. This large difference in the molecular weight easily allowed identifying the polymers in the mixture of both. With the help of diffusion ordered nuclear magnetic resonance spectroscopy, the complete and temperature-stable precipitation of the porphyrin containing copolymer was observed, proving the expected attractive interaction and supramolecular network formation.

  3. Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment.

    Science.gov (United States)

    Rangel-Castilla, Leonardo; Russin, Jonathan J; Martinez-Del-Campo, Eduardo; Soriano-Baron, Hector; Spetzler, Robert F; Nakaji, Peter

    2014-09-01

    Arteriovenous malformations (AVMs) are classically described as congenital static lesions. However, in addition to rupturing, AVMs can undergo growth, remodeling, and regression. These phenomena are directly related to cellular, molecular, and physiological processes. Understanding these relationships is essential to direct future diagnostic and therapeutic strategies. The authors performed a search of the contemporary literature to review current information regarding the molecular and cellular biology of AVMs and how this biology will impact their potential future management. A PubMed search was performed using the key words "genetic," "molecular," "brain," "cerebral," "arteriovenous," "malformation," "rupture," "management," "embolization," and "radiosurgery." Only English-language papers were considered. The reference lists of all papers selected for full-text assessment were reviewed. Current concepts in genetic polymorphisms, growth factors, angiopoietins, apoptosis, endothelial cells, pathophysiology, clinical syndromes, medical treatment (including tetracycline and microRNA-18a), radiation therapy, endovascular embolization, and surgical treatment as they apply to AVMs are discussed. Understanding the complex cellular biology, physiology, hemodynamics, and flow-related phenomena of AVMs is critical for defining and predicting their behavior, developing novel drug treatments, and improving endovascular and surgical therapies.

  4. Concept of a Cloud Service for Data Preparation and Computational Control on Custom HPC Systems in Application to Molecular Dynamics

    Directory of Open Access Journals (Sweden)

    Puzyrkov Dmitry

    2018-01-01

    Full Text Available At the present stage of computer technology development it is possible to study the properties and processes in complex systems at molecular and even atomic levels, for example, by means of molecular dynamics methods. The most interesting are problems related with the study of complex processes under real physical conditions. Solving such problems requires the use of high performance computing systems of various types, for example, GRID systems and HPC clusters. Considering the time consuming computational tasks, the need arises of software for automatic and unified monitoring of such computations. A complex computational task can be performed over different HPC systems. It requires output data synchronization between the storage chosen by a scientist and the HPC system used for computations. The design of the computational domain is also quite a problem. It requires complex software tools and algorithms for proper atomistic data generation on HPC systems. The paper describes the prototype of a cloud service, intended for design of atomistic systems of large volume for further detailed molecular dynamic calculations and computational management for this calculations, and presents the part of its concept aimed at initial data generation on the HPC systems.

  5. A novel nano-photonics biosensor concept for rapid molecular diagnostics

    Science.gov (United States)

    Klunder, Dion J. W.; van Herpen, Maarten M. J. W.; Kolesnychenko, Aleksey; Hornix, Eefje; Kahya, Nicoletta; de Boer, Ruth; Stapert, Henk

    2008-04-01

    We present a novel nano-photonics biosensor concept that offers an ultra-high surface specificity and excellent suppression of background signals due to the sample fluid on top of the biosensor. In our contribution, we will briefly discuss the operation principle and fabrication of the biosensor, followed by a more detailed discussion on the experimentally determined performance parameters. Recent results on detection of fluorescently labeled molecules in a highly fluorescent background will be shown, and we will give an outlook on real-time detection of bio-molecules such as proteins and nucleic acids.

  6. Time and dose in carcinogenesis

    International Nuclear Information System (INIS)

    Mayneord, W.V.; Clarke, R.H.

    1978-05-01

    Previous work on the implications of different forms of dose response relationships is extended to include time as a variable, not only in time of irradiation but also in the time of appearance of effects following irradiation. The forms of relationships for time distribution of tumours revealed experimentally for both radiation and chemical carcinogens are first considered. It appears that much data may be correlated in terms of a log-normal distribution of tumour yield following the insult. Further, it is noted, that there is evidence that the median time of tumour appearance may be a function of total dose received or even of dose rate for protracted exposure. Using numerical values of these parameters derived from the biological literature speculative studies have been made of the effects on dose response relationships of using a time distribution of tumour yield, considering both uniform irradiation and point sources. In addition the effects of using dose rate rather than dose to define the log-normal distribution to tumour appearance have been investigated. It is assumed that biological response is directly proportional to dose but that effect is distributed in time. From this linear assumption the appearance of non-linear dose response relationships and apparent thresholds are continually seen. Finally, both the importance of attempting analyses of biological data in terms of stochastic concepts and the need for biological data to test our hypotheses is emphasised. (author)

  7. Multiscale diffusion of a molecular probe in a crowded environment: a concept

    Science.gov (United States)

    Currie, Megan; Thao, Chang; Timerman, Randi; Welty, Robb; Berry, Brenden; Sheets, Erin D.; Heikal, Ahmed A.

    2015-08-01

    Living cells are crowded with macromolecules and organelles. Yet, it is not fully understood how macromolecular crowding affects the myriad of biochemical reactions, transport and the structural stability of biomolecules that are essential to cellular function and survival. These molecular processes, with or without electrostatic interactions, in living cells are therefore expected to be distinct from those carried out in test tube in dilute solutions where excluded volumes are absent. Thus there is an urgent need to understand the macromolecular crowding effects on cellular and molecular biophysics towards quantitative cell biology. In this report, we investigated how biomimetic crowding affects both the rotational and translation diffusion of a small probe (rhodamine green, RhG). For biomimetic crowding agents, we used Ficoll-70 (synthetic polymer), bovine serum albumin and ovalbumin (proteins) at various concentrations in a buffer at room temperature. As a control, we carried out similar measurements on glycerolenriched buffer as an environment with homogeneous viscosity as a function of glycerol concentration. The corresponding bulk viscosity was measured independently to test the validity of the Stokes-Einstein model of a diffusing species undergoing a random walk. For rotational diffusion (ps-ns time scale), we used time-resolved anisotropy measurements to examine potential binding of RhG as a function of the crowding agents (surface structure and size). For translational diffusion (μs-s time scale), we used fluorescence correlation spectroscopy for single-molecule fluctuation analysis. Our results allow us to examine the diffusion model of a molecular probe in crowded environments as a function of concentration, length scale, homogeneous versus heterogeneous viscosity, size and surface structures. These biomimetic crowding studies, using non-invasive fluorescence spectroscopy methods, represent an important step towards understanding cellular biophysics and

  8. Tissue misrepair hypothesis for radiation carcinogenesis

    International Nuclear Information System (INIS)

    Kondo, Sohei

    1991-01-01

    Dose-response curves for chronic leukemia in A-bomb survivors and liver tumors in patients given Thorotrast (colloidal thorium dioxide) show large threshold effects. The existence of these threshold effects can be explained by the following hypothesis. A high dose of radiation causes a persistent wound in a cellrenewable tissue. Disorder of the injured cell society partly frees the component cells from territorial restraints on their proliferation, enabling them to continue development of their cellular functions toward advanced autonomy. This progression might be achieved by continued epigenetic and genetic changes as a result of occasional errors in the otherwise concerted healing action of various endogeneous factors recruited for tissue repair. Carcinogenesis is not simply a single-cell problem but a cell-society problem. Therefore, it is not warranted to estimate risk at low doses by linear extrapolation from cancer data at high doses without knowledge of the mechanism of radiation carcinogenesis. (author) 57 refs

  9. Inflammatory and redox reactions in colorectal carcinogenesis.

    Science.gov (United States)

    Guina, Tina; Biasi, Fiorella; Calfapietra, Simone; Nano, Mario; Poli, Giuseppe

    2015-03-01

    It has been established that there is a relationship between chronic inflammation and cancer development. The constant colonic inflammation typical of inflammatory bowel diseases is now considered a risk factor for colorectal carcinoma (CRC) development. The inflammatory network of signaling molecules is also required during the late phases of carcinogenesis, to enable cancer cells to survive and to metastasize. Oxidative reactions are an integral part of the inflammatory response, and are generally associated with CRC development. However, when the malignant phenotype is acquired, increased oxidative status induces antioxidant defenses in cancer cells, favoring their aggressiveness. This contradictory behavior of cancer cells toward redox status is of great significance for potential anticancer therapies. This paper summarizes the essential background information relating to the molecules involved in regulating oxidative stress and inflammation during carcinogenesis. Understanding more of their function in CRC stages might provide the foundation for future developments in CRC treatment. © 2015 New York Academy of Sciences.

  10. Lymphotoxin prevention of diethylnitrosamine carcinogenesis in vivo

    International Nuclear Information System (INIS)

    Ransom, J.H.; Evans, C.H.; DiPaolo, J.A.

    1982-01-01

    Development of intervention measures to control cancer would be facilitated by being able to monitor in vivo carcinogenesis by in vitro quantitation of early indices of neoplastic transformation to assess the in vivo effectiveness of preventive-therapeutic measures. Pregnant Syrian golden hamsters were used in an in vivo-in vitro transplacental model of carcinogenesis to determine the extent that in vivo administration of immunologic hormone preparations along with chemical carcinogen would prevent morphologic transformation assessed in vitro. Pregnant hamsters at 10-11 days of gestation were given injections ip of 3 mg diethylnitrosamine (DENA)/100 g body weight and were killed 2 days later when fetal cells were seeded for colony formation. The frequency of morphologically transformed colonies was assessed after 7 days of growth. Cloning efficiency and mean transformation frequency after DENA exposure were 3.6% and 1 X 10(-4) per cell seeded, respectively. The ip injection of an immunologic hormone preparation reduced the transformation frequency by 46%. The hormone preparation, containing 10,000 U of lymphotoxin but no detectable interferon, was the ultrafiltered lymphokines (greater than 10,000 mol wt) from phytohemagglutinin-stimulated hamster peritoneal leukocytes. The effect of lymphotoxin on cocarcinogenic exposure of fetal cells to DENA in vivo followed by X-irradiation in vitro was also determined. Cells exposed to 250 rad in vitro had a cloning efficiency of 0.5% and a transformation frequency of 0.4 X 10(-4) per cell seeded. After DENA injection and X-irradiation, the transformation frequency increased to 1 X 10(-4) and was inhibited 64% by lymphotoxin in vivo. Thus immunologic hormones (e.g., lymphotoxin) can prevent carcinogenesis in vivo. Furthermore, in vitro quantitation of transformation is a rapid means for evaluating therapeutic and autochthonous effector mechanisms for their ability to prevent or otherwise modulate carcinogenesis in vivo

  11. Radiation carcinogenesis and related radiobiology. Special listing

    International Nuclear Information System (INIS)

    1978-01-01

    This Special Listing of Current Cancer Research Projects is a service of the International Cancer Research Data Bank (ICRDB) program of the National Cancer Institute. Each listing contains descriptions of ongoing projects in one selected cancer research area. The descriptions are provided by cancer scientists in about 50 different countries. Research areas covered in this listing are: Human cancer and exposure to radiation; experimental radiation carcinogenesis and radiation biology

  12. Ab initio molecular dynamics: basic concepts, current trends and novel applications

    International Nuclear Information System (INIS)

    Tuckerman, Mark E

    2002-01-01

    The field of ab initio molecular dynamics (AIMD), in which finite temperature molecular dynamics (MD) trajectories are generated with forces obtained from accurate 'on the fly' electronic structure calculations, is a rapidly evolving and growing technology that allows chemical processes in condensed phases to be studied in an accurate and unbiased way. This article is intended to present the basics of the AIMD method as well as to provide a broad survey of the state of the art of the field and showcase some of its capabilities. Beginning with a derivation of the method from the Born-Oppenheimer approximation, issues including the density functional representation of electronic structure, basis sets, calculation of observables and the Car-Parrinello extended Lagrangian algorithm are discussed. A number of example applications, including liquid structure and dynamics and aqueous proton transport, are presented in order to highlight some of the current capabilities of the approach. Finally, advanced topics such as inclusion of nuclear quantum effects, excited states and scaling issues are addressed. (topical review)

  13. A Critical Review of the Concept of Transgenic Plants: Insights into Pharmaceutical Biotechnology and Molecular Farming.

    Science.gov (United States)

    Abiri, Rambod; Valdiani, Alireza; Maziah, Mahmood; Shaharuddin, Noor Azmi; Sahebi, Mahbod; Yusof, Zetty Norhana Balia; Atabaki, Narges; Talei, Daryush

    2016-01-01

    Using transgenic plants for the production of high-value recombinant proteins for industrial and clinical applications has become a promising alternative to using conventional bioproduction systems, such as bacteria, yeast, and cultured insect and animal cells. This novel system offers several advantages over conventional systems in terms of safety, scale, cost-effectiveness, and the ease of distribution and storage. Currently, plant systems are being utilised as recombinant bio-factories for the expression of various proteins, including potential vaccines and pharmaceuticals, through employing several adaptations of recombinant processes and utilizing the most suitable tools and strategies. The level of protein expression is a critical factor in plant molecular farming, and this level fluctuates according to the plant species and the organs involved. The production of recombinant native and engineered proteins is a complicated procedure that requires an inter- and multi-disciplinary effort involving a wide variety of scientific and technological disciplines, ranging from basic biotechnology, biochemistry, and cell biology to advanced production systems. This review considers important plant resources, affecting factors, and the recombinant-protein expression techniques relevant to the plant molecular farming process.

  14. Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment.

    Science.gov (United States)

    Teoh, Seong Lin; Das, Srijit

    2016-11-01

    Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

  15. Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics

    International Nuclear Information System (INIS)

    Chen Shuhui; Wang Yiwen; Hsu Jueliang; Chang Hongyi; Wang Chiyun; Shen Potsun; Chiang Chiwu; Chuang Jingjing; Tsai Hungwen; Gu Powen; Chang Fangchih; Liu Hsiaosheng; Chow Nanhaw

    2010-01-01

    To investigate the molecular mechanisms of arsenic (As)-associated carcinogenesis, we performed proteomic analysis on E7 immortalized human uroepithelial cells after treatment with As in vitro. Quantitative proteomics was performed using stable isotope dimethyl labeling coupled with two-dimensional liquid chromatography peptide separation and mass spectrometry (MS)/MS analysis. Among 285 proteins, a total of 26 proteins were upregulated (ratio > 2.0) and 18 proteins were downregulated (ratio < 0.65) by As treatment, which are related to nucleotide binding, lipid metabolism, protein folding, protein biosynthesis, transcription, DNA repair, cell cycle control, and signal transduction. This study reports the potential significance of nucleophosmin (NPM) in the As-related bladder carcinogenesis. NPM was universally expressed in all of uroepithelial cell lines examined, implying that NPM may play a role in human bladder carcinogenesis. Upregulation of NPM tends to be dose- and time-dependent after As treatment. Expression of NPM was associated with cell proliferation, migration and anti-apoptosis. On the contrary, soy isoflavones inhibited the expression of NPM in vitro. The results suggest that NPM may play a role in the As-related bladder carcinogenesis, and soybean-based foods may have potential in the suppression of As/NPM-related tumorigenesis.

  16. Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis.

    Science.gov (United States)

    Wattenberg, Elizabeth V

    2007-01-01

    Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na(+),K(+)-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

  17. Genetic alterations during radiation-induced carcinogenesis

    International Nuclear Information System (INIS)

    Kodama, Seiji

    1995-01-01

    This paper reviews radiation-induced genetic alterations and its carcinogenesis, focusing on the previous in vitro assay outcome. A colony formation assay using Syrian hamster fetal cells and focus formation assay using mouse C3H10T1/2 cells are currently available to find malignant transformation of cells. Such in vitro assays has proposed the hypothesis that radiation-induced carcinogenesis arises from at least two-stage processes; i.e., that an early step induced by irradiation plays an important role in promoting the potential to cause the subsequent mutation. A type of genetic instability induced by radiation results in a persistently elevated frequency of spontaneous mutations, so-called the phenomenon of delayed reproductive death. One possible mechanism by which genetic instability arises has been shown to be due to the development of abnormality in the gene group involved in the maintenance mechanism of genome stability. Another possibility has also been shown to stem from the loss of telomere (the extremities of a chromosome). The importance of search for radiation-induced genetic instability is emphasized in view of the elucidation of carcinogenesis. (N.K.)

  18. Risk assessment of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Kai, Michiaki

    2012-01-01

    This commentary describes the radiation cancer risk assessed by international organizations other than ICRP, assessed for radon and for internal exposure, in the series from the aspect of radiation protection of explaining the assessments done until ICRP Pub. 103. Statistic significant increase of cancer formation is proved at higher doses than 100-200 mSv. At lower doses, with use of mathematical model, United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) reported the death probability due to the excess lifetime risk (ELR) at 100 mSv of 0.36-0.77% for solid tumors and 0.03-0.05% for leukemia, and NRC in US, the risk of exposure-induced prevalence and death (REID) per 100 thousands persons of 800 (male)/1,310 (female) and 410/610, respectively. Both are essentially based on findings in A-bomb survivors. The assessment for Rn is described here not on dose. UK and US analyses of pooled raw data in case control studies revealed the significant increase of lung cancer formation at as low level as 100 Bq Rn/m3. Their analyses also showed the significance of smoking, which had been realized as a confounding factor in risk analysis of Rn for uranium miners. The death probability until the age of 85 y was found to be 1.2 x 10 -4 in non-smokers and 24 x 10 -4 in smokers/ Working Level Month (WLM). Increased thyroid cancer incidence has been known in Chernobyl Accident, which is realized as a result of internal exposure of radioiodine; however, the relationship between the internal dose to thyroid and its cancer prevalence resembles that in the case of external exposure. There is no certain evidence against the concept that risk of internal exposure is similar to and/or lower than, the external one although assessment of the internal exposure risk accompanies uncertainty depending on the used model and ingested dose. International Commission on Radiological Protection (ICRP) recommendations hitherto have been important and precious despite

  19. The geometric phase in quantum systems foundations, mathematical concepts, and applications in molecular and condensed matter physics

    CERN Document Server

    Böhm, Arno; Koizumi, Hiroyasu; Niu, Qian; Zwanziger, Joseph

    2003-01-01

    Aimed at graduate physics and chemistry students, this is the first comprehensive monograph covering the concept of the geometric phase in quantum physics from its mathematical foundations to its physical applications and experimental manifestations It contains all the premises of the adiabatic Berry phase as well as the exact Anandan-Aharonov phase It discusses quantum systems in a classical time-independent environment (time dependent Hamiltonians) and quantum systems in a changing environment (gauge theory of molecular physics) The mathematical methods used are a combination of differential geometry and the theory of linear operators in Hilbert Space As a result, the monograph demonstrates how non-trivial gauge theories naturally arise and how the consequences can be experimentally observed Readers benefit by gaining a deep understanding of the long-ignored gauge theoretic effects of quantum mechanics and how to measure them

  20. Mechanisms of caffeine-induced inhibition of UVB carcinogenesis

    Directory of Open Access Journals (Sweden)

    Allan H Conney

    2013-06-01

    Full Text Available Sunlight-induced nonmelanoma skin cancer is the most prevalent cancer in the United States with more than 2 million cases per year. Several studies have shown an inhibitory effect of caffeine administration on UVB-induced skin cancer in mice, and these studies are paralleled by epidemiology studies that indicate an inhibitory effect of coffee drinking on nonmelanoma skin cancer in humans. Strikingly, decaffeinated coffee consumption had no such inhibitory effect.Mechanism studies indicate that caffeine has a sunscreen effect that inhibits UVB-induced formation of thymine dimers and sunburn lesions in the epidermis of mice. In addition, caffeine administration has a biological effect that enhances UVB-induced apoptosis thereby enhancing the elimination of damaged precancerous cells, and caffeine administration also enhances apoptosis in tumors. Caffeine administration enhances UVB-induced apoptosis by p53-dependent and p53-independent mechanisms. Exploration of the p53-independent effect indicated that caffeine administration enhanced UVB-induced apoptosis by inhibiting the UVB-induced increase in ATR-mediated formation of phospho-Chk1 (Ser345 and abolishing the UVB-induced decrease in cyclin B1 which resulted in caffeine-induced premature and lethal mitosis in mouse skin. In studies with cultured primary human keratinocytes, inhibition of ATR with siRNA against ATR inhibited Chk1 phosphorylation and enhanced UVB-induced apoptosis. Transgenic mice with decreased epidermal ATR function that were irradiated chronically with UVB had 69% fewer tumors at the end of the study compared with irradiated littermate controls with normal ATR function. These results, which indicate that genetic inhibition of ATR (like pharmacologic inhibition of ATR via caffeine inhibits UVB-induced carcinogenesis and supports the concept that ATR-mediated phosphorylation of Chk1 is an important target for caffeine’s inhibitory effect on UVB-induced carcinogenesis.

  1. Celecoxib prevents colitis associated colon carcinogenesis: an upregulation of apoptosis.

    Science.gov (United States)

    Setia, Shruti; Nehru, Bimla; Sanyal, Sankar N

    2014-12-01

    Uncontrolled cell proliferation and suppressed apoptosis are the critical events transforming a normal cell to a cancerous one wherein the inflammatory microenvironment supports this oncogenic transformation. The process of colon carcinogenesis may be aggravated in chronic inflammatory conditions such as ulcerative colitis where non-steroidal anti-inflammatory drugs (NSAIDs) may effectively prevent the cellular and molecular events. Western blots and immunofluorescent analysis of DNA mismatch repair enzymes, cell cycle regulators and pro- and anti-apoptotic proteins were performed in dextran sulfate sodium (DSS)-induced ulcerative colitis and 1,2-dimethyl benz(a)anthracene (DMH)-induced colon cancer. Also, apoptotic studies were done in isolated colonocytes using fluorescent staining and in paraffin sections using TUNEL assay. An upregulation of cell cycle regulators: cyclin D1/cdk4 and cyclin E/cdk2 and anti-apoptotic Bcl-2, along with the suppression of DNA repair enzymes: MLH1 and MSH2; tumour suppressors: p53, p21and Rb and pro-apoptotic proteins: Bax and Bad were observed in the DSS, DMH and DSS+DMH groups. Proliferating cell nuclear antigen (PCNA) was also overexpressed in these groups. The ultimate executioner of the apoptotic pathway; caspase-3, was suppressed in these groups. Apoptotic studies in colonocytes and paraffin sections revealed suppressed apoptosis in these groups. These effects were corrected with the administration of a second generation NSAID, celecoxib along with the treatment of DSS and DMH. The chemopreventive action of celecoxib in colitis mediated colon carcinogenesis may include the regulation of DNA mismatch repair enzymes, cell cycle check points, cell proliferation and apoptosis. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  2. Molecular design concept for multi-kilovolt x-ray amplification. Final report, December 13, 1990--December 14, 1993

    International Nuclear Information System (INIS)

    Rhodes, C.K.; McPherson, A.; Boyer, K.

    1994-01-01

    The goal of this program is the construction of an X-ray laser in the multi-kilovolt regime which can serve as a vital enabling technology in the broad and fundamental field of materials science. Experimental findings indicate that an entirely new technique for amplification at X-ray wavelengths is feasible. This method involves the combination of (a) a recently discovered mode of multiphoton coupling to molecules which efficiently yields core excited ions, (b) a new channeled mode of propagation for spatial organization, and (c) an ultrahigh brightness subpicosecond laser technology. The concept of molecular X-ray laser design, which involves matching the conditions of excitation to the molecular structure, enables the inner-shell excitation to be selectively achieved. Basically, the molecular approach enables the copious generation of a highly excited species to occur rapidly in an environment characteristic of dense cold matter, a situation exceptionally conducive to X-ray amplification. High energy efficiency and wavelength tunability also appear as intrinsic features of this method. Experimental data concerning the study of five cases [Xe(N), Xe(M), Xe(L), Kr(M), and Kr(L)], spanning-spectrally from ∼ 80 eV to ∼ 5 keV, have (1) established the important role of cluster formation, (2) verified the scaling of this phenomenon into the kilovolt region, (3) demonstrated the production of hollow atoms having multiple inner-shell vacancies, (4) provided evidence for the crucial influence of coherent electronic motions on the strength of the multiphoton coupling, (5) led to the conclusion that a regime of strong-coupling exists in which multi-electron ejection from an inner-shell can occur with high probability, (6) revealed the scaling in atomic number which potently favors heavy atoms, and (7) combined the multiphoton induced X-ray emission from clusters with channeled propagation

  3. Interaction Between Dietary Factors and Inflammation in Prostate Carcinogenesis

    National Research Council Canada - National Science Library

    De Marzo, Angelo M

    2007-01-01

    We are investigating whether inflammation can enhance prostate carcinogenesis in a rat model of dietary charred meat carcinogen induced cancers, and, whether antioxidant and other chemopreventative...

  4. Interactions between Dietary Factors and Inflammation in Prostate Carcinogenesis

    National Research Council Canada - National Science Library

    DeMarzo, Angelo M

    2006-01-01

    We are investigating whether inflammation can enhance prostate carcinogenesis in a rat model of dietary charred meat carcinogen induced cancers, and, whether antioxidant and other chemopreventative...

  5. Application of evolutionary games to modeling carcinogenesis.

    Science.gov (United States)

    Swierniak, Andrzej; Krzeslak, Michal

    2013-06-01

    We review a quite large volume of literature concerning mathematical modelling of processes related to carcinogenesis and the growth of cancer cell populations based on the theory of evolutionary games. This review, although partly idiosyncratic, covers such major areas of cancer-related phenomena as production of cytotoxins, avoidance of apoptosis, production of growth factors, motility and invasion, and intra- and extracellular signaling. We discuss the results of other authors and append to them some additional results of our own simulations dealing with the possible dynamics and/or spatial distribution of the processes discussed.

  6. Mechanisms of carcinogenesis prevention by flavonoids

    Directory of Open Access Journals (Sweden)

    G. A. Belitsky

    2014-01-01

    Full Text Available The mechanisms of anticancerogenic effects of flavanoids and isocyanates from the plants widely consumed in the midland belt of Russia were reviewed. Data of studies both in vitro and in vivo were analyzed. Special attention was paid to inhibition of targets responsible for carcinogen metabolic activation, carcinogenesis promotion and tumor progression as well as neoangiogenesis. Besides that the antioxidant properties of flavonoids and their effects on cell cycle regulation, apoptosis initiation and cell mobility were considered.

  7. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun-Hee; Hong, Kyung-Sook; Hong, Hua [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Hahm, Ki Baik, E-mail: hahmkb@gachon.ac.kr [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Department of Gastroenterology, Gachon Graduate School of Medicine, Gil Hospital, Incheon 406-840 (Korea, Republic of)

    2011-07-25

    Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  8. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    International Nuclear Information System (INIS)

    Kim, Eun-Hee; Hong, Kyung-Sook; Hong, Hua; Hahm, Ki Baik

    2011-01-01

    Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis

  9. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ki Baik Hahm

    2011-07-01

    Full Text Available Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  10. Skin carcinogenesis in man and in experimental models

    International Nuclear Information System (INIS)

    Hecker, E.; Jung, E.G.; Marks, F.; Tilgen, W.

    1993-01-01

    This book presents an updated overview of the current state of the art in scientific, experimental and clinical investigations on the generation and the prevention of cancer of the skin. From the achievements presented, marked refinements in the assessment of the risk of cancer, by environmental and endogenous factors, including tumor virus, will be stimulated. They include the problem of the stratospheric 'ozone holes' above both poles of the earth causing much public concern as expressed by current headlines in the media and by the United Nations Environmental Program. Moreover, new ideas will merge for developing specific approaches to explore the mechanistic, i.e. ultimately the molecular-biological, causes of skin cancer and others. In addition, the experimental utilization of oncogens and of other techniques of molecular biology at all levels of the biology of tissues and cells, may open up entirely new facets in the research on skin cancer. Detailed knowledge of the mechanistic aspects of skin carcinogenesis may give important hints with respect to 'tailor-make' and utilize new anti-tumor agents in the therapy of skin cancer for the benefit of the cancer patient. (orig.). 67 figs., 44 tabs

  11. Defining the role of polyamines in colon carcinogenesis using mouse models

    Directory of Open Access Journals (Sweden)

    Natalia A Ignatenko

    2011-01-01

    Full Text Available Genetics and diet are both considered important risk determinants for colorectal cancer, a leading cause of death in the US and worldwide. Genetically engineered mouse (GEM models have made a significant contribution to the characterization of colorectal cancer risk factors. Reliable, reproducible, and clinically relevant animal models help in the identification of the molecular events associated with disease progression and in the development of effictive treatment strategies. This review is focused on the use of mouse models for studying the role of polyamines in colon carcinogenesis. We describe how the available mouse models of colon cancer such as the multiple intestinal neoplasia (Min mice and knockout genetic models facilitate understanding of the role of polyamines in colon carcinogenesis and help in the development of a rational strategy for colon cancer chemoprevention.

  12. Curcumin: the spicy modulator of breast carcinogenesis.

    Science.gov (United States)

    Banik, Urmila; Parasuraman, Subramani; Adhikary, Arun Kumar; Othman, Nor Hayati

    2017-07-19

    Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer.

  13. Radiation carcinogenesis: Epidemiology and biological significance

    International Nuclear Information System (INIS)

    Boice, J.D.; Fraumeni, J.F.

    1984-01-01

    Epidemiologic studies of populations exposed to radiation have led to the identification of a preventable cause of cancer, but in the long run perhaps the most important contribution of radiation studies will be to provide insights into the basic processes of human carcinogenesis. In this volume, key investigators of major epidemiologic projects summarize their observations to date, including information to help assess the effects of low-level exposures. Experimentalists and theorists emphasize the relevance of laboratory and epidemiologic data in elucidating carcinogenic risks and mechanisms in man. This volume was prepared with several objectives in mind: (a) organize and synthesize knowledge on radiation carcinogenesis through epidemiologic and experimental approaches; (b) illustrate and explore ways of utilizing this information to gain insights into the fundamental mechanisms of cancer development; (c) stimulate the formation of hypotheses suited to experimental or epidemiologic testing, theoretical modeling, and multidisciplinary approaches; and (d) identify recent advances that clarify dose-response relationships and the influence of low-dose exposures, provide leads to carcinogenic mechanisms and host-environmental interactions, and suggest strategies for future research and preventive action

  14. Initiation-promotion skin carcinogenesis and immunological competence.

    Science.gov (United States)

    Curtis, G L; Stenbäck, F; Ryan, W L

    1975-10-01

    The immune competence of mice during initiation-promotion skin carcinogenesis was determined by skin allograft rejection and lymphocyte mitogenesis. The carcinogen 7, 12-dimethylbenzanthracene inhibited the cellular immune competence of mice while lymphocytes from croton oil treated mice had enhanced PWM response. Chlorphenesin, a stimulator of cellular immunity, was found to inhibit tumorigenesis in initiation-promotion skin carcinogenesis when injected during promotion.

  15. Actin Immobilization on Chitin for Purifying Myosin II: A Laboratory Exercise That Integrates Concepts of Molecular Cell Biology and Protein Chemistry

    Science.gov (United States)

    de Souza, Marcelle Gomes; Grossi, Andre Luiz; Pereira, Elisangela Lima Bastos; da Cruz, Carolina Oliveira; Mendes, Fernanda Machado; Cameron, Luiz Claudio; Paiva, Carmen Lucia Antao

    2008-01-01

    This article presents our experience on teaching biochemical sciences through an innovative approach that integrates concepts of molecular cell biology and protein chemistry. This original laboratory exercise is based on the preparation of an affinity chromatography column containing F-actin molecules immobilized on chitin particles for purifying…

  16. Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice

    Energy Technology Data Exchange (ETDEWEB)

    Sur, Subhayan, E-mail: subhayansur18@gmail.com [Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal (India); Pal, Debolina; Roy, Rituparna; Barua, Atish [Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal (India); Roy, Anup [North Bengal Medical College and Hospital, West Bengal (India); Saha, Prosenjit [Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal (India); Panda, Chinmay Kumar, E-mail: ckpanda.cnci@gmail.com [Dept. of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata 700 026, West Bengal (India)

    2016-06-01

    The aim of this study is to understand the molecular mechanisms of N-nitrosodiethylamine (NDEA) induced multi-organ carcinogenesis in tongue and liver of the same mouse and restriction of carcinogenesis by Epigallocatechin gallate (EGCG) and Theaflavin (TF), if any. For that purpose, cellular proliferation/apoptosis, prevalence of CD44 positive stem cell population and expressions of some key regulatory genes of self renewal Wnt and Hedgehog (Hh) pathways and some of their associated genes were analyzed in the NDEA induced tongue and liver lesions in absence or presence of EGCG/TF. Chronic NDEA exposure in oral cavity could decrease mice body weights and induce tongue and liver carcinogenesis with similar histological stages (severe dysplasia up to 30th weeks of NDEA administration). Increasing mice body weights were seen in continuous and post EGCG/TF treated groups. EGCG/TF treatment could restrict both the carcinogenesis at similar histological stages showing potential chemopreventive effect in continuous treated groups (mild dysplasia) followed by pre treatment (moderate dysplasia) and therapeutic efficacy in post treated groups (mild dysplasia) up to 30th week. The mechanism of carcinogenesis by NDEA and restriction by the EGCG/TF in both tongue and liver were similar and found to be associated with modulation in cellular proliferation/apoptosis and prevalence of CD44 positive population. The up-regulation of self renewal Wnt/β-catenin, Hh/Gli1 pathways and their associated genes Cyclin D1, cMyc and EGFR along with down regulation of E-cadherin seen during the carcinogenesis processes were found to be modulated during the restriction processes by EGCG/TF. - Highlights: • Simultaneous tongue and liver carcinogenesis in mice by oral NDEA administration • Restriction of both carcinogenesis by EGCG and TF at early pre-malignant stages • The mechanisms of carcinogenesis and restriction were similar in both the organs. • Changes in proliferation

  17. Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis simultaneously induced by N-nitrosodiethylamine in mice

    International Nuclear Information System (INIS)

    Sur, Subhayan; Pal, Debolina; Roy, Rituparna; Barua, Atish; Roy, Anup; Saha, Prosenjit; Panda, Chinmay Kumar

    2016-01-01

    The aim of this study is to understand the molecular mechanisms of N-nitrosodiethylamine (NDEA) induced multi-organ carcinogenesis in tongue and liver of the same mouse and restriction of carcinogenesis by Epigallocatechin gallate (EGCG) and Theaflavin (TF), if any. For that purpose, cellular proliferation/apoptosis, prevalence of CD44 positive stem cell population and expressions of some key regulatory genes of self renewal Wnt and Hedgehog (Hh) pathways and some of their associated genes were analyzed in the NDEA induced tongue and liver lesions in absence or presence of EGCG/TF. Chronic NDEA exposure in oral cavity could decrease mice body weights and induce tongue and liver carcinogenesis with similar histological stages (severe dysplasia up to 30th weeks of NDEA administration). Increasing mice body weights were seen in continuous and post EGCG/TF treated groups. EGCG/TF treatment could restrict both the carcinogenesis at similar histological stages showing potential chemopreventive effect in continuous treated groups (mild dysplasia) followed by pre treatment (moderate dysplasia) and therapeutic efficacy in post treated groups (mild dysplasia) up to 30th week. The mechanism of carcinogenesis by NDEA and restriction by the EGCG/TF in both tongue and liver were similar and found to be associated with modulation in cellular proliferation/apoptosis and prevalence of CD44 positive population. The up-regulation of self renewal Wnt/β-catenin, Hh/Gli1 pathways and their associated genes Cyclin D1, cMyc and EGFR along with down regulation of E-cadherin seen during the carcinogenesis processes were found to be modulated during the restriction processes by EGCG/TF. - Highlights: • Simultaneous tongue and liver carcinogenesis in mice by oral NDEA administration • Restriction of both carcinogenesis by EGCG and TF at early pre-malignant stages • The mechanisms of carcinogenesis and restriction were similar in both the organs. • Changes in proliferation

  18. Oxidative stress and inflammation in liver carcinogenesis

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    Natalia Olaya

    2007-02-01

    series of transcription factors. Moreover, in addition to direct production of ROS by these pathogens, liver infiltration by activated phagocytic cells provides an additional source of ROS production that promotes oxidative stress via interleukin or NO production that can damage proteins, lipids and DNA.

    Nuclear MSI was demonstrated first in familial hereditary colorectal cancer (HNPCC and then in sporadic cancers, primarily digestive tract cancers such as colorectal, gastric and pancreatic cancers.In HCC, although nuclear MSI has been shown in some studies (15,18, there is as yet no direct evidence of alteration of the MMR genes and the biological and the clinicopathological significance of the lowlevel MSI seen in HCC is unclear. MSI has also been shown to occur in inflammatory tissues such as chronic hepatitis and cirrhosis as well as in ulcerative colitis, chronic pancreatitis and in non digestive inflammatory diseases such as rheumatoid arthritis.

    Recently, the role of mitochondria in carcinogenesis has been under numerous investigation, in part because their prominent role in apoptosis, ROS production and other aspects of tumour biology. The mitochondrial genome is particularly susceptible to mutations because of the high level of ROS generation in this organelle, coupled with a relatively low level of DNA repair. Somatic mutations of mitochondrial DNA (mtDNA have been shown in HCC as was also observed MSI. These findings suggest a potential role for mitochondrial genome instability in the early steps of tumorigenesis.

    Ischemia-reperfusion injury can occur in several situations and is a major cause of cell damage during surgery. Cells and tissues subjected to hypoxia by prolonged ischemia become acidic

  19. Information dynamics in carcinogenesis and tumor growth.

    Science.gov (United States)

    Gatenby, Robert A; Frieden, B Roy

    2004-12-21

    The storage and transmission of information is vital to the function of normal and transformed cells. We use methods from information theory and Monte Carlo theory to analyze the role of information in carcinogenesis. Our analysis demonstrates that, during somatic evolution of the malignant phenotype, the accumulation of genomic mutations degrades intracellular information. However, the degradation is constrained by the Darwinian somatic ecology in which mutant clones proliferate only when the mutation confers a selective growth advantage. In that environment, genes that normally decrease cellular proliferation, such as tumor suppressor or differentiation genes, suffer maximum information degradation. Conversely, those that increase proliferation, such as oncogenes, are conserved or exhibit only gain of function mutations. These constraints shield most cellular populations from catastrophic mutator-induced loss of the transmembrane entropy gradient and, therefore, cell death. The dynamics of constrained information degradation during carcinogenesis cause the tumor genome to asymptotically approach a minimum information state that is manifested clinically as dedifferentiation and unconstrained proliferation. Extreme physical information (EPI) theory demonstrates that altered information flow from cancer cells to their environment will manifest in-vivo as power law tumor growth with an exponent of size 1.62. This prediction is based only on the assumption that tumor cells are at an absolute information minimum and are capable of "free field" growth that is, they are unconstrained by external biological parameters. The prediction agrees remarkably well with several studies demonstrating power law growth in small human breast cancers with an exponent of 1.72+/-0.24. This successful derivation of an analytic expression for cancer growth from EPI alone supports the conceptual model that carcinogenesis is a process of constrained information degradation and that malignant

  20. Radiation carcinogenesis in mouse thymic lymphomas

    International Nuclear Information System (INIS)

    Kominami, Ryo; Niwa, Ohtsura

    2006-01-01

    Ionizing radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of radiation-induced mouse thymic lymphomas, one of the classic models in radiation carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the ''indirect mechanism'' for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility. (author)

  1. Dysregulation of Autophagy Contributes to Anal Carcinogenesis.

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    Evie H Carchman

    Full Text Available Autophagy is an intracellular catabolic process that removes and recycles unnecessary/dysfunctional cellular components, contributing to cellular health and survival. Autophagy is a highly regulated cellular process that responds to several intracellular signals, many of which are deregulated by human papillomavirus (HPV infection through the expression of HPV-encoded oncoproteins. This adaptive inhibitory response helps prevent viral clearance. A strong correlation remains between HPV infection and the development of squamous cell carcinoma (SCC of the anus, particularly in HIV positive and other immunosuppressed patients. We hypothesize that autophagy is inhibited by HPV-encoded oncoproteins thereby promoting anal carcinogenesis (Fig 1.HPV16 transgenic mice (K14E6/E7 and non-transgenic mice (FVB/N, both of which do not spontaneously develop anal tumors, were treated topically with the chemical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA, to induce anal cancer. The anuses at different time points of treatment (5, 10, 15 and 20 weeks were analyzed using immunofluorescence (IF for two key autophagy marker proteins (LC3β and p62 in addition to histological grading. The anuses from the K14E6/E7 mice were also analyzed for visual evidence of autophagic activity by electron microscopy (EM. To see if there was a correlation to humans, archival anal specimens were assessed histologically for grade of dysplasia and then analyzed for LC3β and p62 protein content. To more directly examine the effect of autophagic inhibition on anal carcinogenesis, nontransgenic mice that do not develop anal cancer with DMBA treatment were treated with a known pharmacologic inhibitor of autophagy, chloroquine, and examined for tumor development and analyzed by IF for autophagic proteins.Histologically, we observed the progression of normal anoderm to invasive SCC with DMBA treatment in K14E6/E7 mice but not in nontransgenic, syngeneic FVB/N background control mice

  2. Role of retinoic receptors in lung carcinogenesis

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    Renyi-Vamos Ferenc

    2008-07-01

    Full Text Available Abstract Several in vitro and in vivo studies have examined the positive and negative effects of retinoids (vitamin A analogs in premalignant and malignant lesions. Retinoids have been used as chemopreventive and anticancer agents because of their pleiotropic regulator function in cell differentiation, growth, proliferation and apoptosis through interaction with two types of nuclear receptors: retinoic acid receptors and retinoid X receptors. Recent investigations have gradually elucidated the function of retinoids and their signaling pathways and may explain the failure of earlier chemopreventive studies. In this review we have compiled basic and recent knowledge regarding the role of retinoid receptors in lung carcinogenesis. Sensitive and appropriate biological tools are necessary for screening the risk population and monitoring the efficacy of chemoprevention. Investigation of retinoid receptors is important and may contribute to the establishment of new strategies in chemoprevention for high-risk patients and in the treatment of lung cancer.

  3. Effect of complex polyphenols on colon carcinogenesis.

    Science.gov (United States)

    Caderni, G; Remy, S; Cheynier, V; Morozzi, G; Dolara, P

    1999-06-01

    Complex polyphenols and tannins from wine (WCPT) are being considered increasingly as potential cancer chemopreventive agents, since epidemiological studies suggest that populations consuming a high amount of polyphenols in the diet may have a lower incidence of some types of cancer. We studied the effect of WCPT on a series of parameters related to colon carcinogenesis in rats. WCPT were administered to F344 rats at a dose of 14 or 57 mg/kg/d, mixed with the diet. The higher dose is about ten times the exposure to polyphenols of a moderate drinker of red wine. In rats treated with WCPT, we measured fecal bile acids and long chain fatty acids, colon mucosa cell proliferation, apoptosis and, after administration of colon carcinogens, the number and size of aberrant crypt foci (ACF) and nuclear aberrations. Colon mucosa proliferation was not varied by chronic administration (90 d) of WCPT (14 or 57 mg/kg/d). The highest dose of WCPT decreased the number of cells in the colon crypts, but did not increase apoptosis. WCPT (57 mg/kg) administered before or after the administration of azoxymethane (AOM) did not vary the number or multiplicity of ACF in the colon. The number of nuclear aberrations (NA) in colon mucosa was studied after administration of 1,2-dimethylhydrazine (DMH) and 2-amino-3-methylimidazo (4,5-f)quinoline (IQ), colon-specific carcinogens which require metabolic activation. The effect of DMH and IQ was not varied by pre-feeding WCPT (57 mg/kg) for 10 d. Similarly, the levels of total, secondary bile acids and long chain fatty acids did not varied significantly in animals fed WCPT for 90 d. WCPT administration does not influence parameters related to colon carcinogenesis in the rat.

  4. Radiation-induced mammary carcinogenesis in rodent models. What's different from chemical carcinogenesis?

    International Nuclear Information System (INIS)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Iizuka, Daisuke; Daino, Kazuhiro; Takabatake, Takashi; Okamoto, Mieko; Kakinuma, Shizuko; Shimada, Yoshiya

    2009-01-01

    Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models. (author)

  5. A novel numerical model to predict the morphological behavior of magnetic liquid marbles using coarse grained molecular dynamics concepts

    Science.gov (United States)

    Polwaththe-Gallage, Hasitha-Nayanajith; Sauret, Emilie; Nguyen, Nam-Trung; Saha, Suvash C.; Gu, YuanTong

    2018-01-01

    Liquid marbles are liquid droplets coated with superhydrophobic powders whose morphology is governed by the gravitational and surface tension forces. Small liquid marbles take spherical shapes, while larger liquid marbles exhibit puddle shapes due to the dominance of gravitational forces. Liquid marbles coated with hydrophobic magnetic powders respond to an external magnetic field. This unique feature of magnetic liquid marbles is very attractive for digital microfluidics and drug delivery systems. Several experimental studies have reported the behavior of the liquid marbles. However, the complete behavior of liquid marbles under various environmental conditions is yet to be understood. Modeling techniques can be used to predict the properties and the behavior of the liquid marbles effectively and efficiently. A robust liquid marble model will inspire new experiments and provide new insights. This paper presents a novel numerical modeling technique to predict the morphology of magnetic liquid marbles based on coarse grained molecular dynamics concepts. The proposed model is employed to predict the changes in height of a magnetic liquid marble against its width and compared with the experimental data. The model predictions agree well with the experimental findings. Subsequently, the relationship between the morphology of a liquid marble with the properties of the liquid is investigated. Furthermore, the developed model is capable of simulating the reversible process of opening and closing of the magnetic liquid marble under the action of a magnetic force. The scaling analysis shows that the model predictions are consistent with the scaling laws. Finally, the proposed model is used to assess the compressibility of the liquid marbles. The proposed modeling approach has the potential to be a powerful tool to predict the behavior of magnetic liquid marbles serving as bioreactors.

  6. Ionizing radiation, inflammation, and their interactions in colon carcinogenesis in Mlh1-deficient mice.

    Science.gov (United States)

    Morioka, Takamitsu; Miyoshi-Imamura, Tomoko; Blyth, Benjamin J; Kaminishi, Mutsumi; Kokubo, Toshiaki; Nishimura, Mayumi; Kito, Seiji; Tokairin, Yutaka; Tani, Shusuke; Murakami-Murofushi, Kimiko; Yoshimi, Naoki; Shimada, Yoshiya; Kakinuma, Shizuko

    2015-03-01

    Genetic, physiological and environmental factors are implicated in colorectal carcinogenesis. Mutations in the mutL homolog 1 (MLH1) gene, one of the DNA mismatch repair genes, are a main cause of hereditary colon cancer syndromes such as Lynch syndrome. Long-term chronic inflammation is also a key risk factor, responsible for colitis-associated colorectal cancer; radiation exposure is also known to increase colorectal cancer risk. Here, we studied the effects of radiation exposure on inflammation-induced colon carcinogenesis in DNA mismatch repair-proficient and repair-deficient mice. Male and female Mlh1(-/-) and Mlh1(+/+) mice were irradiated with 2 Gy X-rays when aged 2 weeks or 7 weeks and/or were treated with 1% dextran sodium sulfate (DSS) in drinking water for 7 days at 10 weeks old to induce mild inflammatory colitis. No colon tumors developed after X-rays and/or DSS treatment in Mlh1(+/+) mice. Colon tumors developed after DSS treatment alone in Mlh1(-/-) mice, and exposure to radiation prior to DSS treatment increased the number of tumors. Histologically, colon tumors in the mice resembled the subtype of well-to-moderately differentiated adenocarcinomas with tumor-infiltrating lymphocytes of human Lynch syndrome. Immunohistochemistry revealed that expression of both p53 and β-catenin and loss of p21 and adenomatosis polyposis coli proteins were observed at the later stages of carcinogenesis, suggesting a course of molecular pathogenesis distinct from typical sporadic or colitis-associated colon cancer in humans. In conclusion, radiation exposure could further increase the risk of colorectal carcinogenesis induced by inflammation under the conditions of Mlh1 deficiency. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  7. In vivo cell kinetics in breast carcinogenesis

    International Nuclear Information System (INIS)

    Bai, Maria; Agnantis, Niki J; Kamina, Sevasti; Demou, Asimina; Zagorianakou, Panayiota; Katsaraki, Aphroditi; Kanavaros, Panayiotis

    2001-01-01

    Disruption of the balance between apoptosis and proliferation is considered to be an important factor in the development and progression of tumours. In the present study we determined the in vivo cell kinetics along the spectrum of apparently normal epithelium, hyperplasia, preinvasive lesions and invasive carcinoma, in breast tissues affected by fibrocystic changes in which preinvasive and/or invasive lesions developed, as a model of breast carcinogenesis. A total of 32 areas of apparently normal epithelium and 135 ductal proliferative and neoplastic lesions were studied. More than one epithelial lesion per case were analyzed. The apoptotic index (AI) and the proliferative index (PI) were expressed as the percentage of TdT-mediated dUTP-nick end-labelling (TUNEL) and Ki-67-positive cells, respectively. The PI/AI (P/A index) was calculated for each case. The AIs and PIs were significantly higher in hyperplasia than in apparently normal epithelium (P = 0.04 and P = 0.0005, respectively), in atypical hyperplasia than in hyperplasia (P = 0.01 and P = 0.04, respectively) and in invasive carcinoma than in in situ carcinoma (P < 0.001 and P < 0.001, respectively). The two indices were similar in atypical hyperplasia and in in situ carcinoma. The P/A index increased significantly from normal epithelium to hyperplasia (P = 0.01) and from preinvasive lesions to invasive carcinoma (P = 0.04) whereas it was decreased (non-significantly) from hyperplasia to preinvasive lesions. A strong positive correlation between the AIs and the PIs was found (r = 0.83, P < 0.001). These findings suggest accelerating cell turnover along the continuum of breast carcinogenesis. Atypical hyperplasias and in situ carcinomas might be kinetically similar lesions. In the transition from normal epithelium to hyperplasia and from preinvasive lesions to invasive carcinoma the net growth of epithelial cells results from a growth imbalance in favour of proliferation. In the transition from hyperplasia

  8. The Dose Response Relationship for Radiation Carcinogenesis

    Science.gov (United States)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  9. Comfrey (Symphytum officinale. L. and Experimental Hepatic Carcinogenesis: A Short-Term Carcinogenesis Model Study

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    Maria Fernanda Pereira Lavieri Gomes

    2010-01-01

    Full Text Available Comfrey or Symphytum officinale (L. (Boraginaceae is a very popular plant used for therapeutic purposes. Since the 1980s, its effects have been studied in long-term carcinogenesis studies, in which Comfrey extract is administered at high doses during several months and the neoplastic hepatic lesions are evaluated. However, the literature on this topic is very poor considering the studies performed under short-term carcinogenesis protocols, such as the ‘resistant hepatocyte model’ (RHM. In these studies, it is possible to observe easily the phenomena related to the early phases of tumor development, since pre-neoplastic lesions (PNLs rise in about 1–2 months of chemical induction. Herein, the effects of chronic oral treatment of rats with 10% Comfrey ethanolic extract were evaluated in a RHM. Wistar rats were sequentially treated with N-nitrosodiethylamine (ip and 2-acetilaminofluorene (po, and submitted to hepatectomy to induce carcinogenesis promotion. Macroscopic/microscopic quantitative analysis of PNL was performed. Non-parametric statistical tests (Mann–Whitney and χ2 were used, and the level of significance was set at P ≤ 0.05. Comfrey treatment reduced the number of pre-neoplastic macroscopic lesions up to 1 mm (P ≤ 0.05, the percentage of oval cells (P = 0.0001 and mitotic figures (P = 0.007, as well as the number of Proliferating Cell Nuclear Antigen (PCNA positive cells (P = 0.0001 and acidophilic pre-neoplastic nodules (P = 0.05. On the other hand, the percentage of cells presenting megalocytosis (P = 0.0001 and vacuolar degeneration (P = 0.0001 was increased. Scores of fibrosis, glycogen stores and the number of nucleolus organizing regions were not altered. The study indicated that oral treatment of rats with 10% Comfrey alcoholic extract reduced cell proliferation in this model.

  10. Comfrey (Symphytum Officinale. l.) and Experimental Hepatic Carcinogenesis: A Short-term Carcinogenesis Model Study.

    Science.gov (United States)

    Gomes, Maria Fernanda Pereira Lavieri; de Oliveira Massoco, Cristina; Xavier, José Guilherme; Bonamin, Leoni Villano

    2010-06-01

    Comfrey or Symphytum officinale (L.) (Boraginaceae) is a very popular plant used for therapeutic purposes. Since the 1980s, its effects have been studied in long-term carcinogenesis studies, in which Comfrey extract is administered at high doses during several months and the neoplastic hepatic lesions are evaluated. However, the literature on this topic is very poor considering the studies performed under short-term carcinogenesis protocols, such as the 'resistant hepatocyte model' (RHM). In these studies, it is possible to observe easily the phenomena related to the early phases of tumor development, since pre-neoplastic lesions (PNLs) rise in about 1-2 months of chemical induction. Herein, the effects of chronic oral treatment of rats with 10% Comfrey ethanolic extract were evaluated in a RHM. Wistar rats were sequentially treated with N-nitrosodiethylamine (ip) and 2-acetilaminofluorene (po), and submitted to hepatectomy to induce carcinogenesis promotion. Macroscopic/microscopic quantitative analysis of PNL was performed. Non-parametric statistical tests (Mann-Whitney and χ(2)) were used, and the level of significance was set at P ≤ 0.05. Comfrey treatment reduced the number of pre-neoplastic macroscopic lesions up to 1 mm (P ≤ 0.05), the percentage of oval cells (P = 0.0001) and mitotic figures (P = 0.007), as well as the number of Proliferating Cell Nuclear Antigen (PCNA) positive cells (P = 0.0001) and acidophilic pre-neoplastic nodules (P = 0.05). On the other hand, the percentage of cells presenting megalocytosis (P = 0.0001) and vacuolar degeneration (P = 0.0001) was increased. Scores of fibrosis, glycogen stores and the number of nucleolus organizing regions were not altered. The study indicated that oral treatment of rats with 10% Comfrey alcoholic extract reduced cell proliferation in this model.

  11. Carcinogenesis induced by low-dose radiation

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    Piotrowski Igor

    2017-11-01

    Full Text Available Although the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.

  12. Dysbiosis of the microbiome in gastric carcinogenesis.

    Science.gov (United States)

    Castaño-Rodríguez, Natalia; Goh, Khean-Lee; Fock, Kwong Ming; Mitchell, Hazel M; Kaakoush, Nadeem O

    2017-11-21

    The gastric microbiome has been proposed as an etiological factor in gastric carcinogenesis. We compared the gastric microbiota in subjects presenting with gastric cancer (GC, n = 12) and controls (functional dyspepsia (FD), n = 20) from a high GC risk population in Singapore and Malaysia. cDNA from 16S rRNA transcripts were amplified (515F-806R) and sequenced using Illumina MiSeq 2 × 250 bp chemistry. Increased richness and phylogenetic diversity but not Shannon's diversity was found in GC as compared to controls. nMDS clustered GC and FD subjects separately, with PERMANOVA confirming a significant difference between the groups. H. pylori serological status had a significant impact on gastric microbiome α-diversity and composition. Several bacterial taxa were enriched in GC, including Lactococcus, Veilonella, and Fusobacteriaceae (Fusobacterium and Leptotrichia). Prediction of bacterial metabolic contribution indicated that serological status had a significant impact on metabolic function, while carbohydrate digestion and pathways were enriched in GC. Our findings highlight three mechanisms of interest in GC, including enrichment of pro-inflammatory oral bacterial species, increased abundance of lactic acid producing bacteria, and enrichment of short chain fatty acid production pathways.

  13. Pulmonary carcinogenesis from plutonium-containing particles

    International Nuclear Information System (INIS)

    Thomas, R.G.; Smith, D.M.; Anderson, E.C.

    1980-01-01

    Induction of lung tumors by various types of radiation is of paramount concern to the nuclear industry. The data presented were obtained by exposing the pulmonary system of Syrian hamsters to particles of zirconium oxide containing various amounts of either plutonium-238 or -239 as the alpha radiation source. These particles were injected intravenously and lodged permanently in the capillary bed of the lung. When less than 20% of the lung tissue was irradiated, simulating the ''hot particle'' mode, tumors were not evident with lung burdens up to 500 nCi plutonium. More diffuse irradiation significantly increased the tumor incidence, with lung burdens of 50 to 150 nCi. When plutonium-laden microspheres were administered intratracheally, tumor production was considerably increased and the addition of 3 mg of iron oxide intratracheally further increased the incidence. Using the zirconium oxide matrix for the carrier of plutonium in aerosol particles produced tumor incidences of up to 50% in Syrian hamsters exposed by inhalation. Initial pulmonary (alveolar) burdens reached 100 nCi of plutonium. Similar inhalation studies using plutonium dioxide alone (no matrix) failed to produce any increase in lung tumorigenesis. The results are discussed in terms of possible mechanisms necessary for lung carcinogenesis. (H.K.)

  14. Experimental carcinogenesis induced by incorporated plutonium

    International Nuclear Information System (INIS)

    Oghiso, Yoichi

    1999-01-01

    The carcinogenic effects of an alpha-emitter, 239 Pu, were investigated by animal experiments as focused on both pulmonary tumors after inhalation exposures to insoluble oxide aerosols and tumor spectra induced by injection of soluble citrate. The life-span study using Wistar strain rats exposed to Pu dioxide aerosols has shown differential dose-related responses of malignancies and histopathological phenotypes of lung tumors, suggesting a threshold dose around 1.0 Gy of the lung dose. As abnormality of tumor-related genes could be supposed for the background of pulmonary carcinogenesis, the mutations of p53 tumor suppressor gene were examined by PCR-SSCP analysis using DNA fragments extracted from lung tumors. While mutations were detected in 23 cases (about 28%) among 82 lung tumors, their relations to either malignancies, histological phenotypes, dose, or oncogenesis are not yet to be elucidated. The life-span study using C3H strain mice injected with Pu citrate has shown contrast dose responses between osteosarcomas and lymphoid tumors around 10 Gy of the skeletal dose, and further indicated specific tumor spectra differed from low LET radiation exposures as shown by much more frequency of B cell type leukemic lymphomas and none of myeloid leukemias. (author)

  15. Radiation carcinogenesis from a membrane perspective

    Energy Technology Data Exchange (ETDEWEB)

    Petkau, A

    1980-01-01

    Radiation damage in phospholipid membranes involves free radical chain reactions which propagate on their own. These reactions oxidize the constituent fatty acids (LH) to alkyl radicals (L) which upon oxygenation, form lipid hydroperoxides (LOOH), some of which absorb light at 232 nm. The response (R) of these membranes to irradiation from tritium (/sup 3/H) in tritiated water increases with dose (D) in accordance with R = aD/sup m/, where m = 1.44 +- 0.30 in the absence of superoxide dismutase and 0.80 +- 0.14 in its presence. The parameter a is expressible in terms of dose rate (..delta..D/..delta..t) by a = c (..delta..D/..delta..t)/sup -n/, where n = 1.18 +- 0.05 in the absence of superoxide dismutase and 0.82 +- 0.02 in its presence. Thus, R = cD/sup m/..delta..D/..delta..t)/sup -n/ where the values of m, n depend on the presence or absence of the free radical scavenger, superoxide dismutase. From this composite relationship, the response per annum for 100 to 250 millirem/y is calculable and found to differ qualitatively, that is, in the absence of superoxide dismutase the response increases whereas in the enzyme's presence it decreases. The latter trend is reminiscent of the correlation between radiation dose rate and the per annum malignant mortality rate in humans. This coincidence is interesting in that LOOH are linked in the literature to several forms of carcinogenesis.

  16. Inflammation, oxidative DNA damage, and carcinogenesis

    International Nuclear Information System (INIS)

    Lewis, J.G.; Adams, D.O.

    1987-01-01

    Inflammation has long been associated with carcinogenesis, especially in the promotion phase. The mechanism of action of the potent inflammatory agent and skin promoter 12-tetradecanoyl phorbol-13-acetate (TPA) is unknown. It is though that TPA selectively enhances the growth of initiated cells, and during this process, initiated cells progress to the preneoplastic state and eventually to the malignant phenotype. The authors and others have proposed that TPA may work, in part, by inciting inflammation and stimulating inflammatory cells to release powerful oxidants which then induce DNA damage in epidermal cells. Macrophages cocultured with target cells and TPA induce oxidized thymine bases in the target cells. This process is inhibited by both catalase and inhibitors of lipoxygenases, suggesting the involvement of both H 2 O 2 and oxidized lipid products. In vivo studies demonstrated that SENCAR mice, which are sensitive to promotion by TPA, have a more intense inflammatory reaction in skin that C57LB/6 mice, which are resistant to promotion by TPA. In addition, macrophages from SENCAR mice release more H 2 O 2 and metabolites of AA, and induce more oxidative DNA damage in cocultured cells than macrophages from C57LB/6 mice. These data support the hypothesis that inflammation and the release of genotoxic oxidants may be one mechanism whereby initiated cells receive further genetic insults. They also further complicate risk assessment by suggesting that some environmental agents may work indirectly by subverting host systems to induce damage rather than maintaining homeostasis

  17. Hypoxia and Angiogenesis in Endometrioid Endometrial Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Nicole Horrée

    2007-01-01

    Full Text Available Background: Hypoxia-inducible factor 1α (HIF-1α plays an essential role in the adaptive response of cells to hypoxia, triggering biologic events associated with aggressive tumor behavior. Methods: Expression of HIF-1α and proteins in the HIF-1α pathway (Glut-1, CAIX, VEGF in paraffin-embedded specimens of normal (n = 17, premalignant (n = 17 and endometrioid endometrial carcinoma (n = 39 was explored by immunohistochemistry, in relation to microvessel density (MVD. Results: HIF-1α overexpression was absent in inactive endometrium but present in hyperplasia (61% and carcinoma (87%, with increasing expression in a perinecrotic fashion pointing to underlying hypoxia. No membranous expression of Glut-1 and CAIX was noticed in inactive endometrium, in contrast with expression in hyperplasia (Glut-1 0%, CAIX 61%, only focal and diffuse and carcinoma (Glut-1 94.6%, CAIX 92%, both mostly perinecrotically. Diffuse HIF-1α was accompanied by activation of downstream targets. VEGF was significantly higher expressed in hyperplasias and carcinomas compared to inactive endometrium. MVD was higher in hyperplasias and carcinomas than in normal endometrium (p < 0.001. Conclusion: HIF-1α and its downstream genes are increasingly expressed from normal through premalignant to endometrioid adenocarcinoma of the endometrium, paralleled by activation of its downstream genes and increased angiogenesis. This underlines the potential importance of hypoxia and its key regulator HIF-1α in endometrial carcinogenesis.

  18. Collective studies on carcinogenesis due to exposure to radiation

    International Nuclear Information System (INIS)

    Yamashita, Hisao

    1980-01-01

    Carcinogenesis was found in 150 of 25,692 patients who had received radiotherapy for benign diseases. Of primary diseases subjected to radiotherapy, skin diseases were the most. Carcinogenesis was found in 26 of 7,230 patients with skin diseases (0.36%) and 18 in 2286 patients with tuberculous cervical lymphadenitis (0.79%). The sites of carcinogenesis was the skin in 51 patients, the hypopharynx in 43, and the larynx in 18. Carcinogenesis was also found in 140 of 220,361 patients who had received radiotherapy for malignant tumors. As primary cancer, cancer of the cervix uteri was found in 59 of 48,662 patients, and breast cancer was found in 20 of 27,967 patients. As radiation-induced cancer, leukemia was found in 18 patients, soft tissue sarcoma in 18, skin cancer in 10, osteosarcoma in 6, cancer of the hypopharynx in 6, and cancer of the cervical esophagus in 6. It is necessary to differentiate cancer due to exposure to radiation from delayed recurrent cancer and double cancer. Irradiation fields should be restricted as small as possible in order to reduce carcinogenesis. As leukemia and carcinoma were found in a-bomb survivors exposed to very small dose of a-bomb radiation, carcinogenic mechanisms by chromosome aberrations, carcinogenic rates from a viewpoint of epidemiology, and other factors which influenced carcinogenesis are being investigated. (Tsunoda, M.)

  19. Expression Patterns of Cancer Stem Cell Markers During Specific Celecoxib Therapy in Multistep Rat Colon Carcinogenesis Bioassays.

    Science.gov (United States)

    Salim, Elsayed I; Hegazi, Mona M; Kang, Jin Seok; Helmy, Hager M

    2016-01-01

    The purpose of this study was to investigate the role of colon cancer stem cells (CSCs) during chemicallyinduced rat multi-step colon carcinogenesis with or without the treatment with a specific cyclooxygenase-2 inhibitor drug (celecoxib). Two experiments were performed, the first, a short term 12 week colon carcinogenesis bioassay in which only surrogate markers for colon cancer, aberrant crypt foci (ACF) lesions, were formed. The other experiment was a medium term colon cancer rat assay in which tumors had developed after 32 weeks. Treatment with celecoxib lowered the numbers of ACF, as well as the tumor volumes and multiplicities after 32 weeks. Immunohistochemical proliferating cell nuclear antigen (PCNA) labeling indexes LI (%) were downregulated after treatment by celecoxib. Also different cell surface antigens known to associate with CSCs such as the epithelial cell adhesion molecule (EpCAM), CD44 and CD133 were compared between the two experiments and showed differential expression patterns depending on the stage of carcinogenesis and treatment with celecoxib. Flow cytometric analysis demonstrated that the numbers of CD133 cells were increased in the colonic epithelium after 12 weeks while those of CD44 but not CD133 cells were increased after 32 weeks. Moreover, aldehyde dehydrogenase-1 activity levels in the colonic epithelium (a known CSC marker) detected by ELISA assay were found down-regulated after 12 weeks, but were up-regulated after 32 weeks. The data have also shown that the protective effect of celecoxib on these specific markers and populations of CSCs and on other molecular processes such as apoptosis targeted by this drug may vary depending on the genetic and phenotypic stages of carcinogenesis. Therefore, uncovering these distinction roles of CSCs during different phases of carcinogenesis and during specific treatment could be useful for targeted therapy.

  20. Flexible mechanoprosthesis made from woven ultra-high-molecular-weight polyethylene fibres : proof of concept in a chronic sheep model

    NARCIS (Netherlands)

    Basir, Amir; Grobben, Remco B.; Cramer, Maarten Jan; van Herwaarden, Joost A.; Vink, Aryan; Pasterkamp, Gerard; Kluin, Jolanda; Gründeman, Paul F.

    2017-01-01

    OBJECTIVES: Ultra-high-molecular-weight polyethylene (UHMWPE) fibres are flexible, have high tensile strength, and platelet and bacterial adhesion is low. Therefore, UHMWPE may overcome limitations of current mechanical valves and bioprostheses. In this study, the biocompatibility and functionality

  1. Catalytic NH3 Synthesis using N2 /H2 at Molecular Transition Metal Complexes: Concepts for Lead Structure Determination using Computational Chemistry.

    Science.gov (United States)

    Hölscher, Markus; Leitner, Walter

    2017-09-07

    While industrial NH 3 synthesis based on the Haber-Bosch-process was invented more than a century ago, there is still no molecular catalyst available which reduces N 2 in the reaction system N 2 /H 2 to NH 3 . As the many efforts of experimentally working research groups to develop a molecular catalyst for NH 3 synthesis from N 2 /H 2 have led to a variety of stoichiometric reductions it seems justified to undertake the attempt of systematizing the various approaches of how the N 2 molecule might be reduced to NH 3 with H 2 at a transition metal complex. In this contribution therefore a variety of intuition-based concepts are presented with the intention to show how the problem can be approached. While no claim for completeness is made, these concepts intend to generate a working plan for future research. Beyond this, it is suggested that these concepts should be evaluated with regard to experimental feasibility by checking barrier heights of single reaction steps and also by computation of whole catalytic cycles employing density functional theory (DFT) calculations. This serves as a tool which extends the empirically driven search process and expands it by computed insights which can be used to rationalize the various challenges which must be met. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Carcinogenesis of the Oral Cavity: Environmental Causes and Potential Prevention by Black Raspberry.

    Science.gov (United States)

    El-Bayoumy, Karam; Chen, Kun-Ming; Zhang, Shang-Min; Sun, Yuan-Wan; Amin, Shantu; Stoner, Gary; Guttenplan, Joseph B

    2017-01-17

    Worldwide, cancers of the oral cavity and pharynx comprise the sixth most common malignancies. Histologically, more than 90% of oral cancers are squamous cell carcinoma (SCC). Epidemiologic data strongly support the role of exogenous factors such as tobacco, alcohol, and human papilloma virus infection as major causative agents. Avoidance of risk factors has only been partially successful, and survival rates have not improved despite advances in therapeutic approaches. Therefore, new or improved approaches to prevention and/or early detection are critical. Better understanding of the mechanisms of oral carcinogenesis can assist in the development of novel biomarkers for early detection and strategies for disease prevention. Toward this goal, several animal models for carcinogenesis in the oral cavity have been developed. Among these are xenograft, and transgenic animal models, and others employing the synthetic carcinogens such as 7,12-dimethylbenz[a]anthracene in hamster cheek pouch and 4-nitroquinoline-N-oxide in rats and mice. Additional animal models employing environmental carcinogens such as benzo[a]pyrene and N'-nitrosonornicotine have been reported. Each model has certain advantages and disadvantages. Models that (1) utilize environmental carcinogens, (2) reflect tumor heterogeneity, and (3) accurately represent the cellular and molecular changes involved in the initiation and progression of oral cancer in humans could provide a realistic platform. To achieve this goal, we introduced a novel nonsurgical mouse model to study oral carcinogenesis induced by dibenzo[a,l]pyrene (DB[a,l]P), an environmental pollutant and tobacco smoke constituent, and its diol epoxide metabolite (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene [(±)-anti-DB[a,l]PDE]. On the basis of a detailed comparison of oral cancer induced by DB[a,l]P with that induced by the other above-mentioned oral carcinogens with respect to dose, duration, species and

  3. Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse

    Directory of Open Access Journals (Sweden)

    Kimura Shioko

    2012-12-01

    Full Text Available Abstract Background The CCAAT/enhancer binding proteins (C/EBPs play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. Results A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. Conclusions The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy.

  4. Classical and molecular genetics of malignant melanoma and dysplastic naevi

    International Nuclear Information System (INIS)

    Traupe, H.; Macher, E.

    1988-01-01

    The authors conclude that the prevailing concept of monogenic autosomaldominant inheritance of dysplastic naevi and familial melanoma is not compatible with the principles of formal (Mendelian) genetics. The concept of polygenic inheritance offers instead a sound basis to explain familial aggregation of dysplastic naevi and melanoma. The various genes involved have not yet been identified at the molecular level. The recent advances made possible by modern DNA technology have given us a new view of carcinogenesis. In human malignant melanoma, chromosomes 1, 6, 7 are of particular interest and oncogenes located on these chromosomes may be involved with the initiation, promotion and progression of melanoma. Carcinogenesis is viewed as a multistep process and even tumour initiation requires the input of at least two independent oncogenes. Molecular genetics thus adds an important argument for the existence of a polygenic predisposition to melanoma. The concept of polygenic inheritance is not restricted to familial melanoma, but implies that all melanomas basically share the same predisposition and are due to similar genetic mechanisms. In some patients an inherited genetic predisposition is of great importance, whereas in others (the majority) environmental factors (e.g. UV-light-induced mutations) will be the cause of initial steps in the malignant transformation. The concept of polygenic inheritance has consequences for the management of our patients. In contrast to simple Mendelian inheritance, the risk for dysplastic naevi and melanoma is not constantly 50%, but increases with the number of family members already affected. Persons belonging to families with more that 2 affected close relatives should be considered at high risk regardless of the dysplastic naevus status. Strict surveillance of this patient group is warranted for melanoma prevention

  5. Introduction to the cellular and molecular biology of cancer

    National Research Council Canada - National Science Library

    Selby, P. (Peter); Knowles, Margaret A

    2005-01-01

    ... A. Prigent 186xii CONTENTS 12 Apoptosis: molecular physiology and significance for cancer therapeutics Dean A. Fennell 210 13 Mechanisms of viral carcinogenesis Paul Farrell 229 14 Cytokines and canc...

  6. Molecular medicine and concepts of disease: the ethical value of a conceptual analysis of merging biomedical technologies.

    NARCIS (Netherlands)

    Boenink, Marianne

    2009-01-01

    Although it is now generally acknowledged that new biomedical technologies often produce new definitions and sometimes even new concepts of disease, this observation is rarely used in research that anticipates potential ethical issues in emerging technologies. This article argues that it is useful

  7. Molecular Effects of Polymorphism in the 3'UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins.

    Directory of Open Access Journals (Sweden)

    Mayumi Sugimoto

    Full Text Available Conception rates among dairy cows in Japan have declined in recent decades. To enhance our understanding of the genes involved in conception rates, we conducted a genome-wide association study (GWAS using 822 Holsteins and identified a single-nucleotide polymorphism (SNP associated with conception rate: A+169G in the 3' untranslated region (UTR of unc-5 homolog C (UNC5C. Cows with higher conception rates carried the A polymorphism in the UNC5C 3'UTR. Luciferase assays and quantitative analysis of allele ratios revealed that UNC5C transcripts with the A polymorphism were expressed at higher levels than those carrying the G polymorphism. UNC5C transmits either pro- or anti-apoptotic signals depending on the availability of its ligand, Netrin-1. UNC5C expression is negatively regulated by reproductive homeobox X-linked 5 (Rhox5, and the Rhox5 locus is methylated by G9a methyltransferase. G9a-knockout mice have previously been demonstrated to be subfertile, and we found that UNC5C, G9a, and Netrin-1 expression levels increased from the 4-cell stage to the blastocyst stage in fertilized murine embryos, whereas Rhox5 expression decreased. Repression of UNC5C, G9a, or Netrin-1 or forced expression of Rhox5 in the anterior nucleus stage inhibited development to the blastocyst stage, suggesting that cows carrying the G polymorphism in UNC5C might have lower conception rates because of the poor development of preimplantation embryos. This study provides novel insights into the role of UNC5C during embryonic development.

  8. Flexible mechanoprosthesis made from woven ultra-high-molecular-weight polyethylene fibres: proof of concept in a chronic sheep model

    NARCIS (Netherlands)

    Basir, Amir; Grobben, Remco B.; Cramer, Maarten Jan; van Herwaarden, Joost A.; Vink, Aryan; Pasterkamp, Gerard; Kluin, Jolanda; Gründeman, Paul F.

    2017-01-01

    OBJECTIVES: Ultra-high-molecular-weight polyethylene (UHMWPE) fibres are flexible, have high tensile strength, and platelet and bacterial adhesion is low. Therefore, UHMWPE may overcome limitations of current mechanical valves and bioprostheses. In this study, the bio-compatibility and functionality

  9. Concept - or no concept

    DEFF Research Database (Denmark)

    Thorsteinsson, Uffe

    1999-01-01

    Discussion about concept in industrial companies. A method for mapping of managerial concept in specific area is shown......Discussion about concept in industrial companies. A method for mapping of managerial concept in specific area is shown...

  10. STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis.

    Science.gov (United States)

    Mehra, Karishma; Mehrad, Mitra; Ning, Geng; Drapkin, Ronny; McKeon, Frank D; Xian, Wa; Crum, Christopher P

    2011-01-01

    The events leading to the most common and most lethal ovarian carcinoma - high grade serous carcinoma - have been poorly understood. However, the detailed pathologic study of asymptomatic women with germ-line BRCA 1 or BRCA2 (BCRA+) mutations has unearthed an early malignancy, serous tubal intraepithelial carcinomas (STIC), which has linked many peritoneal and ovarian serous carcinomas to the fimbria. The distinction between high-grade serous and endometrioid carcinomas continues to narrow, with shared alterations in expression of pTEN, PAX2 and p53. Moreover, the discovery of clonal alterations in p53 in benign tubal epithelium, - p53 signatures - has established a foundation for a serous cancer precursor in the fimbria. We have expanded this concept to include a generic secretory cell outgrowth (SCOUT) in the fallopian tube that is associated with altered PAX2 expression. As the repertoire of gene alterations is expanded and its link to serous carcinogenesis clarified, a cogent pathway to high-grade Mullerian carcinomas will emerge. This will challenge conventional thinking about ovarian carcinogenesis but will provide a new template for studies of ovarian cancer prevention.

  11. Downregulation of keratin 76 expression during oral carcinogenesis of human, hamster and mouse.

    Directory of Open Access Journals (Sweden)

    Srikant Ambatipudi

    Full Text Available Keratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development.We evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL, oral squamous cell carcinoma (OSCC and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO mice.We observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue.The present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted.

  12. Multistage models of carcinogenesis and their implications for dose-response models and risk projections

    International Nuclear Information System (INIS)

    Hoel, D.G.

    1992-01-01

    Multistage models are used to both describe the biological steps in developing a cancer and as a mathematical description of the relationship of exposure to tumor incidence. With the rapid development of molecular biology the stages of tumor development are becoming understood. Specifically, the effect and role of proto-oncogenes and suppressor genes are exciting developments in the field of carcinogenesis. Mathematically the field has moved from the original Armitage-Doll multistage model to the more current cell kinetic models. These latter models attempt to describe both the rate of cell mutation and the birth-death process involved in clonal expansion. This then allows modeling of both initiation and promotion or cellular proliferation. The field of radiation carcinogenesis has a considerable body of data and knowledge. Unfortunately, relatively little work has been done with the cell kinetic models as to estimation of tumor incidence. This may be due to the newness of kinetic models in general. The field holds promise and it is essential if we are to develop better human risk estimates from exposure to ionizing radiation. (author)

  13. Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Hector Alvarez

    2011-03-01

    Full Text Available Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1 in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery.

  14. Chemical and radiation carcinogenesis. Progress report

    International Nuclear Information System (INIS)

    1983-07-01

    Gamma radiation, as a quantitative perturbation reference, has been related to oxygen toxicity as the unavoidable background risk due to living in an oxygen atmosphere. The basic mechanisms shared by gamma irradiation and oxygen toxicity have been studied. The response to these two perturbations has been characterized at the molecular level through DNA chemistry and monoclonal antibodies, and by cellular biological responses. The investigation of cellular responses is being extended to the molecular level through a study of alteration of gene arrangement and gene expression. Concentration has been on the study of the involvement of the evolutionally conserved repetitive DNA sequences shared by hamster and man. Such sequences were found and some have been isolated in plasmids. Two cellular systems were chosen for investigation, the embryonic/adult mesenchymal system and the hematopoietic tissues system. Concentration has been on the isolation, properties, and response to perturbation of the progenitor cells and the stem cell populations

  15. Towards a systemic paradigm in carcinogenesis: linking epigenetics and genetics.

    Science.gov (United States)

    Burgio, Ernesto; Migliore, Lucia

    2015-04-01

    For at least 30 years cancer has been defined as a genetic disease and explained by the so-called somatic mutation theory (SMT), which has dominated the carcinogenesis field. Criticism of the SMT has recently greatly increased, although still not enough to force all SMT supporters to recognize its limits. Various researchers point out that cancer appears to be a complex process concerning a whole tissue; and that genomic mutations, although variably deleterious and unpredictably important in determining the establishment of the neoplastic phenotype, are not the primary origin for a malignant neoplasia. We attempt to describe the inadequacies of the SMT and demonstrate that epigenetics is a more logical cause of carcinogenesis. Many previous models of carcinogenesis fall into two classes: (i) in which some biological changes inside cells alone lead to malignancy; and (ii) requiring changes in stroma/extracellular matrix. We try to make clear that in the (ii) model genomic instability is induced by persistent signals coming from the microenvironment, provoking epigenetic and genetic modifications in tissue stem cells that can lead to cancer. In this perspective, stochastic mutations of DNA are a critical by-product rather then the primary cause of cancer. Indirect support for such model of carcinogenesis comes from the in vitro and vivo experiments showing apparent 'reversion' of cancer phenotypes obtained via physiological factors of cellular differentiation (cytokines and other signaling molecules) or drugs, even if the key mutations are not 'reversed'.

  16. A challenge to mutation theory of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Watanabe, Masami

    2006-01-01

    This paper presents an objection against the commonly accepted mutation theory in radiation carcinogenesis. First, author's studies of X-ray irradiated syrian hamster embryo (SHE) cells on malignant morphological changes and mutational change of HGPRT gene showed that the changing patterns were quite different, and as well, other studies in mice gave the essentially similar results. Thus radiation-induced carcinogenesis in cells does not simply occur by an accumulation of radiation-induced mutation. Second, as cultured cells usually used for oncogenesis studies already have the infinitively proliferative ability, the author used the primary cell culture obtained from the rodent embryo. Even those cells became immortal to be cancerous after repeated culture passage with the higher frequency of 10 3 -10 4 relative to somatic cell mutation. Cells thus seem to be easily changeable to cancerous ones. Bystander effect can cause transformation in non-irradiated cells and genetic instability by radiation can form the potentially unstable chromatin region, which induces telomere instability. The author has found that, while short-lived radicals yielded by X-ray irradiation attack DNA to induce cell death and chromosome aberration, long-lived radicals in biomolecules do not, but can cause mutation and carcinogenesis, which are reduced by vitamine C supplementation. The author concludes that the primary target in the radiation carcinogenesis in cells and even in the whole individuals is conceivably protein and not DNA. (T.I.)

  17. Chronology of p53 protein accumulation in gastric carcinogenesis

    NARCIS (Netherlands)

    Craanen, M. E.; Blok, P.; Dekker, W.; Offerhaus, G. J.; Tytgat, G. N.

    1995-01-01

    p53 Protein accumulation in early gastric carcinoma was studied in relation to the histological type (Lauren classification) and the type of growth pattern, including the chronology of p53 protein accumulation during carcinogenesis. Forty five, paraffin embedded gastrectomy specimens from early

  18. Carcinogenesis related to intense pulsed light and UV exposure

    DEFF Research Database (Denmark)

    Hedelund, L; Lerche, C; Wulf, H C

    2006-01-01

    This study examines whether intense pulsed light (IPL) treatment has a carcinogenic potential itself or may influence ultraviolet (UV)-induced carcinogenesis. Secondly, it evaluates whether UV exposure may influence IPL-induced side effects. Hairless, lightly pigmented mice (n=144) received three...

  19. Hypoxia and cell cycle deregulation in endometrial carcinogenesis

    NARCIS (Netherlands)

    Horrée, N.

    2007-01-01

    Because uterine endometrial carcinoma is the most common malignancy of the female genital tract and 1 of every 5 patients dies of this disease, understanding the mechanisms of carcinogenesis and progression of endometrial carcinoma is important. In general, this thesis can be summarized as a study

  20. Conception and synthesis of new molecular platforms based on cryptophanes. Application for the encapsulation of xenon and metallic cations in aqueous solution

    International Nuclear Information System (INIS)

    Chapellet, Laure-Lise

    2015-01-01

    Cryptophanes are molecular receptors known for their complexation properties of various substrates. Over the last fifteen years, cryptophanes were the subject of numerous studies for they can be used to obtain biosensors for xenon MRI. This field has experienced significant growth and advances to the point were in vivo applications are now envisioned, provided that large amounts of biosensors can be synthesized. More recently, polyphenolic cryptophanes have been studied for their ability to encapsulate monovalent metallic cations like Cs"+ and Tl"+ in aqueous solution. This could lead to applications for depollution of contaminated water sources but would require, once again, the synthesis of large amounts of cryptophanes.The work carried out during this thesis focus on the conception and the synthesis of new molecular platforms that could either be used to obtain new hyper-polarized xenon biosensors or to encapsulate monovalent metallic cations as Cs"+ and Tl"+. Synthetic routes have been developed to produce good amounts of a variety of new hydrosoluble molecular platforms designed for each application. The encapsulation properties of these new host molecules were studied through NMR of the encapsulated nucleus, circular dichroism or isothermal calorimetry. In each case, the new platforms meet the expected requirements thus opening the door for the envisioned applications. (author)

  1. Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.

    Science.gov (United States)

    Kravchenko, Julia; Akushevich, Igor; Seewaldt, Victoria L; Abernethy, Amy P; Lyerly, H Kim

    2011-07-01

    The observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.

  2. Colorectal carcinogenesis-update and perspectives

    DEFF Research Database (Denmark)

    Raskov, Hans; Pommergaard, Hans-Christian; Burcharth, Jakob

    2014-01-01

    Colorectal cancer (CRC) is a very common malignancy in the Western World and despite advances in surgery, chemotherapy and screening, it is still the second leading cause of cancer deaths in this part of the world. Numerous factors are found important in the development of CRC including colonocyte....... To identify early cancers, screening programs have been initiated, and the leading strategy has been the use of faecal occult blood testing followed by colonoscopy in positive cases. Regarding the treatment of colorectal cancer, significant advances have been made in the recent decade. The molecular targets...

  3. New concepts in molecular imaging: non-invasive MRI spotting of proteolysis using an Overhauser effect switch.

    Directory of Open Access Journals (Sweden)

    Philippe Mellet

    Full Text Available Proteolysis, involved in many processes in living organisms, is tightly regulated in space and time under physiological conditions. However deregulation can occur with local persistent proteolytic activities, e.g. in inflammation, cystic fibrosis, tumors, or pancreatitis. Furthermore, little is known about the role of many proteases, hence there is a need of new imaging methods to visualize specifically normal or disease-related proteolysis in intact bodies.In this paper, a new concept for non invasive proteolysis imaging is proposed. Overhauser-enhanced Magnetic Resonance Imaging (OMRI at 0.2 Tesla was used to monitor the enzymatic hydrolysis of a nitroxide-labeled protein. In vitro, image intensity switched from 1 to 25 upon proteolysis due to the associated decrease in the motional correlation time of the substrate. The OMRI experimental device used in this study is consistent with protease imaging in mice at 0.2 T without significant heating. Simulations show that this enzymatic-driven OMRI signal switch can be obtained at lower frequencies suitable for larger animals or humans.The method is highly sensitive and makes possible proteolysis imaging in three dimensions with a good spatial resolution. Any protease could be targeted specifically through the use of taylor-made cleavable macromolecules. At short term OMRI of proteolysis may be applied to basic research as well as to evaluate therapeutic treatments in small animal models of experimental diseases.

  4. Effectiveness of Bioactive Food Components in Experimental Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Emília Hijová

    2009-01-01

    Full Text Available The aim of the present study was the evaluation of possible protective effects of selected bioactive food components in experimental N,N-dimethylhydrazine (DMH-induced colon carcinogenesis. Wistar albino rats (n = 92 were fed a high fat diet or conventional laboratory diet. Two weeks after the beginning of the trial, DMH injections were given to six groups of rats at the dose of 20 mg/kg b.w. twice weekly. The activity of bacterial enzymes in faeces and serum bile acid concentrations were determined. High fat diet, DMH injections, and their combination significantly increased the activies of β-galactosidase, β-glucuronidase, and α-glucosidase (p p < 0.001, as well as the bile acid concentration compared to the group at the highest risk. The protective effects of selected bioactive food components in experimentally induced colon carcinogenesis allow for their possible use in cancer prevention or treatment.

  5. Experimental Hepatic Carcinogenesis: Oxidative Stress and Natural Antioxidants

    Directory of Open Access Journals (Sweden)

    Velid Unsal

    2017-08-01

    Full Text Available Hepatocellular carcinoma is one of the most common cancers in the world, and it is influenced by agents such as DEN, 2-AAF, phenobarbital, alcohol, aflatoxin B1 metabolite or hepatitis viruses (B and C. Oxidative stress is becoming recognized as a key factor in the progression of hepatocarcinogenesis. Reactive oxygen species can play a leading role in initiation and promotion of hepatic carcinogenesis. The metabolites of DEN Diethylnitrosamine (DEN mediate the binding of tumour promoters by covalently binding to the DNA with one or two oxidation-providing electrons. 2-AAF is the inducer of DEN, and it is involved in tumour formation in the bladder and liver. Reactive Oxygen species (ROS; carbohydrates, lipids, DNA and enzymes, such as affect all important structures. Additionally, an excessive amount of ROS is highly toxic to cells. Antioxidants are protects against ROS, toxic substances, carcinogens. This review focuses on the literature on studies of Hepatic Carcinogenesis, oxidative stress and antioxidant therapy.

  6. Modelling carcinogenesis after radiotherapy using Poisson statistics: implications for IMRT, protons and ions

    Energy Technology Data Exchange (ETDEWEB)

    Jones, Bleddyn [Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ (United Kingdom)], E-mail: Bleddyn.Jones@rob.ox.ac.uk

    2009-06-01

    Current technical radiotherapy advances aim to (a) better conform the dose contours to cancers and (b) reduce the integral dose exposure and thereby minimise unnecessary dose exposure to normal tissues unaffected by the cancer. Various types of conformal and intensity modulated radiotherapy (IMRT) using x-rays can achieve (a) while charged particle therapy (CPT)-using proton and ion beams-can achieve both (a) and (b), but at greater financial cost. Not only is the long term risk of radiation related normal tissue complications important, but so is the risk of carcinogenesis. Physical dose distribution plans can be generated to show the differences between the above techniques. IMRT is associated with a dose bath of low to medium dose due to fluence transfer: dose is effectively transferred from designated organs at risk to other areas; thus dose and risk are transferred. Many clinicians are concerned that there may be additional carcinogenesis many years after IMRT. CPT reduces the total energy deposition in the body and offers many potential advantages in terms of the prospects for better quality of life along with cancer cure. With C ions there is a tail of dose beyond the Bragg peaks, due to nuclear fragmentation; this is not found with protons. CPT generally uses higher linear energy transfer (which varies with particle and energy), which carries a higher relative risk of malignant induction, but also of cell death quantified by the relative biological effect concept, so at higher dose levels the frank development of malignancy should be reduced. Standard linear radioprotection models have been used to show a reduction in carcinogenesis risk of between two- and 15-fold depending on the CPT location. But the standard risk models make no allowance for fractionation and some have a dose limit at 4 Gy. Alternatively, tentative application of the linear quadratic model and Poissonian statistics to chromosome breakage and cell kill simultaneously allows estimation of

  7. Experimental gastric carcinogenesis in Cebus apella nonhuman primates.

    Directory of Open Access Journals (Sweden)

    Joana de Fátima Ferreira Borges da Costa

    Full Text Available The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU. Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9(th day though on the 14(th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940(th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the

  8. The relevance of cell transformation to carcinogenesis in vivo

    International Nuclear Information System (INIS)

    Little, J.B.

    1989-01-01

    Despite the caveats concerning rodent as opposed to human cell transformation systems, the author concludes there are several areas in which cell transformation studies with rodent cells have shown clear relevance to carcinogenesis in vivo, especially studies of carcinogenic effects of high LET radiation, particularly dependence on dose rate. In vitro studies firmly established the generality of promotion by phorbol esters tumour promotors. Initial studies on suppression of transformation, notably by protease inhibitors, has led to the confirmation of this phenomenon in in vivo carcinogenesis; development of inhibitor preparations from natural sources suitable for long-term supplementation in human diet, is under investigation. The potential importance of these modifiers is further emphasized by mechanistic studies suggesting that radiation may initiate a large fraction of exposed cell population, and expression of transformation may be controlled to a large extent by environmental conditions including the presence of promoting or suppressing agents. Finally, cell transformation systems offer the opportunity for mechanistic studies of the initial stages of carcinogenesis. Provocative results have arisen in several areas consistent with findings in experimental animals. (author)

  9. Cellular adaptation as an important response during chemical carcinogenesis

    International Nuclear Information System (INIS)

    Farber, E.

    1992-01-01

    Since disease processes are largely expressions of how living organisms react and respond to perturbations in the external and internal environments, adaptive or protective responses and their modulations and mechanisms are of the greatest concern in fundamental studies of disease pathogenesis. Such considerations are also of the greatest relevance in toxicology, including how living organisms respond to low levels of single and multiple xenobiotics and radiations. As the steps and mechanisms during cancer development are studied in greater depth, phenomena become apparent that suggest that adaptive reactions and responses may play important or even critical roles in the process of carcinogenesis. The question becomes whether the process of carcinogenesis is fundamentally an adversarial one (i.e., an abnormal cell in a vulnerable host), or is it more in the nature of a physiological selection or differentiation, which has survival value for the host as an adaptive phenomena? The very early initial interactions of mutagenic chemical carcinogens, radiations and viruses with DNA prejudice most to consider the adversarial 'abnormal' view as the appropriate one. Yet, the unusually common nature of the earliest altered rare cells that appear during carcinogenesis, their unusually bland nature, and their spontaneous differentiation to normal-appearing adult liver should be carefully considered

  10. Silica-induced Chronic Inflammation Promotes Lung Carcinogenesis in the Context of an Immunosuppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Javier Freire

    2013-08-01

    Full Text Available The association between inflammation and lung tumor development has been clearly demonstrated. However, little is known concerning the molecular events preceding the development of lung cancer. In this study, we characterize a chemically induced lung cancer mouse model in which lung cancer developed in the presence of silicotic chronic inflammation. Silica-induced lung inflammation increased the incidence and multiplicity of lung cancer in mice treated with N-nitrosodimethylamine, a carcinogen found in tobacco smoke. Histologic and molecular analysis revealed that concomitant chronic inflammation contributed to lung tumorigenesis through induction of preneoplastic changes in lung epithelial cells. In addition, silica-mediated inflammation generated an immunosuppressive microenvironment in which we observed increased expression of programmed cell death protein 1 (PD-1, transforming growth factor-β1, monocyte chemotactic protein 1 (MCP-1, lymphocyte-activation gene 3 (LAG3, and forkhead box P3 (FOXP3, as well as the presence of regulatory T cells. Finally, the K-RAS mutational profile of the tumors changed from Q61R to G12D mutations in the inflammatory milieu. In summary, we describe some of the early molecular changes associated to lung carcinogenesis in a chronic inflammatory microenvironment and provide novel information concerning the mechanisms underlying the formation and the fate of preneoplastic lesions in the silicotic lung.

  11. Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis

    Directory of Open Access Journals (Sweden)

    Van Veldhuizen Peter J

    2011-01-01

    Full Text Available Abstract Background Despite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood. Results We show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1. Conclusions In conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.

  12. A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

    Science.gov (United States)

    Koppang, N; Rivenson, A; Reith, A; Dahle, H K; Evensen, O; Hoffmann, D

    1992-11-01

    During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

  13. A central role for heme iron in colon carcinogenesis associated with red meat intake.

    Science.gov (United States)

    Bastide, Nadia M; Chenni, Fatima; Audebert, Marc; Santarelli, Raphaelle L; Taché, Sylviane; Naud, Nathalie; Baradat, Maryse; Jouanin, Isabelle; Surya, Reggie; Hobbs, Ditte A; Kuhnle, Gunter G; Raymond-Letron, Isabelle; Gueraud, Françoise; Corpet, Denis E; Pierre, Fabrice H F

    2015-03-01

    Epidemiology shows that red and processed meat intake is associated with an increased risk of colorectal cancer. Heme iron, heterocyclic amines, and endogenous N-nitroso compounds (NOC) are proposed to explain this effect, but their relative contribution is unknown. Our study aimed at determining, at nutritional doses, which is the main factor involved and proposing a mechanism of cancer promotion by red meat. The relative part of heme iron (1% in diet), heterocyclic amines (PhIP + MeIQx, 50 + 25 μg/kg in diet), and NOC (induced by NaNO₂+ NaNO₂; 0.17 + 0.23 g/L of drinking water) was determined by a factorial design and preneoplastic endpoints in chemically induced rats and validated on tumors in Min mice. The molecular mechanisms (genotoxicity, cytotoxicity) were analyzed in vitro in normal and Apc-deficient cell lines and confirmed on colon mucosa. Heme iron increased the number of preneoplastic lesions, but dietary heterocyclic amines and NOC had no effect on carcinogenesis in rats. Dietary hemoglobin increased tumor load in Min mice (control diet: 67 ± 39 mm²; 2.5% hemoglobin diet: 114 ± 47 mm², P = 0.004). In vitro, fecal water from rats given hemoglobin was rich in aldehydes and was cytotoxic to normal cells, but not to premalignant cells. The aldehydes 4-hydroxynonenal and 4-hydroxyhexenal were more toxic to normal versus mutated cells and were only genotoxic to normal cells. Genotoxicity was also observed in colon mucosa of mice given hemoglobin. These results highlight the role of heme iron in the promotion of colon cancer by red meat and suggest that heme iron could initiate carcinogenesis through lipid peroxidation. . ©2015 American Association for Cancer Research.

  14. [Carcinogenesis and its mechanism of mutant-type[12Asp]K-ras4B gene].

    Science.gov (United States)

    Gui, Li-ming; Wei, Li-hui; Zhang, Ying-mei; Wang, Jian-liu; Wang, Ying; Chen, Ying; Ma, Da-long

    2002-01-01

    Ras gene plays an important role in the extra- and intra-cellular signal transduction pathway. It mediates series cascade reactions, and eventually actives transcriptional factors in nucleus. It is unknown on the mechanism of carcinogenesis of Ras gene in endometrial carcinoma, though K-ras mutant is very common in endometrial atypical hyperplasia and carcinoma. On basis of discovering the mutation in 12th codon of K-ras in endometrial carcinoma cell line, HEC-1A, we explored the carcinogenesis and molecular mechanism of mutant-type [12Asp] K-ras4B gene. (1) Full-length [12Asp]K-ras4B cDNA was amplified with RT-PCR, then inserted into pcDI eukaryotic expressive vector. (2) Morphological change, growth kinetics in vitro and tumorigencity in nude mice in vivo after-before transfection were observed. (3) To test the cell growth kinetics by methyl thiazolium tetrazolium (MTT) and [3H]thymidine incorporation method. (1) The authors have successfully constructed eukaryotic expression plasmid pcDI-[12Asp] K-ras4B; (2) To confirm that [12Asp] K-ras4B mutant can trigger the neoplastic transformation of NIH3T3 cells by test in vitro and in vivo. (3) After pMCV-RasN17 plasmid, a Ras mutant were transfected into pcDI-[12Asp] K-ras4B cells, the growth of this cell were restrained significantly in comparison with control group. (4) These findings indicate the expression of RafS621A resulted in remarkable inhibition in proliferation of pcDI-[12Asp]K-ras4B cell (P ras4B cell growth (P ras4B gene alone is able to cause neoplastic transformation in NIH3T3 cells in vitro and in vivo. (2) [12Asp]K-ras4B-induced NIH3T3 cells neoplastic transformation required Raf signaling pathway.

  15. Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2012-01-01

    Full Text Available One of the key features of hepatocellular carcinoma (HCC is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR, a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss "combination chemoprevention" using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

  16. Bacterial infection increases risk of carcinogenesis by targeting mitochondria

    DEFF Research Database (Denmark)

    Strickertsson, Jesper A.B.; Desler, Claus; Rasmussen, Lene Juel

    2017-01-01

    pathways, and compares the impact of the bacterial alteration of mitochondrial function to that of cancer. Bacterial virulence factors have been demonstrated to induce mutations of mitochondrial DNA (mtDNA) and to modulate DNA repair pathways of the mitochondria. Furthermore, virulence factors can induce...... or impair the intrinsic apoptotic pathway. The effect of bacterial targeting of mitochondria is analogous to behavior of mitochondria in a wide array of tumours, and this strongly suggests that mitochondrial targeting of bacteria is a risk factor for carcinogenesis....

  17. The PTEN/NRF2 Axis Promotes Human Carcinogenesis

    DEFF Research Database (Denmark)

    Rojo, Ana I; Rada, Patricia; Mendiola, Marta

    2014-01-01

    and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). INNOVATION: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3....../β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. CONCLUSION: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514....

  18. Etiologic related studies of ultraviolet light-mediated carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Black, H S; Chan, J T

    1976-01-01

    Comparisons were made of cholesterol-5..cap alpha.. 6..cap alpha..-epoxide (CAE) levels in skin of hairless mice maintained on a regular or antioxidant supplemented diet and receiving chronic ultraviolet light (UVL) radiation over an 18-week period. Cholesterol-5..cap alpha.., 6..cap alpha..-epoxide levels in skin of animals on antioxidant supplemented diet, while reaching a peak four weeks after that of animals on regular diet, thereafter were consistently higher. Dietary antioxidants nevertheless had an inhibitory effect on UVL-induced tumors. These data are inconsistent with the theory of CAE involvement as an ultimate carcinogen in UVL-mediated carcinogenesis.

  19. Punica granatum and its therapeutic implications on breast carcinogenesis: A review.

    Science.gov (United States)

    Vini, Ravindran; Sreeja, Sreeharshan

    2015-01-01

    Punica granatum has a recorded history of pharmacological properties which can be attributed to its rich reservoir of phytochemicals. Investigations in recent years have established its tremendous potential as an antitumorogenic agent against various cancers including breast cancer, which is the second leading cause of cancer-related deaths in women. The plausible role of Punica as a therapeutic agent, as an adjuvant in chemotherapy, and its dietary implications as chemopreventive agent in breast cancer have been explored. Mechanistic studies have revealed that Punica extracts and its components, individually or in combination, can modulate and target key proteins and genes involved in breast cancer. Our earlier finding also demonstrated the role of methanolic extract of pomegranate pericarp in reducing proliferation in breast cancer by binding to estrogen receptor at the same time not affecting uterine weight unlike estradiol or tamoxifen. This review analyses other plausible mechanisms of Punica in preventing the progression of breast cancer and how it can possibly be a therapeutic agent by acting at various steps of carcinogenesis including proliferation, invasion, migration, metastasis, angiogenesis, and inflammation via various molecular mechanisms. © 2015 International Union of Biochemistry and Molecular Biology.

  20. Molecular Classification and Correlates in Colorectal Cancer

    OpenAIRE

    Ogino, Shuji; Goel, Ajay

    2008-01-01

    Molecular classification of colorectal cancer is evolving. As our understanding of colorectal carcinogenesis improves, we are incorporating new knowledge into the classification system. In particular, global genomic status [microsatellite instability (MSI) status and chromosomal instability (CIN) status] and epigenomic status [CpG island methylator phenotype (CIMP) status] play a significant role in determining clinical, pathological and biological characteristics of colorectal cancer. In thi...

  1. [THE ROLE OF ESTROGENS IN THE CARCINOGENESIS OF LUNG CANCER].

    Science.gov (United States)

    Uchikova, E; Uchikov, A; Dimitrakova, E; Uchikov, P

    2016-01-01

    Morbidity and mortality from lung cancer has dramatically increased in women as compared to men over the past few years. Historically, smoking has been considered the major risk factor for lung cancer regardless of gender. Several recent lines of evidence implicate gender differences in the observed differences in prevalence and histologic type which cannot be explained based on the carcinogenic action of nicotine. Several recent studies underscore the importance of reproductive and hormonal factors in the carcinogenesis of lung cancer Lung cancer morbidity and mortality in Bulgaria was 16.2/100000 women and 14.6/ 100000 women, resp. Lung cancer morbidity in Europe was 39/100000 women. Lung cancer is extremely sensitive to estrogens. The latter act directly or as effect modifiers for the relationship between smoking and lung cancer. Further research examining the relationship between serum estrogen levels and the estrogen receptor expression in normal and tumor lung tissue samples can help elucidate the importance of reproductive and hormonal (exogenous and endogenous) factors in the carcinogenesis of lung cancer.

  2. Is radiation an appropriate model for chemical mutagenesis and carcinogenesis

    International Nuclear Information System (INIS)

    Bond, V.P.

    1982-01-01

    This chapter attempts to show why the quadratic, or ''linear quadratic,'' relationship holds for organ dose-single cell radiation effects, and to explore the extension of this relationship to chemical exposures in general. Demonstrates that although the ''αD + βD 2 relationship'' may be unexpected for normal pharmacologicalmedical dose-response relationships, a linear, no-threshold curve of this kind is expected for all stochastic-type (accidental or risk) situations with health consequences (e.g. all common accidents) including exposure to ''low-level radiation'' (LLR). Discusses the stochastic or risk approach, relevant radiobiology, and the stochastic for chemicals. Assumes that even though actual mutational rates cannot be expected to apply to the relevance of Tradescantia or any other single cell system as a predictor for mutagenesis and carcinogenesis in animals and man, the cardinal principles of genetics largely transcend species and the particular environment in which the cell is located. Concludes that with regard to LLR, the curve shapes and other relationships developed for Tradescantia would be expected to apply in principle to animal and human mutagenesis and carcinogenesis

  3. Etoricoxib in the Prevention of Rat Mammary Carcinogenesis

    Directory of Open Access Journals (Sweden)

    P. Orendáš

    2007-01-01

    Full Text Available Several experimental studies suggest that non-steroidal antiinflammatory drugs have chemopreventive effects in mammary carcinogenesis. In this study, tumour suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2 etoricoxib in the prevention of N-methyl-Nnitrosourea (NMU-induced mammary carcinogenesis in Sprague-Dawley rats were evaluated. Etoricoxib was administered in the diet, at two concentrations: 1 0.01 mg/g (ETO 0.001% and 2 0.025 mg/g (ETO 0.0025%. Although the chemopreventive effects were not statistically significant, remarkable tumour suppressive effects with the concentration of ETO 0.0025% were recorded. The incidence decreased by 4.31% and tumour frequency per group decreased by 6.67% when compared to the control group. Latency (the period from carcinogen administration to the first tumour appearance increased by 7.28% in dose-dependent manner. The results of our experiments point to dose-dependent tumour suppressive effects of a higher concentration of etoricoxib (ETO 0.0025% when compared to the control group. They suggest that higher etoricoxib concentrations may enhance its tumour suppressive effects.

  4. Experimental photoimmunology: immunologic ramifications of UV-induced carcinogenesis

    International Nuclear Information System (INIS)

    Daynes, R.A.; Bernhard, E.J.; Gurish, M.F.; Lynch, D.H.

    1981-01-01

    The use of animal model systems to investigate the sequence of events which lead to the induction and progression of skin tumors following chronic ultraviolet light (UVL) exposure has clearly shown that the direct mutagenic effects of UVL is only one of the components involved in this process. In spite of the fact that overt carcinogenesis is only one of the many effects produced by UV light, most hypotheses as to the mechanism by which UVL can cause the mutations necessary to achieve the transformed phenotype have focused on the direct effects of UVL on DNA and the generation of carcinogenic compounds. Investigations during the last 5 yr, however, have clearly demonstrated that immunologic factors are also critically important in the pathogenesis of UV-induced skin cancers. A complete understanding of UV-carcinogenesis must therefore consider the mechanisms which allow the transformed cell to evade immunologic rejection by the host in addition to those aspects which deal with conversion of a normal cell to a cancer cell. It is the object of this review to provide both a historical account of the work which established the immunologic consequences of chronic UVL exposure and the results of recent experiments designed to investigate the kinetics and mechanisms by which UVL affects the immunologic apparatus. In addition, a hypothetical model is presented to explain the sequence of events which ultimately lead to the emergence of the suppressor T-cells which regulate antitumor immune responses

  5. Inherent aerobic capacity-dependent differences in breast carcinogenesis.

    Science.gov (United States)

    Thompson, Henry J; Jones, Lee W; Koch, Lauren G; Britton, Steven L; Neil, Elizabeth S; McGinley, John N

    2017-09-01

    Although regular physical activity is associated with improvement in aerobic capacity and lower breast cancer risk, there are heritable sets of traits that affect improvement in aerobic capacity in response to physical activity. Although aerobic capacity segregates risk for a number of chronic diseases, the effect of the heritable component on cancer risk has not been evaluated. Therefore, we investigated breast carcinogenesis in rodent models of heritable fitness in the absence of induced physical activity. Female offspring of N:NIH rats selectively bred for low (LIAC) or high (HIAC) inherent aerobic capacity were injected intraperitoneally with 1-methyl-1-nitrosurea (70 mg/kg body wt). At study termination 33 weeks post-carcinogen, cancer incidence (14.0 versus 47.3%; P < 0.001) and multiplicity (0.18 versus 0.85 cancers per rat; P < 0.0001) were significantly decreased in HIAC versus LIAC rats, respectively. HIAC had smaller visceral and subcutaneous body fat depots than LIAC and activity of two proteins that regulated the mammalian target of rapamycin, protein kinase B (Akt), and adenosine monophosphate-activated protein kinase were suppressed and activated, respectively, in HIAC. Although many factors distinguish between HIAC and LIAC, it appears that the protective effect of HIAC against breast carcinogenesis is mediated, at least in part, via alterations in core metabolic signaling pathways deregulated in the majority of human breast cancers. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Glutaminolysis and carcinogenesis of oral squamous cell carcinoma.

    Science.gov (United States)

    Cetindis, Marcel; Biegner, Thorsten; Munz, Adelheid; Teriete, Peter; Reinert, Siegmar; Grimm, Martin

    2016-02-01

    Glutaminolysis is a crucial factor for tumor metabolism in the carcinogenesis of several tumors but has not been clarified for oral squamous cell carcinoma (OSCC) yet. Expression of glutaminolysis-related solute carrier family 1, member 5 (SLC1A5)/neutral amino acid transporter (ASCT2), glutaminase (GLS), and glutamate dehydrogenase (GLDH) was analyzed in normal oral mucosa (n = 5), oral precursor lesions (simple hyperplasia, n = 11; squamous intraepithelial neoplasia, SIN I-III, n = 35), and OSCC specimen (n = 42) by immunohistochemistry. SLC1A5/ASCT2 and GLS were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue, while GLDH was weakly detected. Compared with SIN I-III SLC1A5/ASCT2 and GLS expression were significantly increased in OSCC. GLDH expression did not significantly differ from SIN I-III compared with OSCC. This study shows the first evidence of glutaminolysis-related SLC1A5/ASCT2, GLS, and GLDH expression in OSCC. The very weak GLDH expression indicates that glutamine metabolism is rather related to nucleotide or protein/hexosamine biosynthesis or to the function as an antioxidant (glutathione) than to energy production or generation of lactate through entering the tricarboxylic acid cycle. Overcoming glutaminolysis by targeting c-Myc oncogene (e.g. by natural compounds) and thereby cross-activation of mammalian target of rapamycin complex 1 or SLC1A5/ASCT2, GLS inhibitors may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

  7. Sewage sludge does not induce genotoxicity and carcinogenesis

    Science.gov (United States)

    Silva, Paula Regina Pereira; Barbisan, Luis Fernando; Dagli, Maria Lúcia Zaidan; Saldiva, Paulo Hilário Nascimento

    2012-01-01

    Through a series of experiments, the genotoxic/mutagenic and carcinogenic potential of sewage sludge was assessed. Male Wistar rats were randomly assigned to four groups: Group 1 - negative control; Group 2 - liver carcinogenesis initiated by diethylnitrosamine (DEN; 200 mg/kg i.p.); Group 3 and G4-liver carcinogenesis initiated by DEN and fed 10,000 ppm or 50,000 ppm of sewage sludge. The animals were submitted to a 70% partial hepatectomy at the 3rd week. Livers were processed for routine histological analysis and immunohistochemistry, in order to detect glutathione S-transferase positive altered hepatocyte foci (GST-P+ AHF). Peripheral blood samples for the comet assay were obtained from the periorbital plexus immediately prior to sacrificing. Polychromatic erythrocytes (PCEs) were analyzed in femoral bone-marrow smears, and the frequencies of those micronucleated (MNPCEs) registered. There was no sewage-sludge-induced increase in frequency of either DNA damage in peripheral blood leucocytes, or MNPCEs in the femoral bone marrow. Also, there was no increase in the levels of DNA damage, in the frequency of MNPCEs, and in the development of GST-P AHF when compared with the respective control group. PMID:23055806

  8. Role of the chronic bacterial infection in urinary bladder carcinogenesis

    International Nuclear Information System (INIS)

    Higgy, N.A.

    1985-01-01

    The purpose of this thesis was to determine whether or not bacterial infection of the urinary bladder had a role in urinary bladder carcinogenesis. To investigate this proposition, four separate studies were conducted. The first study developed an experimental animal model where bacterial infection of the urinary bladder could be introduced and maintained for a period in excess of one year. The method of infection, inoculation of bacteria (Escherichia coli type 04) subserosally into the vesical wall, successfully caused persistent infection in the majority of animals. In the second study the temporal effects of bacterial infection on the induction of urothelial ornithine decarboxylase (ODC) and 3 H-thymidine uptake and DNA synthesis were examined. Bacterial infection of the urinary bladder induced urothelial ODC with a peak in enzyme activity 6 hr after infection. 3 H-Thymidine uptake and DNA synthesis peaked 48 hr after infection and coincided with the urothelial hyperplasia that occurred in response to the infection. In the third study the specific bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was given to rats concurrent with the urinary bacterial infection. In the fourth study rats were administered sodium nitrate and either dibutylamine or piperazine in the drinking water. The infected group developed bladder tumors while none were detected in the non-infected rats. From these studies it may be concluded that bacterial infection may have a significant role in the process of urinary bladder carcinogenesis

  9. Thrombospondin-1 in a Murine Model of Colorectal Carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Zenaida P Lopez-Dee

    Full Text Available Colorectal Cancer (CRC is one of the late complications observed in patients suffering from inflammatory bowel diseases (IBD. Carcinogenesis is promoted by persistent chronic inflammation occurring in IBD. Understanding the mechanisms involved is essential in order to ameliorate inflammation and prevent CRC. Thrombospondin 1 (TSP-1 is a multidomain glycoprotein with important roles in angiogenesis. The effects of TSP-1 in colonic tumor formation and growth were analyzed in a model of inflammation-induced carcinogenesis. WT and TSP-1 deficient mice (TSP-1-/- of the C57BL/6 strain received a single injection of azoxymethane (AOM and multiple cycles of dextran sodium sulfate (DSS to induce chronic inflammation-related cancers. Proliferation and angiogenesis were histologically analyzed in tumors. The intestinal transcriptome was also analyzed using a gene microarray approach. When the area containing tumors was compared with the entire colonic area of each mouse, the tumor burden was decreased in AOM/DSS-treated TSP-1-/- versus wild type (WT mice. However, these lesions displayed more angiogenesis and proliferation rates when compared with the WT tumors. AOM-DSS treatment of TSP-1-/- mice resulted in significant deregulation of genes involved in transcription, canonical Wnt signaling, transport, defense response, regulation of epithelial cell proliferation and metabolism. Microarray analyses of these tumors showed down-regulation of 18 microRNAs in TSP-1-/- tumors. These results contribute new insights on the controversial role of TSP-1 in cancer and offer a better understanding of the genetics and pathogenesis of CRC.

  10. International Activities in Radiation-Induced Carcinogenesis. Survey Paper

    Energy Technology Data Exchange (ETDEWEB)

    Komarov, E. [World Health Organization, Geneva (Switzerland)

    1969-11-15

    During the past 10 years special attention has been paid to the problem of late effects of radiation and in particular to radiation-induced carcinogenesis and leukaemogenesis. In the UNSCEAR report of 1958-1962 this.problem was mentioned as being of considerable importance from the point of view of estimation of risk to the population from environmental radiation. In 1964 a special report was prepared by UNSCEAR on radiation- induced carcinogenesis. In the ICRP publication No. 8, a chapter dealing with assessment of somatic risks discussed the problem of leukaemia and other neoplasms and particularly stressed the problem of thyroid carcinoma-and bone sarcoma. WHO panels of experts discussed the problem in 1960-1966 and made some recommendations for international activity in this field. In spite of the amount of scientific attention that has been given in recent years to experimental radiobiology in animals and lower forms, it has become abundantly clear that information directly applicable to humans is woefully inadequate and that there is a desperate need for carefully collected data from man on which to base public health planning and day to day work in radiation protection. This has long been recognized in the technical program of WHO in the emphasis given to the practical importance of epidemiology in human radiobiology and the degree to which it depends upon international collaboration.

  11. Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication

    Science.gov (United States)

    Takahashi, Yasushi; Uno, Kaname; Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Asano, Naoki; Asanuma, Kiyotaka; Shimosegawa, Tooru

    2018-01-01

    Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini-Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let-7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication. PMID:29719591

  12. Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment.

    Science.gov (United States)

    Kaiser, Jan Christian; Meckbach, Reinhard; Eidemüller, Markus; Selmansberger, Martin; Unger, Kristian; Shpak, Viktor; Blettner, Maria; Zitzelsberger, Horst; Jacob, Peter

    2016-12-01

    Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology. © The Author 2016. Published by Oxford University Press.

  13. Concepts on the pathogenesis of adolescent idiopathic scoliosis. Bone growth and mass, vertebral column, spinal cord, brain, skull, extra-spinal left-right skeletal length asymmetries, disproportions and molecular pathogenesis.

    Science.gov (United States)

    Burwell, R Geoffrey; Dangerfield, Peter H; Freeman, Brian J C

    2008-01-01

    There is no generally accepted scientific theory for the causes of adolescent idiopathic scoliosis (AIS). Encouraging advances thought to be related to AIS pathogenesis have recently been made in several fields including anthropometry of bone growth, bone mass, spinal growth modulation, extra-spinal left-right skeletal length asymmetries and disproportions, magnetic resonance imaging of vertebral column, spinal cord, brain, skull, and molecular pathogenesis. These advances are leading to the evaluation of new treatments including attempts at minimally invasive surgery on the spine and peri-apical ribs. Several concepts of AIS are outlined indicating their clinical applications but not their research potential. The concepts, by derivation morphological, molecular and mathematical, are addressed in 15 sections: 1) initiating and progressive factors; 2) relative anterior spinal overgrowth; 3) dorsal shear forces that create axial rotational instability; 4) rotational preconstraint; 5) uncoupled, or asynchronous, spinal neuro-osseous growth; 6) brain, nervous system and skull; 7) a novel neuro-osseous escalator concept based on a putative abnormality of two normal polarized processes namely, a) increasing skeletal dimensions, and b) the CNS body schema - both contained within a neuro-osseous timing of maturation (NOTOM) concept; 8) transverse plane pelvic rotation, skeletal asymmetries and developmental theory; 9) thoraco-spinal concept; 10) origin in contracture at the hips; 11) osteopenia; 12) melatonin deficiency; 13) systemic melatonin-signaling pathway dysfunction; 14) platelet calmodulin dysfunction; and 15) biomechanical spinal growth modulation. From these concepts, a collective model for AIS pathogenesis is formulated. The central concept of this model includes the body schema of the neural systems, widely-studied in adults, that control normal posture and coordinated movements with frames of reference in the posterior parietal cortex. The escalator concept

  14. Molecular markers in transitional cell carcinoma of the bladder: New insights into mechanisms and prognosis

    Directory of Open Access Journals (Sweden)

    Behfar Ehdaie

    2008-01-01

    Full Text Available Urothelial carcinoma is potentially life-threatening and expensive to treat since for many patients, the diagnosis entails a lifetime of surveillance to detect recurrent disease. Advancements in technology have provided an understanding of the molecular mechanisms of carcinogenesis and defined distinct pathways in tumorigenesis and progression. At the molecular level, urothelial carcinoma is being seen as a disease with distinct pathways of carcinogenesis and progression and thus markers of these processes should be used as both diagnostics and predictors of progression and patient outcome. Herein we present a selective overview of the molecular underpinning of urothelial carcinogenesis and progression and discuss the potential for proteins involved in these processes to serve as biomarkers. The discovery of biomarkers has enabled the elucidation of targets for novel therapeutic agents to disrupt the deregulation underlying the development and progression of urothelial carcinogenesis.

  15. Dietary tomato and lycopene impact androgen signaling- and carcinogenesis-related gene expression during early TRAMP prostate carcinogenesis

    Science.gov (United States)

    Wan, Lei; Tan, Hsueh-Li; Thomas-Ahner, Jennifer M.; Pearl, Dennis K.; Erdman, John W.; Moran, Nancy E.; Clinton, Steven K.

    2014-01-01

    Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4-10 wk-of-age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone-repletion (2.5 mg/kg/d initiated 1 wk after castration). Ten-wk-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia (PIN). Of the 200 prostate cancer-related genes measured by quantitative NanoString®, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (Plycopene feeding (Srd5a1) and by tomato-feeding (Srd5a2, Pxn, and Srebf1). Additionally, tomato-feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, while lycopene-feeding significantly reduced expression of neuroendocrine differentiation-related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early stages of prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk. PMID:25315431

  16. The Effect of Interactive, Three Dimensional, High Speed Simulations on High School Science Students' Conceptions of the Molecular Structure of Water.

    Science.gov (United States)

    Hakerem, Gita; And Others

    The Water and Molecular Networks (WAMNet) Project uses graduate student written Reduced Instruction Set Computing (RISC) computer simulations of the molecular structure of water to assist high school students learn about the nature of water. This study examined: (1) preconceptions concerning the molecular structure of water common among high…

  17. Data on efficacy of umbelliferone on glycoconjugates and immunological marker in 7,12-dimethylbenz(aanthracene induced oral carcinogenesis

    Directory of Open Access Journals (Sweden)

    Annamalai Vijayalakshmi

    2017-12-01

    Full Text Available Umbelliferone, a phenolic coumarin and dietary agent is believed to play a key role in pharmacological activities including anti-cancer and anti-oxidants effect in various in vitro and in vivo models. In present data on the pre-treatment of umbelliferone (30 mg/kg b.w. for 16 weeks to 7,12-dimethylbenz(aanthracene induced hamsters provides protection on cellular integrity by observing the status of cell surface glycoconjugates in the circulation and buccal mucosa and cytokeratin immunoexpression in the buccal mucosa of experimental animals. Data presented in this article brief that umbelliferone exhibits potent to clear cell surface abnormalities in buccal tissues and circulation during carcinogenesis and restored the expression of cytokeratin effect against 7,12-dimethylbenz(aanthracene induced hamster buccal pouch carcinogenesis, which is attributes to its inhibitory role on glycoprotein synthesis or on the activity of the glycosyltransferase. In an article associates with this data set given the relevance to the research article entitled “Dose responsive efficacy of umbelliferone on lipid peroxidation, anti-oxidant, and xenobiotic metabolism in 7,12-dimethylbenz(aanthracene-induced oral carcinogenesis” namely Vijayalakshmi and Sindhu, 2017 assessed 100% tumour formation in 7,12-dimethylbenz(aanthracene treated hamsters and oral administration of umbelliferone at a dose of 30 mg/kg b.w to 7,12-dimethylbenz(aanthracene treated hamsters prevents tumour incidence, restores the status of the biochemical markers in circulation and buccal mucosa and also dysregulation in the expression of molecular markers. Given the relevance to this article entitled “Berberine protects cellular integrity during 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis in golden Syrian hamsters” namely Sindhu and Manoharan 2010, which were based on spectrophotometry and florescence microscope analysis. Keywords: Oral cancer, 7

  18. Molecular mechanisms of cancer

    National Research Council Canada - National Science Library

    Weber, Georg F

    2007-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Section I. General Mechanisms of Transformation 1. Theories of Carcinogenesis...

  19. Biological parameters for lung cancer in mathematical models of carcinogenesis

    International Nuclear Information System (INIS)

    Jacob, P.; Jacob, V.

    2003-01-01

    Applications of the two-step model of carcinogenesis with clonal expansion (TSCE) to lung cancer data are reviewed, including those on atomic bomb survivors from Hiroshima and Nagasaki, British doctors, Colorado Plateau miners, and Chinese tin miners. Different sets of identifiable model parameters are used in the literature. The parameter set which could be determined with the lowest uncertainty consists of the net proliferation rate gamma of intermediate cells, the hazard h 55 at an intermediate age, and the hazard H? at an asymptotically large age. Also, the values of these three parameters obtained in the various studies are more consistent than other identifiable combinations of the biological parameters. Based on representative results for these three parameters, implications for the biological parameters in the TSCE model are derived. (author)

  20. Altered DNA methylation: a secondary mechanism involved in carcinogenesis.

    Science.gov (United States)

    Goodman, Jay I; Watson, Rebecca E

    2002-01-01

    This review focuses on the role that DNA methylation plays in the regulation of normal and aberrant gene expression and on how, in a hypothesis-driven fashion, altered DNA methylation may be viewed as a secondary mechanism involved in carcinogenesis. Research aimed at discerning the mechanisms by which chemicals can transform normal cells into frank carcinomas has both theoretical and practical implications. Through an increased understanding of the mechanisms by which chemicals affect the carcinogenic process, we learn more about basic biology while, at the same time, providing the type of information required to make more rational safety assessment decisions concerning their actual potential to cause cancer under particular conditions of exposure. One key question is: does the mechanism of action of the chemical in question involve a secondary mechanism and, if so, what dose may be below its threshold?

  1. Collagen mRNA levels changes during colorectal cancer carcinogenesis

    DEFF Research Database (Denmark)

    Skovbjerg, Hanne; Anthonsen, Dorit; Lothe, Inger M B

    2009-01-01

    BACKGROUND: Invasive growth of epithelial cancers is a complex multi-step process which involves dissolution of the basement membrane. Type IV collagen is a major component in most basement membranes. Type VII collagen is related to anchoring fibrils and is found primarily in the basement membrane...... zone of stratified epithelia. Immunohistochemical studies have previously reported changes in steady-state levels of different alpha(IV) chains in several epithelial cancer types. In the present study we aimed to quantitatively determine the mRNA levels of type IV collagen (alpha1/alpha 4/alpha 6......) and type VII collagen (alpha1) during colorectal cancer carcinogenesis. METHODS: Using quantitative RT-PCR, we have determined the mRNA levels for alpha1(IV), alpha 4(IV), alpha 6(IV), and alpha1(VII) in colorectal cancer tissue (n = 33), adenomas (n = 29) and in normal tissue from the same individuals...

  2. Studies on the multistage nature of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.; Ley, R.D.; Grube, D.; Staffeldt, E.

    1980-01-01

    With low dose levels of ionizing or ultraviolet radiation, the number of initiation events exceeds the number of tumors that grow to a detectable size. Ionizing radiation, which is a complete carcinogen, appears to be a more effective initiator than an enhancer or promoter. However, the initiation and promotion aspects of ionizing radiation have been studied in very few organ systems. In the case of UVR, with or without photosensitizers such as psoralens, the requirement of a relatively large number of exposures for carcinogenesis suggests that the expression of the initiated cells as frank tumors requires a number of events spread out over the time of the development of the tumor. Both ionizing and ultraviolet radiation are, perhaps, underutilized as tools for probing the mechanism of both initiation and promotion

  3. Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

    International Nuclear Information System (INIS)

    Andreev, S. G.; Eidelman, Y. A.; Salnikov, I. V.; Khvostunov, I. K.

    2006-01-01

    Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed. (authors)

  4. Oxidative DNA base modifications as factors in carcinogenesis

    International Nuclear Information System (INIS)

    Olinski, R.; Jaruga, P.; Zastawny, T.H.

    1998-01-01

    Reactive oxygen species can cause extensive DNA modifications including modified bases. Some of the DNA base damage has been found to possess premutagenic properties. Therefore, if not repaired, it can contribute to carcinogenesis. We have found elevated amounts of modified bases in cancerous and precancerous tissues as compared with normal tissues. Most of the agents used in anticancer therapy are paradoxically responsible for induction of secondary malignancies and some of them may generate free radicals. The results of our experiments provide evidence that exposure of cancer patients to therapeutic doses of ionizing radiation and anticancer drugs cause base modifications in genomic DNA of lymphocytes. Some of these base damages could lead to mutagenesis in critical genes and ultimately to secondary cancers such as leukemias. This may point to an important role of oxidative base damage in cancer initiation. Alternatively, the increased level of the modified base products may contribute to genetic instability and metastatic potential of tumor cells. (author)

  5. Carcinogenesis related to intense pulsed light and UV exposure

    DEFF Research Database (Denmark)

    Hedelund, L; Lerche, C; Wulf, H C

    2006-01-01

    This study examines whether intense pulsed light (IPL) treatment has a carcinogenic potential itself or may influence ultraviolet (UV)-induced carcinogenesis. Secondly, it evaluates whether UV exposure may influence IPL-induced side effects. Hairless, lightly pigmented mice (n=144) received three...... observation period. Side effects were evaluated clinically. No tumors appeared in untreated control mice or in just IPL-treated mice. Skin tumors developed in UV-exposed mice independently of IPL treatments. The time it took for 50% of the mice to first develop skin tumor ranged from 47 to 49 weeks...... in preoperative UV-exposed mice (p=0.94) and from 22 to 23 weeks in pre- and postoperative UV-exposed mice (p=0.11). IPL rejuvenation of lightly pigmented skin did not induce pigmentary changes (p=1.00). IPL rejuvenation of UV-pigmented skin resulted in an immediate increased skin pigmentation and a subsequent...

  6. Paradoxes in carcinogenesis: New opportunities for research directions

    Directory of Open Access Journals (Sweden)

    Kramer Barnett S

    2007-08-01

    Full Text Available Abstract Background The prevailing paradigm in cancer research is the somatic mutation theory that posits that cancer begins with a single mutation in a somatic cell followed by successive mutations. Much cancer research involves refining the somatic mutation theory with an ever increasing catalog of genetic changes. The problem is that such research may miss paradoxical aspects of carcinogenesis for which there is no likely explanation under the somatic mutation theory. These paradoxical aspects offer opportunities for new research directions that should not be ignored. Discussion Various paradoxes related to the somatic mutation theory of carcinogenesis are discussed: (1 the presence of large numbers of spatially distinct precancerous lesions at the onset of promotion, (2 the large number of genetic instabilities found in hyperplastic polyps not considered cancer, (3 spontaneous regression, (4 higher incidence of cancer in patients with xeroderma pigmentosa but not in patients with other comparable defects in DNA repair, (5 lower incidence of many cancers except leukemia and testicular cancer in patients with Down's syndrome, (6 cancer developing after normal tissue is transplanted to other parts of the body or next to stroma previously exposed to carcinogens, (7 the lack of tumors when epithelial cells exposed to a carcinogen were transplanted next to normal stroma, (8 the development of cancers when Millipore filters of various pore sizes were was inserted under the skin of rats, but only if the holes were sufficiently small. For the latter paradox, a microarray experiment is proposed to try to better understand the phenomena. Summary The famous physicist Niels Bohr said "How wonderful that we have met with a paradox. Now we have some hope of making progress." The same viewpoint should apply to cancer research. It is easy to ignore this piece of wisdom about the means to advance knowledge, but we do so at our peril.

  7. Relevance of CCL3/CCR5 axis in oral carcinogenesis.

    Science.gov (United States)

    da Silva, Janine Mayra; Moreira Dos Santos, Tálita Pollyanna; Sobral, Lays Martin; Queiroz-Junior, Celso Martins; Rachid, Milene Alvarenga; Proudfoot, Amanda E I; Garlet, Gustavo Pompermaier; Batista, Aline Carvalho; Teixeira, Mauro Martins; Leopoldino, Andréia Machado; Russo, Remo Castro; Silva, Tarcília Aparecida

    2017-08-01

    The chemokine CCL3 is a chemotactic cytokine crucial for inflammatory cell recruitment in homeostatic and pathological conditions. CCL3 might stimulate cancer progression by promoting leukocyte accumulation, angiogenesis and tumour growth. The expression of CCL3 and its receptors CCR1 and CCR5 was demonstrated in oral squamous cell carcinoma (OSCC), but their role was not defined. Here, the functions of CCL3 were assessed using a model of chemically induced tongue carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). Lineages of OSCC were used to analyse the effects of CCL3 in vitro . The 4NQO-induced lesions exhibited increased expression of CCL3, CCR1 and CCR5. CCL3 -/- and CCR5 -/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1 -/- mice. Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3 -/- and CCR5 -/- mice. OSCC from CCL3 -/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-β1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice. In vitro , CCL3 induced invasion and production of CCL5, IL-6, MMP -2, -8, -9. Blockage of CCL3 in vitro using α-CCL3 or Evasin-1 (a CCL3-binding protein) impaired tumour cell invasion. In conclusion, CCL3/CCR5 axis has pro-tumourigenic effects in oral carcinogenesis. The induction of inflammatory and angiogenic pathways and eosinophils recruitment appear to be the underlying mechanism explaining these effects. These data reveal potential protective effects of CCL3 blockade in oral cancer.

  8. Protein expression analysis of inflammation-related colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Yasui Yumiko

    2009-01-01

    Full Text Available Background: Chronic inflammation is a risk factor for colorectal cancer (CRC development. The aim of this study was to determine the differences in protein expression between CRC and the surrounding nontumorous colonic tissues in the mice that received azoxymethane (AOM and dextran sodium sulfate (DSS using a proteomic analysis. Materials and Methods: Male ICR mice were given a single intraperitoneal injection of AOM (10 mg/kg body weight, followed by 2% (w/v DSS in their drinking water for seven days, starting one week after the AOM injection. Colonic adenocarcinoma developed after 20 weeks and a proteomics analysis based on two-dimensional gel electrophoresis and ultraflex TOF/TOF mass spectrometry was conducted in the cancerous and nontumorous tissue specimens. Results: The proteomic analysis revealed 21 differentially expressed proteins in the cancerous tissues in comparison to the nontumorous tissues. There were five markedly increased proteins (beta-tropomyosin, tropomyosin 1 alpha isoform b, S100 calcium binding protein A9, and an unknown protein and 16 markedly decreased proteins (Car1 proteins, selenium-binding protein 1, HMG-CoA synthase, thioredoxin 1, 1 Cys peroxiredoxin protein 2, Fcgbp protein, Cytochrome c oxidase, subunit Va, ETHE1 protein, and 7 unknown proteins. Conclusions: There were 21 differentially expressed proteins in the cancerous tissues of the mice that received AOM and DSS. Their functions include metabolism, the antioxidant system, oxidative stress, mucin production, and inflammation. These findings may provide new insights into the mechanisms of inflammation-related colon carcinogenesis and the establishment of novel therapies and preventative strategies to treat carcinogenesis in the inflamed colon.

  9. Role of oxidative stress in cadmium toxicity and carcinogenesis

    International Nuclear Information System (INIS)

    Liu Jie; Qu Wei; Kadiiska, Maria B.

    2009-01-01

    Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged exposures. Reactive oxygen species (ROS) are often implicated in Cd toxicology. This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis. Cd-generated superoxide anion, hydrogen peroxide, and hydroxyl radicals in vivo have been detected by the electron spin resonance spectra, which are often accompanied by activation of redox sensitive transcription factors (e.g., NF-κB, AP-1 and Nrf2) and alteration of ROS-related gene expression. It is generally agreed upon that oxidative stress plays important roles in acute Cd poisoning. However, following long-term Cd exposure at environmentally-relevant low levels, direct evidence for oxidative stress is often obscure. Alterations in ROS-related gene expression during chronic exposures are also less significant compared to acute Cd poisoning. This is probably due to induced adaptation mechanisms (e.g., metallothionein and glutathione) following chronic Cd exposures, which in turn diminish Cd-induced oxidative stress. In chronic Cd-transformed cells, less ROS signals are detected with fluorescence probes. Acquired apoptotic tolerance renders damaged cells to proliferate with inherent oxidative DNA lesions, potentially leading to tumorigenesis. Thus, ROS are generated following acute Cd overload and play important roles in tissue damage. Adaptation to chronic Cd exposure reduces ROS production, but acquired Cd tolerance with aberrant gene expression plays important roles in chronic Cd toxicity and carcinogenesis.

  10. Mushroom Ganoderma lucidum Prevents Colitis-Associated Carcinogenesis in Mice

    Science.gov (United States)

    Sliva, Daniel; Loganathan, Jagadish; Jiang, Jiahua; Jedinak, Andrej; Lamb, John G.; Terry, Colin; Baldridge, Lee Ann; Adamec, Jiri; Sandusky, George E.; Dudhgaonkar, Shailesh

    2012-01-01

    Background Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT). The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. Methods/Principal Findings Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF) formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. Conclusions Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer. PMID:23118901

  11. Challenging the Myth: Transvaginal Mesh is Not Associated with Carcinogenesis.

    Science.gov (United States)

    Chughtai, Bilal; Sedrakyan, Art; Mao, Jialin; Thomas, Dominique; Eilber, Karyn S; Clemens, J Quentin; Anger, Jennifer T

    2017-10-01

    We sought to determine if there was a potential link between synthetic polypropylene mesh implantation for transvaginal pelvic organ prolapse and stress urinary incontinence, and carcinogenesis using statewide administrative data. Women who underwent transvaginal surgery for pelvic organ prolapse or stress urinary incontinence with mesh between January 2008 and December 2009 in New York State were identified using ICD-9-CM procedure codes and CPT-4 codes. Patients in the mesh cohort were individually matched to 2 control cohorts based on comorbidities and procedure date. Carcinogenesis was determined before and after matching at 1, 2 and 3 years, and during the entire followup time. A total of 2,229 patients who underwent mesh based pelvic organ prolapse surgery and 10,401 who underwent sling surgery for stress urinary incontinence between January 2008 and December 2009 were included in the study. Mean followup was 6 years (range 5 to 7). Exact matching between the mesh and control cohorts resulted in 1,870 pairs for pelvic organ prolapse mesh and cholecystectomy (1:2), 1,278 pairs for pelvic organ prolapse mesh and hysterectomy (1:1), 7,986 pairs for sling and cholecystectomy (1:1) and 3,810 pairs for sling and hysterectomy (1:1). Transvaginal mesh implantation was not associated with an increased risk of a cancer diagnosis (pelvic/local cancers or any cancer) at 1 year and during the entire followup of up to 7 years. Transvaginal surgery with implantation of mesh was not associated with the development of malignancy at a mean followup of 6 years. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  12. [Colorectal cancer (CCR): genetic and molecular alterations].

    Science.gov (United States)

    Juárez-Vázquez, Clara Ibet; Rosales-Reynoso, Mónica Alejandra

    2014-01-01

    The aim of this review is to present a genetic and molecular overview of colorectal carcinogenesis (sporadic and hereditary origin) as a multistage process, where there are a number of molecular mechanisms associated with the development of colorectal cancer and genomic instability that allows the accumulation of mutations in proto-oncogenes and tumor suppressor genes, chromosomal instability, and methylation and microsatellite instability, and the involvement of altered expression of microRNAs' prognosis factors.

  13. Present status of theories and data analyses of mathematical models for carcinogenesis

    International Nuclear Information System (INIS)

    Kai, Michiaki; Kawaguchi, Isao

    2007-01-01

    Reviewed are the basic mathematical models (hazard functions), present trend of the model studies and that for radiation carcinogenesis. Hazard functions of carcinogenesis are described for multi-stage model and 2-event model related with cell dynamics. At present, the age distribution of cancer mortality is analyzed, relationship between mutation and carcinogenesis is discussed, and models for colorectal carcinogenesis are presented. As for radiation carcinogenesis, models of Armitage-Doll and of generalized MVK (Moolgavkar, Venson, Knudson, 1971-1990) by 2-stage clonal expansion have been applied to analysis of carcinogenesis in A-bomb survivors, workers in uranium mine (Rn exposure) and smoking doctors in UK and other cases, of which characteristics are discussed. In analyses of A-bomb survivors, models above are applied to solid tumors and leukemia to see the effect, if any, of stage, age of exposure, time progression etc. In miners and smokers, stages of the initiation, promotion and progression in carcinogenesis are discussed on the analyses. Others contain the analyses of workers in Canadian atomic power plant, and of patients who underwent the radiation therapy. Model analysis can help to understand the carcinogenic process in a quantitative aspect rather than to describe the process. (R.T.)

  14. The Role of Macrophage Migration Inhibitory Factor (MIF) in Ultraviolet Radiation-Induced Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimizu, Tadamichi [Department of Dermatology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, 930-0194, Toyama (Japan)

    2010-08-09

    Ultraviolet (UV) radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn) of the skin, while chronic exposure to solar UV radiation causes photo-aging, immunosuppression, and ultimately, carcinogenesis of the skin. After skin damage by UV radiation, the cells are known to secrete many cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α. and macrophage migration inhibitory factor (MIF). MIF was originally identified as a lymphokine that concentrates macrophages at inflammatory loci, and is known to be a potent activator of macrophages in vivo. MIF is considered to play an important role in cell-mediated immunity. Since the molecular cloning of MIF cDNA, MIF has been re-evaluated as a proinflammatory cytokine and pituitary-derived hormone that potentiates endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. This article reviews the latest findings on the roles of MIF with regard to UV-induced skin cancer.

  15. The Role of Macrophage Migration Inhibitory Factor (MIF) in Ultraviolet Radiation-Induced Carcinogenesis

    International Nuclear Information System (INIS)

    Shimizu, Tadamichi

    2010-01-01

    Ultraviolet (UV) radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn) of the skin, while chronic exposure to solar UV radiation causes photo-aging, immunosuppression, and ultimately, carcinogenesis of the skin. After skin damage by UV radiation, the cells are known to secrete many cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α. and macrophage migration inhibitory factor (MIF). MIF was originally identified as a lymphokine that concentrates macrophages at inflammatory loci, and is known to be a potent activator of macrophages in vivo. MIF is considered to play an important role in cell-mediated immunity. Since the molecular cloning of MIF cDNA, MIF has been re-evaluated as a proinflammatory cytokine and pituitary-derived hormone that potentiates endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. This article reviews the latest findings on the roles of MIF with regard to UV-induced skin cancer

  16. The Role of Macrophage Migration Inhibitory Factor (MIF in Ultraviolet Radiation-Induced Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tadamichi Shimizu

    2010-08-01

    Full Text Available Ultraviolet (UV radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn of the skin, while chronic exposure to solar UV radiation causes photo-aging, immunosuppression, and ultimately, carcinogenesis of the skin. After skin damage by UV radiation, the cells are known to secrete many cytokines, including interleukin (IL-1, IL-6, tumor necrosis factor (TNF-α. and macrophage migration inhibitory factor (MIF. MIF was originally identified as a lymphokine that concentrates macrophages at inflammatory loci, and is known to be a potent activator of macrophages in vivo. MIF is considered to play an important role in cell-mediated immunity. Since the molecular cloning of MIF cDNA, MIF has been re-evaluated as a proinflammatory cytokine and pituitary-derived hormone that potentiates endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. This article reviews the latest findings on the roles of MIF with regard to UV-induced skin cancer.

  17. Boolean network model for cancer pathways: predicting carcinogenesis and targeted therapy outcomes.

    Directory of Open Access Journals (Sweden)

    Herman F Fumiã

    Full Text Available A Boolean dynamical system integrating the main signaling pathways involved in cancer is constructed based on the currently known protein-protein interaction network. This system exhibits stationary protein activation patterns--attractors--dependent on the cell's microenvironment. These dynamical attractors were determined through simulations and their stabilities against mutations were tested. In a higher hierarchical level, it was possible to group the network attractors into distinct cell phenotypes and determine driver mutations that promote phenotypic transitions. We find that driver nodes are not necessarily central in the network topology, but at least they are direct regulators of central components towards which converge or through which crosstalk distinct cancer signaling pathways. The predicted drivers are in agreement with those pointed out by diverse census of cancer genes recently performed for several human cancers. Furthermore, our results demonstrate that cell phenotypes can evolve towards full malignancy through distinct sequences of accumulated mutations. In particular, the network model supports routes of carcinogenesis known for some tumor types. Finally, the Boolean network model is employed to evaluate the outcome of molecularly targeted cancer therapies. The major find is that monotherapies were additive in their effects and that the association of targeted drugs is necessary for cancer eradication.

  18. Role of Free Radicals, Oxidative Stress and Xenobiotics in Carcinogenesis by Environmental Pollutants

    Directory of Open Access Journals (Sweden)

    Dibyajyoti Saha

    2014-09-01

    Full Text Available Carcinogenesis by many small molecular weight chemicals involves either a direct action of the chemical on cellular DNA or metabolism of the parent chemical to an active or ultimate form, which can than react with cellular DNA to produce a permanent chemical change in a DNA structure. A free radical is an atom or molecule that has one or more unpaired electron(s. These are highly reactive species capable of wide spread, indiscriminate oxidation and per oxidation of proteins, lipids and DNA which can lead to significant cellular damage and even tissue and/or organ failure. . Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. Xenobiotics are a compound that is foreign to the body. Xenobiotics can produce a variety of biological effects, including pharmacologic responses, toxicity, genes, immunologic reactions and cancer. Oxidative stress is a leading cause to damage cells by oxidation. The rate at which oxidative damage is induced (input and the rate at which it is efficiently repaired and removed (output. This communication highlights the role of carcinogens as environmental pollutants with the possible mechanism of free radicals, oxidative stress and xenobiotics.

  19. The association between methylated CDKN2A and cervical carcinogenesis, and its diagnostic value in cervical cancer: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Li J

    2016-08-01

    Full Text Available Jinyun Li,1,2,* Chongchang Zhou,1,* Haojie Zhou,3,* Tianlian Bao,1 Tengjiao Gao,1 Xiangling Jiang,1 Meng Ye1,2 1Department of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, 2Department of Medical Oncology, Affiliated Hospital, Ningbo University, 3Department of Molecular Diagnosis, Ningbo Diagnostic Pathology Center, Ningbo, Zhejiang, People’s Republic of China *These authors are co-first authors of this work Background: Cervical cancer is the second deadliest gynecologic malignancy, characterized by apparently precancerous lesions and cervical intraepithelial neoplasia (CIN, and having a long course from the development of CIN to cervical cancer. Cyclin-dependent kinase inhibitor 2A (CDKN2A is a well-documented tumor suppressor gene and is commonly methylated in cervical cancer. However, the relationship between methylated CDKN2A and carcinogenesis in cervical cancer is inconsistent, and the diagnostic accuracy of methylated CDKN2A is underinvestigated. In this study, we attempted to quantify the association between CDKN2A methylation and the carcinogenesis of cervical cancer, and its diagnostic power.Methods: We systematically reviewed four electronic databases and identified 26 studies involving 1,490 cervical cancers, 1,291 CINs, and 964 controls. A pooled odds ratio (OR with corresponding 95% confidence intervals (95% CI was calculated to evaluate the association between methylated CDKN2A and the carcinogenesis of cervical cancer. Specificity, sensitivity, the area under the receiver operating characteristic curve, and the diagnostic odds ratio were computed to assess the effect of methylated CDKN2A in the diagnosis of cervical cancer.Results: Our results indicated an upward trend in the methylation frequency of CDKN2A in the carcinogenesis of cervical cancer (cancer vs control: OR =23.67, 95% CI =15.54–36.06; cancer vs CIN: OR =2.53, 95% CI =1.79–3.5; CIN vs control: OR =9.68, 95% CI =5.82–16.02. The

  20. ING Genes Work as Tumor Suppressor Genes in the Carcinogenesis of Head and Neck Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Xiaohan Li

    2011-01-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most common cancer in the world. The evolution and progression of HNSCC are considered to result from multiple stepwise alterations of cellular and molecular pathways in squamous epithelium. Recently, inhibitor of growth gene (ING family consisting of five genes, ING1 to ING5, was identified as a new tumor suppressor gene family that was implicated in the downregulation of cell cycle and chromatin remodeling. In contrast, it has been shown that ING1 and ING2 play an oncogenic role in some cancers, this situation being similar to TGF-β. In HNSCC, the ING family has been reported to be downregulated, and ING translocation from the nucleus to the cytoplasm may be a critical event for carcinogenesis. In this paper, we describe our recent results and briefly summarize current knowledge regarding the biologic functions of ING in HNSCC.

  1. Modulation of Estrogen Chemical Carcinogenesis by Botanical Supplements used for Postmenopausal Women’s Health

    Science.gov (United States)

    Snelten, Courtney S.; Dietz, Birgit; Bolton, Judy L.

    2012-01-01

    Breast cancer risk has been associated with long-term estrogen exposure including traditional hormone therapy (HT, formally hormone replacement therapy). To avoid traditional HT and associated risks, women have been turning to botanical supplements such as black cohosh, red clover, licorice, hops, dong gui, and ginger to relieve menopausal symptoms despite a lack of efficacy evidence. The mechanisms of estrogen carcinogenesis involve both hormonal and chemical pathways. Botanical supplements could protect women from estrogen carcinogenesis by modulating key enzymatic steps [aromatase, P4501B1, P4501A1, catechol-O-methyltransferase (COMT), NAD(P)H quinone oxidoreductase 1 (NQO1), and reactive oxygen species (ROS) scavenging] in estradiol metabolism leading to estrogen carcinogenesis as outlined in Figure 1. This review summarizes the influence of popular botanical supplements used for women’s health on these key steps in the estrogen chemical carcinogenesis pathway, and suggests that botanical supplements may have added chemopreventive benefits by modulating estrogen metabolism. PMID:24223609

  2. Investigating the Role of FIP200 in Mammary Carcinogenesis Using a Transgenic Mouse Model

    National Research Council Canada - National Science Library

    Nagy, Tamas

    2007-01-01

    ...) deletion in mammary-specific polyoma middle-T transgenic mice. We monitored mammary carcinogenesis in positive control (FAKFlox/Flox; MMTV-PyVT) and target (FAKFlox/Flox; MMTV-Cre; MMTV-PyVT) females...

  3. Age and Space Irradiation Modulate Tumor Progression: Implications for Carcinogenesis Risk

    Data.gov (United States)

    National Aeronautics and Space Administration — Age plays a major role in tumor incidence and is an important consideration when modeling the carcinogenesis process or estimating cancer risks. Epidemiological data...

  4. The level of claudin-7 is reduced as an early event in colorectal carcinogenesis

    DEFF Research Database (Denmark)

    Lange, Jette Bornholdt; Friis, Stine; Godiksen, Sine

    2011-01-01

    -regulation of the oncogenic serine protease, matriptase, induces leakiness in epithelial barriers both in vivo and in vitro. We found in an in-silico search tight co-regulation between matriptase and claudin-7 expression. We have previously shown that the matriptase expression level decreases during colorectal carcinogenesis....... In the present study we investigated whether claudin-7 expression is likewise decreased during colorectal carcinogenesis, thereby causing or contributing to the compromised epithelial leakiness of dysplastic tissue....

  5. A generalized theory of carcinogenesis due to chronodisruption.

    Science.gov (United States)

    Erren, Thomas C; Reiter, Russel J

    2008-12-01

    For two decades, research has been suggested and conducted into the causation and development of cancers in seemingly diverse and unrelated populations such as blind individuals, shift-workers, flight personnel, Arctic residents and subsets of sleepers. One common denominator of these investigations is "melatonin". Another common denominator is that all these studies implicitly pursued the validity of the so-called "melatonin hypothesis", of a corollary and of associated predictions which can be united in our proposed theory of "carcinogenesis due to chronodisruption". The new theory suggests that the various predictions investigated between 1987 and 2008 represent different aspects of the same problem. Indeed, abundant experimental evidence supports the notion that the final common cause of many cases of cancer may be what has been termed chronodisruption (CD), a relevant disturbance of the temporal organization or order of physiology, endocrinology, metabolism and behaviour. While melatonin as a key time messenger and time keeper can be a marker of CD, it is probably only partially related to the differential cancer occurrence apparent in individuals who chronically or frequently experience an excess or deficit of chronodisruption.

  6. Lineage fate of ductular reactions in liver injury and carcinogenesis.

    Science.gov (United States)

    Jörs, Simone; Jeliazkova, Petia; Ringelhan, Marc; Thalhammer, Julian; Dürl, Stephanie; Ferrer, Jorge; Sander, Maike; Heikenwalder, Mathias; Schmid, Roland M; Siveke, Jens T; Geisler, Fabian

    2015-06-01

    Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.

  7. Experimental pulmonary carcinogenesis by radon and its daughters

    International Nuclear Information System (INIS)

    Sato, Fumiaki

    1989-01-01

    Information on experimental pulmonary carcinogenesis by radon and its daughters has come mostly from experiments carried out in France and United States of America. In rats a dose response relation was estimated to be linear with dose at low dose region. Studies of rats exposed daily to radon and radon daughters indicated that the frequency of pulmonary cancer at total exposure greater than 3000 WLM was greater when the exposure rates were low. At low total exposures the dose-rate effect was less apparent. Cigarette smoke increased the pulmonary cancer in rats but decreased in dogs. The decrease may be due to a decrease of absorbed doses with increased secretion of mucus and to an enhancement of mucociliary clearance. After inhalation of 222 Ru at equilibrium with radon daughters, rats were inoculated intrapleurally with asbestos fibres or glass fibres. The additive co-carcinogenic effects of this type of insult were demonstrated by the increased incidence of malignant thoracic tumours. As for species differences, dogs and hamsters are relatively resistant to cancer induction and rats are sensitive. While bronchogenic carcinomas are the most frequently observed radiation-induced pulmonary cancer in humans, bronchioloalveolar carcinomas are the most frequent type in most animal species. (author)

  8. Carcinogenesis in mice after low doses and dose rates

    International Nuclear Information System (INIS)

    Ullrich, R.L.

    1979-01-01

    The results from the experimental systems reported here indicate that the dose-response curves for tumor induction in various tissues cannot be described by a single model. Furthermore, although the understanding of the mechanisms involved in different systems is incomplete, it is clear that very different mechanisms for induction are involved. For some tumors the mechanism of carcinogenesis may be mainly a result of direct effects on the target cell, perhaps involving one or more mutations. While induction may occur, in many instances, through such direct effects, the eventual expression of the tumor can be influenced by a variety of host factors including endocrine status, competence of the immune system, and kinetics of target and interacting cell populations. In other tumors, indirect effects may play a major role in the initiation or expression of tumors. Some of the hormone-modulated tumors would fall into this class. Despite the complexities of the experimental systems and the lack of understanding of the types of mechanisms involved, in nearly every example the tumorigenic effectiveness per rad of low-LET radiation tends to decrease with decreasing dose rate. For some tumor types the differences may be small or may appear only with very low dose rates, while for others the dose-rate effects may be large

  9. Effects of retinoids on ultraviolet-induced carcinogenesis

    International Nuclear Information System (INIS)

    Epstein, J.H.

    1981-01-01

    The evidence for effects of the retinoids on UV-induced carcinogenesis is sparse. Clinical observations indicate that topical RA can cause significant regression of premalignant actinic keratoses. Also there is some evidence that this agent can cause dissolution of some basal cell epitheliomas. However this latter effect does not appear to be of therapeutic value. Systemic retinoids are of little value in the treatment of premalignant and malignant cutaneous lesions though 13-cis-retinoic acid might be of use in the basal cell nevus syndrome. Examination of the influence of the retinoids on photocarcinogenesis essentially has been confined to RA and animal experimentation. RA in nontoxic concentrations can both stimulate and inhibit photocarcinogenesis depending upon the circumstances of the study. The mechanisms of these responses are not clear. Influences on DNA synthesis directly and/or indirectly or on immune responses may be involved in both effects. Preliminary studies with oral 13-cis-retinoic acid have not demonstrated any effects to date on UV-induced skin cancer formation

  10. Influence of animal age upon antioxidant-modified UV carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Black, H S [Photobiology Laboratory, Veterans Administration Medical Center, Houston, TX (USA); McCann, V [Baylor Univ., Houston, TX (USA). Coll. of Medicine; Thornby, J I [Biostatistics Section, Research Service, Veterans Administration Medical Center, Houston, TX (USA)

    1982-08-01

    Studies were undertaken to examine the effects of animal age on the anticarcinogenic properties of antioxidants. Female hairless mice, 2.5, 4.5 and 9.5 months of age, were subjected to daily irradiation from Westinghouse BZS-WLG lamps for 19 weeks. Experimental groups of animals were maintained on a commercial rodent meal supplemented with a 2% (w/w) antioxidant mixture. Control groups received only the meal. Tumour latency, expressed as median time to tumor development, was significantly greater for all age groups receiving antioxidants than for their similarly aged controls. However, the response to antioxidants appeared to decrease with age and the antioxidant effect was significantly less in the 9.5 month-old group than in the 2.5 month-old group. Likewise, the two youngest groups receiving antioxidants demonstrated a significantly fewer number of tumors per animal. It is concluded that animal age influences the degree of photoprotection provided by antioxidants. Whether this effect is related to dietary intake, and thus dependent upon resident antioxidant levels, is unknown. Nevertheless, dietary antioxidants provide significant protection in young animals against carcinogenesis induced by radiation of predominantly UVB wavelengths.

  11. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis

    Directory of Open Access Journals (Sweden)

    Yezaz Ahmed Ghouri

    2017-01-01

    Full Text Available Since the 1970s, the epidemic of hepatocellular carcinoma (HCC has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

  12. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis.

    Science.gov (United States)

    Ghouri, Yezaz Ahmed; Mian, Idrees; Rowe, Julie H

    2017-01-01

    Since the 1970s, the epidemic of hepatocellular carcinoma (HCC) has spread beyond the Eastern Asian predominance and has been increasing in Northern hemisphere, especially in the United States (US) and Western Europe. It occurs more commonly in males in the fourth and fifth decades of life. Among all cancers, HCC is one of the fastest growing causes of death in the US and poses a significant economic burden on healthcare. Chronic liver disease due to hepatitis B virus or hepatitis C virus and alcohol accounts for the majority of HCC cases. Incidence of nonalcoholic fatty liver disease has been on the risem and it has also been associated with the development of HCC. Its pathogenesis varies based on the underlying etiological factor although majority of cases develop in the setting of background cirrhosis. Carcinogenesis of HCC includes angiogenesis, chronic inflammation, and tumor macroenvironment and microenvironment. There is a significant role of both intrinsic genetic risk factors and extrinsic influences such as alcohol or viral infections that lead to the development of HCC. Understanding its etiopathogenesis helps select appropriate diagnostic tests and treatments.

  13. Short-term carcinogenesis evaluation of Casearia sylvestris

    Directory of Open Access Journals (Sweden)

    Cleide A.S. Tirloni

    Full Text Available Abstract Casearia sylvestris Sw., Salicaceae, is an important medicinal plant widely used in Brazil for the treatment of various cardiovascular disorders. This species was included as of interest by Brazilian Unified Health System. Although preclinical studies described cardiovascular protective effects and apparent absence of toxicity, no studies have evaluated its carcinogenic potential. In this study, we proposed a short-term carcinogenesis evaluation of C. sylvestris in Wistar rats, aiming to check the safety of this species to use it as proposed by Brazilian Unified Health System. C. sylvestris leaves were obtained and the crude extract was prepared by maceration from methanol/water. Wistar rats were orally treated for 12 weeks with 50, 250 or 500 mg kg−1 of crude extract or vehicle. Body weight, daily morbidity and mortality were monitored. Blood and bone marrow samples were collect for micronucleus test, comet assay and tumor markers evaluation. Vital organs were removed to macro and histopathological analyses. The crude extract did not induce mutagenic and genotoxic effects and no alterations were observed in important tumor markers. Finally, no detectable signs of injury through gross pathology or histopathological examinations were observed. Our results certify the absence of the crude extract toxicity, indicating its safety, even at prolonged exposure as proposed by Brazilian Unified Health System.

  14. Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

    Directory of Open Access Journals (Sweden)

    Heidrun Hirner

    Full Text Available Simian virus 40 (SV40 is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA

  15. Immunophenotypic Analysis in Early Müllerian Serous Carcinogenesis.

    Science.gov (United States)

    Nafisi, Houman; Ghorab, Zeina; Ismill, Nadia; Dubé, Valerie; Plotkin, Anna; Han, Guangming; Cesari, Matthew; Lu, Fang-I; Saad, Reda; Khalifa, Mahmoud; Nofech-Mozes, Sharon

    2015-09-01

    Studies on the immunophenotypes of early forms of serous carcinoma arising from female genital tract are limited. We aimed to examine p53, p16(Ink4a), estrogen receptor (ER), progesterone receptor (PR), ERBB2, WT1, and Ki-67 protein expression in endometrial intraepithelial carcinoma (n=29), serous tubal intraepithelial lesion (n=4) and carcinoma (STIC, n=10), and the putative precursor p53 signature (n=11). Among endometrial intraepithelial carcinoma, 80% demonstrated p53 overexpression and 10% were consistent with a null phenotype. p16(Ink4a) immunostaining were observed in all endometrial intraepithelial carcinoma cases. ER, PR, ERBB2, and WT1 were positive in 54%, 25%, 11%, and 18% of cases, respectively. STIC cases demonstrated p53 overexpression and null phenotype in 90% and 10%, respectively. All STIC cases were p16(Ink4a) and WT1 positive, whereas ER and PR were positive in 70% and 20%, respectively. All STICs were negative for ERBB2. Among serous tubal intraepithelial lesion cases, 75% demonstrated p53 overexpression and 25% a null phenotype. p53 was positive in all 11 p53 signature cases, whereas p16(Ink4a) was universally negative. Finally, ER and PR were positive in 100% and 73% of p53 signature cases, respectively. These results suggest that p16(Ink4a) has a role in early Müllerian serous carcinogenesis but is absent in the earliest noncommitted lesion. p16(Ink4a) immunohistochemistry can be used as an adjunct confirmatory tool in p53-null cases with limited surface area.

  16. Relationship to carcinogenesis of repetitive low-dose radiation exposure

    International Nuclear Information System (INIS)

    Ootsuyama, Akira

    2016-01-01

    We studied the carcinogenic effects caused by repetitive irradiation at a low dose, which has received attention in recent years, and examined the experimental methods used to evaluate radiation-induced carcinogenesis. For this experiment, we selected a mouse with as few autochthonous cancers as possible. Skin cancer was selected as the target for analysis, because it is a rare cancer in mice. Beta-rays were selected as the radiation source. The advantage of using beta-rays is weaker penetration power into tissues, thus protecting organs, such as the digestive and hematogenous organs. The benefit of our experimental method is that only skin cancer requires monitoring, and it is possible to perform long-term experiments. The back skin of mice was exposed repetitively to beta-rays three times a week until the occurrence of cancer or death, and the dose per exposure ranged from 0.5 to 11.8 Gy. With the high-dose range (2.5-11.8 Gy), the latency period and carcinogenic rate were almost the same in each experimental group. When the dose was reduced to 1-1.5 Gy, the latency period increased, but the carcinogenic rate remained. When the dose was further reduced to 0.5 Gy, skin cancer never happened, even though we continued irradiation until death of the last mouse in this group. The lifespan of 0.5 Gy group mice was the same as that of the controls. We showed that the 0.5 Gy dose did not cause cancer, even in mice exposed repetitively throughout their life span, and thus refer to 0.5 Gy as the threshold-like dose. (author)

  17. Colorectal carcinogenesis: Review of human and experimental animal studies

    Directory of Open Access Journals (Sweden)

    Tanaka Takuji

    2009-01-01

    Full Text Available This review gives a comprehensive overview of cancer development and links it to the current understanding of tumorigenesis and malignant progression in colorectal cancer. The focus is on human and murine colorectal carcinogenesis and the histogenesis of this malignant disorder. A summary of a model of colitis-associated colon tumorigenesis (an AOM/DSS model will also be presented. The earliest phases of colorectal oncogenesis occur in the normal mucosa, with a disorder of cell replication. The large majority of colorectal malignancies develop from an adenomatous polyp (adenoma. These can be defined as well-demarcated masses of epithelial dysplasia, with uncontrolled crypt cell proliferation. When neoplastic cells pass through the muscularis mucosa and infiltrate the submucosa, they are malignant. Carcinomas usually originate from pre-existing adenomas, but this does not imply that all polyps undergo malignant changes and does not exclude de novo oncogenesis. Besides adenomas, there are other types of pre-neoplasia, which include hyperplastic polyps, serrated adenomas, flat adenomas and dysplasia that occurs in the inflamed colon in associated with inflammatory bowel disease. Colorectal neoplasms cover a wide range of pre-malignant and malignant lesions, many of which can easily be removed during endoscopy if they are small. Colorectal neoplasms and/or pre-neoplasms can be prevented by interfering with the various steps of oncogenesis, which begins with uncontrolled epithelial cell replication, continues with the formation of adenomas and eventually evolves into malignancy. The knowledge described herein will help to reduce and prevent this malignancy, which is one of the most frequent neoplasms in some Western and developed countries.

  18. Interaction between APC and Fen1 during breast carcinogenesis.

    Science.gov (United States)

    Narayan, Satya; Jaiswal, Aruna S; Law, Brian K; Kamal, Mohammad A; Sharma, Arun K; Hromas, Robert A

    2016-05-01

    Aberrant DNA base excision repair (BER) contributes to malignant transformation. However, inter-individual variations in DNA repair capacity plays a key role in modifying breast cancer risk. We review here emerging evidence that two proteins involved in BER - adenomatous polyposis coli (APC) and flap endonuclease 1 (Fen1) - promote the development of breast cancer through novel mechanisms. APC and Fen1 expression and interaction is increased in breast tumors versus normal cells, APC interacts with and blocks Fen1 activity in Pol-β-directed LP-BER, and abrogation of LP-BER is linked with cigarette smoke condensate-induced transformation of normal breast epithelial cells. Carcinogens increase expression of APC and Fen1 in spontaneously immortalized human breast epithelial cells, human colon cancer cells, and mouse embryonic fibroblasts. Since APC and Fen1 are tumor suppressors, an increase in their levels could protect against carcinogenesis; however, this does not seem to be the case. Elevated Fen1 levels in breast and lung cancer cells may reflect the enhanced proliferation of cancer cells or increased DNA damage in cancer cells compared to normal cells. Inactivation of the tumor suppressor functions of APC and Fen1 is due to their interaction, which may act as a susceptibility factor for breast cancer. The increased interaction of APC and Fen1 may occur due to polypmorphic and/or mutational variation in these genes. Screening of APC and Fen1 polymorphic and/or mutational variations and APC/Fen1 interaction may permit assessment of individual DNA repair capability and the risk for breast cancer development. Such individuals might lower their breast cancer risk by reducing exposure to carcinogens. Stratifying individuals according to susceptibility would greatly assist epidemiologic studies of the impact of suspected environmental carcinogens. Additionally, a mechanistic understanding of the interaction of APC and Fen1 may provide the basis for developing new and

  19. Biogenic silica fibre promotes carcinogenesis in mouse skin.

    Science.gov (United States)

    Bhatt, T; Coombs, M; O'Neill, C

    1984-10-15

    Silica fibres derived from plants are common contaminants of human diet in certain regions of the world where oesophageal cancer reaches extremely high incidences. We show here that one of these types of fibre (derived from Phalaris canariensis L) promotes the occurrence of tumours in the skin of mice initiated with a polycyclic carcinogen. Three experiments are described. In the first, the grain which bears these fibres was added to the diet. This did not result in any abnormality in any part of the gastrointestinal tract, but there was a significant induction of tumours in the skin around the mouth and nose; these were the areas of the body surface which most frequently came into contact with the grain. In the second experiment, the mice were separated from the grain by an intervening wire gauze barrier; a similar number of tumours appeared on initiated mice treated in this way. In this case, contact now occurred most frequently on the dorsal surface, which was rubbed against the gauze barrier, and it was on this surface that the tumours appeared. No tumours appeared if the grain was removed. In the third experiment, pure fibres were isolated from the surface of the grain and boiled in strong nitric acid so as to remove any organic material. When these acid-cleaned fibres were applied to the initiated skin with light pressure, they promoted carcinogenesis in the same way as croton oil. In each experiment the majority of tumours produced were benign neoplasms, together with at least one squamous carcinoma. It seems possible that the size and shape of these fibres are the critical properties determining their promoting activity. Their mean diameter is 15 microns, their modal length close to 200 microns, and they are sharply pointed with a tip diameter of 0.5 micron.

  20. Cell cycle progression, but not genotoxic activity, mainly contributes to citrinin-induced renal carcinogenesis

    International Nuclear Information System (INIS)

    Kuroda, Ken; Ishii, Yuji; Takasu, Shinji; Kijima, Aki; Matsushita, Kohei; Watanabe, Maiko; Takahashi, Haruo; Sugita-Konishi, Yoshiko; Sakai, Hiroki; Yanai, Tokuma; Nohmi, Takehiko; Ogawa, Kumiko; Umemura, Takashi

    2013-01-01

    Citrinin (CTN) is a food-contaminating mycotoxin that efficiently induces renal tumors in rats. However, the modes of carcinogenic action are still unknown, preventing assessment of the risks of CTN in humans. In the present study, the proliferative effects of CTN and its causal factors were investigated in the kidneys of gpt delta rats. In addition, three in vivo genotoxicity assays (reporter gene mutation using gpt delta rats and comet and micronucleus assays using F344 rats) were performed to clarify whether CTN was genotoxic in vivo. CTN was administrated at 20 and 40 mg/kg/day, the higher dose being the maximal tolerated dose and a nearly carcinogenic dose. In the kidney cortex of gpt delta rats, significant increases in the labeling indices of proliferating cell nuclear antigen (PCNA)-positive cells were observed at all doses of CTN. Increases in the mRNA expression levels of Ccna2, Ccnb1, Ccne1, and its transcription factor E2f1 were also detected, suggesting induction of cell cycle progression at all tested doses of CTN. However, histopathological changes were found only in rats treated with the higher dose of CTN, which was consistent with increases in the mRNA expression levels of mitogenic factors associated with tissue damage/regeneration, such as Hgf and Lcn2, at the same dose. Thus, the proliferative effects of CTN may result not only from compensatory reactions, but also from direct mitogenic action. Western blot analysis showed that ERK phosphorylation was increased at all doses, implying that cell cycle progression may be mediated by activation of the ERK pathway. On the other hand, in vivo genotoxicity analyses were negative, implying that CTN did not have the potential for inducing DNA damage, gene mutations, or chromosomal aberrations. The overall data clearly demonstrated the molecular events underlying CTN-induced cell cycle progression, which could be helpful to understand CTN-induced renal carcinogenesis

  1. Comparative evaluation of antiproliferative, antiangiogenic and apoptosis inducing potential of black tea polyphenols in the hamster buccal pouch carcinogenesis model

    Directory of Open Access Journals (Sweden)

    Prathiba Duvuru

    2007-01-01

    Full Text Available Abstract Background To evaluate the relative chemopreventive efficacy of two black tea polyphenols, Polyphenon-B [P-B] and BTF-35 on 7,12-dimethylbenz [a]anthracene (DMBA-induced hamster buccal pouch (HBP carcinogenesis. Methods Hamsters were divided into 6 groups. The right buccal pouches of animals in groups 1–3 were painted with 0.5% of DMBA three times a week for 14 weeks. While hamsters in group 1 received no further treatment, animals in groups 2 and 3 received diet containing 0.05% P-B and BTF-35 respectively, four weeks before DMBA painting that was continued until the end of the experiments. Animals in groups 4 and 5 were given P-B and BTF-35 alone respectively as in groups 2 and 3. Group 6 animals served as the untreated control. All the animals were sacrificed after 18 weeks. The expression of p21, cyclin D1, glutathione S-transferase pi (GST-P, nuclear factor kappa B (NF-κB, Bcl-2, Bax, cytochrome C, caspase-3, caspase-9, poly(ADP-ribose polymerase (PARP, cytokeratins and vascular endothelial growth factor (VEGF was analysed by RT-PCR, immunohistochemical and Western blot analyses. Results DMBA treated animals developed buccal pouch carcinomas that displayed increased expression of p21, cyclin D1, GST-P, NF-κB, cytokeratins, VEGF and Bcl-2 with decreased expression of Bax, cytochrome C, caspase-3, caspase-9, and PARP. Dietary administration of both P-B and BTF-35 reduced the incidence of DMBA-induced HBP carcinomas by modulating markers of cell proliferation, cell survival, tumour infiltration, angiogenesis, and apoptosis. Conclusion The results of the present study provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. The greater efficacy of BTF-35 in inhibiting HBP carcinogenesis and modulating multiple molecular targets may have a potential role in the prevention of oral cancer.

  2. Chemical and Molecular Biological Aspects of Alkylhydrazine-Induced Carcinogenesis in Human Cells in Vitro. Revised

    Science.gov (United States)

    1984-04-01

    DMH) and the metabolite methylazoxymethanol acetate ( MAMA ) have been shown to induce cancer in vivo in several species of rodents producing a variety of...The Pharmaceutical and Toxicological Research Institute (PTRI) I Co-Director, Developmental Chemotherapeutics, OSU Comprehensive Cancer Center...NNL[Methyl-l 4 C] I -dimethylhydrazine) of high specific activity Chapter III - Synthesis of (14 C] -labeled methylazoxymethanol 13 acetate ( MAMA ) of

  3. Histological and molecular analysis of Fallopian tube precursors in pelvic serous carcinogenesis

    NARCIS (Netherlands)

    Bijron, J.G.

    2012-01-01

    Epithelial ovarian cancer is the second most common gynaecological cancer, but has the highest fatality-to-case rate, which can be primarily attributed to diagnosis delay due to rapid disease progression and location. This is especially true for the serous subtype, which shows some form of pelvic

  4. Concepts of formal concept analysis

    Science.gov (United States)

    Žáček, Martin; Homola, Dan; Miarka, Rostislav

    2017-07-01

    The aim of this article is apply of Formal Concept Analysis on concept of world. Formal concept analysis (FCA) as a methodology of data analysis, information management and knowledge representation has potential to be applied to a verity of linguistic problems. FCA is mathematical theory for concepts and concept hierarchies that reflects an understanding of concept. Formal concept analysis explicitly formalizes extension and intension of a concept, their mutual relationships. A distinguishing feature of FCA is an inherent integration of three components of conceptual processing of data and knowledge, namely, the discovery and reasoning with concepts in data, discovery and reasoning with dependencies in data, and visualization of data, concepts, and dependencies with folding/unfolding capabilities.

  5. O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis.

    Science.gov (United States)

    Duan, Fangfang; Wu, Hao; Jia, Dongwei; Wu, Weicheng; Ren, Shifang; Wang, Lan; Song, Shushu; Guo, Xinying; Liu, Fenglin; Ruan, Yuanyuan; Gu, Jianxin

    2018-06-01

    Aberrant oncogenic mRNA translation and protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal receptor for activated C-kinase 1 (RACK1) promoted chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis. The site(s) of RACK1 for O-GlcNAcylation was mapped by mass spectrometry analysis. HCC cell lines were employed to examine the effects of RACK1 O-GlcNAcylation on the translation of oncogenic factors and behaviors of tumor cells in vitro. Transgenic knock-in mice were used to detect the role of RACK1 O-GlcNAcylation in modulating HCC tumorigenesis in vivo. The correlation of RACK1 O-GlcNAcylation with tumor progression and relapse were analyzed in clinical HCC samples. We found that ribosomal RACK1 was highly modified by O-GlcNAc at Ser122. O-GlcNAcylation of RACK1 enhanced its protein stability, ribosome binding and interaction with PKCβII (PRKCB), leading to increased eukaryotic translation initiation factor 4E phosphorylation and translation of potent oncogenes in HCC cells. Genetic ablation of RACK1 O-GlcNAcylation at Ser122 dramatically suppressed tumorigenesis, angiogenesis, and metastasis in vitro and in diethylnitrosamine (DEN)-induced HCC mouse model. Increased RACK1 O-GlcNAcylation was also observed in HCC patient samples and correlated with tumor development and recurrence after chemotherapy. These findings demonstrate that RACK1 acts as key mediator linking O-GlcNAc metabolism to cap-dependent translation during HCC tumorigenesis. Targeting RACK1 O-GlcNAcylation provides promising options for HCC treatment. O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 at the amino acid serine122 promotes its stability, ribosome localization and interaction

  6. Contribution to the study of markers in lungs carcinogenesis and analysis of factors predicting the benefit of chemotherapy

    International Nuclear Information System (INIS)

    Olaussen, K.A.

    2006-06-01

    A better definition of early bio markers in lung carcinogenesis should enhance the development of molecular means to perform screening, diagnostic, and chemo-prevention of patients at high risk of lung cancer. We studied epigenetic deregulation of multiple promoters (p16(INK4a), HOX A9, MAGE A 1 et MAGE B2) in sputum samples from smokers at high risk and from patients with non-small cell lung cancer (N.S.C.L.C.). This molecular test, based on easily accessible sample,s can be modulated according to the aims of the investigator (e.g. screening or confirmation of diagnosis). Secondly, we have studied two candidate proteins as predictive markers of the benefit of adjuvant chemotherapy in patients with resected lung cancer. The multivariate analysis shows that tumor expression of the catalytic sub-unit of telomerase is not able to predict survival in patients included in the lAL T study' of adjuvant chemotherapy. However, tumor expression of the DNA repair protein ERCC1 identifies a sub-group of patients (ERCC1 negative) whose chances of survival are increased by 35% by means of cisplatin-based adjuvant chemotherapy. Further, tumor ERCC1 expression has a positive prognostic value in the non-treated control group. The need for a deeper understanding in cancerology of the physiological role of the ERCC1 endonuclease is discussed in this thesis. (author)

  7. Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

    Science.gov (United States)

    Lazennec, Gwendal

    2006-01-01

    Ovarian cancer is one of the leading cause of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed. PMID:16399219

  8. Estimating radiation-induced cancer risk using MVK two-stage model for carcinogenesis

    International Nuclear Information System (INIS)

    Kai, M.; Kusama, T.; Aoki, Y.

    1993-01-01

    Based on the carcinogenesis model as proposed by Moolgavkar et al., time-dependent relative risk models were derived for projecting the time variation in excess relative risk. If it is assumed that each process is described by time-independent linear dose-response relationship, the time variation in excess relative risk is influenced by the parameter related with the promotion process. The risk model based carcinogenesis theory would play a marked role in estimating radiation-induced cancer risk in constructing a projection model or transfer model

  9. [Histologic study on impeding leukoplakia carcinogenesis of golden hamster cheek pouch about Erigeron breviscapus (Vant) Hand-Mazz].

    Science.gov (United States)

    Zhou, C T; Zhong, W J; Hua, L; Hu, H F; Jin, Z G

    2000-06-01

    To observe the effect of Erigeron breviscapus (Vant) Hand Mazz (HEr) in impeding oral leukoplakia carcinogenesis, and to seek effective Chinese herb medicine that can impede precarcinoma of oral mucosas. 132 golden hamsters were randomly divided into model group (60 animals), HEr group (60 animals), and control group 12 animals. Salley's leukoplakia carcinogenesis model of golden hamster cheek pouch was used in this study. HEr was injected into the stomach to impede evolution of carcinogenesis. Pathological specimens were observed via naked eye and light microscope between model group and HEr group. Results were compared. Observation via naked-eye showed that leukoplakia rate of HEr group (18.2%) was lower than that of model group (27.3%). Observation via light microscope showed that carcinogenesis rate descended one fold and displasia rate descended 0.4 fold in HEr group. HEr has exact effect in impeding leukoplakia carcinogenesis.

  10. Participation in a Year-Long CURE Embedded into Major Core Genetics and Cellular and Molecular Biology Laboratory Courses Results in Gains in Foundational Biological Concepts and Experimental Design Skills by Novice Undergraduate Researchers†

    Science.gov (United States)

    Peteroy-Kelly, Marcy A.; Marcello, Matthew R.; Crispo, Erika; Buraei, Zafir; Strahs, Daniel; Isaacson, Marisa; Jaworski, Leslie; Lopatto, David; Zuzga, David

    2017-01-01

    This two-year study describes the assessment of student learning gains arising from participation in a year-long curriculum consisting of a classroom undergraduate research experience (CURE) embedded into second-year, major core Genetics and Cellular and Molecular Biology (CMB) laboratory courses. For the first course in our CURE, students used micro-array or RNAseq analyses to identify genes important for environmental stress responses by Saccharomyces cerevisiae. The students were tasked with creating overexpressing mutants of their genes and designing their own original experiments to investigate the functions of those genes using the overexpression and null mutants in the second CURE course. In order to evaluate student learning gains, we employed three validated concept inventories in a pretest/posttest format and compared gains on the posttest versus the pretest with student laboratory final grades. Our results demonstrated that there was a significant correlation between students earning lower grades in the Genetics laboratory for both years of this study and gains on the Genetics Concept Assessment (GCA). We also demonstrated a correlation between students earning lower grades in the Genetics laboratory and gains on the Introductory Molecular and Cell Biology Assessment (IMCA) for year 1 of the study. Students furthermore demonstrated significant gains in identifying the variable properties of experimental subjects when assessed using the Rubric for Experimental (RED) design tool. Results from the administration of the CURE survey support these findings. Our results suggest that a year-long CURE enables lower performing students to experience greater gains in their foundational skills for success in the STEM disciplines. PMID:28904646

  11. Repair and regeneration: opportunities for carcinogenesis from tissue stem cells

    OpenAIRE

    Perryman, Scott V; Sylvester, Karl G

    2007-01-01

    This review will discuss the mechanisms of repair and regeneration in various tissue types and how dysregulation of these mechaisms may lead to cancer. Normal homeostasis involves a careful balance between cell loss and cell renewal. Stem and progenitor cells perform these biologic processes as the functional units of regeneration during both tissue homeostasis and repair. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue led to the conc...

  12. Combination of computational methods, adsorption isotherms and selectivity tests for the conception of a mixed non-covalent-semi-covalent molecularly imprinted polymer of vanillin.

    Science.gov (United States)

    Puzio, Kinga; Delépée, Raphaël; Vidal, Richard; Agrofoglio, Luigi A

    2013-08-06

    A novel molecularly imprinted polymer (MIP) for vanillin was prepared by photo initiated polymerization in dichloromethane using a mixed semi-covalent and non-covalent imprinting strategy. Taking polymerisable syringaldehyde as "dummy" template, acrylamide was chosen as functional monomer on B3LYP/6-31+G(d,p) density functional theory computational method basis with counterpoise. The binding parameters for the recognition of vanillin on imprinted polymers were studied with three different isotherm models (Langmuir, bi-Langmuir and Langmuir-Freundlich) and compared. The results indicate an heterogeneity of binding sites. It was found and proved by DFT calculations that the specific binding of vanillin in the cavities is due to non-covalent interactions of the template with the hydroxyphenyl- and the amide-moieties. The binding geometry of vanillin in the MIP cavity was also modelled. The obtained MIP is highly specific for vanillin (with an imprinting factor of 7.4) and was successfully applied to the extraction of vanillin from vanilla pods, red wine spike with vanillin, natural and artificial vanilla sugar with a recovery of 80%. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. Endocrine disruptors in female reproductive tract development and carcinogenesis

    OpenAIRE

    Ma, Liang

    2009-01-01

    Growing concerns over endocrine disrupting chemicals (EDCs) and their effects on human fetal development and adult health have promoted research into the underlying molecular mechanisms of endocrine disruption. Gene targeting technology has allowed insight into the genetic pathways governing reproductive tract development and how exposure to EDCs during a critical developmental window can alter reproductive tract development, potentially forming the basis for adult diseases. This review prima...

  14. Mammalian cell transformation: Mechanisms of carcinogenesis and assays for carcinogens

    International Nuclear Information System (INIS)

    Barrett, J.C.; Tennant, R.W.

    1985-01-01

    This book contains nine sections, each consisting of several papers. The section titles are: Molecular Changes in Cell Transformation; Differentiation, Growth Control, and Cell Transformation; Mutagenesis and Cell Transformation; Tumor Promotion and Cell Transformation; Mechanisms of Transformation of Human Fibroblasts; Mechanisms of Transformation of Epithelial Cells; Mechanisms of C 3 H 10T12 Cell Transformation; Mechanisms of Radiation-Induced Cell Transformation; and Use of Cell Transformation Assays for Carcinogen Testing

  15. Lactobacillus salivarius Ren prevent the early colorectal carcinogenesis in 1, 2-dimethylhydrazine-induced rat model.

    Science.gov (United States)

    Zhu, J; Zhu, C; Ge, S; Zhang, M; Jiang, L; Cui, J; Ren, F

    2014-07-01

    The objective of this study was to investigate the impact of Lactobacillus salivarius Ren (LS) on modulating colonic micro flora structure and influencing host colonic health in a rat model with colorectal precancerous lesions. Male F344 rats were injected with 1, 2-dimethylhydrazine (DMH) and treated with LS of two doses (5 × 10(8) and 1 × 10(10) CFU kg(-1) body weight) for 15 weeks. The colonic microflora profiles, luminal metabolites, epithelial proliferation and precancerous lesions [aberrant crypt foci (ACF)] were determined. A distinct segregation of colonic microflora structures was observed in LS-treated group. The abundance of one Prevotella-related strain was increased, and the abundance of one Bacillus-related strain was decreased by LS treatment. These changes were accompanied by increased short-chain fatty acid levels and decreased azoreductase activity. LS treatment also reduced the number of ACF by c. 40% and suppressed epithelial proliferation. Lactobacillus salivarius Ren improved the colonic microflora structures and the luminal metabolisms in addition preventing the early colorectal carcinogenesis in DMH-induced rat model. Colonic microflora is an important factor in colorectal carcinogenesis. Modulating the structural shifts of microflora may provide a novel option for preventing colorectal carcinogenesis. This study suggested a potential probiotic-based approach to modulate the intestinal microflora in the prevention of colorectal carcinogenesis. © 2014 The Society for Applied Microbiology.

  16. E-cadherin Mediates the Preventive Effect of Vitamin D3 in Colitis-associated Carcinogenesis.

    Science.gov (United States)

    Xin, Yu; He, Longmei; Luan, Zijian; Lv, Hong; Yang, Hong; Zhou, Ying; Zhao, Xinhua; Zhou, Weixun; Yu, Songlin; Tan, Bei; Wang, Hongying; Qian, Jiaming

    2017-09-01

    Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. Here, we evaluated if vitamin D3 has a preventive effect on colitis-associated carcinogenesis. Administration of azoxymethane (AOM), followed with dextran sulfate sodium (DSS), was used to simulate colitis-associated colon cancer in mice. The supplement of vitamin D3 at different dosages (15, 30, 60 IU·g·w), started before AOM or immediately after DSS treatment (post 60), was sustained to the end of the experiment. Dietary vitamin D3 significantly reduced the number of tumors and tumor burden in a dose-dependent manner. Of note, vitamin D3 in high doses showed significant preventive effects on carcinogenesis regardless of administration before or after AOM-DSS treatment. Cell proliferation decreased in vitamin D3 groups compared with the control group after inhibition of expression of β-catenin and its downstream target gene cyclin D1 in the colon. In vitro, vitamin D3 reduced the transcriptional activity and nuclear level of β-catenin, and it also increased E-cadherin expression and its binding affinity for β-catenin. Moreover, repression of E-cadherin was rescued by supplemental vitamin D3 in mouse colons. Taken together, our results indicate that vitamin D3 effectively suppressed colonic carcinogenesis in the AOM-DSS mouse model. Our findings further suggest that upregulation of E-cadherin contributes to the preventive effect of vitamin D3 on β-catenin activity.

  17. Role of Stat in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

    International Nuclear Information System (INIS)

    Macias, E.; Rao, D.; DiGiovanni, J.; DiGiovanni, J.; DiGiovanni, J.

    2013-01-01

    Signal transducer and activator of transcription 3 (Stat) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat-deficient mice have revealed that Stat plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat-deficient mouse models has demonstrated that Stat is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat in skin tumor progression. Studies using similar Stat-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat is an attractive target for skin cancer prevention and treatment.

  18. Epidemiological studies on radiation carcinogenesis in human populations following acute exposure: nuclear explosions and medical radiation

    International Nuclear Information System (INIS)

    Fabrikant, J.I.

    1981-05-01

    The current knowledge of the carcinogenic effect of radiation in man is considered. The discussion is restricted to dose-incidence data in humans, particularly to certain of those epidemiological studies of human populations that are used most frequently for risk estimation for low-dose radiation carcinogenesis in man. Emphasis is placed solely on those surveys concerned with nuclear explosions and medical exposures

  19. Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments

    International Nuclear Information System (INIS)

    Rajkumar, Lakshmanaswamy; Guzman, Raphael C; Yang, Jason; Thordarson, Gudmundur; Talamantes, Frank; Nandi, Satyabrata

    2004-01-01

    Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis. Seven-week-old virgin Lewis rats were given N-methyl-N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7–21 days by subcutaneous implantation of silastic capsules. In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers. The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations

  20. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria - A systematic review.

    Science.gov (United States)

    Dias-Jácome, Emanuel; Libânio, Diogo; Borges-Canha, Marta; Galaghar, Ana; Pimentel-Nunes, Pedro

    2016-09-01

    Helicobacter pylori is the strongest risk factor for gastric cancer. However, recent advances in DNA sequencing technology have revealed a complex microbial community in the stomach that could also contribute to the development of gastric cancer. The aim of this study was to present recent scientific evidence regarding the role of non-Helicobacter pylori bacteria in gastric carcinogenesis. A systematic review of original articles published in PubMed in the last ten years related to gastric microbiota and gastric cancer in humans was performed. Thirteen original articles were included. The constitution of gastric microbiota appears to be significantly affected by gastric cancer and premalignant lesions. In fact, differences in gastric microbiota have been documented, depending on Helicobacter pylori status and gastric conditions, such as non-atrophic gastritis, intestinal metaplasia and cancer. Gastric carcinogenesis can be associated with an increase in many bacteria (such as Lactobacillus coleohominis, Klebsiella pneumoniae or Acinetobacter baumannii) as well as decrease in others (such as Porphyromonas spp, Neisseria spp, Prevotella pallens or Streptococcus sinensis). However, there is no conclusive data that confirms if these changes in microbiota are a cause or consequence of the process of carcinogenesis. Even though there is limited evidence in humans, microbiota differences between normal individuals, pre-malignant lesions and gastric cancer could suggest a progressive shift in the constitution of gastric microbiota in carcinogenesis, possibly resulting from a complex cross-talk between gastric microbiota and Helicobacter pylori. However, further studies are needed to elucidate the specific role (if any) of different microorganisms.

  1. Mammary carcinogenesis in rats: basic facts and recent results in Brookhaven

    International Nuclear Information System (INIS)

    Shellabarger, C.J.; Stone, J.P.; Holtzman, s.

    1982-01-01

    Some research results from experiments investigating neutron-induced mammary carcinogenesis in rats are presented. The additive effects of neutrons and 3-methylcholanthrene on mammary adenocarcinoma were determined. Synergism between diethylstilbestrol and neutrons was likewise studied. Differences in mammary neoplastic response between strains of laboratory rats was also investigated

  2. Radiation carcinogenesis. Comprehensive three-year progress report, 1 May 1972--15 March 1976

    International Nuclear Information System (INIS)

    Warren, S.; Gates, O.

    1976-03-01

    Progress is reported on studies on the pathological effects of various doses of x radiation on rats and mice, with emphasis on radioinduced carcinogenesis in parabiont rats with one of the pair exposed to 1000 R of whole body x radiation and the other shielded. Results are included from studies on alterations in metabolic parameters and life span induced by irradiation

  3. Dietary fish oil (MaxEPA) enhances pancreatic carcinogenesis in azaserine-treated rats

    NARCIS (Netherlands)

    Appel, M.J.; Woutersen, R.A.

    1996-01-01

    In the present study the putative chemopreventive effect of dietary fish oil (MaxEPA) on azaserine-induced pancreatic carcinogenesis in rats was investigated. Groups of rats were maintained on a semipurified low-fat (LF; 5 wt%) diet or on semipurified high-fat (HF; 25 wt%) diets containing 5 wt%

  4. Null effect of dietary restriction on prostate carcinogenesis in the Wistar-Unilever rat.

    Science.gov (United States)

    McCormick, David L; Johnson, William D; Haryu, Todd M; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

    2007-01-01

    Chronic dietary restriction inhibits carcinogenesis in several sites in laboratory animals. To determine the effects of dietary restriction on prostate carcinogenesis, prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate (50 mg/day; 21 days); testosterone propionate (100 mg/kg/day; 3 days); N-methyl-N-nitrosourea [MNU; 30 mg/kg; single dose]; and testosterone (subcutaneous implants of 2 pellets containing 40 mg each). Dietary restriction (0% [ad libitum control], 15%, or 30%) was initiated 2 wk post-MNU, and continued until study termination at 12 mo. Dietary restriction induced a rapid suppression of body weight gain but conferred no protection against prostate carcinogenesis. 74% of carcinogen-treated ad libitum controls developed accessory sex gland cancers, versus cancer incidences of 64% and 72% in groups restricted by 15% and 30%, respectively. Similarly, 44% of dietary controls developed cancers limited to the dorsolateral/prostate, versus incidences of 45% and 53% in groups restricted by 15% and 30%. The results of the present study do not support the hypothesis that prostate carcinogenesis can be prevented by reducing caloric intake. Reducing mean body weight by up to 25% through chronic dietary restriction has no effect on the induction of prostate cancers in the Wistar-Unilever rat model.

  5. Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Labib, Sarah, E-mail: Sarah.Labib@hc-sc.gc.ca; Guo, Charles H., E-mail: Charles.Guo@hc-sc.gc.ca; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca; Yauk, Carole L., E-mail: Carole.Yauk@hc-sc.gc.ca; White, Paul A., E-mail: Paul.White@hc-sc.gc.ca; Halappanavar, Sabina, E-mail: Sabina.Halappanavar@hc-sc.gc.ca

    2013-12-01

    Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I

  6. Molecular similarity measures.

    Science.gov (United States)

    Maggiora, Gerald M; Shanmugasundaram, Veerabahu

    2011-01-01

    Molecular similarity is a pervasive concept in chemistry. It is essential to many aspects of chemical reasoning and analysis and is perhaps the fundamental assumption underlying medicinal chemistry. Dissimilarity, the complement of similarity, also plays a major role in a growing number of applications of molecular diversity in combinatorial chemistry, high-throughput screening, and related fields. How molecular information is represented, called the representation problem, is important to the type of molecular similarity analysis (MSA) that can be carried out in any given situation. In this work, four types of mathematical structure are used to represent molecular information: sets, graphs, vectors, and functions. Molecular similarity is a pairwise relationship that induces structure into sets of molecules, giving rise to the concept of chemical space. Although all three concepts - molecular similarity, molecular representation, and chemical space - are treated in this chapter, the emphasis is on molecular similarity measures. Similarity measures, also called similarity coefficients or indices, are functions that map pairs of compatible molecular representations that are of the same mathematical form into real numbers usually, but not always, lying on the unit interval. This chapter presents a somewhat pedagogical discussion of many types of molecular similarity measures, their strengths and limitations, and their relationship to one another. An expanded account of the material on chemical spaces presented in the first edition of this book is also provided. It includes a discussion of the topography of activity landscapes and the role that activity cliffs in these landscapes play in structure-activity studies.

  7. Molecular basis of colorectal cancer: Towards an individualized management?

    Directory of Open Access Journals (Sweden)

    J. Perea

    Full Text Available Colorectal cancer (CRC has become a highly relevant condition nowadays. In this respect, advances in the understanding of its molecular basis are key for an adequate management. From the time when the adenoma-carcinoma sequence was formulated as a carcinogenesis model to this day, when, among other things, three major carcinogenic pathways have been identified, the CRC concept has evolved from that of a single disease to the notion that each CRC is a differentiated condition in itself. The suppressor or chromosome instability pathway, the mutator or microsatellite instability pathway, and the methylator or CpG island methylation pathway allow various phenotypes to be identified within CRC. Similarly, the presence of different changes in certain genes confers several behaviors on CRC from both the prognostic and responsive standpoints to specific therapies. However, this apparent complexity does help develop the clinical management of this disease through the identification of novel, more specific therapy targets, and also markers for various behaviors within the condition, which will most likely lead us to an individualized management for these patients.

  8. Induction of human breast cell carcinogenesis by triclocarban and intervention by curcumin

    Energy Technology Data Exchange (ETDEWEB)

    Sood, Shilpa; Choudhary, Shambhunath; Wang, Hwa-Chain Robert, E-mail: hcrwang@utk.edu

    2013-09-06

    Highlights: •Triclocarban exposure induces breast epithelial cell carcinogenesis. •Triclocarban induces the Erk–Nox pathway, ROS elevation, and DNA damage. •Physiological doses of triclocarban induce cellular carcinogenesis. •Non-cytotoxic curcumin blocks triclocarban-induced carcinogenesis and pathways. -- Abstract: More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens and co-carcinogens. To identify co-carcinogens with abilities to induce cellular pre-malignancy, we studied the activity of triclocarban (TCC), an antimicrobial agent commonly used in household and personal care products. Here, we demonstrated, for the first time, that chronic exposure to TCC at physiologically-achievable nanomolar concentrations resulted in progressive carcinogenesis of human breast cells from non-cancerous to pre-malignant. Pre-malignant carcinogenesis was measured by increasingly-acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth and increased cell proliferation, without acquisition of cellular tumorigenicity. Long-term TCC exposure also induced constitutive activation of the Erk–Nox pathway and increases of reactive oxygen species (ROS) in cells. A single TCC exposure induced transient induction of the Erk–Nox pathway, ROS elevation, increased cell proliferation, and DNA damage in not only non-cancerous breast cells but also breast cancer cells. Using these constitutively- and transiently-induced changes as endpoints, we revealed that non-cytotoxic curcumin was effective in intervention of TCC-induced cellular pre-malignancy. Our results lead us to suggest that the co-carcinogenic potential of TCC should be seriously considered in epidemiological studies to reveal the significance of TCC in the development of sporadic breast cancer. Using TCC-induced transient and constitutive endpoints as targets will likely help identify non-cytotoxic preventive

  9. COMET concept

    International Nuclear Information System (INIS)

    Alsmeyer, H.; Tromm, W.

    1995-01-01

    Studies of the COMET core catcher concept developed for a future PWR have been continued. The concept is based on the spreading of a core melt on a sacrificial layer and its erosion, until a subsequent addition of water from below causes a fragmentation of the melt. A porous solidification of the melt would then admit a complete flooding within a short period. (orig.)

  10. Concept Mapping

    Science.gov (United States)

    Technology & Learning, 2005

    2005-01-01

    Concept maps are graphical ways of working with ideas and presenting information. They reveal patterns and relationships and help students to clarify their thinking, and to process, organize and prioritize. Displaying information visually--in concept maps, word webs, or diagrams--stimulates creativity. Being able to think logically teaches…

  11. Management concepts.

    Science.gov (United States)

    Bittner, Rhonda

    2006-01-01

    Management concepts evolve through time. Health care managers can learn new concepts by evaluating classical management strategies, as well as modern-day strategies. Focusing on quality improvement and team building can help managers align the goals of their departments with the goals of the organization, consequently improving patient care.

  12. Lateral Concepts

    DEFF Research Database (Denmark)

    Gad, Christopher; Bruun Jensen, casper

    2016-01-01

    This essay discusses the complex relation between the knowledges and practices of the researcher and his/her informants in terms of lateral concepts. The starting point is that it is not the prerogative of the (STS) scholar to conceptualize the world; all our “informants” do it too. This creates...... the possibility of enriching our own conceptual repertoires by letting them be inflected by the concepts of those we study. In a broad sense, the lateral means that there is a many-to-many relation between domains of knowledge and practice. However, each specific case of the lateral is necessarily immanent...... to a particular empirical setting and form of inquiry. In this sense lateral concepts are radically empirical since it locates concepts within the field. To clarify the meaning and stakes of lateral concepts, we first make a contrast between lateral anthropology and Latour’s notion of infra-reflexivity. We end...

  13. Concept theory

    DEFF Research Database (Denmark)

    Hjørland, Birger

    2009-01-01

      Concept theory is an extremely broad, interdisciplinary and complex field of research related to many deep fields with very long historical traditions without much consensus. However, information science and knowledge organization cannot avoid relating to theories of concepts. Knowledge...... organizing systems (e.g. classification systems, thesauri and ontologies) should be understood as systems basically organizing concepts and their semantic relations. The same is the case with information retrieval systems. Different theories of concepts have different implications for how to construe......, evaluate and use such systems. Based on "a post-Kuhnian view" of paradigms this paper put forward arguments that the best understanding and classification of theories of concepts is to view and classify them in accordance with epistemological theories (empiricism, rationalism, historicism and pragmatism...

  14. Chromosomal damage as markers of genotoxic effect and carcinogenesis

    Czech Academy of Sciences Publication Activity Database

    Vodička, Pavel; Polívková, Z.; Mušák, L.; Dušinská, M.; Vodenková, Soňa; Vymetálková, Veronika; Kroupa, Michal; Vodičková, Ludmila; Demová, H.; Poláková, Veronika; Ambruš, M.; Kumar, R.; Hemminki, K.

    2015-01-01

    Roč. 116, č. 2015 (2015), s. 56-63 ISSN 1214-6994. [15th Central European Lung Cancer Conference including Best of WCLC 2015. 28.11.2015-30.11.2015, Praha] R&D Projects: GA ČR(CZ) GAP304/12/1585; GA ČR(CZ) GA15-14789S; GA MZd(CZ) NT14329; GA MZd(CZ) NT14056; GA MŠk LH13061; GA MŠk(CZ) LD14050 Institutional support: RVO:68378041 Keywords : chromosomal aberrations * malignant transformation * incident cancer patients * cancer risk * CIN * DNA repair Subject RIV: EB - Genetics ; Molecular Biology

  15. Conception of Brownian coil

    OpenAIRE

    Zhang, Jiayuan

    2018-01-01

    This article proposes a conception of Brownian coil. Brownian coil is a tiny coil with the same size of pollen. Once immersed into designed magnetic field and liquid, the coil will be moved and deformed macroscopically, due to the microscopic thermodynamic molecular collisions. Such deformation and movement will change the magnetic flux through the coil, by which an ElectroMotive Force (EMF) is produced. In this work, Brownian heat exchanger and Brownian generator are further designed to tran...

  16. Dietary chlorophyllin abrogates TGFβ signaling to modulate the hallmark capabilities of cancer in an animal model of forestomach carcinogenesis.

    Science.gov (United States)

    Thiyagarajan, Paranthaman; Kavitha, Krishnamurthy; Thautam, Avaneesh; Dixit, Madhulika; Nagini, Siddavaram

    2014-07-01

    Transforming growth factor (TGF) β signaling pathway plays a central role in the regulation of a wide range of cellular processes involved in the acquisition of the malignant phenotype. The objective of the present study was to examine the effect of chlorophyllin, a semisynthetic derivative of chlorophyll on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)--induced rat forestomach carcinogenesis based on the modulation of TGFβ signaling and the downstream target genes associated with cell proliferation, apoptosis evasion, angiogenesis, invasion, and metastasis. We determined the effect of dietary chlorophyllin on TGFβ signaling and the downstream events-cell proliferation, apoptosis evasion, angiogenesis, invasion, and metastasis by semiquantitative and quantitative reverse transcription (RT)-PCR, Western blot, and immunohistochemical analyses. We further validated the inhibition of TGFβ signaling by chlorophyllin by performing molecular docking studies. We found that dietary supplementation of chlorophyllin at 4-mg/kg bw inhibits the development of MNNG-induced forestomach carcinomas by downregulating the expression of TGFβ RI, TGFβ RII, and Smad 2 and 4 and upregulating Smad 7, thereby abrogating canonical TGFβ signaling. Docking interactions also confirmed the inhibition of TGFβ signaling by chlorophyllin via inactivating TGFβ RI. Furthermore, attenuation of TGFβ signaling by chlorophyllin also blocked cell proliferation, angiogenesis, invasion, and metastasis, and induced mitochondria-mediated cell death. Dietary chlorophyllin that simultaneously abrogates TGFβ signaling pathway and the key hallmark events of cancer appear to be an ideal candidate for cancer chemoprevention.

  17. Molecular Biology of Pancreatic Cancer: How Useful Is It in Clinical Practice?

    OpenAIRE

    George H Sakorafas; Vasileios Smyrniotis

    2012-01-01

    Context During the recent two decades dramatic advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis. It is currently accepted that pancreatic cancer has a genetic component. The real challenge is now how these impressive advances could be used in clinical practice. Objective To critically present currently available data regarding clinical application of molecular biology in pancreatic cancer. Methods Reports about clinical implications of molecular bio...

  18. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices

    Directory of Open Access Journals (Sweden)

    Farrukh Aqil

    2017-02-01

    Full Text Available Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish rat model. Female ACI rats were given either control diet (AIN 93M or diet supplemented with 7.5% (w/w of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα. The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92

  19. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices.

    Science.gov (United States)

    Aqil, Farrukh; Jeyabalan, Jeyaprakash; Munagala, Radha; Ravoori, Srivani; Vadhanam, Manicka V; Schultz, David J; Gupta, Ramesh C

    2017-02-16

    Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% ( w / w ) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in

  20. Age dependencies in the modelling of radiation carcinogenesis

    International Nuclear Information System (INIS)

    Kellerer, A.M.; GSF, Neuherberg; Barclay, D.

    1992-01-01

    Models for the dose and age dependence of radiation induced cancer have been based primarily on the follow-up of the atomic bomb survivors. Two different concepts have been deduced for leukaemias and for other cancers. The excess leukaemias appear in a distinct temporal wave with a maximum 5 to 10 years after radiation exposure; the distribution is more narrow for younger ages, but there is little dependence of the total attributable risk on age at exposure. For other cancers the latent periods are longer and, according to the current interpretation, the excess rates are then proportional to the age specific spontaneous rates, so that most excess cases would arise at old age. The factors of proportionality, and thus the attributable risks, are assumed to be markedly higher for young ages at exposure. It is argued here, that there is no firm support for this interpretation. (author)

  1. Pathogenesis and biomarkers of carcinogenesis in ulcerative colitis

    DEFF Research Database (Denmark)

    Thorsteinsdottir, Sigrun; Gudjonsson, Thorkell; Nielsen, Ole Haagen

    2011-01-01

    on the current understanding of the pathogenesis of ulcerative colitis-associated colorectal cancer and how this knowledge can be transferred into patient management to assist clinicians and pathologists in identifying patients with ulcerative colitis who have an increased risk of colorectal cancer. Inflammation......One of the most serious complications of ulcerative colitis is the development of colorectal cancer. Screening patients with ulcerative colitis by standard histological examination of random intestinal biopsy samples might be inefficient as a method of cancer surveillance. This Review focuses......-driven mechanisms of DNA damage, including the generation and effects of reactive oxygen species, microsatellite instability, telomere shortening and chromosomal instability, are reviewed, as are the molecular responses to genomic stress. We also discuss how these mechanisms can be translated into usable biomarkers...

  2. Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.

    Science.gov (United States)

    Kirma, Nameer B; Tekmal, Rajeshwar R

    2012-09-01

    Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. EGFR Activation and Ultraviolet Light‐Induced Skin Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Taghrid B. El-Abaseri

    2007-01-01

    Full Text Available The epidermal growth factor receptor (EGFR regulates the proliferation of keratinocytes through multiple mechanisms that differ depending on the localization of the cell within the skin. Ultraviolet (UV irradiation, the main etiologic factor in the development of skin cancer, also activates the receptor. In this review, we discuss how the UV-induced activation of EGFR regulates the response of the skin to UV. UV-induced EGFR activation increases keratinocyte proliferation, suppresses apoptosis, and augments and accelerates epidermal hyperplasia in response to UV. Pharmacological inhibition of the UV-induced activation of EGFR in a genetically initiated mouse skin tumorigenesis model suppresses tumorigenesis and the activation of mitogen-activated protein (MAP kinases and phosphatidyl inositol-3-kinase (PI3K/AKT signaling pathways. EGFR has pleiotropic, complex, and cell-type-specific functions in cutaneous keratinocytes; suggesting that the receptor is an appropriate target for the development of molecularly targeted therapies for skin cancer and other pathologies.

  4. Travelling Concepts

    DEFF Research Database (Denmark)

    Simonsen, Karen-Margrethe

    2013-01-01

    Review of "Travelling Concepts, Metaphors, and Narratives: Literary and Cultural Studies in an Age of Interdisciplinary Research" ed. by Sibylle Baumgarten, Beatrice Michaelis and Ansagar Nünning, Trier; Wissenschaftlicher Verlag Trier, 2012......Review of "Travelling Concepts, Metaphors, and Narratives: Literary and Cultural Studies in an Age of Interdisciplinary Research" ed. by Sibylle Baumgarten, Beatrice Michaelis and Ansagar Nünning, Trier; Wissenschaftlicher Verlag Trier, 2012...

  5. The pleiotropic roles of transforming growth factor beta inhomeostasis and carcinogenesis of endocrine organs.

    Energy Technology Data Exchange (ETDEWEB)

    Fleisch, Markus C.; Maxwell, Christopher A.; Barcellos-Hoff,Mary-Helen

    2006-01-13

    Transforming growth factor beta (TGF-beta) is a ubiquitous cytokine that plays a critical role in numerous pathways regulating cellular and tissue homeostasis. TGF-beta is regulated by hormones and is a primary mediator of hormone response in uterus, prostate and mammary gland. This review will address the role of TGF-beta in regulating hormone dependent proliferation and morphogenesis. The subversion of TGF-beta regulation during the processes of carcinogenesis, with particular emphasis on its effects on genetic stability and epithelial to mesenchymal transition (EMT), will also be examined. An understanding of the multiple and complex mechanisms of TGF-beta regulation of epithelial function, and the ultimate loss of TGF-beta function during carcinogenesis, will be critical in the design of novel therapeutic interventions for endocrine-related cancers.

  6. The influence of chromosome density variations on the increase in nuclear disorder strength in carcinogenesis

    International Nuclear Information System (INIS)

    Kim, Jun Soo; Pradhan, Prabhakar; Backman, Vadim; Szleifer, Igal

    2011-01-01

    Microscopic structural changes have long been observed in cancer cells and used as a marker in cancer diagnosis. Recent development of an optical technique, partial-wave spectroscopy (PWS), enabled more sensitive detection of nanoscale structural changes in early carcinogenesis in terms of the disorder strength related to density variations. These nanoscale alterations precede the well-known microscopic morphological changes. We investigate the influence of nuclear density variations due to chromosome condensation on changes of disorder strength by computer simulations of model chromosomes. Nuclear configurations with different degrees of chromosome condensation are realized from simulations of decondensing chromosomes and the disorder strength is calculated for these nuclear configurations. We found that the disorder strength increases significantly for configurations with slightly more condensed chromosomes. Coupled with PWS measurements, the simulation results suggest that the chromosome condensation and the resulting spatial density inhomogeneity may represent one of the earliest events in carcinogenesis

  7. Use of medaka as a tool in studies of radiation effects and chemical carcinogenesis

    International Nuclear Information System (INIS)

    Hyodo-Taguchi, Y.; Aoki, K.; Matsudaira, H.

    1982-01-01

    The medaka, Oryzias latipes, a small freshwater oviparous fish, is common in Japan and found in some parts of Asia. Adult fish are 3.0-3.5 cm long and weigh 0.5-0.7 g. The small fish have been used extensively in this laboratory for analysis of radiation effects and for study of chemical carcinogenesis. These fish are relatively easy to rear and their reproductive biology is well known. Recently, inbred strains of the fish have been established by full sister-brother mating. In this report, we will review experimental results using medaka in studies of : 1) radiation effects on spermatogenesis, and 2) induction of hepatic tumors by MAM acetate, we will also review use of medaka in related studies of radiation effects and chemical carcinogenesis. (author)

  8. The effect of synthetic immunomodulator thymogen on radiation carcinogenesis in rats

    International Nuclear Information System (INIS)

    Anisimov, V.N.; Miretskij, G.I.; Morozov, V.G.; Pavel'eva, I.A.; Khavinson, V.Kh.

    1992-01-01

    Five month-old female rats were given a mixture of Sr-90 and Cs-137 in drinking water in the dose of 0.1 and 0.2 μCi/day per animal over 12 months. Some animals received 12 monthly course of a synthetic immunomodulating dipeptide-thymogen in the dose of 5 μg/animal for 5 consecutive days. Radionuclide-treated rats showed higher occurence of tumors on the whole and of breast adenocarcinoma, in particular. Thymogen was shown to inhibit Sr-90- and Cs-137-induced radiation carcinogenesis, namely, a decrease in the total tumor and cancer occurence was observed. The animals receiving thymogen alone showed longer life span, slower rate of aging and lower overall tumor and cancer occurence. In this study, the ability of asynthetic peptide immunomodulator-thymogen to inhibit spontaneous and radionuclide-induced carcinogenesis in female rats was first established

  9. Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C

    OpenAIRE

    Whang, Young Mi; Jo, Ukhyun; Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

    2013-01-01

    Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation ...

  10. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria: a systematic review

    Directory of Open Access Journals (Sweden)

    Emanuel Dias-Jácome

    Full Text Available Background and aim: Helicobacter pylori is the strongest risk factor for gastric cancer. However, recent advances in DNA sequencing technology have revealed a complex microbial community in the stomach that could also contribute to the development of gastric cancer. The aim of this study was to present recent scientific evidence regarding the role of non-Helicobacter pylori bacteria in gastric carcinogenesis. Methods: A systematic review of original articles published in PubMed in the last ten years related to gastric microbiota and gastric cancer in humans was performed. Results: Thirteen original articles were included. The constitution of gastric microbiota appears to be significantly affected by gastric cancer and premalignant lesions. In fact, differences in gastric microbiota have been documented, depending on Helicobacter pylori status and gastric conditions, such as non-atrophic gastritis, intestinal metaplasia and cancer. Gastric carcinogenesis can be associated with an increase in many bacteria (such as Lactobacillus coleohominis, Klebsiella pneumoniae or Acinetobacter baumannii as well as decrease in others (such as Porphyromonas spp, Neisseria spp, Prevotella pallens or Streptococcus sinensis. However, there is no conclusive data that confirms if these changes in microbiota are a cause or consequence of the process of carcinogenesis. Conclusions: Even though there is limited evidence in humans, microbiota differences between normal individuals, pre-malignant lesions and gastric cancer could suggest a progressive shift in the constitution of gastric microbiota in carcinogenesis, possibly resulting from a complex cross-talk between gastric microbiota and Helicobacter pylori. However, further studies are needed to elucidate the specific role (if any of different microorganisms.

  11. Differentiation and carcinogenesis: an integrated multilevel study of mechanisms from molecules to man. Progress report

    International Nuclear Information System (INIS)

    1985-01-01

    This study sought to identify and characterize mesenchymal progenitor cells (MPCs) in vitro, to identify the in vivo equivalent of the in vitro MPCs, and to determine the relationship between the presence or response of these cells both in vitro and eventually in vivo to altered proliferative capacity (in vitro cellular senescence, in vivo organismal aging) and altered susceptibility to carcinogenesis (frequency of in vitro neoplastic transformation and age-related frequency of in vivo cancer incidence). 16 refs

  12. Risks of carcinogenesis from electromagnetic radiation of mobile telephony devices.

    Science.gov (United States)

    Yakymenko, I; Sidorik, E

    2010-07-01

    Intensive implementation of mobile telephony technology in everyday human life during last two decades has given a possibility for epidemiological estimation of long-term effects of chronic exposure of human organism to low-intensive microwave (MW) radiation. Latest epidemiological data reveal a significant increase in risk of development of some types of tumors in chronic (over 10 years) users of mobile phone. It was detected a significant increase in incidence of brain tumors (glioma, acoustic neuroma, meningioma), parotid gland tumor, seminoma in long-term users of mobile phone, especially in cases of ipsilateral use (case-control odds ratios from 1.3 up to 6.1). Two epidemiological studies have indicated a significant increase of cancer incidence in people living close to the mobile telephony base station as compared with the population from distant area. These data raise a question of adequacy of modern safety limits of electromagnetic radiation (EMR) exposure for humans. For today the limits were based solely on the conception of thermal mechanism of biological effects of RF/MW radiation. Meantime the latest experimental data indicate the significant metabolic changes in living cell under the low-intensive (non-thermal) EMR exposure. Among reproducible biological effects of low-intensive MWs are reactive oxygen species overproduction, heat shock proteins expression, DNA damages, apoptosis. The lack of generally accepted mechanism of biological effects of low-intensive non-ionizing radiation doesn't permit to disregard the obvious epidemiological and experimental data of its biological activity. Practical steps must be done for reasonable limitation of excessive EMR exposure, along with the implementation of new safety limits of mobile telephony devices radiation, and new technological decisions, which would take out the source of radiation from human brain.

  13. 65Zn kinetics as a biomarker of DMH induced colon carcinogenesis

    International Nuclear Information System (INIS)

    Chadha, Vijayta Dani

    2012-01-01

    Dietary factors are considered crucial for the prevention of initiating events in the multistep progression of colon carcinoma. There is substantial evidence that zinc may play a pivotal role in host defense against several malignancies, including colon cancer. The present study was conducted to evaluate the kinetics of zinc utilization following experimental colon carcinogenesis in rat model. The rats were segregated into two groups viz., untreated control and DMH treated. Colon carcinogenesis was established through weekly subcutaneous injections of DMH (30mg/Kg body weight) for 16 weeks. Whole body 65 Zn kinetics followed two compartment kinetics, with Tb1 representing the initial fast component of the biological half-life and Tb2, the slower component. The present study revealed a significant depression in the Tb1 and Tb2 components of 65 Zn in DMH treated rats. Further, DMH treatment caused a significant increase in the percent uptake values of 65 Zn in the colon, small intestine, kidney and blood, whereas a significant decrease was observed in the liver. Subcellular distribution revealed a significant increase in 65 Zn uptake in the mitochondrial and microsomal fractions following 16 weeks of DMH supplementation. The present study demonstrated a slow mobilization of zinc during promotion of experimentally induced colon carcinogenesis and provides a physiological basis for the role of zinc in colon tumorigenesis, a paradigm which may have clinical implications in the management of colon cancer. (author)

  14. Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid

    International Nuclear Information System (INIS)

    Cui Lunbiao; Shi Yuan; Dai Guidong; Pan Hongxin; Chen Jianfeng; Song Ling; Wang Shouling; Chang, Hebron C.; Sheng Hongbing; Wang Xinru

    2006-01-01

    The effect of terephthalic acid (TPA) on urinary bladder carcinogenesis was examined. Male Wistar rats were initiated by injection of N-Methyl-N-Nitrosourea (MNU) (20 mg/kg b.w. ip) twice a week for 4 weeks, then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO 3 ) or 1% TPA for the next 22 weeks, and then euthanized. 5% TPA treatment induced a high incidence of urinary bladder calculi and a large amount of precipitate. Though 5% TPA plus 4% Sodium bicarbonate (NaHCO 3 ) and 1% TPA treatment did not induce urinary bladder calculi formation, they resulted in a moderate increase in urinary precipitate. Histological examination of urinary bladder revealed that MNU-5% TPA treatment resulted in a higher incidence of simple hyperplasia, papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer than MNU control. MNU-5% TPA plus 4% Sodium bicarbonate (NaHCO 3 ) and 1% TPA treatment increased slightly the incidence of simple hyperplasia and PN hyperplasia (not statistically significant). The major elements of the precipitate are phosphorus, potassium, sulfur, chloride, calcium and TPA. The present study indicated that the calculi induced by TPA had a strong promoting activity on urinary bladder carcinogenesis and the precipitate containing calcium terephthalate (CaTPA) may also have weak promoting activity on urinary bladder carcinogenesis

  15. Mast cells are dispensable for normal and activin-promoted wound healing and skin carcinogenesis.

    Science.gov (United States)

    Antsiferova, Maria; Martin, Caroline; Huber, Marcel; Feyerabend, Thorsten B; Förster, Anja; Hartmann, Karin; Rodewald, Hans-Reimer; Hohl, Daniel; Werner, Sabine

    2013-12-15

    The growth and differentiation factor activin A is a key regulator of tissue repair, inflammation, fibrosis, and tumorigenesis. However, the cellular targets, which mediate the different activin functions, are still largely unknown. In this study, we show that activin increases the number of mature mast cells in mouse skin in vivo. To determine the relevance of this finding for wound healing and skin carcinogenesis, we mated activin transgenic mice with CreMaster mice, which are characterized by Cre recombinase-mediated mast cell eradication. Using single- and double-mutant mice, we show that loss of mast cells neither affected the stimulatory effect of overexpressed activin on granulation tissue formation and reepithelialization of skin wounds nor its protumorigenic activity in a model of chemically induced skin carcinogenesis. Furthermore, mast cell deficiency did not alter wounding-induced inflammation and new tissue formation or chemically induced angiogenesis and tumorigenesis in mice with normal activin levels. These findings reveal that mast cells are not major targets of activin during wound healing and skin cancer development and also argue against nonredundant functions of mast cells in wound healing and skin carcinogenesis in general.

  16. Deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 knockout mice.

    Science.gov (United States)

    Zhang, Danqing; Kobayashi, Toshiyuki; Kojima, Tetsuo; Kanenishi, Kenji; Hagiwara, Yoshiaki; Abe, Masaaki; Okura, Hidehiro; Hamano, Yoshitomo; Sun, Guodong; Maeda, Masahiro; Jishage, Kou-ichi; Noda, Tetsuo; Hino, Okio

    2011-04-01

    Genetic crossing experiments were performed between tuberous sclerosis-2 (Tsc2) KO and expressed in renal carcinoma (Erc) KO mice to analyze the function of the Erc/mesothelin gene in renal carcinogenesis. We found the number and size of renal tumors were significantly less in Tsc2+/-;Erc-/- mice than in Tsc2+/-;Erc+/+ and Tsc2+/-;Erc+/- mice. Tumors from Tsc2+/-;Erc-/- mice exhibited reduced cell proliferation and increased apoptosis, as determined by proliferating cell nuclear antigen (Ki67) and TUNEL analysis, respectively. Adhesion to collagen-coated plates in vitro was enhanced in Erc-restored cells and decreased in Erc-suppressed cells with siRNA. Tumor formation by Tsc2-deficient cells in nude mice was remarkably suppressed by stable knockdown of Erc with shRNA. Western blot analysis showed that the phosphorylation of focal adhesion kinase, Akt and signal transducer and activator of transcription protein 3 were weaker in Erc-deficient/suppressed cells compared with Erc-expressed cells. These results indicate that deficiency of the Erc/mesothelin gene ameliorates renal carcinogenesis in Tsc2 KO mice and inhibits the phosphorylation of several kinases of cell adhesion mechanism. This suggests that Erc/mesothelin may have an important role in the promotion and/or maintenance of carcinogenesis by influencing cell-substrate adhesion via the integrin-related signal pathway. © 2011 Japanese Cancer Association.

  17. Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats.

    Science.gov (United States)

    Martin, O C B; Lin, C; Naud, N; Tache, S; Raymond-Letron, I; Corpet, D E; Pierre, F H

    2015-01-01

    Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme-induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis.

  18. Recent progress in nickel carcinogenesis. [Cornybacterium; E. coli; S. typhimurium; B. subtillis

    Energy Technology Data Exchange (ETDEWEB)

    Sunderman, F.W. Jr.

    1984-01-01

    Research on nickel carcinogenesis from 1979 to 1983 is reviewed. Epidemiological studies have strengthened the evidence that workers in nickel refineries have increased risks of lung and sinonasal cancers, but have not substantiated increased risks of respiratory cancers in other nickel-exposed workers. Carcinogenesis bioassays have demonstrated carcinogenicity of certain nickel sulfide, hydroxide, selenide, arsenide, antimonide, and telluride compounds following parenteral administration to rodents. Positive bacterial mutagenesis tests have been obtained with Ni(II) in Cornybacterium, but not in E. coli, S. typhimurium, or B. subtilis. Transformation assays of several soluble and crystalline Ni compounds have been positive in Syrian hamster embryo cells. Ni(II) binds to DNA, RNA, and nucleoproteins, and becomes localized in nucleoli. Genotoxic effects of Ni include: (a) chromosomal aberrations, including sister-chromatid exchanges, (b) DNA strandbreaks and DNA-protein cross-links, (c) inhibition of DNA and RNA synthesis, (d) infidelity of DNA transcription, and (e) mutations at the HGPRTase locus in Chinese hamster cells and the TK locus in mouse lymphoma cells. These findings are consistent with somatic mutation as the mechanism for initiation of nickel carcinogenesis. Ni compounds cause reversible transition of double-stranded poly(dG-dC) DNA from the right-handed B-helix to the left-handed Z-helix, suggesting a mechanism whereby nickel might modulate oncogene expression. 99 references, 6 tables.

  19. Carcinogenesis associated with parasites other than Schistosoma, Opisthorchis and Clonorchis: A systematic review.

    Science.gov (United States)

    Machicado, Claudia; Marcos, Luis A

    2016-06-15

    Only three helminths (Schistosoma haematobium, Opisthorchis viverrini and Clonorchis sinensis) are directly associated with carcinogenesis in humans whereas the role of other parasites in cancer remains unclear. This study aimed to perform a systematic review to identify recent insights in the role of other parasite infections in carcinogenesis. We conducted systematic searches of MEDLINE and EMBASE on July 2015. Our primary outcome was the association between parasitic infections and carcinogenesis. Out of 1,266 studies, 19 were selected for detailed evaluation (eight for helminths and 11 for protozoa). The mechanisms of helminth-induced cancer included chronic inflammation, sustained proliferation, modulation of the host immune system, reprogramming of glucose metabolism and redox signaling, induction of genomic instability and destabilization of suppressor tumor proteins, stimulation of angiogenesis, resisting cell death, and activation of invasion and metastasis. In addition to the current knowledge, the following parasites were found in cancers or tumors: Echinococcus, Strongyloides, Fasciola, Heterakis, Platynosomum and Trichuris. Additional parasites were found in this systematic review that could potentially be associated with cancers or tumors but further evidence is needed to elaborate a cause-effect relationship. © 2016 UICC.

  20. Quantification of nanoscale density fluctuations by electron microscopy: probing cellular alterations in early carcinogenesis

    International Nuclear Information System (INIS)

    Pradhan, Prabhakar; Damania, Dhwanil; Turzhitsky, Vladimir; Subramanian, Hariharan; Backman, Vadim; Joshi, Hrushikesh M; Dravid, Vinayak P; Roy, Hemant K; Taflove, Allen

    2011-01-01

    Most cancers are curable if they are diagnosed and treated at an early stage. Recent studies suggest that nanoarchitectural changes occur within cells during early carcinogenesis and that such changes precede microscopically evident tissue alterations. It follows that the ability to comprehensively interrogate cell nanoarchitecture (e.g., macromolecular complexes, DNA, RNA, proteins and lipid membranes) could be critical to the diagnosis of early carcinogenesis. We present a study of the nanoscale mass-density fluctuations of biological tissues by quantifying their degree of disorder at the nanoscale. Transmission electron microscopy images of human tissues are used to construct corresponding effective disordered optical lattices. The properties of nanoscale disorder are then studied by statistical analysis of the inverse participation ratio (IPR) of the spatially localized eigenfunctions of these optical lattices at the nanoscale. Our results show an increase in the disorder of human colonic epithelial cells in subjects harboring early stages of colon neoplasia. Furthermore, our findings strongly suggest that increased nanoscale disorder correlates with the degree of tumorigenicity. Therefore, the IPR technique provides a practicable tool for the detection of nanoarchitectural alterations in the earliest stages of carcinogenesis. Potential applications of the technique for early cancer screening and detection are also discussed

  1. A Review of ERCC1 Gene in Bladder Cancer: Implications for Carcinogenesis and Resistance to Chemoradiotherapy

    Directory of Open Access Journals (Sweden)

    Atsunari Kawashima

    2012-01-01

    Full Text Available The excision repair cross-complementing group 1 (ERCC1 gene performs a critical incision step in DNA repair and is reported to be correlated with carcinogenesis and resistance to drug or ionizing radiation therapy. We reviewed the correlation between ERCC1 and bladder cancer. In carcinogenesis, several reports discussed the relation between ERCC1 single nucleotide polymorphisms and carcinogenesis in bladder cancer only in case-control studies. Regarding the relation between ERCC1 and resistance to chemoradiotherapy, in vitro and clinical studies indicate that ERCC1 might be related to resistance to radiation therapy rather than cisplatin therapy. It is controversial whether ERCC1 predicts prognosis of bladder cancer treated with cisplatin-based chemotherapy. Tyrosine kinase receptors or endothelial-mesenchymal transition are reported to regulate the expression of ERCC1, and further study is needed to clarify the mechanism of ERCC1 expression and resistance to chemoradiotherapy in vitro and to discover novel therapies for advanced and metastatic bladder cancer.

  2. A Review of ERCC1 Gene in Bladder Cancer: Implications for Carcinogenesis and Resistance to Chemoradiotherapy.

    Science.gov (United States)

    Kawashima, Atsunari; Takayama, Hitoshi; Tsujimura, Akira

    2012-01-01

    The excision repair cross-complementing group 1 (ERCC1) gene performs a critical incision step in DNA repair and is reported to be correlated with carcinogenesis and resistance to drug or ionizing radiation therapy. We reviewed the correlation between ERCC1 and bladder cancer. In carcinogenesis, several reports discussed the relation between ERCC1 single nucleotide polymorphisms and carcinogenesis in bladder cancer only in case-control studies. Regarding the relation between ERCC1 and resistance to chemoradiotherapy, in vitro and clinical studies indicate that ERCC1 might be related to resistance to radiation therapy rather than cisplatin therapy. It is controversial whether ERCC1 predicts prognosis of bladder cancer treated with cisplatin-based chemotherapy. Tyrosine kinase receptors or endothelial-mesenchymal transition are reported to regulate the expression of ERCC1, and further study is needed to clarify the mechanism of ERCC1 expression and resistance to chemoradiotherapy in vitro and to discover novel therapies for advanced and metastatic bladder cancer.

  3. Review: the Contribution of both Nature and Nurture to Carcinogenesis and Progression in Solid Tumours.

    Science.gov (United States)

    Hyndman, Iain Joseph

    2016-04-01

    Cancer is a leading cause of mortality worldwide. Cancer arises due to a series of somatic mutations that accumulate within the nucleus of a cell which enable the cell to proliferate in an unregulated manner. These mutations arise as a result of both endogenous and exogenous factors. Genes that are commonly mutated in cancer cells are involved in cell cycle regulation, growth and proliferation. It is known that both nature and nurture play important roles in cancer development through complex gene-environment interactions; however, the exact mechanism of these interactions in carcinogenesis is presently unclear. Key environmental factors that play a role in carcinogenesis include smoking, UV light and oncoviruses. Angiogenesis, inflammation and altered cell metabolism are important factors in carcinogenesis and are influenced by both genetic and environmental factors. Although the exact mechanism of nature-nurture interactions in solid tumour formation are not yet fully understood, it is evident that neither nature nor nurture can be considered in isolation. By understanding more about gene-environment interactions, it is possible that cancer mortality could be reduced.

  4. The scientific basis for the establishment of threshold levels and dose response relationships of carcinogenesis

    International Nuclear Information System (INIS)

    1975-01-01

    The International Atomic Energy Agency hosted a two day Symposium from 2-3 December 1974 at its Headquarters, organized by the 'International Academy for Environmental Safety and the Forum fur Wissenschaft, Wirtschaft und Politik' on the subject 'Scientific Basis for the Establishment of Threshold. Levels and Dose Response Relationships of Carcinogenesis'. Following an introductory paper by the Radiation Biology Section of the Agency on 'Radiation Carcinogenesis - Dose Response Relationship, Threshold and Risk Estimates', a series of papers dealt with this problem in chemical carcinogenesis.It was suggested that more experiments should be done using non-human primates for tests of carcinogens, especially chemicals. Preliminary experiments using monkeys with a potent carcinogen - nitrosoamine - indicate that there could possibly be a dose where no effect can be observed during the 5 year period of study. It was also pointed out that the overall cost/benefit and risk/ benefit relationships should be taken into consideration in determining limits for chemicals which are potentially carcinogenic but are used routinely by the public and industries; these considerations have been weighed in setting exposure limits for radiation

  5. Molecular alterations in childhood thyroid cancer after Chernobyl accident and low-dose radiation risk

    International Nuclear Information System (INIS)

    Suzuki, Keiji; Mitsutake, Norisato; Yamashita, Shunichi

    2012-01-01

    The linear no-threshold (LNT) model of radiation carcinogenesis has been used for evaluating the risk from radiation exposure. While the epidemiological studies have supported the LNT model at doses above 100 mGy, more uncertainties are still existed in the LNT model at low doses below 100 mGy. Thus, it is urged to clarify the molecular mechanisms underlying radiation carcinogenesis. After the Chernobyl accident in 1986, significant amount of childhood thyroid cancer has emerged in the children living in the contaminated area. As the incidence of sporadic childhood thyroid cancer is very low, it is quite evident that those cancer cases have been induced by radiation exposure caused mainly by the intake of contaminated foods, such as milk. Because genetic alterations in childhood thyroid cancers have extensively been studied, it should provide a unique chance to understand the molecular mechanisms of radiation carcinogenesis. In a current review, molecular signatures obtained from the molecular studies of childhood thyroid cancer after Chernobyl accident have been overviewed, and new roles of radiation exposure in thyroid carcinogenesis will be discussed. (author)

  6. Apoptosis and Molecular Targeting Therapy in Cancer

    Science.gov (United States)

    Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

    2014-01-01

    Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

  7. Metallothioneins in human tumors and potential roles in carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Cherian, M. George; Jayasurya, A.; Bay, Boon-Huat

    2003-12-10

    Metallothioneins (MT) are a group of low-molecular weight, cysteine rich intracellular proteins, which are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins have been associated with protection against DNA damage, oxidative stress and apoptosis. Moreover, MT may potentially activate certain transcriptional factors by donating zinc. Although MT is a cytosolic protein in resting cells, it can be translocated transiently to the cell nucleus during cell proliferation and differentiation. A number of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder. However, MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. In certain tumors such as germ cell carcinoma, the expression of MT is closely related to the tumor grade and proliferative activity. Increased expression of MT has also been observed in less differentiated tumors. Thus, expression of MT may be a potential prognostic marker for certain tumors. There are few reports on the expression of the different isoforms of MT which have been analyzed by specific gene probes. They reveal that certain isoforms are expressed in specific cell types. The factors which can influence MT induction in human tumors are not yet understood. Down-regulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes such as the p53 tumor suppressor gene. In vitro studies using human cancer cells suggest a possible role for p53 and the estrogen-receptor on the expression and induction of MT in epithelial neoplastic cells

  8. Metallothioneins in human tumors and potential roles in carcinogenesis

    International Nuclear Information System (INIS)

    Cherian, M. George; Jayasurya, A.; Bay, Boon-Huat

    2003-01-01

    Metallothioneins (MT) are a group of low-molecular weight, cysteine rich intracellular proteins, which are encoded by a family of genes containing at least 10 functional isoforms in human. The expression and induction of these proteins have been associated with protection against DNA damage, oxidative stress and apoptosis. Moreover, MT may potentially activate certain transcriptional factors by donating zinc. Although MT is a cytosolic protein in resting cells, it can be translocated transiently to the cell nucleus during cell proliferation and differentiation. A number of studies have shown an increased expression of MT in various human tumors of the breast, colon, kidney, liver, lung, nasopharynx, ovary, prostate, salivary gland, testes, thyroid and urinary bladder. However, MT is down-regulated in certain tumors such as hepatocellular carcinoma and liver adenocarcinoma. Hence, the expression of MT is not universal to all human tumors, but may depend on the differentiation status and proliferative index of tumors, along with other tissue factors and gene mutations. In certain tumors such as germ cell carcinoma, the expression of MT is closely related to the tumor grade and proliferative activity. Increased expression of MT has also been observed in less differentiated tumors. Thus, expression of MT may be a potential prognostic marker for certain tumors. There are few reports on the expression of the different isoforms of MT which have been analyzed by specific gene probes. They reveal that certain isoforms are expressed in specific cell types. The factors which can influence MT induction in human tumors are not yet understood. Down-regulation of MT synthesis in hepatic tumors may be related to hypermethylation of the MT-promoter or mutation of other genes such as the p53 tumor suppressor gene. In vitro studies using human cancer cells suggest a possible role for p53 and the estrogen-receptor on the expression and induction of MT in epithelial neoplastic cells

  9. Molecular events leading to HPV-induced high grade neoplasia

    Directory of Open Access Journals (Sweden)

    Saskia M. Wilting

    2016-12-01

    Full Text Available Cervical cancer is initiated by high-risk types of the human papillomavirus (hrHPV and develops via precursor stages, called cervical intraepithelial neoplasia (CIN. High-grade CIN lesions are considered true precancerous lesions when the viral oncogenes E6 and E7 are aberrantly expressed in the dividing cells. This results in abolishment of normal cell cycle control via p53 and pRb degradation. However, it has become clear that these viral oncogenes possess additional oncogenic properties, including interference with the DNA methylation machinery and mitotic checkpoints. Identification of the resulting molecular events leading to high-grade neoplasia will 1 increase our understanding of cervical carcinogenesis, 2 yield biomarkers for early diagnosis, and 3 identify therapeutic targets for HPV-induced (pre cancerous lesions.This review will briefly summarise current advances in our understanding of the molecular alterations in the host cell genome that occur during HPV-induced carcinogenesis.

  10. Basic concepts

    International Nuclear Information System (INIS)

    Dorner, B.

    1999-01-01

    The basic concepts of neutron scattering as a tool for studying the structure and the dynamics of condensed matter. Theoretical aspects are outlined, the two different cases of coherent and incoherent scattering are presented. The issue of resolution, coherence volume and the role of monochromators are also discussed. (K.A.)

  11. Simple Concepts

    Czech Academy of Sciences Publication Activity Database

    Materna, Pavel

    2013-01-01

    Roč. 28, č. 3 (2013), s. 295-319 ISSN 0353-5150 R&D Projects: GA ČR(CZ) GAP401/10/0792 Institutional support: RVO:67985955 Keywords : concept * constructions * set-theoretical paradigm Subject RIV: AA - Philosophy ; Religion

  12. Epigenome remodelling in breast cancer: insights from an early in vitro model of carcinogenesis.

    Science.gov (United States)

    Locke, Warwick J; Clark, Susan J

    2012-11-15

    Epigenetic gene regulation has influence over a diverse range of cellular functions, including the maintenance of pluripotency, differentiation, and cellular identity, and is deregulated in many diseases, including cancer. Whereas the involvement of epigenetic dysregulation in cancer is well documented, much of the mechanistic detail involved in triggering these changes remains unclear. In the current age of genomics, the development of new sequencing technologies has seen an influx of genomic and epigenomic data and drastic improvements in both resolution and coverage. Studies in cancer cell lines and clinical samples using next-generation sequencing are rapidly delivering spectacular insights into the nature of the cancer genome and epigenome. Despite these improvements in technology, the timing and relationship between genetic and epigenetic changes that occur during the process of carcinogenesis are still unclear. In particular, what changes to the epigenome are playing a driving role during carcinogenesis and what influence the temporal nature of these changes has on cancer progression are not known. Understanding the early epigenetic changes driving breast cancer has the exciting potential to provide a novel set of therapeutic targets or early-disease biomarkers or both. Therefore, it is important to find novel systems that permit the study of initial epigenetic events that potentially occur during the first stages of breast cancer. Non-malignant human mammary epithelial cells (HMECs) provide an exciting in vitro model of very early breast carcinogenesis. When grown in culture, HMECs are able to temporarily escape senescence and acquire a pre-malignant breast cancer-like phenotype (variant HMECs, or vHMECs). Cultured HMECs are composed mainly of cells from the basal breast epithelial layer. Therefore, vHMECs are considered to represent the basal-like subtype of breast cancer. The transition from HMECs to vHMECs in culture recapitulates the epigenomic

  13. Astrophysical Concepts

    CERN Document Server

    Harwit, Martin

    2006-01-01

    This classic text, aimed at senior undergraduates and beginning graduate students in physics and astronomy, presents a wide range of astrophysical concepts in sufficient depth to give the reader a quantitative understanding of the subject. Emphasizing physical concepts, the book outlines cosmic events but does not portray them in detail: it provides a series of astrophysical sketches. For this fourth edition, nearly every part of the text has been reconsidered and rewritten, new sections have been added to cover recent developments, and others have been extensively revised and brought up to date. The book begins with an outline of the scope of modern astrophysics and enumerates some of the outstanding problems faced in the field today. The basic physics needed to tackle these questions are developed in the next few chapters using specific astronomical processes as examples. The second half of the book enlarges on these topics and shows how we can obtain quantitative insight into the structure and evolution of...

  14. Introductory concepts

    International Nuclear Information System (INIS)

    Barnes, W.E.

    1983-01-01

    Physical theories are commonly classified as being either ''classical'' or ''modern''. The reasons for this distinction are both historical and substantive. Limited in the sophistication of their measuring instruments, early scientists proposed theories appropriate for the description of the simplest and most accessible physical phenomena, e.g., the trajectories of the planets. Because of the class of phenomena observed, certain beliefs came to underlie all classical theories with regard to the nature of time, space, matter, etc. For example, the idea was undisputed that an object has at all times both a definite position and velocity. Not until the interior of the atom and the nature of electromagnetic radiation were explored was it discovered that the concepts of classical physics are inadequate to deal with many phenomena. A reassessment of fundamental postulates led to the formulation of modern physics which, it is believed, successfully treats the behavior of all physical systems. To gain an understanding of the rudiments of modern physics, one proceeds as the early scientists did by first mastering the classical concepts that emerge from their intuitive picture of the world. Modifications of these concepts are subsequently introduced which allow a more accurate treatment of physical phenomena, particularly atomic and nuclear systems

  15. Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

    Science.gov (United States)

    Roy, Hemant K; Kunte, Dhananjay P; Koetsier, Jennifer L; Hart, John; Kim, Young L; Liu, Yang; Bissonnette, Marc; Goldberg, Michael; Backman, Vadim; Wali, Ramesh K

    2006-08-01

    Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

  16. The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis.

    Science.gov (United States)

    Kawaguchi, Koichiro; Kinameri, Ayumi; Suzuki, Shunsuke; Senga, Shogo; Ke, Youqiang; Fujii, Hiroshi

    2016-02-15

    FABPs (fatty-acid-binding proteins) are a family of low-molecular-mass intracellular lipid-binding proteins consisting of ten isoforms. FABPs are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting these ligands to the appropriate compartments in the cell. FABP5 is overexpressed in multiple types of tumours. Furthermore, up-regulation of FABP5 is strongly associated with poor survival in triple-negative breast cancer. However, the mechanisms underlying the specific up-regulation of the FABP5 gene in these cancers remain poorly characterized. In the present study, we determined that FABP5 has a typical CpG island around its promoter region. The DNA methylation status of the CpG island in the FABP5 promoter of benign prostate cells (PNT2), prostate cancer cells (PC-3, DU-145, 22Rv1 and LNCaP) and human normal or tumour tissue was assessed by bisulfite sequencing analysis, and then confirmed by COBRA (combined bisulfite restriction analysis) and qAMP (quantitative analysis of DNA methylation using real-time PCR). These results demonstrated that overexpression of FABP5 in prostate cancer cells can be attributed to hypomethylation of the CpG island in its promoter region, along with up-regulation of the direct trans-acting factors Sp1 (specificity protein 1) and c-Myc. Together, these mechanisms result in the transcriptional activation of FABP5 expression during human prostate carcinogenesis. Importantly, silencing of Sp1, c-Myc or FABP5 expression led to a significant decrease in cell proliferation, indicating that up-regulation of FABP5 expression by Sp1 and c-Myc is critical for the proliferation of prostate cancer cells. © 2016 Authors; published by Portland Press Limited.

  17. In vitro modeling of human pancreatic duct epithelial cell transformation defines gene expression changes induced by K-ras oncogenic activation in pancreatic carcinogenesis.

    Science.gov (United States)

    Qian, Jiaying; Niu, Jiangong; Li, Ming; Chiao, Paul J; Tsao, Ming-Sound

    2005-06-15

    Genetic analysis of pancreatic ductal adenocarcinomas and their putative precursor lesions, pancreatic intraepithelial neoplasias (PanIN), has shown a multistep molecular paradigm for duct cell carcinogenesis. Mutational activation or inactivation of the K-ras, p16(INK4A), Smad4, and p53 genes occur at progressive and high frequencies in these lesions. Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and is found early in the PanIN-carcinoma sequence, but its functional roles remain poorly understood. We show here that the expression of K-ras(G12V) oncogene in a near diploid HPV16-E6E7 gene immortalized human pancreatic duct epithelial cell line originally derived from normal pancreas induced the formation of carcinoma in 50% of severe combined immunodeficient mice implanted with these cells. A tumor cell line established from one of these tumors formed ductal cancer when implanted orthotopically. These cells also showed increased activation of the mitogen-activated protein kinase, AKT, and nuclear factor-kappaB pathways. Microarray expression profiling studies identified 584 genes whose expression seemed specifically up-regulated by the K-ras oncogene expression. Forty-two of these genes have been reported previously as differentially overexpressed in pancreatic cancer cell lines or primary tumors. Real-time PCR confirmed the overexpression of a large number of these genes. Immunohistochemistry done on tissue microarrays constructed from PanIN and pancreatic cancer samples showed laminin beta3 overexpression starting in high-grade PanINs and occurring in >90% of pancreatic ductal carcinoma. The in vitro modeling of human pancreatic duct epithelial cell transformation may provide mechanistic insights on gene expression changes that occur during multistage pancreatic duct cell carcinogenesis.

  18. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    International Nuclear Information System (INIS)

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-01-01

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C → A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C → T, two C → A, one C → G, and one A → T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab

  19. Role of atypical chemokine receptor ACKR2 in experimental oral squamous cell carcinogenesis.

    Science.gov (United States)

    da Silva, Janine Mayra; Dos Santos, Tálita Pollyanna Moreira; Saraiva, Adriana Machado; Fernandes de Oliveira, Ana Laura; Garlet, Gustavo Pompermaier; Batista, Aline Carvalho; de Mesquita, Ricardo Alves; Russo, Remo Castro; da Silva, Tarcília Aparecida

    2018-03-14

    Chemokines and chemokine receptors are critical in oral tumourigenesis. The atypical chemokine receptor ACKR2 is a scavenger of CC chemokines controlling the availability of these molecules at tumour sites, but the role of ACKR2 in the context of oral carcinogenesis is unexplored. In this study, wild-type (WT) and ACKR2 deficient mice (ACKR2 -/- ) were treated with chemical carcinogen 4-nitroquinoline-1-oxide (4NQO) for induction of oral carcinogenesis. Tongues were collected for macro and microscopic analysis and to evaluate the expression of ACKRs, CC chemokines and its receptors, inflammatory cytokines, angiogenic factors, adhesion molecules and extracellular matrix components. An increased expression of ACKR2 in squamous cell carcinoma (SCC) lesions of 4NQO-treated WT mice was observed. No significant differences were seen in the ACKR1, ACKR3 and ACKR4 mRNA expression comparing SCC lesions from WT and ACKR2 -/- treated mice. Significantly higher expression of CCL2, IL-6 and IL-17 was detected in ACKR2 -/- treated mice. In contrast, the expression of other CC-chemokines, and receptors, angiogenic factors, adhesion molecules and extracellular matrix components were similarly increased in SCC lesions of both groups. Clinical and histopathological analysis revealed no differences in inflammatory cell recruitment and in the SCC incidence comparing WT and ACKR2 -/- treated mice. The results suggest that ACKR2 expression regulates inflammation in tumour-microenvironment but the absence of ACKR2 does not impact chemically-induced oral carcinogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Iron and thiols as two major players in carcinogenesis: friends or foes?

    Science.gov (United States)

    Toyokuni, Shinya

    2014-01-01

    Iron is the most abundant metal in the human body and mainly works as a cofactor for proteins such as hemoglobin and various enzymes. No independent life forms on earth can survive without iron. However, excess iron is intimately associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Biomolecules with redox-active sulfhydryl function(s) (thiol compounds) are necessary for the maintenance of mildly reductive cellular environments to counteract oxidative stress, and for the execution of redox reactions for metabolism and detoxification. Involvement of glutathione S-transferase and thioredoxin has long attracted the attention of cancer researchers. Here, I update recent findings on the involvement of iron and thiol compounds during carcinogenesis and in cancer cells. It is now recognized that the cystine/glutamate transporter (antiporter) is intimately associated with ferroptosis, an iron-dependent, non-apoptotic form of cell death, observed in cancer cells, and also with cancer stem cells; the former with transporter blockage but the latter with its stabilization. Excess iron in the presence of oxygen appears the most common known mutagen. Ironically, the persistent activation of antioxidant systems via genetic alterations in Nrf2 and Keap1 also contributes to carcinogenesis. Therefore, it is difficult to conclude the role of iron and thiol compounds as friends or foes, which depends on the quantity/distribution and induction/flexibility, respectively. Avoiding further mutation would be the most helpful strategy for cancer prevention, and myriad of efforts are being made to sort out the weaknesses of cancer cells.

  1. Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C.

    Science.gov (United States)

    Whang, Young Mi; Jo, Ukhyun; Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

    2013-01-01

    Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

  2. Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C.

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    Young Mi Whang

    Full Text Available Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE cells (NHBE, BEAS-2B, 1799, 1198 and 1170I at different malignant stages established by exposure to cigarette smoke condensate (CSC. Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

  3. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression.

    Science.gov (United States)

    Bonkhoff, Helmut

    2018-01-01

    The androgen receptor (AR) is the classical target for prostate cancer prevention and treatment, but more recently estrogens and their receptors have also been implicated in prostate cancer development and tumor progression. Recent experimental and clinical data were reviewed to elucidate pathogenetic mechanisms how estrogens and their receptors may affect prostate carcinogenesis and tumor progression. The estrogen receptor beta (ERβ) is the most prevalent ER in the human prostate, while the estrogen receptor alpha (ERα) is restricted to basal cells of the prostatic epithelium and stromal cells. In high grade prostatic intraepithelial neoplasia (HGPIN), the ERα is up-regulated and most likely mediates carcinogenic effects of estradiol as demonstrated in animal models. The partial loss of the ERβ in HGPIN indicates that the ERβ acts as a tumor suppressor. The tumor promoting function of the TMPRSS2-ERG fusion, a major driver of prostate carcinogenesis, is triggered by the ERα and repressed by the ERβ. The ERβ is generally retained in hormone naïve and metastatic prostate cancer, but is partially lost in castration resistant disease. The progressive emergence of the ERα and ERα-regulated genes (eg, progesterone receptor (PR), PS2, TMPRSS2-ERG fusion, and NEAT1) during prostate cancer progression and hormone refractory disease suggests that these tumors can bypass the AR by using estrogens and progestins for their growth. In addition, nongenomic estrogen signaling pathways mediated by orphan receptors (eg, GPR30 and ERRα) has also been implicated in prostate cancer progression. Increasing evidences demonstrate that local estrogen signaling mechanisms are required for prostate carcinogenesis and tumor progression. Despite the recent progress in this research topic, the translation of the current information into potential therapeutic applications remains highly challenging and clearly warrants further investigation. © 2017 Wiley Periodicals, Inc.

  4. Dysregulation of microRNAs in colonic field carcinogenesis: implications for screening.

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    Dhananjay P Kunte

    Full Text Available Colorectal cancer (CRC screening tests often have a trade-off between efficacy and patient acceptability/cost. Fecal tests (occult blood, methylation engender excellent patient compliance but lack requisite performance underscoring the need for better population screening tests. We assessed the utility of microRNAs (miRNAs as markers of field carcinogenesis and their potential role for CRC screening using the azoxymethane (AOM-treated rat model. We found that 63 miRNAs were upregulated and miR-122, miR-296-5p and miR-503# were downregulated in the uninvolved colonic mucosa of AOM rats. We monitored the expression of selected miRNAs in colonic biopsies of AOM rats at 16 weeks and correlated it with tumor development. We noted that the tumor bearing rats had significantly greater miRNA modulation compared to those without tumors. The miRNAs showed good diagnostic performance with an area under the receiver operator curve (AUROC of >0.7. We also noted that the miRNA induction in the colonic mucosa was mirrorred in the mucus layer fecal colonocytes isolated from AOM rat stool and the degree of miRNA induction was greater in the tumor bearing rats compared to those without tumors. Lastly, we also noted significant miRNA modulation in the Pirc rats- the genetic model of colon carcinogenesis, both in the uninvolved colonic mucosa and the fecal colonocytes. We thus demonstrate that miRNAs are excellent markers of field carcinogenesis and could accurately predict future neoplasia. Based on our results, we propose an accurate, inexpensive, non-invasive miRNA test for CRC risk stratification based on rectal brushings or from abraded fecal colonocytes.

  5. Chemoprevention by Probiotics During 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis in Rats.

    Science.gov (United States)

    Walia, Sohini; Kamal, Rozy; Dhawan, D K; Kanwar, S S

    2018-04-01

    Probiotics are believed to have properties that lower the risk of colon cancer. However, the mechanisms by which they exert their beneficial effects are relatively unknown. To assess the impact of probiotics in preventing induction of colon carcinogenesis in rats. The rats were divided into six groups viz., normal control, Lactobacillus plantarum (AdF10)-treated, Lactobacillus rhamnosus GG (LGG)-treated, 1,2-dimethylhydrazine (DMH)-treated, L. plantarum (AdF10) + DMH-treated and L. rhamnosus GG (LGG) + DMH-treated. Both the probiotics were supplemented daily at a dose of 2 × 10 10 cells per day. DMH at a dose of 30 mg/kg body weight was administered subcutaneously twice a week for the first 4 weeks and then once every week for a duration of 16 weeks. Glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase as protein expression of genes involved in apoptosis were assessed during DMH-induced colon carcinogenesis in rats. DMH treatment decreased the activity of GSH, GPx, GST, SOD and catalase. However, AdF10 and LGG supplementation to DMH-treated rats significantly increased the activity of these enzymes. Further, DMH treatment revealed alterations in the protein expressions of various genes involved in the p53-mediated apoptotic pathway such as p53, p21, Bcl-2, Bax, caspase-9 and caspase-3, which, however, were shifted towards normal control levels upon simultaneous supplementation with probiotics. The present study suggests that probiotics can provide protection against oxidative stress and apoptotic-related protein disregulation during experimentally induced colon carcinogenesis.

  6. Thermodynamic considerations on the role of heat and mass transfer in biochemical causes of carcinogenesis

    Science.gov (United States)

    Lucia, Umberto; Grisolia, Giulia; Ponzetto, Antonio; Deisboeck, Thomas S.

    2018-01-01

    Cellular homoeostasis involves a continuous interaction between the cell and its microenvironment. As such, active and passive transport of ions, nutrients, molecules and water are the basis for biochemical-physical cell life. These transport phenomena change the internal and external ionic concentrations, and, as a consequence, the cell membrane's electric potential and the pH. In this paper we focus on the relationship between these ion transport-induced pH and membrane voltage changes to highlight their impact on carcinogenesis. The preliminary results suggest a critical role for Cl- in driving tumour transformation towards a more malignant phenotype.

  7. Prevention of Lung Carcinogenesis by Suppressing Pathogenic CD4 T Cells

    Science.gov (United States)

    2017-05-01

    intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells . Nat Med, 2016. 22(3): p. 319-23.   ...stable population of YFP+  cells  similar  to  innate  IL‐17–producing  cells  (e.g., γδ T  cells ) during acute infection (Fig.2) , which is in sharp contrast...AWARD NUMBER: W81XWH-16-1-0100 TITLE: Prevention of Lung Carcinogenesis by Suppressing Pathogenic CD4 T Cells PRINCIPAL INVESTIGATOR: Seon Hee

  8. Is the role of the environment in carcinogenesis overestimated. [Individual health status, modifying factor

    Energy Technology Data Exchange (ETDEWEB)

    Calabrese, E J

    1979-01-01

    The dominant role of the physical and chemical environment in the development of cancer is challenged. Analyses of the etiology of skin, bladder, respiratory and gastric cancers are presented which demonstrate the considerable extent to which one's health status may modify the initiation and promotion of environmentally asociated cancers. It is concluded that although environmental factors may initiate and/or promote 85 to 90 percent of all cancers this is misleading since it neglects the critical role of the individual's health status as a factor modifying carcinogenesis.

  9. Thyroid cancer. Reevaluation of an experimental model for radiogenic endocrine carcinogenesis

    International Nuclear Information System (INIS)

    Clifton, K.H.

    1984-11-01

    The status of experimental studies of radiogenic thyroid cancer is appraised, and some older data are reinterpreted in the light of more recent findings. Problems of thyroid dosimetry, particularly the dosimetry of internal radioiodides, are discussed. The steps in radiation carcinogenesis during the acute phase, the latent phase, and the phase of tumor growth are discussed in terms of thyroid epithelial cell population changes. The roles of three cell populations (undamaged or completely repaired epithelial cells, oncogenically initiated cells, and terminally damaged but functionally competent cells) in neoplasia are described. Finally, the implications for man of these experimental results and conclusions are discussed. 89 refs., 4 figs

  10. Environmental pollution and DNA methylation: carcinogenesis, clinical significance, and practical applications.

    Science.gov (United States)

    Cao, Yi

    2015-09-01

    Environmental pollution is one of the main causes of human cancer. Exposures to environmental carcinogens result in genetic and epigenetic alterations which induce cell transformation. Epigenetic changes caused by environmental pollution play important roles in the development and progression of environmental pollution-related cancers. Studies on DNA methylation are among the earliest and most conducted epigenetic research linked to cancer. In this review, the roles of DNA methylation in carcinogenesis and their significance in clinical medicine were summarized, and the effects of environmental pollutants, particularly air pollutants, on DNA methylation were introduced. Furthermore, prospective applications of DNA methylation to environmental pollution detection and cancer prevention were discussed.

  11. Radiation carcinogenesis

    International Nuclear Information System (INIS)

    Fry, R.J.M.

    1976-01-01

    The risk of iatrogenic tumors with radiation therapy is so outweighed by the benefit of cure that estimates of risk have not been considered necessary. However, with the introduction of chemotherapy, combined therapy, and particle radiation therapy, the comparative risks should be examined. In the case of radiation, total dose, fractionation, dose rate, dose distribution, and radiation quality should be considered in the estimation of risk. The biological factors that must be considered include incidence of tumors, latent period, degree of malignancy, and multiplicity of tumors. The risk of radiation induction of tumors is influenced by the genotype, sex, and age of the patient, the tissues that will be exposed, and previous therapy. With chemotherapy the number of cells at risk is usually markedly higher than with radiation therapy. Clearly the problem of the estimation of comparative risks is complex. This paper presents the current views on the comparative risks and the importance of the various factors that influence the estimation of risk

  12. A importância do gene p53 na carcinogênese humana The importance of the p53 gene in human carcinogenesis

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    Agnes C. Fett-Conte

    2002-04-01

    Full Text Available Existem várias razões que justificam o título de "guardião do genoma" do gene P53. Seu envolvimento, direto ou indireto, tem sido observado na etiopatogenia de praticamente todas as neoplasias humanas, incluindo as leucemias e linfomas. Conhecer seus mecanismos de ação é fundamental para compreender os aspectos moleculares da carcinogênese. O presente trabalho apresenta uma revisão sobre as características deste gene e sua importância no diagnóstico, prognóstico e terapêutica, o que faz dele um alvo em potencial das estratégias de terapia gênica.There are several reasons which justify the name of 'guardian of the genome' given to the P53 gene. Its involvement either directly or indirectly has been observed in the pathology of practically all human neoplasias, including leukemia and lymphomas. Knowledge of its mechanisms of action is fundamental to understand molecular aspects of carcinogenesis. This work presents a revision of the characteristics of this gene and its importance in the diagnosis, prognosis and treatment and why this makes it a potential target for gene therapy strategies.

  13. End-Binding Protein 1 (EB1) Up-regulation is an Early Event in Colorectal Carcinogenesis

    Science.gov (United States)

    Stypula-Cyrus, Yolanda; Mutyal, Nikhil N.; Cruz, Mart Angelo Dela; Kunte, Dhananjay P.; Radosevich, Andrew J.; Wali, Ramesh; Roy, Hemant K.; Backman, Vadim

    2014-01-01

    End-binding protein (EB1) is a microtubule protein that binds to the tumor suppressor adenomatous polyposis coli (APC). While EB1 is implicated as a potential oncogene, its role in cancer progression is unknown. Therefore, we analyzed EB1/APC expression at the earliest stages of colorectal carcinogenesis and in the uninvolved mucosa ("field effect") of human and animal tissue. We also performed siRNA-knockdown in colon cancer cell lines. EB1 is up-regulated in early and field carcinogenesis in the colon, and the cellular/nano-architectural effect of EB1 knockdown depended on the genetic context. Thus, dysregulation of EB1 is an important early event in colon carcinogenesis. PMID:24492008

  14. An experimental study on carcinogenesis related to localized fibrosis in the lung

    International Nuclear Information System (INIS)

    Ohwada, Hidemi; Hayashi, Yutaka; Seki, Masatoshi.

    1980-01-01

    The present series of experiments was carried out in order to see what role pre-existing localized fibrosis plays in carcinogenesis of the lung. Hemorrhagic infarction was produced in the lung of 180 male Wistar rats by injecting 0.05 ml of hexachlorotetrafluorobutane into the tail vein. This resulted in localized fibrosis in the lung 3 months later. One hundred and fifteen rats were alive 3 months after administration of the chemical. Of these animals, 30 were given no further treatment (control). The remaining 85 rats were given intratracheal instillation of 0.2 μCi of polonium-210 once a week, a total of 15 times. It was subsequently found that lung carcinoma was induced in close proximity to the localized pulmonary fibrosis in 3 of 26 rats (11.5%) during the period from completion of the 15 weekly administrations of polonium-210 until the end of this experiment (21 months after the 1st instillation of polonium-210). Polonium-210 was found to be deposited in the fibrous thickening of the alveolus around the subpleural fibrotic lesion, bronchial epithelium, and peribronchial lymph apparati at the initial period of administration of polonium-210, but during the period of pulmonary carcinogenesis, it was deposited in the localized fibrotic lesion in the lung and in a few cancer cells. This suggests that polonium-210 deposited in the pulmonary fibrotic lesion remains there over a long period of time, indicating a reduced clearance ability at this site. (author)

  15. Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

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    Hitoshi Nakagama

    2011-02-01

    Full Text Available Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropylamine (BOP into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5’ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.

  16. Evaluation of carcinogenic potential of diuron in a rat mammary two-stage carcinogenesis model.

    Science.gov (United States)

    Grassi, Tony Fernando; Rodrigues, Maria Aparecida Marchesan; de Camargo, João Lauro Viana; Barbisan, Luís Fernando

    2011-04-01

    This study aimed to evaluate the carcinogenic potential of the herbicide Diuron in a two-stage rat medium-term mammary carcinogenesis model initiated by 7,12-dimethylbenz(a)anthracene (DMBA). Female seven-week-old Sprague-Dawley (SD) rats were allocated to six groups: groups G1 to G4 received intragastrically (i.g.) a single 50 mg/kg dose of DMBA; groups G5 and G6 received single administration of canola oil (vehicle of DMBA). Groups G1 and G5 received a basal diet, and groups G2, G3, G4, and G6 were fed the basal diet with the addition of Diuron at 250, 1250, 2500, and 2500 ppm, respectively. After twenty-five weeks, the animals were euthanized and mammary tumors were histologically confirmed and quantified. Tumor samples were also processed for immunohistochemical evaluation of the expressions of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, estrogen receptor-α (ER-α), p63, bcl-2, and bak. Diuron treatment did not increase the incidence or multiplicity of mammary tumors (groups G2 to G4 versus Group G1). Also, exposure to Diuron did not alter tumor growth (cell proliferation and apoptosis indexes) or immunoreactivity to ER-α, p63 (myoephitelial marker), or bcl-2 and bak (apoptosis regulatory proteins). These findings indicate that Diuron does not have a promoting potential on mammary carcinogenesis in female SD rats initiated with DMBA.

  17. Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

    Science.gov (United States)

    Ochi, Atsuo; Graffeo, Christopher S.; Zambirinis, Constantinos P.; Rehman, Adeel; Hackman, Michael; Fallon, Nina; Barilla, Rocky M.; Henning, Justin R.; Jamal, Mohsin; Rao, Raghavendra; Greco, Stephanie; Deutsch, Michael; Medina-Zea, Marco V.; Saeed, Usama Bin; Ego-Osuala, Melvin O.; Hajdu, Cristina; Miller, George

    2012-01-01

    Pancreatic ductal adenocarcinoma is an aggressive cancer that interacts with stromal cells to produce a highly inflammatory tumor microenvironment that promotes tumor growth and invasiveness. The precise interplay between tumor and stroma remains poorly understood. TLRs mediate interactions between environmental stimuli and innate immunity and trigger proinflammatory signaling cascades. Our finding that TLR7 expression is upregulated in both epithelial and stromal compartments in human and murine pancreatic cancer led us to postulate that carcinogenesis is dependent on TLR7 signaling. In a mouse model of pancreatic cancer, TLR7 ligation vigorously accelerated tumor progression and induced loss of expression of PTEN, p16, and cyclin D1 and upregulation of p21, p27, p53, c-Myc, SHPTP1, TGF-β, PPARγ, and cyclin B1. Furthermore, TLR7 ligation induced STAT3 activation and interfaced with Notch as well as canonical NF-κB and MAP kinase pathways, but downregulated expression of Notch target genes. Moreover, blockade of TLR7 protected against carcinogenesis. Since pancreatic tumorigenesis requires stromal expansion, we proposed that TLR7 ligation modulates pancreatic cancer by driving stromal inflammation. Accordingly, we found that mice lacking TLR7 exclusively within their inflammatory cells were protected from neoplasia. These data suggest that targeting TLR7 holds promise for treatment of human pancreatic cancer. PMID:23023703

  18. Role of Helicobacter pylori infection in gastric carcinogenesis: Current knowledge and future directions

    Science.gov (United States)

    Sokic-Milutinovic, Aleksandra; Alempijevic, Tamara; Milosavljevic, Tomica

    2015-01-01

    Helicobacter pylori (H. pylori) plays a role in the pathogenesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence: (1) eradication of the already present infection; and (2) immunization (prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available. PMID:26556993

  19. Role of MLH1 methylation in esophageal cancer carcinogenesis and its clinical significance.

    Science.gov (United States)

    Li, Jinyun; Ye, Dong; Wang, Lei; Peng, Yingying; Li, Qun; Deng, Hongxia; Zhou, Chongchang

    2018-01-01

    The mutL homolog-1 ( MLH1 ) is a DNA mismatch repair gene and has been reported to be frequently methylated in numerous cancers. However, the association between MLH1 methylation and esophageal cancer (EC), as well as its clinical significance, remains unclear. Hence, we conducted a systematic meta-analysis based on 19 articles (including 1384 ECs, 345 premalignant lesions, and 1244 healthy controls). Our analysis revealed that the frequency of MLH1 methylation was significantly elevated during EC carcinogenesis. In addition, we observed that MLH1 promoter methylation was associated with age (odds ratio [OR]=1.79; 95% CI =1.20-2.66), advanced tumor grade (OR=3.7; 95% CI =2.37-5.77), lymph node metastasis (OR=2.65; 95% CI =1.81-3.88), distant metastasis (OR=7.60; 95% CI =1.23-47.19), advanced clinical stage (OR=4.46; 95% CI =2.88-6.91), and poor prognosis in EC patients (hazard ratio =1.64, 95% CI =1.00-2.69). The pooled sensitivity, specificity, and area under the curve of MLH1 methylation in EC patients versus healthy individuals were 0.15, 0.99, and 0.77, respectively. Our findings indicate that MLH1 methylation is involved in the carcinogenesis, progression, and metastasis of EC. Moreover, methylated MLH1 could be a potential diagnostic and prognostic biomarker for EC.

  20. Stimulatory effects of curcumin and quercetin on posttranslational modifications of p53 during lung carcinogenesis.

    Science.gov (United States)

    Zhang, P; Zhang, Xy

    2018-06-01

    Lung cancer is responsible for increase in mortality due to cancer-related deaths, and new approaches are being explored for the betterment of the situation. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP-treated, BP + curcumin-treated, BP + quercetin-treated, and BP + curcumin + quercetin-treated groups. The morphological and histological analyses of tumor nodules confirmed lung carcinogenesis22 weeks after weeks single intraperitoneal injection of BP at a dose of 100 mg/kg body weight to mice. Curcumin and quercetin when administered individually as well as in combination significantly elevated the expression of acetylated-p53, which was otherwise depressed due to BP treatment. Also, both the phytochemicals significantly reduced the BP-inflicted increased levels of phosphorylated-p53. Furthermore, observed increase in the number of apoptotic cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), assay and increased activities of caspase 3 and 9 confirmed the induction of apoptosis by curcumin and quercetin. Moreover, the histological slides also showed noticeable improvement in the histoarchitecture of lungs by phytochemicals. The present study concludes that prophylactic treatment with curcumin and quercetin induces apoptosis in the lungs by modulation of p53 posttranslational modifications.

  1. Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Hisataka Moriwaki

    2012-01-01

    Full Text Available Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1/IGF-1 receptor (IGF-1R axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC and hepatocellular carcinoma (HCC. However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA, which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.

  2. CDB-4124, a progesterone receptor modulator, inhibits mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis.

    Science.gov (United States)

    Wiehle, Ronald; Lantvit, Daniel; Yamada, Tohru; Christov, Konstantin

    2011-03-01

    CDB-4124 (Proellex or telapristone acetate) is a modulator of progesterone receptor (PR) signaling, which is currently employed in preclinical studies for prevention and treatment of breast cancer and has been used in clinical studies for treatment of uterine fibroids and endometriosis. Here we provide evidence for its action on steroid hormone-signaling, cell cycle-regulated genes and in vivo on mammary carcinogenesis. When CDB-4124 is given to rats at 200 mg/kg for 24 months, it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. Also, CDB-4124 given as subcutaneous pellets at two different doses suppressed, dose dependently, N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis. The high dose (30 mg, over 84 days) increased tumor latency from 66 ± 24 days to 87 ± 20 days (P CDB-4124 inhibited cell proliferation and induced apoptosis in MNU-induced mammary tumors, which correlated with a decreased proportion of PR(+) tumor cells and with decreased serum progesterone. CDB-4124 did not affect serum estradiol. In a mechanistic study employing T47D cells we found that CDB-4124 suppressed G(1)/G(0)-S transition by inhibiting CDK2 and CDK4 expressions, which correlated with inhibition of estrogen receptor (ER) expression. Taken together, these data indicate that CDB-4124 can suppress the development of precancerous lesions and carcinogen-induced ER(+) mammary tumors in rats, and may have implications for prevention and treatment of human breast cancer.

  3. Alterations of global histone H4K20 methylation during prostate carcinogenesis

    Directory of Open Access Journals (Sweden)

    Behbahani Turang E

    2012-03-01

    Full Text Available Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3 at different stages of prostate cancer (PCA carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113, non-malignant prostate disease (n = 27, metastatic hormone-naive PCA (mPCA, n = 30 and castration-resistant PCA (CRPC, n = 34. Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

  4. Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

    International Nuclear Information System (INIS)

    Takahashi, Mami; Hori, Mika; Mutoh, Michihiro; Wakabayashi, Keiji; Nakagama, Hitoshi

    2011-01-01

    Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5′ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention

  5. Aggravation of serum Hepatocyte Growth Factor levels during hepato carcinogenesis in Rats

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.; Ghareeb, N.A.

    2010-01-01

    Hepatocyte growth factor (HGF) has an essential role during liver development and it plays an important role in the regeneration and repair of injured tissues and acting as a mitogen, motogen and morphogens for a variety of epithelial cells. The role of HGF in carcinogenesis is in straggle and so, the present study aimed to through light through the level of HGF during different steps of carcinogenesis. Forty male rats were given diethylnitrosamine (DEN) in drinking water (100 mg/l) for up to 16 weeks. Eight rats were sacrificed at 8, 12 and 16 weeks. Besides, 8 hepatoma bearing rats were exposed to a single dose gamma irradiation (3 Gy) were sacrificed after 2 weeks from exposure (2 rats died, 36 hrs post irradiation) and 8 hepatoma bearing rats were sacrificed after 4 weeks from receiving a combined antioxidant (N-acetylcysteine and Lmethionine). Serum HGF was assayed by enzyme linked immunosorbent assay (ELISA). Serum HGF level in DEN treated rats and in exposed hepatoma bearing rats was significantly higher than in control rats whereas, serum HGF level after treatment with N acetylcysteine and L-methionine for 4 weeks was significantly decreased than DEN treated rats and concluded that serum HGF may play a role during promotion and progression of hepatocellular carcinoma (HCC) and during treatment

  6. Cell Cycle Phase Abnormalities Do Not Account for Disordered Proliferation in Barrett's Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Pierre Lao-Sirieix

    2004-11-01

    Full Text Available Barrett's esophagus (BE epithelium is the precursor lesion for esophageal adenocarcinoma. Cell cycle proteins have been advocated as biomarkers to predict the malignant potential in BE. However, whether disruption of the cell cycle plays a causal role in Barrett's carcinogenesis is not clear. Specimens from the Barrett's dysplasia—carcinoma sequence were immunostained for cell cycle phase markers (cyclin D1 for G1; cyclin A for S, G2, and M; cytoplasmic cyclin B1 for G2; and phosphorylated histone 3 for M phase and expressed as a proportion of proliferating cells. Flow cytometric analysis of the cell cycle phase of prospective biopsies was also performed. The proliferation status of nondysplastic BE was similar to gastric antrum and D2, but the proliferative compartment extended to the luminal surface. In dysplastic samples, the number of proliferating cells correlated with the degree of dysplasia (P < .001. The overall levels of cyclins A and B1 correlated with the degree of dysplasia (P < .001. However, the cell cycle phase distribution measured with both immunostaining and flow cytometry was conserved during all stages of BE, dysplasia, and cancer. Hence, the increased proliferation seen in Barrett's carcinogenesis is due to abnormal cell cycle entry or exit, rather than a primary abnormality within the cell cycle.

  7. Experimental Animal Models of Pancreatic Carcinogenesis for Prevention Studies and Their Relevance to Human Disease

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Mami, E-mail: mtakahas@ncc.go.jp; Hori, Mika; Mutoh, Michihiro [Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan); Wakabayashi, Keiji [Graduate School of Nutritional and Environmental Sciences, University of Shizuoka, Yada 52-1, Suruga-ku, Shizuoka 422-8526 (Japan); Nakagama, Hitoshi [Division of Cancer Development System, Carcinogenesis Research Group, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045 (Japan)

    2011-02-09

    Pancreatic cancer is difficult to cure, so its prevention is very important. For this purpose, animal model studies are necessary to develop effective methods. Injection of N-nitrosobis(2-oxopropyl)amine (BOP) into Syrian golden hamsters is known to induce pancreatic ductal adenocarcinomas, the histology of which is similar to human tumors. Moreover, K-ras activation by point mutations and p16 inactivation by aberrant methylation of 5′ CpG islands or by homozygous deletions have been frequently observed in common in both the hamster and humans. Thus, this chemical carcinogenesis model has an advantage of histopathological and genetic similarity to human pancreatic cancer, and it is useful to study promotive and suppressive factors. Syrian golden hamsters are in a hyperlipidemic state even under normal dietary conditions, and a ligand of peroxizome proliferator-activated receptor gamma was found to improve the hyperlipidemia and suppress pancreatic carcinogenesis. Chronic inflammation is a known important risk factor, and selective inhibitors of inducible nitric oxide synthase and cyclooxygenase-2 also have protective effects against pancreatic cancer development. Anti-inflammatory and anti-hyperlipidemic agents can thus be considered candidate chemopreventive agents deserving more attention.

  8. Chemopreventive effect of artesunate in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

    Directory of Open Access Journals (Sweden)

    Sazal Patyar

    2017-01-01

    Full Text Available Artesunate (ART is a semisynthetic derivative of artemisinin. Artemisinin and its derivatives have shown profound cytotoxicity and antitumor activity in addition to antimalarial activity in various studies. As the in vivo chemopreventive efficacy of ART in colon carcinogenesis has not been investigated so far, the aim of the current study was to study the chemopreventive effect of ART in 1,2-dimethylhydrazine (DMH-induced rat colon carcinogenesis. Animals were divided into four groups (n = 6: Group I - vehicle (1 mM ethylenediaminetetraacetic acid, Group II - DMH (20 mg/kg, Group III - DMH + 5-fluorouracil (81 mg/kg, Group IV - DMH + ART (6.7 mg/kg. After completion of 15 weeks of treatment, rats were sacrificed under ether anesthesia by cervical dislocation for assessment of lipid peroxidation (LPO, antioxidant status, average number of aberrant crypt foci (ACF, and cytokine levels. ART administration significantly decreased the average number of ACF/microscopic field. Similarly, LPO level was decreased and antioxidant activities were enhanced after ART treatment. ART decreased the levels of proinflammatory cytokines and induced apoptosis in the colons of DMH-treated rats. The results of this study suggest that ART has a beneficial effect against chemically induced colonic preneoplastic progression in rats.

  9. Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis

    Science.gov (United States)

    Scott, RE; Ghule, PN; Stein, JL; Stein, GS

    2015-01-01

    The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with p = e−13 to e−36. Cell cycle expression networks show species, sex and tissue variability and they are enriched in mRNA transcripts associated with mitosis many of which are associated with chromosomal instability. PMID:25808367

  10. Candidate mechanisms accounting for effects of physical activity on breast carcinogenesis.

    Science.gov (United States)

    Thompson, Henry J; Jiang, Weiqin; Zhu, Zongjian

    2009-09-01

    Evidence is strong that a reduction in risk for breast cancer is associated with moderate to vigorous physical activity (PA); however, there is limited understanding of the role of type, intensity, duration, and frequency of PA and their mechanisms in accounting for this health benefit. The objective of this review is to stimulate investigations of candidate mechanisms that may account for the effects of the intensity and duration of aerobic PA on breast cancer risk and tumor burden. Three hypotheses are considered: 1) the mTOR network hypothesis: PA inhibits carcinogenesis by suppressing the activation of the mTOR signaling network in mammary carcinomas; 2) the hormesis hypothesis: the carcinogenic response to PA is nonlinear and accounted for by a physiological cellular stress response; and 3) the metabolic reprogramming hypothesis: PA limits the amount of glucose and glutamine available to mammary carcinomas thereby inducing apoptosis because tumor-associated metabolic programming is reversed. To link these hypotheses to systemic effects of PA, it is recommended that consideration be given to determining: 1) what contracting muscle releases into circulation or removes from circulation that would directly modulate the carcinogenic process in epithelial cells; 2) whether the effects of muscle contraction on epithelial cell carcinogenesis are exerted in an endocrine, paracrine, autocrine, or intracrine manner; and 3) if the effects of muscle contraction on malignant cells differ from effects on normal or premalignant cells that do not manifest the hallmarks of malignancy. (c) 2009 IUBMB

  11. A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Ling Shao

    Full Text Available Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3, a ubiquitin-editing enzyme that restricts NFκB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min. While A20(FL/FL villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL villin-Cre APC(min/+ mice contain far greater numbers and larger colonic polyps than control APC(min mice. We find that A20 binds to the β-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of β-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the β-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting β-catenin signaling and preventing colon tumorigenesis.

  12. Enhancement of broccoli indole glucosinolates by methyl jasmonate treatment and effects on prostate carcinogenesis.

    Science.gov (United States)

    Liu, Ann G; Juvik, John A; Jeffery, Elizabeth H; Berman-Booty, Lisa D; Clinton, Steven K; Erdman, John W

    2014-11-01

    Broccoli is rich in bioactive components, such as sulforaphane and indole-3-carbinol, which may impact cancer risk. The glucosinolate profile of broccoli can be manipulated through treatment with the plant stress hormone methyl jasmonate (MeJA). Our objective was to produce broccoli with enhanced levels of indole glucosinolates and determine its impact on prostate carcinogenesis. Brassica oleracea var. Green Magic was treated with a 250 μM MeJA solution 4 days prior to harvest. MeJA-treated broccoli had significantly increased levels of glucobrassicin, neoglucobrassicin, and gluconasturtiin (P broccoli powder, or 10% MeJA broccoli powder. Diets were fed throughout the study until termination at 20 weeks of age. Hepatic CYP1A was induced with MeJA broccoli powder feeding, indicating biological activity of the indole glucosinolates. Following ∼ 15 weeks on diets, neither of the broccoli treatments significantly altered genitourinary tract weight, pathologic score, or metastasis incidence, indicating that broccoli powder at 10% of the diet was ineffective at reducing prostate carcinogenesis in the TRAMP model. Whereas broccoli powder feeding had no effect in this model of prostate cancer, our work demonstrates the feasibility of employing plant stress hormones exogenously to stimulate changes in phytochemical profiles, an approach that may be useful for optimizing bioactive component patterns in foods for chronic-disease-prevention studies.

  13. Environment and breast cancer - the role of xenooestrogens in breast cancer carcinogenesis

    International Nuclear Information System (INIS)

    Plesnicar, A.; Kralj, B.; Druzina, B.; Kovac, V.

    2002-01-01

    Background. The survival rate of breast cancer patients has not changed much in the last few decades in developed countries. In order to improve the efficacy of breast cancer prevention and treatment, the role of xenooestrogens in the mechanisms of its development has been evaluated. These industrial chemicals bear little structural resemblance to each other and bind to the oestrogen receptors of exposed cells and/or trigger oestrogenic responses in laboratory test systems. Exposure to xenooestrogens has been regarded as a risk factor for carcinogenesis and a preventable cause of breast carcinoma. Several epidemiological and experimental studies in in vivo and in in vitro conditions of the influence of xenooestrogens on the occurrence of breast cancer have been conducted in the last decades and have shown ambiguous results. Conclusions. No increase in breast carcinoma incidence could be found in women who were exposed to relatively high concentrations of xenooestrogens for extended periods and small quantities of these compounds that are present in the environment probably cannot act as etiological agents for the occurrence of this disease. A multi step approach is suggested regarding the sequence of studies and measures that should be taken to further assess the importance of xenooestrogens on breast cancer carcinogenesis. (author)

  14. [In vitro and in vivo effects of mango pulp (Mangifera indica cv. Azucar) in colon carcinogenesis].

    Science.gov (United States)

    Corrales-Bernal, Andrea; Amparo Urango, Luz; Rojano, Benjamín; Maldonado, Maria Elena

    2014-03-01

    Mango pulp contains ascorbic acid, carotenoids, polyphenols, terpenoids and fiber which are healthy and could protect against colon cancer. The aim of this study was to evaluate the antiproliferative and preventive capacity of an aqueous extract of Mangifera indica cv. Azúcar on a human colon adenocarcinoma cell line (SW480) and in a rodent model of colorectal cancer, respectively. The content of total phenolics, flavonoids and carotenoids were also analyzed in the extract. SW480 cell growth was inhibited in a dose and time dependent manner by 22.3% after a 72h exposure to the extract (200 µg/ mL). Colon carcinogenesis was initiated in Balb/c mice by two intra-peritoneal injections of azoxymethane (AOM) at the third and fourth week of giving mango in drinking water (0.3%, 0.6%, 1.25%). After 10 weeks of treatment, in the colon of mice receiving 0.3% mango, aberrant crypt foci formation was inhibited more than 60% (p=0,05) and the inhibition was dose-dependent when compared with controls receiving water. These results show that mango pulp, a natural food, non toxic, part of human being diet, contains bioactive compounds able to reduce growth of tumor cells and to prevent the appearance of precancerous lesions in colon during carcinogenesis initiation.

  15. Mathematical concepts

    CERN Document Server

    Jost, Jürgen

    2015-01-01

    The main intention of this book is to describe and develop the conceptual, structural and abstract thinking of mathematics. Specific mathematical structures are used to illustrate the conceptual approach; providing a deeper insight into mutual relationships and abstract common features. These ideas are carefully motivated, explained and illustrated by examples so that many of the more technical proofs can be omitted. The book can therefore be used: ·         simply as an overview of the panorama of mathematical structures and the relations between them, to be supplemented by more detailed texts whenever you want to acquire a working knowledge of some structure ·         by itself as a first introduction to abstract mathematics ·         together with existing textbooks, to put their results into a more general perspective ·         to gain a new and hopefully deeper perspective after having studied such textbooks Mathematical Concepts has a broader scope and is less detaile...

  16. Nanotechnology Review: Molecular Electronics to Molecular Motors

    Science.gov (United States)

    Srivastava, Deepak; Saini, Subhash (Technical Monitor)

    1998-01-01

    Reviewing the status of current approaches and future projections, as already published in scientific journals and books, the talk will summarize the direction in which computational and experimental nanotechnologies are progressing. Examples of nanotechnological approaches to the concepts of design and simulation of carbon nanotube based molecular electronic and mechanical devices will be presented. The concepts of nanotube based gears and motors will be discussed. The above is a non-technical review talk which covers long term precompetitive basic research in already published material that has been presented before many US scientific meeting audiences.

  17. Molecular sensors and molecular logic gates

    International Nuclear Information System (INIS)

    Georgiev, N.; Bojinov, V.

    2013-01-01

    Full text: The rapid grow of nanotechnology field extended the concept of a macroscopic device to the molecular level. Because of this reason the design and synthesis of (supra)-molecular species capable of mimicking the functions of macroscopic devices are currently of great interest. Molecular devices operate via electronic and/or nuclear rearrangements and, like macroscopic devices, need energy to operate and communicate between their elements. The energy needed to make a device work can be supplied as chemical energy, electrical energy, or light. Luminescence is one of the most useful techniques to monitor the operation of molecular-level devices. This fact determinates the synthesis of novel fluorescence compounds as a considerable and inseparable part of nanoscience development. Further miniaturization of semiconductors in electronic field reaches their limit. Therefore the design and construction of molecular systems capable of performing complex logic functions is of great scientific interest now. In semiconductor devices the logic gates work using binary logic, where the signals are encoded as 0 and 1 (low and high current). This process is executable on molecular level by several ways, but the most common are based on the optical properties of the molecule switches encoding the low and high concentrations of the input guest molecules and the output fluorescent intensities with binary 0 and 1 respectively. The first proposal to execute logic operations at the molecular level was made in 1988, but the field developed only five years later when the analogy between molecular switches and logic gates was experimentally demonstrated by de Silva. There are seven basic logic gates: AND, OR, XOR, NOT, NAND, NOR and XNOR and all of them were achieved by molecules, the fluorescence switching as well. key words: fluorescence, molecular sensors, molecular logic gates

  18. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko; Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H.

    2003-01-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of ∼4 days. After puberty, the doubling time lengthened to ∼30 days. The total number of clonogens in abdominal and inguinal mammary glands was ∼200 in 2-week-old rats, while it was ∼5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics underlie the age

  19. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of {approx}4 days. After puberty, the doubling time lengthened to {approx}30 days. The total number of clonogens in abdominal and inguinal mammary glands was {approx}200 in 2-week-old rats, while it was {approx}5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics

  20. Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression

    International Nuclear Information System (INIS)

    Simiantonaki, Nektaria; Taxeidis, Marios; Jayasinghe, Caren; Kurzik-Dumke, Ursula; Kirkpatrick, Charles James

    2008-01-01

    Hypoxia-inducible factor 1 alpha (HIF-1α) is involved in processes promoting carcinogenesis of many tumors. However, its role in the development of colorectal cancer is unknown. To investigate the significance of HIF-1α during colorectal carcinogenesis and progression we examined its expression in precursor lesions constituting the conventional and serrated pathways, as well as in non-metastatic and metastatic adenocarcinomas. Immunohistochemistry and Western blot is used to analyse HIF-1α expression in normal colonic mucosa, hyperplastic polyps (HPP), sessile serrated adenomas (SSA), low-grade (TA-LGD) and high-grade (TA-HGD) traditional adenomas as well as in non-metastatic and metastatic colorectal adenocarcinomas. Eight colorectal carcinoma cell lines are tested for their HIF-1α inducibility after lipopolysaccharide (LPS) stimulation using western blot and immunocytochemistry. In normal mucosa, HPP and TA-LGD HIF-1α was not expressed. In contast, perinuclear protein accumulation and nuclear expression of HIF-1α were shown in half of the examined SSA and TA-HGD. In all investigated colorectal carcinomas a significant nuclear HIF-1α overexpression compared to the premalignant lesions was observed but a significant correlation with the metastatic status was not found. Nuclear HIF-1α expression was strongly accumulated in perinecrotic regions. In these cases HIF-1α activation was seen in viable cohesive tumor epithelia surrounding necrosis and in dissociated tumor cells, which subsequently die. Enhanced distribution of HIF-1α was also seen in periiflammatory regions. In additional in vitro studies, treatment of diverse colorectal carcinoma cell lines with the potent pro-inflammatory factor lipopolysaccharide (LPS) led to HIF-1α expression and nuclear translocation. We conclude that HIF-1α expression occurs in early stages of colorectal carcinogenesis and achieves a maximum in the invasive stage independent of the metastatic status. Perinecrotic

  1. p21(Waf1/Cip1) expression and the p53/MDM2 feedback loop in gastric carcinogenesis

    NARCIS (Netherlands)

    Craanen, M. E.; Blok, P.; Offerhaus, G. J.; Meijer, G. A.; Dekker, W.; Kuipers, E. J.; Meuwissen, S. G.

    1999-01-01

    Data are non-existent regarding coincidental alterations in the expression of p53 and its downstream target genes MDM2 and p21(Waf1/Cip1) in gastric carcinogenesis. An immunohistochemical study was therefore performed to examine the interrelationships of p53, MDM2, and p21(Waf1/Cip1) expression in a

  2. No evidence for functional inactivation of wild-type p53 protein by MDM2 overexpression in gastric carcinogenesis

    NARCIS (Netherlands)

    Blok, P.; Craanen, M. E.; Dekker, W.; Offerhaus, G. J.; Tytgat, G. N.

    1998-01-01

    Inactivation of wild-type p53 during gastric carcinogenesis is usually caused by mutations within exons 5-8 of the p53 gene leading to mutated, usually immunohistochemically detectable p53 proteins. However, functional inactivation of wild-type p53, mimicking mutational inactivation, may also result

  3. Biologia molecular do câncer colorretal: uma revolução silenciosa em andamento Molecular biology of colorectal cancer: a silent revolution

    Directory of Open Access Journals (Sweden)

    Mauro de Souza Leite Pinho

    2008-09-01

    Full Text Available Embora os estudos sobre biologia molecular permaneçam como a principal expectativa para o surgimento de novos conceitos e recursos para o tratamento do câncer colorretal, a ausência de resultados de real impacto do ponto de vista clínico ao longo dos últimos anos podem representar uma frustração para quem não esteja acompanhando de perto a evolução das pesquisas nesta área. Assim sendo, nosso objetivo no presente texto é apresentar uma breve revisão do caminho percorrido até o momento desde os trabalhos pioneiros sobre carcinogênese colorretal até as pesquisas mais recentes sobre proteômica, demonstrando assim o constante fluxo de grandes avanços os quais possibilitam uma previsão realista a curto ou médio prazo da disponibilização de recursos de amplo impacto, com potencial para alterar de forma relevante os resultados do tratamento desta importante doença.Despite remaining as the main hope for emerging new concepts and strategies for treatment of colorectal cancer, the lack of results with clinical impact over the last years may contribute to frustrate those not entirely aware about current research data. So, the aim of this paper is to present a brief review since the first molecular biology studies in colorectal carcinogenesis until recent advances in proteomics, in order to demonstrate the consistent production of new data supporting a realistic expectancy for a near future availability of high impact resources that may change dramatically the results of treatment of colorectal cancer.

  4. Disruption of adherens junction and alterations in YAP-related proliferation behavior as part of the underlying cell transformation process of alcohol-induced oral carcinogenesis.

    Science.gov (United States)

    Husari, Ayman; Hülter-Hassler, Diana; Steinberg, Thorsten; Schulz, Simon Daniel; Tomakidi, Pascal

    2018-01-01

    Accumulating evidences indicate that alcohol might play a causative in oral cancer. Unfortunately, in vitro cell systems, uncovering the molecular background of the underlying cell transformation process, are rare. Therefore, this study was conducted, to identify molecular changes and characterize their putative cell behavioral consequences in epitheloid (EPI) and fibroblastoid (FIB) oral keratinocyte phenotypes, arising from chronical alcohol treatment. Concerning adherens junctions (AJs), both EPI and FIB showed membrane-bound β-catenin, but exhibited differences for E-cadherin and zyxin. While EPI revealed E-cadherin/β-catenin membrane co-localization, which in parts also applied for zyxin, FIB membranes were devoid of E-cadherin and exhibited marginal zyxin expression. Fetal calf serum (FCS) administration in starved cells promoted proliferation in both keratinocyte phenotypes, whereat EPI and FIB yielded a strikingly modified FCS sensitivity on the temporal scale. Impedance measurement-based cell index detection yielded proliferation stimulation occurring much earlier in FIB (45h). Nuclear preference of the proliferation-associated YAP co-transcription factor in FIB was FCS independent, while it required FCS in EPI. Taken together, the lack of membrane-inherent E-cadherin/β-catenin co-localization together with low zyxin - reveals perturbation of AJ integrity in FIB. Regarding cell behavior, perturbed AJs in FIB correlate with temporal proliferation sensitivity towards FCS. CYF of 5.6 strongly suggests involvement of chromatin-bound YAP in FIB's proliferation temperosensitivity. These molecular differences detected for EPI and FIB are part of the underlying cell transformation process of alcohol-induced oral carcinogenesis, and indicate FIB being in a more advanced transformation stage. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Theoretical Molecular Biophysics

    CERN Document Server

    Scherer, Philipp

    2010-01-01

    "Theoretical Molecular Biophysics" is an advanced study book for students, shortly before or after completing undergraduate studies, in physics, chemistry or biology. It provides the tools for an understanding of elementary processes in biology, such as photosynthesis on a molecular level. A basic knowledge in mechanics, electrostatics, quantum theory and statistical physics is desirable. The reader will be exposed to basic concepts in modern biophysics such as entropic forces, phase separation, potentials of mean force, proton and electron transfer, heterogeneous reactions coherent and incoherent energy transfer as well as molecular motors. Basic concepts such as phase transitions of biopolymers, electrostatics, protonation equilibria, ion transport, radiationless transitions as well as energy- and electron transfer are discussed within the frame of simple models.

  6. Chromosome aberrations induced by radiation. With special reference to possible relation between chromosome aberrations and carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kamada, N [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1980-02-01

    Chromosome aberration seems to be one of the most conspicuous residual abnormalities recognizable in radiation-exposed persons for many years after exposure. Knowledge of the biological significance of these abnormalities seems to be necessary for understanding of the effect of radiation on humans, especially in relation to possible leukemic development. Cytogenetic studies were performed on the bone marrow cells, T and B lymphocytes, and fibroblasts in atomic bomb-survivors who were in apparent good health (105 cases), atomic bomb exposed patients who had prolonged periods of blood disorders which terminated in acute leukemia (8 cases), and who had no such abnormalities (6 cases). All patients with chronic myelocytic leukemia (CML) and a history of atomic bomb exposure showed Philadelphia chromosome, a characteristic chromosome abnormality for CML. The persistent chromosome aberrations of bone marrow cells, T and B lymphocytes found among the atomic bomb survivors with or without blood disorders may give some clue to solve the problems of carcinogenesis.

  7. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    International Nuclear Information System (INIS)

    Takai, Atsushi; Marusawa, Hiroyuki; Chiba, Tsutomu

    2011-01-01

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis

  8. Exosomes participate in the carcinogenesis and the malignant behavior of gastric cancer.

    Science.gov (United States)

    Yan, Yunmeng; Fu, Guangzhen; Ye, Yafei; Ming, Liang

    2017-05-01

    In order to summarize the role of exosomes in invasion and metastasis in gastric cancer (GC). Exosomes are vesicles of endocytic origin ranging from 30 to 100 nm in size; they are composed of a lipid bilayer and contain DNA, mRNA, miRNA, circular RNA and multiple proteins. Recently, increasing evidence shows that exosomes play a crucial role in the tumorigenesis of GC. In this review, we focus on the latest findings on GC exosomes, mainly summarizing their role in invasion and metastasis in GC. Then, exosomes? potential functions as novel diagnostic and therapeutic biomarkers for GC are briefly discussed. At last, we prospect the clinical application perspective of exosomes in GC. Exosomes play a vital role in gastric cancer carcinogenesis and metastasis.

  9. Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

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    N.B.R. Colombo

    2015-01-01

    Full Text Available The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress.

  10. Cell survival following alpha particle irradiation: critical sites and implications for carcinogenesis

    International Nuclear Information System (INIS)

    Lloyd, E.L.; Gemmell, M.A.; Henning, C.B.; Gemmell, D.S.; Zabransky, B.J.

    1976-01-01

    In experiments in which mammalian cells were irradiated with 5.6 MeV alpha particles from a Tandem Van de Graaff machine we have confirmed the finding of others that the mean lethal dose (D 0 ) is about 100 rad, but by measurements of the area of the cell nuclei as irradiated we found that this mean lethal dose corresponds not to 1, as expected, but to about 27 alpha particles per cell nucleus. (The exact number appears to change slightly with cell passage number.) This allows for the possibility that the direct action of alpha particles on the nucleus may be the important event in carcinogenesis, a theory which was previously difficult to accept if a single particle hitting the nucleus anywhere was considered to be lethal. Evidence is presented to implicate the nucleolus as a possible critical site for the inhibition of reproductive integrity of the cell

  11. Combined effects of inhaled plutonium oxide and benzo[a]pyrene on lung carcinogenesis in rats

    International Nuclear Information System (INIS)

    Metivier, H.; Masse, R.; Wahrendorf, J.; Lafuma, J.

    1986-01-01

    This study describes the effect of two intratracheal instillations (5 mg each) of benzo[a]pyrene (BP) on lung carcinogenesis in rats that had previously inhaled three levels of 239 PuO 2 . The BP does not modify survival in the high-level 239 PuO 2 -exposed rats, but markedly reduces survival in the two other groups. Median survival time with BP alone is shorter (666 days) than for the control group (838 days). Tumor incidence was increased by BP exposure, and the tumors were usually fatal, whereas tumors observed after 239 PuO 2 inhalation alone were usually not fatal. Statistical analysis of these data poses a problem because of the need to compare incidental and fatal tumors. 22 refs., 5 figs., 7 tabs

  12. Influences of age and anatomical site on ultraviolet carcinogenesis in BALB/c mice

    International Nuclear Information System (INIS)

    Ebbesen, P.; Kripke, M.L.

    1982-01-01

    Young adult BALB/c mice were mor susceptible to the induction of skin tumors from FS40 sunlamps than were 18-month-old animals. The relative contributions of tissue and host factors to this difference in susceptibility to carcinogenesis were analyzed by reciprocal grafting of skin between young and old animals, followed by repeated exposure of the grafts to UV radiation. More tumors developed in ear skin grafted to the middorsum of young recipients than in that of old recipients, regardless of the age of the skin donor. These ear skin grafts were more susceptible to tumor induction than were comparable grafts of back skin. When large areas of dorsal skin (16 cm2) were grafted to young adult mice, very old skin (greater than 2 yr) was more susceptible to tumor induction than skin that was 1 year old at the start of irradiation

  13. Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric CarcinogenesisSummary

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    Lindsay D. Butcher

    2017-05-01

    Full Text Available Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host’s efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer. Keywords: AP Endonuclease, DNA Damage, H pylori, Gastric Cancer, Oxidative Stress

  14. Resistance of germfree athymic nude mice to two-stage skin carcinogenesis

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    Holland, J.M.; Perkins, E.H.

    1979-01-01

    Germfree athymic and normal littermate mice were compared with respect to their relative sensitivity to single skin application of dimethylbenzanthacine followed either by croton oil or TPA applied as a co-carcinogen. In separate experiments the acute response of both phenotypes to TPA was assessed by histologic examination of skin as well as the incorporttion of tritiated thymidine into acid insoluble material obtained from the isolated epidermis. Nude mice were observed to be less, equal, or more sensitive than normal littermate to topical skin carcinogenesis depending upon experimental variables. The tendency of solvent to spread rapidly on the skin of nude mice appeared to have the greatest influence on susceptibility to papilloma induction. Other factors of potential, although unproven importance, include differences in skin structure, possibly associated with accelerated activity of hair follicles as well as resistance to both the inflammatory and hyperplasiogenic effects of TPA.

  15. Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma

    Directory of Open Access Journals (Sweden)

    Mei-Ying Zhang

    2014-08-01

    Full Text Available Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05. According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM than adenoma and carcinoma (p < 0.05. Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05. Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05, but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM staging, differentiation or serum carcinoembryonic antigen (CEA concentration (p > 0.05. Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05. Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05. It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.

  16. Lack of promotion of colon carcinogenesis by high-oleic safflower oil.

    Science.gov (United States)

    Takeshita, M; Ueda, H; Shirabe, K; Higuchi, Y; Yoshida, S

    1997-04-15

    The nonpromoting effect of olive oil on colon carcinogenesis has been attributed to its high oleic acid content, whereas a positive association of monounsaturated fat in beef tallow with colon tumors has been reported. The effect of constituents other than fatty acids could not be neglected in these experiments. In order to minimize the effects of minor constituents in the oils, the authors compared conventional safflower oil with oil from a mutant strain of safflower that is rich in oleic acid. ICR mice were treated with 1,2-dimethylhydrazine (DMH, 20 mg/kg body weight every week for 12 weeks) and then were fed either a high-fat diet (23.5% by weight), containing safflower oil (HF-LA) or high-oleic safflower oil (HF-OA), or a low-fat diet (5% by weight), containing safflower oil (LF-LA) or high-oleic safflower oil (LF-OA). The test diets were continued until termination of the experiment at 30 weeks after the first administration of DMH. Fatty acid composition of colon phospholipids was determined by gas-liquid chromatography-mass spectrometry. Tumor multiplicity in animals fed the HF-OA diet was indistinguishable from that in animals fed LF-LA or LF-OA. In contrast, animals fed the HF-LA diet had a significantly higher incidence of colon tumors (mostly adenocarcinomas) than the other groups. Fatty acid profiles of colon phospholipids reflected those of the diet. Animals fed a HF-LA diet showed a marked decrease of nervonic acid (C24:1, n-9) in the colon sphingomyelin. These data indicate that oleic acid does not enhance DMH-induced colon carcinogenesis in mice, even when they are fed a high-fat diet.

  17. DPEP1, expressed in the early stages of colon carcinogenesis, affects cancer cell invasiveness.

    Science.gov (United States)

    Toiyama, Yuji; Inoue, Yasuhiro; Yasuda, Hiromi; Saigusa, Susumu; Yokoe, Takeshi; Okugawa, Yoshinaga; Tanaka, Koji; Miki, Chikao; Kusunoki, Masato

    2011-02-01

    We investigated changes in the gene expression profile in colon cancer in order to identify gene markers that may be useful in the management of this disease. The Cancer Genome Anatomy Project was used to detect differences in gene expression between normal and cancer tissue. The overexpression of dipeptidase-1 (DPEP1) in cancer tissue was confirmed in a sample of 76 patients by real-time PCR. To identify the function of DPEP1, RNA interference (RNAi) was used to inactivate this gene in the colon cancer cell line. Immunohistochemical analysis was performed to characterize the pattern of DPEP1 expression in colon cancer. DPEP1 expression in cancer was significantly higher than that in normal tissue. However, DPEP1 expression decreased with pathological differentiation, lymph-node and distant metastasis. Patients with tumors with decreased DPEP1 expression showed a poorer prognosis, and this was also true of patients with tumors who are treated with curative intent. RNAi-mediated DPEP1 reduction in the colon cancer cell line did not result in cell proliferation or apoptosis, but was associated with an increased invasive ability. DPEP1 protein was observed on the apical side of the cancer cells, and is expressed in the early stages of carcinogenesis, even in adenomas of both sporadic colorectal cancer and familial adenomatous polyposis patients. DPEP1 expression in normal colonic mucosa is very low, but it is highly expressed in colorectal adenoma and cancer specimens and is negatively correlated with parameters of pathological aggressiveness and poor prognosis. DPEP1 is expressed in the early stages of colon carcinogenesis and affects cancer cell invasiveness.

  18. The Role of Oxidative Stress in Carcinogenesis Induced by Metals and Xenobiotics

    International Nuclear Information System (INIS)

    Henkler, Frank; Brinkmann, Joep; Luch, Andreas

    2010-01-01

    In addition to a wide range of adverse effects on human health, toxic metals such as cadmium, arsenic and nickel can also promote carcinogenesis. The toxicological properties of these metals are partly related to generation of reactive oxygen species (ROS) that can induce DNA damage and trigger redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses and/or tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics, when certain metabolites are generated that lead to the continuous release of superoxide, as long as the capacity to reduce the resulting dions (quinones) into hydroquinones is maintained. However, the specific significance of superoxide-dependent pathways to carcinogenesis is often difficult to address, because formation of DNA adducts by mutagenic metabolites can occur in parallel. Here, we will review both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides causing DNA damage, ROS may further induce multiple intracellular signaling pathways, notably NF-κB, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells. The significance of these additional modes depends on tissue, cell-type and is often masked by alternate oncogenic mechanisms being activated in parallel

  19. Promoter hypermethylation of KLF4 inactivates its tumor suppressor function in cervical carcinogenesis.

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    Wen-Ting Yang

    Full Text Available OBJECTIVE: The KLF4 gene has been shown to be inactivated in cervical carcinogenesis as a tumor suppressor. However, the mechanism of KLF4 silencing in cervical carcinomas has not yet been identified. DNA methylation plays a key role in stable suppression of gene expression. METHODS: The methylation status of the KLF4 promoter CpG islands was analyzed by bisulfite sequencing (BSQ in tissues of normal cervix and cervical cancer. KLF4 gene expression was detected by RT-PCR, immunohistochemistry and western blot. KLF4 promoter methylation in cervical cancer cell line was determined by BSQ and methylation-specific polymerase chain reaction (MS-PCR. Cell proliferation ability was detected by cell growth curve and MTT assay. RESULTS: The methylated allele was found in 41.90% of 24 cervical cancer tissues but only in 11.11% of 11 normal cervix tissues (P<0.005. KLF4 mRNA levels were significantly reduced in cervical cancer tissues compared with normal cervix tissues (P<0.01 and KLF4 mRNA expression showed a significant negative correlation with the promoter hypermethylation (r = -0.486, P = 0.003. Cervical cancer cell lines also showed a significant negative correlation between KLF4 expression and hypermethylation. After treatment with the demethylating agent 5-Azacytidine (5-Aza, the expression of KLF4 in the cervical cancer cell lines at both mRNA and protein levels was drastically increased, the cell proliferation ability was inhibited and the chemosensitivity for cisplatin was significantly increased. CONCLUSION: KLF4 gene is inactivated by methylation-induced silencing mechanisms in a large subset of cervical carcinomas and KLF4 promoter hypermethylation inactivates the gene's function as a tumor suppressor in cervical carcinogenesis.

  20. Inhibitory effects of Zengshengping fractions on DMBA-induced buccal pouch carcinogenesis in hamsters.

    Science.gov (United States)

    Guan, Xiao-Bing; Sun, Zheng; Chen, Xiao-Xin; Wu, Hong-Ru; Zhang, Xin-Yan

    2012-01-01

    Zengshengping (ZSP) tablets had inhibitory effects on oral precancerous lesions by reducing the incidence of oral cancer. However, the severe liver toxicity caused by systemic administration of ZSP limits the long-term use of this anti-cancer drug. The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of extracts from ZSP, a Chinese herbal drug, on 7, 12-dimethlbenz(a)anthracene (DMBA) induced oral tumors in hamsters. The study also investigated the anti-cancer mechanisms of the ZSP extracts on oral carcinogenesis. DMBA (0.5%) was applied topically to the buccal pouches of Syrian golden hamsters (6 - 8 weeks old) three times per week for six weeks in order to induce the development of oral tumors. Different fractions of ZSP were either applied topically to the oral tumor lesions or fed orally at varying dosages to animals with oral tumors for 18 weeks. Tumor volume was measured by histopathological examination. Tumor cell proliferation was evaluated by counting BrdU labeled cells and by Western blotting for mitogen-activated protein kinase (MAPK) protein levels. The protein levels of apoptosis marker Caspase-3 and regulator Bcl-2 protein were also measured by Western blotting. Topical application of DMBA to the left pouch of hamsters induced oral tumor formation. Animals treated with DMBA showed a loss in body weight while animals treated with ZSP maintained normal body weights. Both the ZSP n-butanol fraction and water fraction significantly reduced tumor volume by 32.6% (P oral tumor lesions and reduced the expression level of MAPK. In addition, ZSP promoted tumor cell apoptosis by increasing Caspase-3 expression but decreasing Bcl-2 protein production. The n-butanol and water fractions of ZSP are effective at inhibiting tumor cell proliferation and stimulating apoptosis in oral cancer suggesting that these fractions have chemopreventive effects on DMBA induced oral carcinogenesis.

  1. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

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    Gokhan Yildiz

    Full Text Available Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal" by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15

  2. Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Marques, Ricardo; Vaz, Cátia V.; Maia, Cláudio J. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Gomes, Madalena [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Gama, Adelina [Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD) (Portugal); Alves, Gilberto; Santos, Cecília R. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Schmitt, Fernando [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Medical Faculty, University of Porto, Porto (Portugal); Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto (Canada); Department of Pathology, University Health Network, Toronto (Canada); Socorro, Sílvia, E-mail: ssocorro@fcsaude.ubi.pt [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal)

    2015-01-15

    Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland. - Highlights: • RGN immunoreactivity was negatively correlated with breast cancer differentiation. • Transgenic overexpression of RGN diminished incidence of carcinogen-induced tumors. • Transgenic overexpression of RGN restricted proliferation and fostered apoptosis. • RGN has a protective role in the carcinogenesis of mammary gland.

  3. Local Acetaldehyde—An Essential Role in Alcohol-Related Upper Gastrointestinal Tract Carcinogenesis

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    Mikko T. Nieminen

    2018-01-01

    Full Text Available The resident microbiome plays a key role in exposure of the upper gastrointestinal (GI tract mucosa to acetaldehyde (ACH, a carcinogenic metabolite of ethanol. Poor oral health is a significant risk factor for oral and esophageal carcinogenesis and is characterized by a dysbiotic microbiome. Dysbiosis leads to increased growth of opportunistic pathogens (such as Candida yeasts and may cause an up to 100% increase in the local ACH production, which is further modified by organ-specific expression and gene polymorphisms of ethanol-metabolizing and ACH-metabolizing enzymes. A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers. This human cancer model proves conclusively the causal relationship between ACH and upper GI tract carcinogenesis and provides novel possibilities for the quantitative assessment of ACH carcinogenicity in the human oropharynx. ACH formed from ethanol present in “non-alcoholic” beverages, fermented food, or added during food preparation forms a significant epidemiologic bias in cancer epidemiology. The same also concerns “free” ACH present in mutagenic concentrations in multiple beverages and foodstuffs. Local exposure to ACH is cumulative and can be reduced markedly both at the population and individual level. At best, a person would never consume tobacco, alcohol, or both. However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups.

  4. SMT or TOFT? How the two main theories of carcinogenesis are made (artificially) incompatible.

    Science.gov (United States)

    Bedessem, Baptiste; Ruphy, Stéphanie

    2015-09-01

    The building of a global model of carcinogenesis is one of modern biology's greatest challenges. The traditional somatic mutation theory (SMT) is now supplemented by a new approach, called the Tissue Organization Field Theory (TOFT). According to TOFT, the original source of cancer is loss of tissue organization rather than genetic mutations. In this paper, we study the argumentative strategy used by the advocates of TOFT to impose their view. In particular, we criticize their claim of incompatibility used to justify the necessity to definitively reject SMT. First, we note that since it is difficult to build a non-ambiguous experimental demonstration of the superiority of TOFT, its partisans add epistemological and metaphysical arguments to the debate. This argumentative strategy allows them to defend the necessity of a paradigm shift, with TOFT superseding SMT. To do so, they introduce a notion of incompatibility, which they actually use as the Kuhnian notion of incommensurability. To justify this so-called incompatibility between the two theories of cancer, they move the debate to a metaphysical ground by assimilating the controversy to a fundamental opposition between reductionism and organicism. We show here that this argumentative strategy is specious, because it does not demonstrate clearly that TOFT is an organicist theory. Since it shares with SMT its vocabulary, its ontology and its methodology, it appears that a claim of incompatibility based on this metaphysical plan is not fully justified in the present state of the debate. We conclude that it is more cogent to argue that the two theories are compatible, both biologically and metaphysically. We propose to consider that TOFT and SMT describe two distinct and compatible causal pathways to carcinogenesis. This view is coherent with the existence of integrative approaches, and suggests that they have a higher epistemic value than the two theories taken separately.

  5. Dietary chromium and nickel enhance UV-carcinogenesis in skin of hairless mice

    International Nuclear Information System (INIS)

    Uddin, Ahmed N.; Burns, Fredric J.; Rossman, Toby G.; Chen, Haobin; Kluz, Thomas; Costa, Max

    2007-01-01

    The skin cancer enhancing effect of chromium (in male mice) and nickel in UVR-irradiated female Skh1 mice was investigated. The dietary vitamin E and selenomethionine were tested for prevention of chromium-enhanced skin carcinogenesis. The mice were exposed to UVR (1.0 kJ/m 2 3x weekly) for 26 weeks either alone, or combined with 2.5 or 5.0 ppm potassium chromate, or with 20, 100 or 500 ppm nickel chloride in drinking water. Vitamin E or selenomethionine was added to the lab chow for 29 weeks beginning 3 weeks before the start of UVR exposure. Both chromium and nickel significantly increased the UVR-induced skin cancer yield in mice. In male Skh1 mice, UVR alone induced 1.9 ± 0.4 cancers/mouse, and 2.5 or 5.0 ppm potassium chromate added to drinking water increased the yields to 5.9 ± 0.8 and 8.6 ± 0.9 cancers/mouse, respectively. In female Skh1 mice, UVR alone induced 1.7 ± 0.4 cancers/mouse, and the addition of 20, 100 or 500 ppm nickel chloride increased the yields to 2.8 ± 0.9, 5.6 ± 0.7 and 4.2 ± 1.0 cancers/mouse, respectively. Neither vitamin E nor selenomethionine reduced the cancer yield enhancement by chromium. These results confirm that chromium and nickel, while not good skin carcinogens per se, are enhancers of UVR-induced skin cancers in Skh1 mice. Data also suggest that the enhancement of UVR-induced skin cancers by chromate may not be oxidatively mediated since the antioxidant vitamin E as well as selenomethionine, found to prevent arsenite-enhanced skin carcinogenesis, failed to suppress enhancement by chromate

  6. [Curcumin inhibited rat colorectal carcinogenesis by activating PPAR-γ: an experimental study].

    Science.gov (United States)

    Liu, Liu-bin; Duan, Chang-nong; Ma, Zeng-yi; Xu, Gang

    2015-04-01

    To explore the chemopreventive effect of curcumin on DMH induced colorectal carcinogenesis and the underlining mechanism. Totally 40 Wistar rats were divided into the model group and the curcumin group by random digit table, 20 in each group. Meanwhile, a normal control group was set up (n =10). A colorectal cancer model was induced by subcutaneously injecting 20 mg/kg DMH. The tumor incidence and the inhibition rate were calculated. The effect of curcumin on the expression of peroxisome proliferator-activated receptor gamma (PPARγ) in rat colon mucosal tissues was observed using immunohistochemistry and Western blot. HT 29 cell line were cultured and divided into a control group, the curcumin + GW9662 (2-chloro-5-nitro-N-4-phenylbenzamide) intervention group, and the curcumin group. The inhibition of different concentrations curcumin on HT29 cell line was detected using MTT. The expression of curcumin on PPARy was also detected using Western blot. The tumor incidence was 80. 00% (12/15 cases) in the model group, obviously higher than that of the curcumin group (58. 82%, 10/17 cases, P manners. The expression of PPARy protein was significantly increased in the GW9662 group and the curcumin group, showing statistical difference when compared with the normal control group (P <0. 01). Compared with the GW9662 group, the expression of PPARγ protein was significantly increased in the curcumin group (P <0. 01). Curcumin could inhibit DMH-induced rat colorectal carcinogenesis and the growth of in vitro cultured HT 29 cell line, which might be achieved by activating PPARy signal transduction pathway.

  7. Role of human papilloma virus in the oral carcinogenesis: An Indian perspective

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    Chocolatewala Noureen

    2009-01-01

    Full Text Available Oral squamous cell carcinoma (OSCC is one of the most common cancers in the Indian subcontinent. Although tobacco and alcohol are the main etiologic factors for nearly three-fourth of these cancers, no definite etiologic factor can be identified in one-fourth of the cases. There is growing evidence that human papilloma virus (HPV may act as a cocarcinogen, along with tobacco, in the causation of oral cancers. The role of HPV in the etiology of anogenital cancers has been firmly established, and infection with this virus has also been shown to have prognostic significance. However, there is no clear evidence to support its involvement in oral carcinogenesis. We searched the PubMed database for all literature published from 1985 to 2008 and performed a systemic review in order to understand the relationship of HPV with oral cancers and its prevalence in various sub-sites in the oral cavity. Association of HPV is strongest for oropharyngeal cancers, especially cancers of the tonsils, followed by those of the base of tongue. High-risk HPV-16 is the predominant type; it commonly affects the younger age-groups, with males appearing to have a predisposition for infection with this strain. Its prevalence increases from normal to dysplasia and finally to cancer. HPV prevalence has been reported to be twice as high in premalignant lesions as in normal mucosa and is nearly five times higher in OSCC. The overall prevalence of HPV in OSCC ranges between 20-50%. OSCCs associated with HPV have been found to have better outcomes, being more responsive to radiotherapy and showing higher survival rates. In view of the association of HPV with OSCC, it should be worthwhile to conduct further experimental studies to elucidate its role in oral carcinogenesis.

  8. Chemically induced immunotoxicity in a medium-term multiorgan bioassay for carcinogenesis with Wistar rats

    International Nuclear Information System (INIS)

    Spinardi-Barbisan, Ana Lucia Tozzi; Kaneno, Ramon; Barbisan, Luis Fernando; Viana de Camargo, Joao Lauro; Rodrigues, Maria Aparecida Marchesan

    2004-01-01

    A variety of chemicals can adversely affect the immune system and influence tumor development. The modifying potential of chemical carcinogens on the lymphoid organs and cytokine production of rats submitted to a medium-term initiation-promotion bioassay for carcinogenesis was investigated. Male Wistar rats were sequentially initiated with N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4hydroxybutyl)nitrosamine (BBN), dihydroxy-di-n-propylnitrosamine (DHPN), and 1,2-dimethylhydrazine (DMH) during 4 weeks. Two initiated groups received phenobarbital (PB) or 2-acetylaminofluorene (2-AAF) for 25 weeks and two noninitiated groups received only PB or 2-AAF. A nontreated group was used as control. Lymphohematopoietic organs, liver, kidneys, lung, intestines, and Zymbal's gland were removed for histological analysis. Interleukin (IL)-2, IL-12, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-10, and transforming growth factor beta1 (TGF-β1) levels were determined by ELISA in spleen cell culture supernatants. At the fourth week, exposure to the initiating carcinogens resulted in cell depletion of the thymus, spleen and bone marrow, and impairment of IL-2, IL-12, and IFN-γ production. However, at the 30th week, no important alterations were observed both in lymphoid organs and cytokine production in the different groups. The results indicate that the initiating carcinogens used in the present protocol exert toxic effects on the lymphoid organs and affect the production of cytokines at the initiation step of carcinogenesis. This early and reversible depression of the immune surveillance may contribute to the survival of initiated cells facilitating the development of future neoplasia

  9. Apoptotic role of natural isothiocyanate from broccoli (Brassica oleracea italica) in experimental chemical lung carcinogenesis.

    Science.gov (United States)

    Kalpana Deepa Priya, D; Gayathri, R; Gunassekaran, G R; Murugan, S; Sakthisekaran, D

    2013-05-01

    Sulforaphane (SFN) [1-isothiocyanato-4-(methylsulfinyl)butane] is a naturally occurring isothiocyanate found in cruciferous vegetables such as broccoli [Brassica oleracea L. var. italica Plenck. (Brassicaceae)]. Since it is among the most potent bioactive components with antioxidant and antitumor properties, it has received intense attention in the recent years for its chemopreventive properties. The present work determined the rehabilitating role in alleviating the oxidative damage caused by benzo(a)pyrene [B(a)P] to biomolecules and the apoptotic cascade mediated by orally administered isothiocyanate-SFN (9 µmol/mouse/day) against B(a)P (100 mg/kg body weight, i.p.) induced pulmonary carcinogenesis in Swiss albino mice. Oxidative damage was assessed by measuring lipid peroxidation, 8-hydroxydeoxyguanosine, hydrogen peroxide (H2O2) production, glycoprotein components, protein carbonyl levels and DNA-protein crosslinks. DNA fragmentation by agarose gel electrophoresis and caspase-3 activity by ELISA proved apoptotic induction by SFN along with the protein expression of Bcl-2, Bax and Cyt c. SFN treatment was found to decrease the H2O2 production (p < 0.001) in cancer induced animals, proving its antioxidant potential. Apoptosis was induced by increasing the release of Cyt c (p < 0.001) from mitochondria, decreasing and increasing the expression of Bcl-2 (p < 0.01) and Bax (p < 0.001), respectively. Caspase-3 activity was also enhanced (p < 0.001) which leads to DNA fragmentation in SFN treated groups. Our results reflect the rehabilitating role of SFN in B(a)P induced lung carcinogenesis.

  10. Raman spectroscopy detects biomolecular changes associated with nanoencapsulated hesperetin treatment in experimental oral carcinogenesis

    International Nuclear Information System (INIS)

    Gurushankar, K; Gohulkumar, M; Krishnakumar, N; Kumar, Piyush; Murali Krishna, C

    2016-01-01

    Recently it has been shown that Raman spectroscopy possesses great potential in the investigation of biomolecular changes of tumor tissues with therapeutic drug response in a non-invasive and label-free manner. The present study is designed to investigate the antitumor effect of hespertin-loaded nanoparticles (HETNPs) relative to the efficacy of native hesperetin (HET) in modifying the biomolecular changes during 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis using a Raman spectroscopic technique. Significant differences in the intensity and shape of the Raman spectra between the control and the experimental tissues at 1800–500 cm −1 were observed. Tumor tissues are characterized by an increase in the relative amount of proteins, nucleic acids, tryptophan and phenylalanine and a decrease in the percentage of lipids when compared to the control tissues. Further, oral administration of HET and its nanoparticulates restored the status of the lipids and significantly decreased the levels of protein and nucleic acid content. Treatment with HETNPs showed a more potent antitumor effect than treatment with native HET, which resulted in an overall reduction in the intensity of several biochemical Raman bands in DMBA-induced oral carcinogenesis being observed. Principal component and linear discriminant analysis (PC–LDA), together with leave-one-out cross validation (LOOCV) on Raman spectra yielded diagnostic sensitivities of 100%, 80%, 91.6% and 65% and specificities of 100%, 65%, 60% and 55% for classification of control versus DMBA, DMBA versus DMBA  +  HET, DMBA versus DMBA  +  HETNPs and DMBA  +  HET versus DMBA  +  HETNPs treated tissue groups, respectively. These results further demonstrate that Raman spectroscopy associated with multivariate statistical algorithms could be a valuable tool for developing a comprehensive understanding of the process of biomolecular changes, and could reveal the signatures of the

  11. Anticarcinogenesis effect of Gynura procumbens (Lour Merr on tongue carcinogenesis in 4NQO-induced rat

    Directory of Open Access Journals (Sweden)

    D. Agustina

    2006-09-01

    Full Text Available In Indonesia Gynura procumbens (Lour Merr leaves have been long used as various cancers medication. Many in vitro and in vivo studies have demonstrated anticarcinogenesis of ethanol extract of Gynura procumbens leaves. The aim of this study was to investigate the anticarcinogenesis of the ethanol extract of Gynura procumbens leaves on 4 nitroquinoline 1-oxide (4NQO-induced rat tongue carcinogenesis. Fifty six 4 week old male Sprague Dawley rats were used in this study and divided into 7 groups. Group 1, 2 and 3 were lingually induced by 4NQO for 8 weeks. In groups 2 and 3 the extract was given simultaneously with or after 4NQO induction finished, each for 10 weeks and 26 weeks, respectively. Groups 4, 5 and 6 were induced by 4NQO for 16 weeks. However, in groups 5 and 6 the extract was given as well simultaneously with or after the 4NQO induction, each for 18 weeks, respectively. Group 7 served as the as untreated control group. The results from microscopical assessment showed that tongue squamous cell carcinomas (SCC developed in 100% (3/3 of group 1. However, only 33.3% (2/6 and 25% (2/8 of rats in groups 2 and 3, respectively demonstrated tongue SCC. Among groups 4, 5 and 6, no significant difference of tongue SCC incidence was observed. From these results it is apparent that the ethanol extract of Gynura procumbens leaves could inhibit the progression of 4NQOinduced rat tongue carcinogenesis in the initiation phase.

  12. Molecular thermodynamics of nonideal fluids

    CERN Document Server

    Lee, Lloyd L

    2013-01-01

    Molecular Thermodynamics of Nonideal Fluids serves as an introductory presentation for engineers to the concepts and principles behind and the advances in molecular thermodynamics of nonideal fluids. The book covers related topics such as the laws of thermodynamics; entropy; its ensembles; the different properties of the ideal gas; and the structure of liquids. Also covered in the book are topics such as integral equation theories; theories for polar fluids; solution thermodynamics; and molecular dynamics. The text is recommended for engineers who would like to be familiarized with the concept

  13. Molecular characterisation of sinonasal carcinomas and their clinical implications.

    Science.gov (United States)

    López, Fernando; Llorente, José Luis; Costales, María; García-Inclán, Cristina; Pérez-Escuredo, Jhudit; Alvarez-Marcos, César; Hermsen, Mario; Suárez, Carlos

    2013-01-01

    Sinonasal carcinomas are rare tumours with an unfavourable prognosis whose management is difficult and complex, leading to high morbidity and mortality despite improvements in the field of surgery and radiotherapy. An elevated number of these tumours can be attributed to occupational exposure. In comparison with other head and neck malignancies, studies of molecular changes in these tumours are infrequent. This review was focused on findings about the epidemiology and molecular and phenotypic characterisation of sinonasal carcinomas, which can potentially be useful for diagnosis and treatment. The increasing knowledge about the molecular biology that underlies their carcinogenesis may help to identify precursor lesions, prognostic markers and markers that predict chemoradiotherapy response and, finally, to identify potential molecular targets that will expand treatment options. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  14. A network-based biomarker approach for molecular investigation and diagnosis of lung cancer

    Directory of Open Access Journals (Sweden)

    Chen Bor-Sen

    2011-01-01

    Full Text Available Abstract Background Lung cancer is the leading cause of cancer deaths worldwide. Many studies have investigated the carcinogenic process and identified the biomarkers for signature classification. However, based on the research dedicated to this field, there is no highly sensitive network-based method for carcinogenesis characterization and diagnosis from the systems perspective. Methods In this study, a systems biology approach integrating microarray gene expression profiles and protein-protein interaction information was proposed to develop a network-based biomarker for molecular investigation into the network mechanism of lung carcinogenesis and diagnosis of lung cancer. The network-based biomarker consists of two protein association networks constructed for cancer samples and non-cancer samples. Results Based on the network-based biomarker, a total of 40 significant proteins in lung carcinogenesis were identified with carcinogenesis relevance values (CRVs. In addition, the network-based biomarker, acting as the screening test, proved to be effective in diagnosing smokers with signs of lung cancer. Conclusions A network-based biomarker using constructed protein association networks is a useful tool to highlight the pathways and mechanisms of the lung carcinogenic process and, more importantly, provides potential therapeutic targets to combat cancer.

  15. Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways

    International Nuclear Information System (INIS)

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Seth, Amlesh; Nafees, Sana; Rashid, Summya; Ali, Nemat; Sultana, Sarwat

    2011-01-01

    Graphical abstract: Diagrammatic presentation of the hypothesis of the article in a concise manner. It reveals the chemopreventive efficacy of GOH possibly through the modulation of multiple molecular targets. GOH inhibits ROS generation, NFκB and PCNA expression thereby abrogating inflammation and proliferation of tubular cells of kidney. Whereas, GOH induces effector caspase-3 expression both through mitochondrial signalling pathway and death receptor signalling pathway. Highlights: → Geraniol modulates renal carcinogenesis in Wistar rats. → It abrogates Fe-NTA induced oxidative stress, inflammation and hyperproliferation. → Promotes apoptosis via induction of both mitochondrial and death receptor pathway. → Thus, inhibits renal carcinogenesis by modulating multiple molecular targets. -- Abstract: In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200 mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NFκB, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein

  16. Instant Update: Considering the Molecular Mechanisms of Mutation & Natural Selection

    Science.gov (United States)

    Hubler, Tina; Adams, Patti; Scammell, Jonathan

    2015-01-01

    The molecular basis of evolution is an important concept to understand but one that students and teachers often find challenging. This article provides training and guidance for teachers on how to present molecular evolution concepts so that students will associate molecular changes with the evolution of form and function in organisms. Included…

  17. Suppression of carcinogenesis in mice by adaptive responses to low dose rate irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Sakai, Kazuo; Iwasaki, Toshiyasu; Hoshi, Yuko; Nomura, Takaharu; Ina, Yasuhiro; Tanooka, Hiroshi [Central Research Institute of Electric Power Industry, Low Dose Radiation Research Center, Komae, Tokyo (Japan)

    2003-07-01

    Effects of prolonged low-dose-rate irradiation on the process of carcinogenesis were examined in mice treated with chemical carcinogen or irradiated with high doses of X-rays. Female ICR mice, 5 week-old, 35 in each group, were exposed to gamma-rays from a {sup 137}Cs source in the long-term low dose rate irradiation facility at CRIEPI. The dose rate was 2.6 mGy/hr (A), 0.96 mGy/hr (B), or 0.30 mGy/hr (C). Thirty-five days later, the mice were injected into the groin with 0.5 mg of methylcholanthrene (MC) dissolved in olive oil and irradiation was continued. Cumulative tumor incidences after 216 days following MC injection were 89% in group A, 76% in group B, and 94% in group C. That in non-irradiated control group was 94%. The difference in the tumor incidence between the control and position B was statistically significant, indicating the suppressive effect of the low dose rate irradiation on the process of MC-induced carcinogenesis with an optimum dose rate around 1 mGy/hr. In B6C3F1 mice, although the suppression of tumor incidence was not observed, there was a significant delay in tumor appearance in the irradiated mice between 100-150 days after MC injection. A group of 20 female C57BL/6N mice, 5 weeks old, were exposed to gamma-rays at 0.95 mGy/hr for 5 weeks. Then, they were exposed weekly to 1.8 Gy whole body X-irradiation (300 kVp) for consecutive 4 weeks to induce thymic lymphoma. Another group received only the fractionated irradiation. The first mouse died from thymic lymphoma appeared 89 days after the last irradiation in the group received only the fractionated irradiation, while 110 days in the group combined with the low dose rate irradiation. (author)

  18. [Changes of expression of miR-155 in colitis-associated colonic carcinogenesis].

    Science.gov (United States)

    Li, Weiwei; Han, Wenxiao; Zhao, Xinhua; Wang, Hongying

    2014-04-01

    To investigate the changes of miR-155 and its target genes in colitis-associated carcinogenesis. Colitis-associated colon cancer was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) in C57BL/6 mice. Mice of three different stages during the development of colon cancer were obtained, named AD1, AD2 and AD3, respectively. A control group of mice without any treatment and a DSS only group representing chronic inflammation without cancer were set up as well. Colon tissue was collected and expression of miR-155 in the colon tissues was measured by real-time fluorescent quantitative PCR. TargetScan and PicTar were used to predict potential target genes of miR-155, which were then preliminarily screened with our gene expression microarray database of AOM-DSS mouse model. Regular PCR was used to confirm the changes of the expression of these potential target genes in AOM-DSS mouse model. Colitis-associated colon cancer was effectively induced by azoxymethane and dextran sulfate sodium in C57BL/6 mice. Histological examination revealed that the evolution process was sequentially from normal, mild dysplasia, moderate dysplasia, and severe dysplasia to adenocarcinoma in the AOM-DSS mouse model. The level of miR-155 was gradually elevated with the formation of colitis-associated colon cancer. There was no significant difference between the levels of miR-155 expression in the DSS group (0.005 6 ± 0.003 7) and control group (0.012 0 ± 0.005 1) (P > 0.05), but the level of miR-155 in the AD3 group (0.054 4 ± 0.027 0) was significantly higher than that of the DSS group (0.005 6 ± 0.003 7)(P Bcorl1, Cacna1c, Rspo2 and Foxo3 were potential target genes of miR-155 in the AOM-DSS mouse model. Changes of Kcna1 and Cacna1c in the AOM-DSS mouse model were validated to be consistent with the changes obtained with the gene expression microarray. The up-regulation of miR-155 is related to colitis-associated carcinogenesis, but is irrelevant to chronic inflammation in the

  19. Aberrant Hypermethylation of SALL3 with HPV Involvement Contributes to the Carcinogenesis of Cervical Cancer.

    Directory of Open Access Journals (Sweden)

    Xing Wei

    Full Text Available This study aimed to investigate the methylation status of the promoter region of spalt-like transcription factor 3 (SALL3 and the expression of SALL3 in cervical cancer to explore the function of this gene in cervical cancer carcinogenesis.The methylation status of SALL3 was detected by methylation-specific PCR, and SALL3 gene expression was assessed by real-time quantitative PCR in the cervical cancer cell lines, SiHa, HeLa and C33A, as well as in cervical cancer tissue samples (n = 23, matched pericarcinomatous tissue samples (n = 23 and normal cervix tissue samples (n = 17. MTT was used to measure the cell viability and proliferation capacity of SiHa and HeLa cells.The SALL3 promoter was completely methylated in SiHa cells, unmethylated in C33A cells and partially methylated in HeLa cells. After treatment of SiHa and HeLa cells with 5 μM and 10 μM of 5-Azacytidine (5-Aza, respectively, the methylation level of the SALL3 promoter decreased and observed increase in the degree of unmethylation in a dose-dependent manner. Moreover, the relative expression of SALL3 mRNA increased as the concentration of 5-Aza increased in SiHa (p<0.05 and HeLa (p<0.05 cells. This above-mentioned increase in SALL3 mRNA in SiHa cells was more remarkable than that observed in HeLa cells. Cell proliferation capacity also decreased after administration of 5-Aza to SiHa and HeLa cells (p<0.05. Methylation of the SALL3 promoter was observed in 15 of 23 (65.21% cervical cancer tissue samples, 15 of 23 (65.21% matched pericarcinomatous tissue samples and 5 of 17 (29.41% normal cervical tissue samples (p<0.05. SALL3 mRNA expression was significantly lower in cervical cancer and pericarcinomatous tissues compared with normal cervical tissues (p<0.05. In all cervix tissue samples, HPV infection was positively associated with hypermethylation of the promoter region of SALL3 (p<0.05, r = 0.408, and the expression of SALL3 mRNA in HPV-positive tissues was lower than that in

  20. Bladder carcinogenesis in rats subjected to ureterosigmoidostomy and treated with L-lysine.

    Science.gov (United States)

    Dornelas, Conceição Aparecida; Santos, Alessandra Marques Dos; Correia, Antonio Lucas Oliveira; Juanes, Camila de Carvalho; Coelho, João Paulo Ferreira; Cunha, Bianca Lopes; Maciel, André Vinicius Vieira; Jamacaru, Francisco Vagnaldo Fechine

    2016-01-01

    to evaluate the effect of L-lysine in the bladder and intestinal epithelia in rats submitted to vesicosigmoidostomy. we divided forty Wistar rats into four groups: group I - control group (Sham); group II - submitted to vesicosigmoidostomy and treated with L-lysine 150mg/kg; group III - submitted only to vesicosigmoidostomy; and group IV - received L-lysine 150mg/kg. After eight weeks the animals were sacrificed. in the bladders of all operated animals we observed simple, papillary and nodular hyperplasia of transitional cells, transitional cell papillomas and squamous metaplasia. As for the occurrence of aberrant crypt foci in the colons of operated animals, we did not observe statistically significant differences in any of the distal, proximal and medium fragments, or in all fragments together (p=1.0000). Although statistically there was no promotion of carcinogenesis in the epithelia of rats treated with L-lysine in the observed time, it was clear the histogenesis of bladder carcinogenesis in its initial phase in all operated rats, this being probably associated with chronic infection and tiny bladder stones. o objetivo deste trabalho é avaliar o efeito da L-lisina nos epitélios vesical e intestinal de ratas submetidas à vesicossigmoidostomia. quarenta ratas Wistar, foram divididas em quatro grupos: grupo I- grupo controle (Sham); grupo II- submetido à vesicossigmoidostomia e tratado com L-lisina 150mg/kg; grupo III- submetido apenas à vesicossigmoidostomia; e grupo IV- recebeu L-lisina 150mg/kg. Após oito semanas os animais foram sacrificados. na bexiga de todos os animais operados observou-se hiperplasia simples, papilar e nodular de células transicionais, papiloma de células transicionais e metaplasia escamosa. Quanto à ocorrência de focos de criptas aberrantes nos colos dos animais operados, não foi evidenciado diferença estatística significante em nenhum dos fragmentos distal, proximal e médio, e todos juntos (P=1,0000). apesar de

  1. Role of infectious agents in the carcinogenesis of brain and head and neck cancers

    Directory of Open Access Journals (Sweden)

    Alibek Kenneth

    2013-02-01

    Full Text Available Abstract This review concentrates on tumours that are anatomically localised in head and neck regions. Brain cancers and head and neck cancers together account for more than 873,000 cases annually worldwide, with an increasing incidence each year. With poor survival rates at late stages, brain and head and neck cancers represent serious conditions. Carcinogenesis is a multi-step process and the role of infectious agents in this progression has not been fully identified. A major problem with such research is that the role of many infectious agents may be underestimated due to the lack of or inconsistency in experimental data obtained globally. In the case of brain cancer, no infection has been accepted as directly oncogenic, although a number of viruses and parasites are associated with the malignancy. Our analysis of the literature showed the presence of human cytomegalovirus (HCMV in distinct types of brain tumour, namely glioblastoma multiforme (GBM and medulloblastoma. In particular, there are reports of viral protein in up to 100% of GBM specimens. Several epidemiological studies reported associations of brain cancer and toxoplasmosis seropositivity. In head and neck cancers, there is a distinct correlation between Epstein-Barr virus (EBV and nasopharyngeal carcinoma (NPC. Considering that almost every undifferentiated NPC is EBV-positive, virus titer levels can be measured to screen high-risk populations. In addition there is an apparent association between human papilloma virus (HPV and head and neck squamous cell carcinoma (HNSCC; specifically, 26% of HNSCCs are positive for HPV. HPV type 16 was the most common type detected in HNSCCs (90% and its dominance is even greater than that reported in cervical carcinoma. Although there are many studies showing an association of infectious agents with cancer, with various levels of involvement and either a direct or indirect causative effect, there is a scarcity of articles covering the role of

  2. 2-deoxy-d-glucose (2-DG) inhibits radiation induced carcinogenesis (skin tumors) in mice

    International Nuclear Information System (INIS)

    Singh, Saurabh; Bhuria, Vikas; Pandey, Sanjay; Saluja, Daman; Dwarakanath, B.S.

    2014-01-01

    One of the late effects of radiation exposure i.e. carcinogenesis is exemplified by atomic bomb survivors, radiotherapy patients and occupational workers. Enhanced glucose metabolism (Warburg's effect) is a fundamental metabolic change in transformed cells which drives tumorigenesis. It is suggested that Dietary Energy Restriction (DER) that targets glucose metabolism may afford protection against radiation-induced carcinogenesis. However, DER is practically difficult to sustain in humans. Therefore, we have hypothesized that the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), a potential energy restriction mimetic agent (ERMA) may impair the process of tumorigenesis as an alternative to DER. In the present studies we investigated the effects of dietary 2-DG on radiation induced papillomas in mice. Swiss albino mice (male) were irradiated with a fractionated dose schedule (1.5 Gy ionizing radiation/week for four weeks) focally on the shaved back followed by the application of tumor promoting agent (TPA) once weekly till the termination of the study. Mice were administered 2-DG (0.2% and 0.4% w/v) containing water starting a week after last irradiation. A significant reduction in the tumor incidence, tumor burden, besides increase in the latency period was observed in the 2-DG fed mice. The average tumor incidence (papillomas formation) was reduced to 25% and 37% in 0.2% and 0.4% 2-DG group respectively from 47% in the control group with a significant delay in the onset. Under these conditions, 2-DG considerably enhanced the level of reduced glutathione (GSH) with a concomitant decrease in the lipid peroxidation. 2-DG fed tumor bearing mice showed decrease in splenic CD4 + to CD8 + T-cell ratio and prevented the tumor induced augmentation of T-regulatory cells (CD4 + CD25 + ) which correlated with an increase in CD8 + (CTLs) cells. Dietary 2-DG also reduced the tumor associated and radiation induced angiogenesis. These observations suggest that dietary 2-DG

  3. Molecular Population Genetics.

    Science.gov (United States)

    Casillas, Sònia; Barbadilla, Antonio

    2017-03-01

    Molecular population genetics aims to explain genetic variation and molecular evolution from population genetics principles. The field was born 50 years ago with the first measures of genetic variation in allozyme loci, continued with the nucleotide sequencing era, and is currently in the era of population genomics. During this period, molecular population genetics has been revolutionized by progress in data acquisition and theoretical developments. The conceptual elegance of the neutral theory of molecular evolution or the footprint carved by natural selection on the patterns of genetic variation are two examples of the vast number of inspiring findings of population genetics research. Since the inception of the field, Drosophila has been the prominent model species: molecular variation in populations was first described in Drosophila and most of the population genetics hypotheses were tested in Drosophila species. In this review, we describe the main concepts, methods, and landmarks of molecular population genetics, using the Drosophila model as a reference. We describe the different genetic data sets made available by advances in molecular technologies, and the theoretical developments fostered by these data. Finally, we review the results and new insights provided by the population genomics approach, and conclude by enumerating challenges and new lines of inquiry posed by increasingly large population scale sequence data. Copyright © 2017 Casillas and Barbadilla.

  4. Magnetismo Molecular (Molecular Magentism)

    Energy Technology Data Exchange (ETDEWEB)

    Reis, Mario S [Universidade Federal Fluminense, Brasil; Moreira Dos Santos, Antonio F [ORNL

    2010-07-01

    The new synthesis processes in chemistry open a new world of research, new and surprising materials never before found in nature can now be synthesized and, as a wonderful result, observed a series of physical phenomena never before imagined. Among these are many new materials the molecular magnets, the subject of this book and magnetic properties that are often reflections of the quantum behavior of these materials. Aside from the wonderful experience of exploring something new, the theoretical models that describe the behavior these magnetic materials are, in most cases, soluble analytically, which allows us to know in detail the physical mechanisms governing these materials. Still, the academic interest in parallel this subject, these materials have a number of properties that are promising to be used in technological devices, such as in computers quantum magnetic recording, magnetocaloric effect, spintronics and many other devices. This volume will journey through the world of molecular magnets, from the structural description of these materials to state of the art research.

  5. Mammary carcinogenesis induced by three consecutive 14 MeV neutron irradiations in Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Jacrot, M.; Mouriquand, J.; Mouriquand, C.

    1978-01-01

    At high doses (400 to 800 rads) the relative biological effectiveness (R.B.E.) of neutrons is two or three times greater than that of X-rays or gamma radiation. The neutron irradiation-induced mammary carcinogenesis threshold, if any, is certainly very low in Sprague-Dawley females. The purpose of this work is to test the possibilities offered by three consecutive 14 MeV neutron irradiations in the mammary carcinogenesis region of Sprague-Dawley rats. The results of these experiments show a hormone-dependence of tumour promotion similar to that observed with chemical carcinogenetic agents. However these tumours, by their recurrences and possible metastases, bear some resemblance to breast cancers in women. Although the tumour induction frequencies seem modest in relation to those obtained with the DMBA model they should nevertheless prove very useful in the study of hormone effects liable to control the appearance of such radioinduced cancers [fr

  6. Chemopreventive effect of Cynodon dactylon (L.) Pers. extract against DMH-induced colon carcinogenesis in experimental animals.

    Science.gov (United States)

    Albert-Baskar, Arul; Ignacimuthu, Savarimuthu

    2010-07-01

    The present study was aimed at evaluating the chemopreventive property of Cynodon dactylon. The antioxidant, antiproliferative and apoptotic potentials of the plant were investigated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, nitric oxide radical scavenging activity (NO(-)) and MTT assay on four cancer cell lines (COLO 320 DM, MCH-7, AGS, A549) and a normal cell line (VERO). In vivo chemopreventive property of the plant extract was studied in DMH-induced colon carcinogenesis. The methanolic extract of C. dactylon was found to be antiproliferative and antioxidative at lower concentrations and induced apoptotic cell death in COLO 320 DM cells. Treatment with methanolic extract of C. dactylon increased the levels of antioxidant enzymes and reduced the number of dysplastic crypts in DMH-induced colon of albino rats. The present investigation revealed the anticancer potential of methanolic extract of C. dactylon in COLO 320 DM cells and experimentally induced colon carcinogenesis in rats.

  7. Conceptions of Parents, Conceptions of Self, and Conceptions of God.

    Science.gov (United States)

    Buri, John R.; Mueller, Rebecca A.

    Different theorists have suggested that an individual's view of God may be related to one's view of one's father, one's mother, or one's self. A study was conducted to examine the relationship of college students' conceptions of the wrathfulness-kindliness of God to their conceptions of their father's and mother's permissiveness, authoritarianism,…

  8. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis

    Science.gov (United States)

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-01-01

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways. PMID:28277539

  9. Protein Kinases and Transcription Factors Activation in Response to UV-Radiation of Skin: Implications for Carcinogenesis

    OpenAIRE

    Laurence A. Marchat; Elena Aréchaga Ocampo; Mavil López Casamichana; Carlos Pérez-Plasencia; César López-Camarillo; Elizbeth Álvarez-Sánchez

    2011-01-01

    Solar ultraviolet (UV) radiation is an important environmental factor that leads to immune suppression, inflammation, photoaging, and skin carcinogenesis. Here, we reviewed the specific signal transduction pathways and transcription factors involved in the cellular response to UV-irradiation. Increasing experimental data supporting a role for p38, MAPK, JNK, ERK1/2, and ATM kinases in the response network to UV exposure is discussed. We also reviewed the participation of NF-?B, AP-1, and NRF2...

  10. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji, E-mail: tmntt08@gmail.com [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Mori, Takayuki [Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502 (Japan); Watanabe, Naoki [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Naiki, Takafumi [Department of Clinical Laboratory, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513 (Japan); Moriwaki, Hisataka [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi [The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501 (Japan)

    2014-07-21

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.

  11. Effects of dietary beef, pork, chicken and salmon on intestinal carcinogenesis in A/J Min/+ mice.

    Directory of Open Access Journals (Sweden)

    Christina Steppeler

    Full Text Available The International Agency for Research on Cancer has classified red meat as "probably carcinogenic to humans" (Group 2A. In mechanistic studies exploring the link between intake of red meat and CRC, heme iron, the pigment of red meat, is proposed to play a central role as a catalyzer of luminal lipid peroxidation and cytotoxicity. In the present work, the novel A/J Min/+ mouse was used to investigate the effects of dietary beef, pork, chicken, or salmon (40% muscle food (dry weight and 60% powder diet on Apc-driven intestinal carcinogenesis, from week 3-13 of age. Muscle food diets did not differentially affect carcinogenesis in the colon (flat ACF and tumors. In the small intestine, salmon intake resulted in a lower tumor size and load than did meat from terrestrial animals (beef, pork or chicken, while no differences were observed between the effects of white meat (chicken and red meat (pork and beef. Additional results indicated that intestinal carcinogenesis was not related to dietary n-6 polyunsaturated fatty acids, intestinal formation of lipid peroxidation products (thiobarbituric acid reactive substances, TBARS, or cytotoxic effects of fecal water on Apc-/+ cells. Notably, the amount of heme reaching the colon appeared to be relatively low in this study. The greatest tumor load was induced by the reference diet RM1, underlining the importance of the basic diets in experimental CRC. The present study in A/J Min/+ mice does not support the hypothesis of a role of red meat in intestinal carcinogenesis.

  12. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis.

    Science.gov (United States)

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-03-09

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.

  13. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    International Nuclear Information System (INIS)

    Tanaka, Takuji; Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei; Mori, Takayuki; Watanabe, Naoki; Naiki, Takafumi; Moriwaki, Hisataka; Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi

    2014-01-01

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation

  14. Interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway in renal carcinogenesis of uninephrectomized rats.

    Science.gov (United States)

    Yang, Ke-Ke; Sui, Yi; Zhou, Hui-Rong; Zhao, Hai-Lu

    2017-05-01

    Renin-angiotensin system and adenosine monophosphate-activated protein kinase signaling pathway both play important roles in carcinogenesis, but the interplay of renin-angiotensin system and adenosine monophosphate-activated protein kinase in carcinogenesis is not clear. In this study, we researched the interaction of renin-angiotensin system and adenosine monophosphate-activated protein kinase in renal carcinogenesis of uninephrectomized rats. A total of 96 rats were stratified into four groups: sham, uninephrectomized, and uninephrectomized treated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Renal adenosine monophosphate-activated protein kinase and its downstream molecule acetyl coenzyme A carboxylase were detected by immunohistochemistry and western blot at 10 months after uninephrectomy. Meanwhile, we examined renal carcinogenesis by histological transformation and expressions of Ki67 and mutant p53. During the study, fasting lipid profiles were detected dynamically at 3, 6, 8, and 10 months. The results indicated that adenosine monophosphate-activated protein kinase expression in uninephrectomized rats showed 36.8% reduction by immunohistochemistry and 89.73% reduction by western blot. Inversely, acetyl coenzyme A carboxylase expression increased 83.3% and 19.07% in parallel to hyperlipidemia at 6, 8, and 10 months. The histopathology of carcinogenesis in remnant kidneys was manifested by atypical proliferation and carcinoma in situ, as well as increased expressions of Ki67 and mutant p53. Intervention with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker significantly prevented the inhibition of adenosine monophosphate-activated protein kinase signaling pathway and renal carcinogenesis in uninephrectomized rats. In conclusion, the novel findings suggest that uninephrectomy-induced disturbance in adenosine monophosphate-activated protein kinase signaling pathway resulted in hyperlipidemia and

  15. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Xiaojun [The Methodist Hospital Research Institute, Houston, TX 77030 (United States); Park, Eunmi [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 (United States); Fischer, Susan M. [Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78967 (United States); Hu, Yinling, E-mail: huy2@mail.nih.gov [Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701 (United States)

    2013-02-15

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside.

  16. Monitoring Autophagy Immunohistochemically and Ultrastructurally during Human Head and Neck Carcinogenesis. Relationship with the DNA Damage Response Pathway †

    Science.gov (United States)

    Havaki, Sophia; Vlachou, Vassiliki; Zampetidis, Christos P.; Selemenakis, Platonas; Kotsinas, Athanassios; Mavrogonatou, Eleni; Rizou, Sophia V.; Kyrodimos, Euthymios; Evangelou, Konstantinos; Kletsas, Dimitris; Giatromanolaki, Alexandra; Gorgoulis, Vassilis G.

    2017-01-01

    Autophagy is a catabolic process that preserves cellular homeostasis. Its exact role during carcinogenesis is not completely defined. Specifically in head and neck cancer, such information from clinical settings that comprise the whole spectrum of human carcinogenesis is very limited. Towards this direction, we examined the in situ status of the autophagy-related factors, Beclin-1, microtubule-associated protein 1 light chain 3, member B (LC3B) and sequestosome 1/p62 (p62) in clinical material covering all histopathological stages of human head and neck carcinogenesis. This material is unique as each panel of lesions is derived from the same patient and moreover we have previously assessed it for the DNA damage response (DDR) activation status. Since Beclin-1, LC3B and p62 reflect the nucleation, elongation and degradation stages of autophagy, respectively, their combined immunohistochemical (IHC) expression profiles could grossly mirror the autophagic flux. This experimental approach was further corroborated by ultrastructural analysis, applying transmission electron microscopy (TEM). The observed Beclin-1/LC3B/p62 IHC patterns, obtained from serial sections analysis, along with TEM findings are suggestive of a declined authophagic activity in preneoplastic lesions that was restored in full blown cancers. Correlating these findings with DDR status in the same pathological stages are indicative of: (i) an antitumor function of autophagy in support to that of DDR, possibly through energy deprivation in preneoplastic stages, thus preventing incipient cancer cells from evolving; and (ii) a tumor-supporting role in the cancerous stage. PMID:28880214

  17. Strawberry Phytochemicals Inhibit Azoxymethane/Dextran Sodium Sulfate-Induced Colorectal Carcinogenesis in Crj: CD-1 Mice

    Directory of Open Access Journals (Sweden)

    Ni Shi

    2015-03-01

    Full Text Available Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg−1 body weight. One week after injection, mice were administered 2% (w/v dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05. The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

  18. Mouse Genetic Models Reveal Surprising Functions of IκB Kinase Alpha in Skin Development and Skin Carcinogenesis

    International Nuclear Information System (INIS)

    Xia, Xiaojun; Park, Eunmi; Fischer, Susan M.; Hu, Yinling

    2013-01-01

    Gene knockout studies unexpectedly reveal a pivotal role for IκB kinase alpha (IKKα) in mouse embryonic skin development. Skin carcinogenesis experiments show that Ikkα heterozygous mice are highly susceptible to chemical carcinogen or ultraviolet B light (UVB) induced benign and malignant skin tumors in comparison to wild-type mice. IKKα deletion mediated by keratin 5 (K5).Cre or K15.Cre in keratinocytes induces epidermal hyperplasia and spontaneous skin squamous cell carcinomas (SCCs) in Ikkα floxed mice. On the other hand, transgenic mice overexpressing IKKα in the epidermis, under the control of a truncated loricrin promoter or K5 promoter, develop normal skin and show no defects in the formation of the epidermis and other epithelial organs, and the transgenic IKKα represses chemical carcinogen or UVB induced skin carcinogenesis. Moreover, IKKα deletion mediated by a mutation, which generates a stop codon in the Ikkα gene, has been reported in a human autosomal recessive lethal syndrome. Downregulated IKKα and Ikkα mutations and deletions are found in human skin SCCs. The collective evidence not only highlights the importance of IKKα in skin development, maintaining skin homeostasis, and preventing skin carcinogenesis, but also demonstrates that mouse models are extremely valuable tools for revealing the mechanisms underlying these biological events, leading our studies from bench side to bedside

  19. Life-shortening and carcinogenesis in mice irradiated neonatally with x rays

    International Nuclear Information System (INIS)

    Sasaki, S.; Kasuga, T.

    1981-01-01

    The characteristics of life-shortening and carcinogenesis were investigated in x-irradiated neonatal B6WFr mice. Animals were irradiated with 24 hr after birth and allowed to complete their normal life span. Mean life span was shortened linearly with doses at a rate of 9.1% per 100 R for females and 9.8% for males. The spectrum of neoplastic diseases was apparently modulated by x irradiation, showing neonatal B6WFr mice to be highly susceptible to the induction of thymic lymphoma, liver tumor, and pituitary tumor. The dose-response relationship for thymice lymphoma could be described by a linear-quadratic model, and linearity could be rejected. Thymic lymphoma developed after a short latent period, resulting in death between 100 and 450 days of age. Liver and pituitary tumors increased with increasing dose up to 400 R and decreased thereafter. The latent period for liver tumor development was apparently shortened with increasing doses. Pituitary tumor developed in excess only in females after a long latent period

  20. Genetic characteristics of mitochondrial DNA was associated with colorectal carcinogenesis and its prognosis.

    Directory of Open Access Journals (Sweden)

    Jae-Ho Lee

    Full Text Available Clinical value of mitochondrial DNA has been described in colorectal cancer (CRC. To clarify its role in colorectal carcinogenesis, mitochondrial microsatellite instability (mtMSI and other markers were investigated in CRCs and their precancerous lesions, as a multitier genetic study. DNA was isolated from paired normal and tumoral tissues in 78 tubular adenomas (TAs, 34 serrated polyps (SPs, and 100 CRCs. mtMSI, nucleus microsatellite instability (nMSI, KRAS mutation, and BRAF mutation were investigated in these tumors and their statistical analysis was performed. mtMSI was found in 30% of CRCs and 21.4% of precancerous lesions. Mitochondrial copy number was higher in SPs than TAs and it was associated with mtMSI in low grade TAs. KRAS and BRAF mutations were mutually exclusive in TAs and SPs. CRCs with mtMSI showed shorter overall survival times than the patients without mtMSI. In CRCs without nMSI or BRAF mutation, mtMSI was a more accurate marker for predicting prognosis. The genetic change of mitochondrial DNA is an early and independent event in colorectal precancerous lesions and mtMSI and mitochondrial contents are associated with the tubular adenoma-carcinoma sequence, resulting in poor prognosis. This result suggested that the genetic change in mitochondrial DNA appears to be a possible prognosis marker in CRC.

  1. Test of the linear-no threshold theory of radiation carcinogenesis for inhaled radon decay products

    International Nuclear Information System (INIS)

    Cohen, B.L.

    1995-01-01

    Data on lung cancer mortality rates vs. average radon concentration in homes for 1,601 U.S. counties are used to test the linear-no threshold theory. The widely recognized problems with ecological studies, as applied to this work, are addressed extensively. With or without corrections for variations in smoking prevalence, there is a strong tendency for lung cancer rates to decrease with increasing radon exposure, in sharp contrast to the increase expected from the theory. The discrepancy in slope is about 20 standard deviations. It is shown that uncertainties in lung cancer rates, radon exposures, and smoking prevalence are not important and that confounding by 54 socioeconomic factors, by geography, and by altitude and climate can explain only a small fraction of the discrepancy. Effects of known radon-smoking prevalence correlations - rural people have higher radon levels and smoke less than urban people, and smokers are exposed to less radon than non-smokers - are calculated and found to be trivial. In spite of extensive efforts, no potential explanation for the discrepancy other than failure of the linear-no threshold theory for carcinogenesis from inhaled radon decay products could be found. (author)

  2. MicroRNA-7/NF-κB signaling regulatory feedback circuit regulates gastric carcinogenesis

    Science.gov (United States)

    Zhao, Xiao-Di; Lu, Yuan-Yuan; Guo, Hao; Xie, Hua-Hong; He, Li-Jie; Shen, Gao-Fei; Zhou, Jin-Feng; Li, Ting; Hu, Si-Jun; Zhou, Lin; Han, Ya-Nan; Liang, Shu-Li; Wang, Xin; Wu, Kai-Chun; Shi, Yong-Quan; Nie, Yong-Zhan

    2015-01-01

    MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of miR-7 repressed RELA and FOS expression and prevented GC cell proliferation and tumorigenesis. These effects were clinically relevant, as low miR-7 expression was correlated with high RELA and FOS expression and poor survival in GC patients. Intriguingly, we found that miR-7 indirectly regulated RELA activation by targeting the IκB kinase IKKε. Furthermore, IKKε and RELA can repress miR-7 transcription, which forms a feedback circuit between miR-7 and nuclear factor κB (NF-κB) signaling. Additionally, we demonstrate that down-regulation of miR-7 may occur as a result of the aberrant activation of NF-κB signaling by Helicobacter pylori infection. These findings suggest that miR-7 may serve as an important regulator in GC development and progression. PMID:26261179

  3. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Marilanda Ferreira Bellini

    2012-01-01

    Full Text Available TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH, overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development.

  4. Differential protective effects of red wine polyphenol extracts (RWEs) on colon carcinogenesis.

    Science.gov (United States)

    Mazué, Frédéric; Delmas, Dominique; Murillo, Genoveva; Saleiro, Diana; Limagne, Emeric; Latruffe, Norbert

    2014-04-01

    Various epidemiological studies have shown that a regular and moderate consumption of red wine is correlated with a decreased relative risk of developing coronary heart disease and cancer. These health benefits are commonly attributed to high contents of polyphenols, particularly resveratrol, representing important sources of antioxidants. However, resveratrol does not seem to be the only bioactive compound present in the wine which contains numerous other polyphenols. The present study investigates the efficiency of red wine extracts (RWEs), containing different polyphenols, on colon cancer cell proliferation in vitro and on colonic aberrant crypt foci (ACF) in vivo. Proliferation, cell cycle analysis and incidence of ACF were monitored to examine the effects of RWEs. RWEs derived from a long vinification process exhibit superior anti-proliferative activity in colon cancer cells and prevent the appearance of ACF in mice. Interestingly, quercetin and resveratrol, representing two major bio-active polyphenols, exhibit synergistic anti-proliferative effects. These data suggest that the efficacy of RWEs on colon carcinogenesis may depend on the polyphenolic content, synergistic interaction of bio-active polyphenols and modulation of cellular uptake of polyphenols.

  5. Relation between radiation-induced tissue injury and its carcinogenesis of the rat small intestine

    Energy Technology Data Exchange (ETDEWEB)

    Tsubouchi, S [Aichi Cancer Center, Nagoya (Japan). Research Inst.; Matsuzawa, T

    1975-06-01

    This study was undertaken to make clear the relationships between radiation-induced tissue injury and its carcinogenesis in the rat small intestine. The abdomens of Wistar rats were irradiated locally with 1000 to 2000 rads. Approximately 2 months following irradiation, visible nodules were found in the intestines of the groups receiving irradiation. Nodule incidence was 80 to 100% in groups that received 1750 or 2000 rads, 50% in the 1500-rad groups, and 3% in the 1000-rad groups, respectively. The histology of the nodules within 70 days postirradiation, revealed adenomatous hyperplasia, including invasion of submucosa, muscle layers, and serosa of the small intestine accompanied by an area of fibrous tissue resulting from desmoplastic reaction by irradiation injury. The nodule within 140 to 300 days postirradiation induced advanced tissue injuried, that is, a polypoid lesion in histology and intestinal nodular adhesion in macroscopic anatomy. Running parallel with the advance of the above mentioned tissue injuries, the nodules in 3 out of 18 rat during 200 to 300 days postirradiation showed mucoid adenocarcinoma.

  6. Radionuclides in cigarettes may lead to carcinogenesis via p16INK4a inactivation

    International Nuclear Information System (INIS)

    Prueitt, Robyn L.; Goodman, Julie E.; Valberg, Peter A.

    2009-01-01

    It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including α-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16 INK4a (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated

  7. Radiation carcinogenesis. Progress report III, 15 March 1975--15 March 1976

    International Nuclear Information System (INIS)

    Warren, S.; Gates, O.

    1976-03-01

    The attention of forensic pathologists has been drawn to the criteria essential for the recognition of radiation death or injury in the hope that such cases will be better recognized and that some false claims of radiation damage might be prevented at the local level. The results of experiments on parabiont rats, one of which had been irradiated with 1000 R of 250 kVp x-ray, the other shielded, are reviewed. With controls and related special studies the total is over 3000 pairs equally divided as to sex. Much information on the relative sensitivity of different tissues and organs to tumor induction is available and is being statistically analyzed. These experiments have provided further evidence of the effectiveness of parabiosis in assuring survival after 1000 R x-radiation and have enabled us to learn of the types of problems that might be expected in the way of late effects in heavily irradiated individuals should they be enabled by effective therapy to survive the acute phases of the radiation syndrome. Additional evidence has been brought out that carcinogenesis in some hormonally dependent tissues and organs is not so much a direct effect of radiation as it is a summation of this effect and of alterations caused by changes in hormonal balance brought about by the radiation

  8. Role of environmental chemicals, processed food derivatives, and nutrients in the induction of carcinogenesis.

    Science.gov (United States)

    Persano, Luca; Zagoura, Dimitra; Louisse, Jochem; Pistollato, Francesca

    2015-10-15

    In recent years it has been hypothesized that cancer stem cells (CSCs) are the actual driving force of tumor formation, highlighting the need to specifically target CSCs to successfully eradicate cancer growth and recurrence. Particularly, the deregulation of physiological signaling pathways controlling stem cell proliferation, self-renewal, differentiation, and metabolism is currently considered as one of the leading determinants of cancer formation. Given their peculiar, slow-dividing phenotype and their ability to respond to multiple microenvironmental stimuli, stem cells appear to be more susceptible to genetic and epigenetic carcinogens, possibly undergoing mutations resulting in tumor formation. In particular, some animal-derived bioactive nutrients and metabolites known to affect the hormonal milieu, and also chemicals derived from food processing and cooking, have been described as possible carcinogenic factors. Here, we review most recent literature in this field, highlighting how some environmental toxicants, some specific nutrients and their secondary products can induce carcinogenesis, possibly impacting stem cells and their niches, thus causing tumor growth.

  9. Dietary Fiber Treatment Corrects the Composition of Gut Microbiota, Promotes SCFA Production, and Suppresses Colon Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Faraz Bishehsari

    2018-02-01

    Full Text Available Epidemiological studies propose a protective role for dietary fiber in colon cancer (CRC. One possible mechanism of fiber is its fermentation property in the gut and ability to change microbiota composition and function. Here, we investigate the role of a dietary fiber mixture in polyposis and elucidate potential mechanisms using TS4Cre × cAPCl°x468 mice. Stool microbiota profiling was performed, while functional prediction was done using PICRUSt. Stool short-chain fatty acid (SCFA metabolites were measured. Histone acetylation and expression of SCFA butyrate receptor were assessed. We found that SCFA-producing bacteria were lower in the polyposis mice, suggesting a decline in the fermentation product of dietary fibers with polyposis. Next, a high fiber diet was given to polyposis mice, which significantly increased SCFA-producing bacteria as well as SCFA levels. This was associated with an increase in SCFA butyrate receptor and a significant decrease in polyposis. In conclusion, we found polyposis to be associated with dysbiotic microbiota characterized by a decline in SCFA-producing bacteria, which was targetable by high fiber treatment, leading to an increase in SCFA levels and amelioration of polyposis. The prebiotic activity of fiber, promoting beneficial bacteria, could be the key mechanism for the protective effects of fiber on colon carcinogenesis. SCFA-promoting fermentable fibers are a promising dietary intervention to prevent CRC.

  10. Suppression of radiation-induced in vitro carcinogenesis by ascorbic acid

    International Nuclear Information System (INIS)

    Tauchi, Hiroshi; Sawada, Shozo

    1993-01-01

    The effects of ascorbic acid on radiation-induced in vitro carcinogenesis have been reported using neoplastic transformation system of C3H 10T1/2 cells. In these reports, no suppressive effect on X-ray-induced transformation was observed with 6 weeks' administration of ascorbic acid (daily addition for 5 days per week) by Kennedy (1984), whereas apparent suppression was observed with daily addition for 7 days by Yasukawa et al (1989). We have tested the effects of ascorbic acid on 60 Co gamma-ray or 252 Cf fission neutron-induced transformation in Balb/c 3T3 cells. The transformation induced by both types of radiations was markedly suppressed when ascorbic acid was daily added to the medium during first 8 days of the post-irradiation period. If ascorbic acid was added for a total of 8 days but with a day's interruption in the middle, the suppression of transformation was decreased. These results suggest that continuous presence of ascorbic acid for a certain number of days is needed to suppress radiation-induced transformation. Since ascorbic acid also suppressed the promotion of radiation-induced transformation by TPA when both chemicals were added together into the medium, ascorbic acid might act on the promotion stage of transformation. Therefore, the effect of ascorbic acid on the distribution of protein kinase C activity was also investigated, and possible mechanisms of suppression of radiation-induced transformation by ascorbic acid will be discussed. (author)

  11. Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development.

    Science.gov (United States)

    Liu, Yingwei; Song, Na; Ren, Kexing; Meng, Shenglan; Xie, Yao; Long, Qida; Chen, Xiancheng; Zhao, Xia

    2013-01-01

    RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (Pcancer cells, but 5-Aza couldn't. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.

  12. Critical pathogenic steps to high risk Helicobacter pylori gastritis and gastric carcinogenesis.

    Science.gov (United States)

    Lee, Inchul

    2014-06-07

    Helicobacter pylori (H. pylori) gastritis may progress to high risk gastropathy and cancer. However, the pathological progression has not been characterized in detail. H. pylori induce persistent inflammatory infiltration. Neutrophils are unique in that they directly infiltrate into foveolar epithelium aiming the proliferative zone specifically. Neutrophilic proliferative zone foveolitis is a critical pathogenic step in H. pylori gastritis inducing intensive epithelial damage. Epithelial cells carrying accumulated genomic damage and mutations show the Malgun (clear) cell change, characterized by large clear nucleus and prominent nucleolus. Malgun cells further undergo atypical changes, showing nuclear folding, coarse chromatin, and multiple nucleoli. The atypical Malgun cell (AMC) change is a novel premalignant condition in high risk gastropathy, which may progress and undergo malignant transformation directly. The pathobiological significance of AMC in gastric carcinogenesis is reviewed. A new diagnosis system of gastritis is proposed based on the critical pathologic steps classifying low and high risk gastritis for separate treatment modality. It is suggested that the regulation of H. pylori-induced neutrophilic foveolitis might be a future therapeutic goal replacing bactericidal antibiotics approach.

  13. Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination

    International Nuclear Information System (INIS)

    Anderson, Lucy M.

    2004-01-01

    The many physiological, biochemical, and structure differences between rodents and humans, especially with regard to gestation and fetal development, invite questions as to the utility of rodent models for the prediction of risk of perinatal carcinogenesis in humans and for extrapolation of mechanistic studies. Here, the relevance of basic generalities, derived from rodent perinatal studies, to human contexts is considered. The cross-species usefulness of these generalities was upheld by the example of carcinogen activation and detoxification as determining factors. These have been established in rodent studies and recently indicted in humans by investigations of genetic polymorphisms in cytochromes P450, N-acetyltransferase, myeloperoxidase, quinone reductase, and glutathione S-transferase. Also, published data have been analyzed comparatively for diethylstilbestrol and irradiation, the two known human transplacental carcinogenic agents. At similar doses to those experienced by humans, both diethylstilbestrol and X- and gamma-irradiation in rodents and dogs yielded increased tumors at rates similar to those for humans. In rodents, there was a clearly negative relationship between total diethylstilbestrol dose and tumors per dose unit, and a similar pattern was suggested for radiation. Diethylstilbestrol had transgenerational effects that did not diminish over three generations. Overall, this analysis of the published literature indicates that there are basic qualitative and quantitative similarities in the responsiveness of human and rodent fetuses to carcinogens, and that dose effects may be complex and in need of further investigation

  14. Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer.

    Directory of Open Access Journals (Sweden)

    Eva Pastille

    2017-09-01

    Full Text Available Inflammatory bowel diseases (IBD are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host's immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs. This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered.

  15. A Systematic Approach to Determining the Identifiability of Multistage Carcinogenesis Models.

    Science.gov (United States)

    Brouwer, Andrew F; Meza, Rafael; Eisenberg, Marisa C

    2017-07-01

    Multistage clonal expansion (MSCE) models of carcinogenesis are continuous-time Markov process models often used to relate cancer incidence to biological mechanism. Identifiability analysis determines what model parameter combinations can, theoretically, be estimated from given data. We use a systematic approach, based on differential algebra methods traditionally used for deterministic ordinary differential equation (ODE) models, to determine identifiable combinations for a generalized subclass of MSCE models with any number of preinitation stages and one clonal expansion. Additionally, we determine the identifiable combinations of the generalized MSCE model with up to four clonal expansion stages, and conjecture the results for any number of clonal expansion stages. The results improve upon previous work in a number of ways and provide a framework to find the identifiable combinations for further variations on the MSCE models. Finally, our approach, which takes advantage of the Kolmogorov backward equations for the probability generating functions of the Markov process, demonstrates that identifiability methods used in engineering and mathematics for systems of ODEs can be applied to continuous-time Markov processes. © 2016 Society for Risk Analysis.

  16. Radiation carcinogenesis. Progress report V, 16 May 1977--15 May 1978

    International Nuclear Information System (INIS)

    Warren, S.; Gates, O.

    1978-01-01

    Experiments are underway on the cocarcinogenic effects of asbestos and carcinogenic hydrocarbons using rats and mice as test objects. None of the protocols of these experiments have as yet been completed. The study of tumorigenesis in irradiated parabiont rats has been completed. Study of the benign tumors indicates that radiation is an effective neoplastic stimulus for only a limited number of organs and tissues, chiefly ovary, adrenal, mammary tissue, islands of Langerhans, and liver. In general the benign tumors did not seriously affect health, and in only a very few animals did they become malignant. The incidence of mali