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Sample records for neoplastic non-random transformation

  1. Neoplastic transformation of human cells

    NASA Technical Reports Server (NTRS)

    Goth-Goldstein, Regine

    1995-01-01

    The goal of this project was to gain a better understanding of the cellular mechanisms of cancer induction by ionizing radiation as a risk assessment for workers subjected to high LET irradiation such as that found in space. The following ions were used for irradiation: Iron, Argon, Neon, and Lanthanum. Two tests were performed: growth in low serum and growth in agar were used as indicators of cell transformation. The specific aims of this project were to: (1) compare the effectiveness of various ions on degree of transformation of a single dose of the same RBE; (2) determine if successive irradiations with the same ion (Ge 600 MeV/u) increases the degree of transformation; (3) test if clones with the greatest degree of transformation produce tumors in nude mice; and (4) construct a cell hybrid of a transformed and control (non-transformed) clone. The cells used for this work are human mammary epithelial cells with an extended lifespan and selected for growth in MEM + 10% serum.

  2. Neoplastic cell transformation by heavy ions.

    PubMed

    Suzuki, M; Watanabe, M; Suzuki, K; Nakano, K; Kaneko, I

    1989-12-01

    We have studied the induction of morphological transformation by heavy ions. Golden hamster embryo cells were irradiated with 95 MeV 14N ions (530 keV/microns), 22 MeV 4He ions (36 keV/microns), and 22 MeV 4He ions with a 100-microns Al absorber (77 keV/microns) which were generated by a cyclotron at the Institute of Physical and Chemical Research in Japan. Colonies were considered to contain neoplastically transformed cells when the cells were densely stacked and made a crisscross pattern. It was shown that the induction of transformation was much more effective with 14N and 4He ions than with gamma or X rays. The relative biological effectiveness (RBE) relative to 60Co gamma rays was 3.3 for 14N ions, 2.4 for 4He ions, and 3.3 for 4He ions with a 100-microns Al absorber. The relationship between RBE and linear energy transfer was qualitatively similar for both cell death and transformation. PMID:2594968

  3. Neoplastic transformation of immortalized human epidermal keratinocytes by ionizing radiation

    SciTech Connect

    Thraves, P.; Salehi, Z.; Dritschilo, A.; Rhim, J.S. )

    1990-02-01

    Efforts to investigate the progression of events that cause human cells to become neoplastic in response to ionizing radiation have been aided by the development of tissue culture systems of epithelial cells. In the present study, nontumorigenic human epidermal keratinocytes immortalized by adenovirus type 12 and simian virus 40 have been transformed by exposure to x-ray irradiation. Such transformants showed morphological alterations, formed colonies in soft agar, and induced carcinomas when transplanted into nude mice, whereas primary human epidermal keratinocytes exposed to radiation in this manner failed to show any evidence of transformation. These findings demonstrate the malignant transformation of human primary epithelial cells in culture by the combined action of a DNA tumor virus and radiation, indicating a multistep process for radiation-induced neoplastic conversion. This in vitro system may be useful as a tool for dissecting the process of radiation-induced neoplastic transformation of human epithelial cells and for detecting previously unreported human oncogenes.

  4. Neoplastic Transformation Induced by Carbon Ions

    SciTech Connect

    Bettega, Daniela Calzolari, Paola; Hessel, Petra; Stucchi, Claudio G.; Weyrather, Wilma K.

    2009-03-01

    Purpose: The objective of this experiment was to compare the oncogenic potential of carbon ion beams and conventional photon beams for use in radiotherapy. Methods and Materials: The HeLa X human skin fibroblast cell line CGL1 was irradiated with carbon ions of three different energies (270, 100, and 11.4 MeV/u). Inactivation and transformation data were compared with those for 15 MeV photons. Results: Inactivation and transformation frequencies for the 270 MeV/u carbon ions were similar to those for 15-MeV photons. The maximal relative biologic effectiveness (RBE{sub {alpha}}) values for 100MeV/u and 11.4 MeV/u carbon ions, respectively, were as follows: inactivation, 1.6 {+-} 0.2 and 6.7 {+-} 0.7; and transformation per surviving cell, 2.5 {+-} 0.6 and 12 {+-} 3. The curve for dose-transformation per cell at risk exhibited a maximum that was shifted toward lower doses at lower energies. Conclusions: Transformation induction per cell at risk for carbon ions in the entrance channel was comparable to that for photons, whereas for the lower energies, 100 MeV/u and 11 MeV/u, which are representative of the energies delivered to the tumor margins and volume, respectively, the probability of transformation in a single cell was greater than it was for photons. In addition, at isoeffective doses with respect to cell killing, the 11.4-MeV/u beam was more oncogenic than were photons.

  5. Neoplastic transformation and tumorigenesis by the human protooncogene MYC.

    PubMed Central

    Ramsay, G M; Moscovici, G; Moscovici, C; Bishop, J M

    1990-01-01

    Damage to the protooncogene MYC has been implicated in the genesis of diverse human tumors, but the tumorigenic potential of the isolated gene has been disputed. Here we report the use of a retroviral vector to test the potency of human MYC for neoplastic transformation in avian cells. We found that sustained and abundant expression of MYC can transform both embryonic fibroblasts and hematopoietic cells and elicit granulocytic leukemias in chickens. Transformation by MYC is accompanied by changes in diverse aspects of cellular phenotype, including morphology, ability to grow in suspension, rate of proliferation, the structure of the cytoskeleton, and the composition of the extracellular matrix. Nevertheless, the biological potency of MYC is inherently constrained when compared to that of the retroviral oncogene v-myc. Our findings enlarge on previous descriptions of neoplastic transformation by MYC and sustain the view that ungoverned expression of the gene can contribute to the genesis of human tumors. Images PMID:2156260

  6. Cellular neoplastic transformation induced by 916 MHz microwave radiation.

    PubMed

    Yang, Lei; Hao, Dongmei; Wang, Minglian; Zeng, Yi; Wu, Shuicai; Zeng, Yanjun

    2012-08-01

    There has been growing concern about the possibility of adverse health effects resulting from exposure to microwave radiations, such as those emitted by mobile phones. The purpose of this study was to investigate the cellular neoplastic transformation effects of electromagnetic fields. 916 MHz continuous microwave was employed in our study to simulate the electromagnetic radiation of mobile phone. NIH/3T3 cells were adopted in our experiment due to their sensitivity to carcinogen or cancer promoter in environment. They were divided randomly into one control group and three microwave groups. The three microwave groups were exposed to 916 MHz EMF for 2 h per day with power density of 10, 50, and 90 w/m(2), respectively, in which 10 w/m(2) was close to intensity near the antenna of mobile phone. The morphology and proliferation of NIH/3T3 cells were examined and furthermore soft agar culture and animal carcinogenesis assay were carried out to determine the neoplastic promotion. Our experiments showed NIH/3T3 cells changed in morphology and proliferation after 5-8 weeks exposure and formed clone in soft agar culture after another 3-4 weeks depending on the exposure intensity. In the animal carcinogenesis study, lumps developed on the back of SCID mice after being inoculated into exposed NIH/3T3 cells for more than 4 weeks. The results indicate that microwave radiation can promote neoplastic transformation of NIH/3T3cells. PMID:22395787

  7. Mechanisms of radiation-induced neoplastic cell transformation

    SciTech Connect

    Yang, T.C.H.; Tobias, C.A.

    1984-04-01

    Studies with cultured mammalian cells demonstrated clearly that radiation can transform cells directly and can enhance the cell transformation by oncogenic DNA viruses. In general, high-LET heavy-ion radiation can be more effective than X and gamma rays in inducing neoplastic cell transformation. Various experimental results indicate that radiation-induced DNA damage, most likely double-strand breaks, is important for both the initiation of cell transformation and for the enhancement of viral transformation. Some of the transformation and enhancement lesions can be repaired properly in the cell, and the amount of irrepairable lesions produced by a given dose depends on the quality of radiation. An inhibition of repair processes with chemical agents can increase the transformation frequency of cells exposed to radiation and/or oncogenic viruses, suggesting that repair mechanisms may play an important role in the radiation transformation. The progression of radiation-transformed cells appears to be a long and complicated process that can be modulated by some nonmutagenic chemical agents, e.g., DMSO. Normal cells can inhibit the expression of transforming properties of tumorigenic cells through an as yet unknown mechanism. The progression and expression of transformation may involve some epigenetic changes in the irradiated cells. 38 references, 15 figures, 1 table.

  8. Neoplastic transformation of human diploid fibroblast cells by chemical carcinogens

    PubMed Central

    Kakunaga, Takeo

    1978-01-01

    Cultured fibroblast cells derived from a skin biopsy sample taken from normal human adult were exposed to a potent carcinogen, 4-nitroquinoline 1-oxide. Alterations of cell growth pattern such as higher density and piling up of cells were noticed in some fractions of cultures that were successively subcultured after nitroquinoline oxide treatment. Morphologically altered cells retained this growth pattern and became established lines of transformed cells without showing the limited life-span characteristic of normal cells in culture. The transformed cells showed a higher saturation density and the ability to grow in soft agar, properties that are usually correlated with neoplastic transformation of cells in culture. Selection of preexisting transformed human cells as a mechanism of this observed transformation seemed unlikely because clones of these normal cells could also be used to assess the transforming effect of nitroquinoline oxide. Preliminary results suggest that numerous cell divisions were required for the development of the transformation after nitroquinoline oxide treatment of these human cells. When the transformed cell lines were injected subcutaneously into nude (athymic) mice, solid tumors were produced at the site of inoculation. Treatment with N-methyl-N′-nitro-N-nitrosoguanidine also induced cell transformation, in a manner similar to treatment with nitroquinoline oxide. However, transformation was not induced with (i) 4-aminoquinoline 1-oxide (a noncarcinogenic derivative of 4-nitroquinoline 1-oxide), (ii) 3-methylcholanthrene (a carcinogen that cannot be metabolically activated by the target cells employed), or (iii) the solvent dimethyl sulfoxide. Images PMID:418410

  9. Neoplastic cell transformation by high-LET radiation: Molecular mechanisms

    NASA Astrophysics Data System (ADS)

    Chui-Hsu Yang, Tracy; Craise, Laurie M.; Mei, Man-Tong; Tobias, Cornelius A.

    Experimental data on molecular mechanisms are essential for understanding the bioeffects of radiation and for developing biophysical models, which can help in determining the shape of dose-response curves at very low doses, e.g., doses less than 1 cGy. Although it has been shown that ionizing radiation can cause neoplastic cell transformation directly, that high-LET heavy ions in general can be more effective than photons in transforming cells, and that the radiogenic cell transformation is a multi-step processes, we know very little about the molecular nature of lesions important for cell transformation, the relationship between lethal and transformational damages, and the evolution of initial damages into final chromosomal aberrations which alter the growth control of cells. Using cultured mouse embryo cells (C3H10T1/2) as a model system, we have collected quantitative data on dose-response curves for heavy ions with various charges and energies. An analysis of these quantitative data suggested that two DNA breaks formed within 80 Å may cause cell transformation and that two DNA breaks formed within 20 Å may be lethal. Through studies with restriction enzymes which produce DNA damages at specific sites, we have found that DNA double strand breaks, including both blunt- and cohesive-ended breaks, can cause cell transformation in vitro. These results indicate that DNA double strand breaks can be important primary lesions for radiogenic cell transformation and that blunt-ended double strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship is similar for HGPRT gene mutation, chromosomal deletion, and cell transformation, suggesting common lesions may be involved in these radiation effects. The high RBE of high-LET radiation for cell killing and neoplastic cell transformation is most likely related to its effectiveness in producing DNA double strand breaks in mammalian cells. At

  10. Inhibition of neoplastic transformation and bioavailability of dietary flavonoid agents.

    PubMed

    Franke, A A; Cooney, R V; Custer, L J; Mordan, L J; Tanaka, Y

    1998-01-01

    Evaluation of unknown biological effects of chemicals including food plant products requires the assessment of bioactivity and bioavailability. Epidemiologic studies show consistently a cancer protective effect of fruit and vegetable consumption, but there is little understanding of which phytochemicals account for this observation. Commonly studied antioxidant micronutrients are less consistently correlated with cancer protection relative to the food groups themselves, suggesting that other phytochemicals or a combination of food products play key roles in preventing cancer. We investigated the effects of the predominant dietary flavonoids and isoflavonoids at inhibiting neoplastic transformation induced by 3-methylcholanthrene in C3H 10T1/2 murine fibroblasts. We found that most phenolic agents tested were equal to or superior to known chemopreventive agents such as carotenoids or vitamins in effectiveness. Hesperetin, hesperidin and catechin were the most potent agents among the flavonoids tested, inhibiting transformation completely when applied at 1.0 microM after exposure to the carcinogen. Structure-activity comparison revealed that among the compounds tested, flavonoids with a vicinal diphenol structure in ring 'B' and a saturated 'C' ring exhibited the strongest effects. Most agents tested showed dose-dependent patterns. Interestingly, the soy isoflavonoids were weakly active except when applied in combination, suggesting a synergistic effect. In addition, HPLC techniques were developed for determining the bioavailability of isoflavonoids in human biological fluids including urine, plasma and breast milk. We observed a relatively fast absorption, distribution and elimination of isoflavonoids including a biphasic pattern probably due to enterohepatic circulation. Total peak isoflavone levels in urine, plasma and in breast milk were found to be 60 microM, 2 microM and 0.2 microM, respectively and were reached 8-12 hours after consumption of soy foods. Levels

  11. The melanocyte differentiation program predisposes to metastasis following neoplastic transformation.

    PubMed Central

    Gupta, Piyush B.; Kuperwasser, Charlotte; Brunet, Jean-Philippe; Ramaswamy, Sridhar; Kuo, Wen-Lin; Gray, Joe W.; Naber, Stephen P.; Weinberg, Robert A.

    2006-01-01

    The aggressive clinical behavior of melanoma has led to the hypothesis that the developmental origins of melanocytes in the neural crest might be relevant for their metastatic propensity. We demonstrate that primary human melanocytes, transformed using a specific set of introduced genes, form melanomas that frequently metastasize to multiple secondary sites, while human fibroblasts and epithelial cells transformed using an identical set of genes generate primary tumors that rarely do so. Importantly, these melanomas exhibit a metastasis spectrum similar to that observed in human patients. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes and not in other cell types analyzed. Analysis of microarray data from human nevi reveals that Slug, a master regulator of neural crest cell specification and migration, correlates in its expression pattern with other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present prior to neoplastic transformation can play a pivotal role in governing melanoma's progression. PMID:16142232

  12. Relationship of Chromosome Changes to Neoplastic Cell Transformation

    PubMed Central

    DiPaolo, Joseph A.; Popescu, Nicolae C.

    1976-01-01

    Chromosomal abnormalities are a frequent concomitant of neoplasia, and although it is tempting to relate these mutations and alterations in chromatin (DNA) function to cancer, their relationship to the initiation or progression of carcinogenesis is unknown. Mammalian cells in culture, after interacting with chemical carcinogens, often exhibit chromosome damage consisting of breaks and exchanges of chromatid material. The pattern of damage of banded metaphases indicates that negative bands are especially vulnerable to the action of chemical carcinogens, probably because of differential chromatin condensation. Damage to individual chromosomes may be random or nonrandom, depending on the species. Cell death can be correlated with chromatid alterations that occur shortly after treatment with chemical carcinogens. There is also a correlation between mutagenic and carcinogenic activity of some chemical carcinogens and the frequency of sister chromatid exchanges. The question of whether specific chromosome changes are absolutely required for neoplastic transformation cannot be answered because of conflicting data and diverse results from studies even with known carcinogens. Cell transformation may occur without any visible chromosome changes. A universal specific numerical or visible structural chromosomal alteration is not necessarily associated with chemical or viral transformation. Chromosome changes are independent of the etiologic agents: different carcinogens may produce transformation associated with the same abnormal chromosomes, but not all transformed lines invariably exhibit the same abnormality, even with the same chemical. In some species, chromosome having nucleolar organizer regions may be more frequently involved in numerical or structural deviations. Progressively growing tumors also may occur as a result of the proliferation of transformed cells without detectable chromosome changes, indicating that tumorigenicity need not be related to an imbalance of

  13. Low Dose Suppression of Neoplastic Transformation in Vitro

    SciTech Connect

    John Leslie Redpath

    2012-05-01

    This grant was to study the low dose suppression of neoplastic transformation in vitro and the shape of the dose-response curve at low doses and dose-rates of ionizing radiation. Previous findings had indicated a suppression of transformation at dose <10cGy of low-LET radiation when delivered at high dose-rate. The present study indicates that such suppression extends out to doses in excess of 100cGy when the dose (from I-125 photons) is delivered at dose-rates as low as 0.2 mGy/min and out to in excess of {approx}25cGy the highest dose studied at the very low dose-rate of 0.5 mGy/day. We also examined dose-rate effects for high energy protons (which are a low-LET radiation) and suppression was evident below {approx}10cGy for high dose-rate delivery and at least out to 50cGy for low dose-rate (20cGy/h) delivery. Finally, we also examined the effect of low doses of 1 GeV/n iron ions (a high-LET radiation) delivered at high dose-rate on transformation at low doses and found a suppression below {approx}10cGy that could be attributable to an adaptive response in bystander cells induced by the associated low-LET delta rays. These results have implications for cancer risk assessment at low doses.

  14. Kinetic Modeling of Damage Repair, Genome Instability, and Neoplastic Transformation

    SciTech Connect

    Stewart, Robert D

    2007-03-17

    Inducible repair and pathway interactions may fundamentally alter the shape of dose-response curves because different mechanisms may be important under low- and high-dose exposure conditions. However, the significance of these phenomena for risk assessment purposes is an open question. This project developed new modeling tools to study the putative effects of DNA damage induction and repair on higher-level biological endpoints, including cell killing, neoplastic transformation and cancer. The project scope included (1) the development of new approaches to simulate the induction and base excision repair (BER) of DNA damage using Monte Carlo methods and (2) the integration of data from the Monte Carlo simulations with kinetic models for higher-level biological endpoints. Methods of calibrating and testing such multiscale biological simulations were developed. We also developed models to aid in the analysis and interpretation of data from experimental assays, such as the pulsed-field gel electrophoresis (PFGE) assay used to quantity the amount of DNA damage caused by ionizing radiation.

  15. Neoplastic cell transformation by high-LET radiation - Molecular mechanisms

    NASA Technical Reports Server (NTRS)

    Yang, Tracy Chui-Hsu; Craise, Laurie M.; Tobias, Cornelius A.; Mei, Man-Tong

    1989-01-01

    Quantitative data were collected on dose-response curves of cultured mouse-embryo cells (C3H10T1/2) irradiated with heavy ions of various charges and energies. Results suggests that two breaks formed on DNA within 80 A may cause cell transformation and that two DNA breaks formed within 20 A may be lethal. From results of experiments with restriction enzymes which produce DNA damages at specific sites, it was found that DNA double strand breaks are important primary lesions for radiogenic cell transformation and that blunt-ended double-strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship for high-LET radiation is similar to that for HGPRT locus mutation, chromosomal deletion, and cell transformation, indicating that common lesions may be involved in these radiation effects.

  16. Neoplastic transformation of hamster embyro cells by heavy ions.

    PubMed

    Han, Z; Suzuki, H; Suzuki, F; Suzuki, M; Furusawa, Y; Kato, T; Ikenaga, M

    1998-01-01

    We have studied the induction of morphological transformation of Syrian hamster embryo cells by low doses of heavy ions with different linear energy transfer (LET), ranging from 13 to 400 keV/micrometer. Exponentially growing cells were irradiated with 12C or 28Si ion beams generated by the Heavy Ion Medical Accelerator in Chiba (HIMAC), inoculated to culture dishes, and transformed colonies were identified when the cells were densely stacked and showed a crisscross pattern. Over the LET range examined, the frequency of transformation induced by the heavy ions increased sharply at very low doses no greater than 5 cGy. The relative biological effectiveness (RBE) of the heavy ions relative to 250 kVp X-rays showed an initial increase with LET, reaching a maximum value of about 7 at 100 keV/micrometer, and then decreased with the further increase in LET. Thus, we confirmed that high LET heavy ions are significantly more effective than X-rays for the induction of in vitro cell transformation. PMID:11542417

  17. Neoplastic cell transformation by energetic heavy ions and its modification with chemical agents

    NASA Technical Reports Server (NTRS)

    Yang, T. C.; Tobias, C. A.

    1984-01-01

    One of the major deleterious late effects of ionizing radiation is related to the induction of neoplasms. In the present report recent experimental results on neoplastic cell transformation by heavy ions are presented, and possible means to circumvent the carcinogenic effect of space radiation are discussed. Biological effects observed in experiments involving the use of energetic heavy ions accelerated at the Bevalac suggest that many of the biological effects observed in earlier space flight experiments may be due to space radiation, particularly cosmic rays. It is found that the effect of radiation on cell transformation is dose-rate dependent. The frequency of neoplastic transformation for a given dose decreases with a decrease of dose rate of Co-60 gamma rays. It is found that various chemical agents give radiation protection, including DMSO.

  18. The Route to HPV-Associated Neoplastic Transformation: A Review of the Literature.

    PubMed

    Tulay, Pinar; Serakinci, Nedime

    2016-01-01

    Human papillomaviruses (HPVs)-small, nonenveloped viruses with double-stranded circular DNA-are believed to have a role in the progression of cancer. However, the exact mechanisms are not well established. The interference of HPV proteins, especially E6 and E7, in the cell cycle is considered to be the main pathway. It is still questioned whether the expression of these proteins or the viral load is more important in neoplastic transformation. Furthermore, HPV is believed to adapt mechanisms to evade the host cell immune system; persistent HPV infection may also play a role in oncogenic transformation by causing genomic instability and local immune suppression. These factors may cause accumulation of genomic alterations within the host cell and integration of the viral genome into the host genome. In recent years, epigenetic modifications, such as methylation, have also been considered to take part in neoplastic transformation. All of these alterations to the genome may be favorable to the development of cancer. This article highlights the association of HPV in neoplastic transformation and cancer progression. PMID:27278883

  19. MOLECULAR MECHANISM OF SUPPRESSION OF NEOPLASTIC TRANSFORMATION BY LOW DOSES OF LOW LET RADIATION

    SciTech Connect

    J.LESIE REDPATH, PH.D.

    2011-03-29

    We are currently funded (9/01-8/04) by the DOE Low Dose Radiation Research Program to examine mechanisms underlying the suppression of neoplastic transformation in vitro by low doses of low LET radiation. For the new studies proposed under Notice 04-21, we intend to follow up on our observation that upregulation of DNA repair may be an important factor and that its importance is dose-dependent. The experimental system will be the human hybrid cell neoplastic transformation assay that we are currently using. We propose to test the following hypothesis: Down-regulation of DNA dsb repair will abrogate the low dose suppression of neoplastic transformation. Using the technique of RNA silencing, it is proposed to test the effect of down-regulation of the two major DNA dsb repair pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ), on the dose response relationship for neoplastic transformation. Based on prior studies, we predict that this will result in abrogation of the suppressive effect at doses in the range 1 to 10 cGy, but not at lower doses. The proposed experiments will also help address the question as to which of the two DNA repair pathways may be the most important in causing suppression of transformation. HR is a pathway that is predominant in S and G2 phase cells and is known to be less error-prone than the NHEJ pathway that is predominant in G1 phase. We hypothesize that down-regulation of HR will result in the most effective abrogation of suppression. An important component of this study will be the determination of the how abrogation of DNA dsb repair impacts the spontaneous transformation frequency, presumably a consequence of endogeneous DNA damage. Experiments will be carried out using partially synchronized populations of cells enriched for G1 and S/G2 respectively. In addition to the endpoint of neoplastic transformation the impact of down-regulation of HR and NHEJ on the formation and disappearance of the DNA dsb marker

  20. The neoplastic transformation potential of mammography X rays and atomic bomb spectrum radiation.

    PubMed

    Heyes, G J; Mill, A J

    2004-08-01

    Considerable controversy currently exists regarding the biological effectiveness of 29 kVp X rays which are used for mammography screening. This issue must be resolved to enable proper evaluation of radiation risks from breast screening. Here a definitive assessment of the biological effectiveness of 29 kVp X rays compared to the quality of radiation to which the atomic bomb survivors were exposed is presented for the first time. The standard radiation sources used were (a) an atomic bomb simulation spectrum and (b) 2.2 MeV electrons from a strontium-90/yttrium-90 (90Sr/90Y) radioactive source. The biological end point used was neoplastic transformation in vitro in CGL1 (HeLa x human fibroblast hybrid) cells. No significant difference was observed for the biological effectiveness of the two high-energy sources for neoplastic transformation. A limiting relative biological effectiveness (RBE(M)) of 4.42 +/- 2.02 was observed for neoplastic transformation by 29 kVp X rays compared to these two sources. This compares with values of 4.67 +/- 3.93 calculated from previously published data and 3.58 +/- 1.77 when the reference radiation was 200 and 220 kVp X rays. This suggests that the risks associated with mammography screening may be approximately five times higher than previously assumed and that the risk-benefit relationship of mammography exposures may need to be re-examined. PMID:15387138

  1. Neoplastic cell transformation by energetic heavy ions and its modification with chemical agents

    NASA Astrophysics Data System (ADS)

    Yang, T. C.; Tobias, C. A.

    For many years we have been interested in understanding the potential carcinogenic effects of cosmic rays. We have studied the oncogenic effects of cosmic rays with accelerator-produced heavy particle radiation and with a cultured mammalian cell system--C3H10T1/2 cells. Our quantitative data obtained with carbon, neon, silicon, and iron particles showed that RBE is both dose and LET dependent for neoplastic cell transformation. RBE is higher at lower dose, and RBE increases with LET up to about 200 keV/μm. In nonproliferation confluent cells, heavy-ion induced transformation damage may not be repairable, although a dose modifying factor of about 1.7 was observed for X-ray radiation. Our recent studies with super-heavy high-energy particles, e.g., 960 MeV/u U235 ions (LET = 1900 keV/μm), indicate that these ions with a high inactivation cross-section can cause neoplastic cell transformation. The induction of cell transformation by radiation can be modified with various chemicals. We have found that the presence of DMSO (either during or many days after irradiation) decreased the transformation frequency significantly. It is, therefore, potentially possible to reduce the oncogenic effect of cosmic rays in space through some chemical protection.

  2. Neoplastic cell transformation by energetic heavy ions and its modification with chemical agents.

    PubMed

    Yang, T C; Tobias, C A

    1984-01-01

    For many years we have been interested in understanding the potential carcinogenic effects of cosmic rays. We have studied the oncogenic effects of cosmic rays with accelerator-produced heavy particle radiation and with a cultured mammalian cell system--C3H10T1/2 cells. Our quantitative data obtained with carbon, neon, silicon, and iron particles showed that RBE is both dose and LET dependent for neoplastic cell transformation. RBE is higher at lower dose, and RBE increases with LET up to about 200 keV/micrometer. In nonproliferation confluent cells, heavy-ion induced transformation damage may not be repairable, although a dose modifying factor of about 1.7 was observed for X-ray radiation. Our recent studies with super-heavy high-energy particles, e.g., 960 MeV/U U235 ions (LET = 1900 keV/micrometer), indicate that these ions with a high inactivation cross-section can cause neoplastic cell transformation. The induction of cell transformation by radiation can be modified with various chemicals. We have found that the presence of DMSO (either during or many days after irradiation) decreased the transformation frequency significantly. It is, therefore, potentially possible to reduce the oncogenic effect of cosmic rays in space through some chemical protection. PMID:11539629

  3. Probiotics against neoplastic transformation of gastric mucosa: effects on cell proliferation and polyamine metabolism.

    PubMed

    Russo, Francesco; Linsalata, Michele; Orlando, Antonella

    2014-10-01

    Gastric cancer is still the second leading cause of cancer death worldwide, accounting for about 10% of newly diagnosed neoplasms. In the last decades, an emerging role has been attributed to the relations between the intestinal microbiota and the onset of both gastrointestinal and non-gastrointestinal neoplasms. Thus, exogenous microbial administration of peculiar bacterial strains (probiotics) has been suggested as having a profound influence on multiple processes associated with a change in cancer risk. The internationally accepted definition of probiotics is live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. The possible effects on the gastrointestinal tract following probiotic administration have been investigated in vitro and in animal models, as well as in healthy volunteers and in patients suffering from different human gastrointestinal diseases. Although several evidences are available on the use of probiotics against the carcinogen Helicobacter pylori, little is still known about the potential cross-interactions among probiotics, the composition and quality of intestinal flora and the neoplastic transformation of gastric mucosa. In this connection, a significant role in cell proliferation is played by polyamines (putrescine, spermidine, and spermine). These small amines are required in both pre-neoplastic and neoplastic tissue to sustain the cell growth and the evidences here provided suggest that probiotics may act as antineoplastic agents in the stomach by affecting also the polyamine content and functions. This review will summarize data on the most widely recognized effects of probiotics against neoplastic transformation of gastric mucosa and in particular on their ability in modulating cell proliferation, paying attention to the polyamine metabolism. PMID:25309063

  4. Neoplastic transformation of cultured mammalian cells by estrogens and estrogenlike chemicals.

    PubMed Central

    Tsutsui, T; Barrett, J C

    1997-01-01

    Estrogens are clearly carcinogenic in humans and rodents but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system and our findings are summarized in this review. 17beta-Estradiol (E2) and diethylstilbestrol (DES) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. Treatment of the cells with E2 or DES fails to induce DNA damage, chromosome aberrations and gene mutations in SHE cells but results in numerical chromosome aberrations (aneuploidy) that could arise from microtubule disruption or disfunction of mitotic apparatus. Estrogen-induced genotoxicity is detected in cells following treatment with estrogen metabolites or following exogenous metabolic activation of estrogens. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. Both aneuploidy induction and DNA damage caused by DNA adduct formation correlate with the estrogen-induced cell transformation and may be important in hormonal carcinogenesis. We propose that multiple effects of estrogens acting together cause genetic alterations leading to cell transformation. PMID:9168005

  5. Prox1-Heterozygosis Sensitizes the Pancreas to Oncogenic Kras-Induced Neoplastic Transformation12

    PubMed Central

    Drosos, Yiannis; Neale, Geoffrey; Ye, Jianming; Paul, Leena; Kuliyev, Emin; Maitra, Anirban; Means, Anna L; Washington, M Kay; Rehg, Jerold; Finkelstein, David B; Sosa-Pineda, Beatriz

    2016-01-01

    The current paradigm of pancreatic neoplastic transformation proposes an initial step whereby acinar cells convert into acinar-to-ductal metaplasias, followed by progression of these lesions into neoplasias under sustained oncogenic activity and inflammation. Understanding the molecular mechanisms driving these processes is crucial to the early diagnostic and prevention of pancreatic cancer. Emerging evidence indicates that transcription factors that control exocrine pancreatic development could have either, protective or facilitating roles in the formation of preneoplasias and neoplasias in the pancreas. We previously identified that the homeodomain transcription factor Prox1 is a novel regulator of mouse exocrine pancreas development. Here we investigated whether Prox1 function participates in early neoplastic transformation using in vivo, in vitro and in silico approaches. We found that Prox1 expression is transiently re-activated in acinar cells undergoing dedifferentiation and acinar-to-ductal metaplastic conversion. In contrast, Prox1 expression is largely absent in neoplasias and tumors in the pancreas of mice and humans. We also uncovered that Prox1-heterozygosis markedly increases the formation of acinar-to-ductal-metaplasias and early neoplasias, and enhances features associated with inflammation, in mouse pancreatic tissues expressing oncogenic Kras. Furthermore, we discovered that Prox1-heterozygosis increases tissue damage and delays recovery from inflammation in pancreata of mice injected with caerulein. These results are the first demonstration that Prox1 activity protects pancreatic cells from acute tissue damage and early neoplastic transformation. Additional data in our study indicate that this novel role of Prox1 involves suppression of pathways associated with inflammatory responses and cell invasiveness. PMID:26992918

  6. Generation of tumor-specific transplantation antigens by UV radiation can occur independently of neoplastic transformation.

    PubMed

    Hostetler, L W; Ananthaswamy, H N; Kripke, M L

    1986-10-15

    The purpose of this study was to determine whether the UV-associated antigens present on tumors induced in mice by chronic UV irradiation could be induced by in vitro irradiation of cells that were already tumorigenic, or whether their occurrence was associated with the primary neoplastic transformation event. Cells of a nonantigenic, spontaneous fibrosarcoma cell line were exposed to UV radiation in vitro, were cloned, and were tested for antigenic properties. A large number of the clones obtained after UV irradiation of the fibrosarcoma cells were highly antigenic (20 of 39), whereas clones derived from unirradiated cultures were not (0 of 10). The antigenic variants did not induce cross-protection among themselves, but induced only variant-specific immunity in vivo. Several antigenic variants were tested for susceptibility to the action of UV-induced suppressor cells, which seem to recognize a common determinant shared among UV-induced tumors. The variants tested were indeed subject to the activity of the UV-induced suppressor lymphocytes. These results demonstrate that the unique antigenic properties exhibited by UV-induced murine skin cancers are also exhibited by cells exposed to UV radiation in vitro. In addition, they imply that the UV-associated antigens arise as a consequence of exposing cells to UV radiation and that they can occur independently of an initial neoplastic transformation event. PMID:3760572

  7. The G protein-coupled estrogen receptor as a modulator of neoplastic transformation.

    PubMed

    Jacenik, Damian; Cygankiewicz, Adam I; Krajewska, Wanda M

    2016-07-01

    Estrogens play a crucial role in the regulation of physiological and pathophysiological processes. These hormones act through specific receptors, most notably the canonical estrogen receptors α and β (ERα and ERβ) and their truncated forms as well as the G protein-coupled estrogen receptor (GPER). Several studies have shown that GPER is expressed in many normal and cancer cells, including those of the breast, endometrium, ovary, testis and lung. Hormonal imbalance is one possible cause of cancer development. An accumulating body of evidence indicates that GPER is involved in the regulation of cancer cell proliferation, migration and invasion, it may act as a mediator of microRNA, and is believed to modulate the inflammation associated with neoplastic transformation. Furthermore, used in various treatment regimens anti-estrogens such as tamoxifen, raloxifen and fulvestrant (ICI 182.780), antagonists/modulators of canonical estrogen receptors, were found to be GPER agonists. This review presents the current knowledge about the potential role of GPER in neoplastic transformation. PMID:27107933

  8. Measuring neoplastic transformation in the hamster cheek pouch using Fourier domain low-coherence interferometry

    NASA Astrophysics Data System (ADS)

    Graf, Robert N.; Chen, Xiaoxin; Brown, William; Wax, Adam

    2008-02-01

    Fourier Domain Low Coherence Interferometry (fLCI) is a promising technique which combines the depth resolution of low coherence interferometry with the sensitivity of light scattering spectroscopy for probing the health of epithelial tissue layers. Our new fLCI system configuration utilizes a white light Xe arc lamp source and a 4-f interferometer which re-images light scattered from the sample onto the detection plane. The system employs an imaging spectrometer at the detection plane to acquire depth resolved profiles from 252 adjacent spatial points without the need for any scanning. The limited spatial coherence of the light source requires the resolution of adjacent spatial points for the generation of depth information. Depth-resolved spectral information is recovered by performing a short-time Fourier transform on the detected spectra, similar to spectroscopic optical coherence tomography. Wavelength dependent variations in scattering intensity are analyzed as a function of depth to obtain information about the neoplastic transformation of the probed cells. Previous studies have demonstrated fLCI as an excellent technique for probing the scatterer morphology of simple phantoms and of in vitro cancer cell monolayers. We now seek to assess the ability of the new fLCI system to measure the health of subsurface tissue layers using the hamster cheek pouch model. Seven hamsters will have one cheek pouch treated with the known carcinogen DMBA. At the conclusion of the 24 week treatment period the animals will be anesthetized and the cheek pouches will be extracted. We will use the fLCI optical system to measure the neoplastic transformation of the in situ subsurface tissue layers in both the normal and DMBA-treated cheek pouches. Traditional histological analysis will be used to verify the fLCI measurements. We expect our results to establish the feasibility of fLCI to distinguish between healthy and dysplastic epithelial tissues in the hamster cheek pouch.

  9. c-Myc dependent initiation of genomic instability during neoplastic transformation.

    PubMed

    Taylor, C; Jalava, A; Mai, S

    1997-01-01

    The dihydrofolate reductase (DHFR) gene is a target of c-Myc in genomic instability. The induced overexpression of c-Myc in cell lines is followed by the amplification and rearrangement of the DHFR gene. Furthermore, the constitutive upregulation of c-Myc protein coincides with genomic instability of the DHFR gene in lymphoid, non-lymphoid and in tumor lines. The amplification of the DHFR gene is locus-specific and independent of species origins. We have now addressed the question whether inducible deregulation of c-Myc is followed by DHFR gene amplification in vivo. We show that the DHFR gene is a target of c-Myc-dependent neoplasia in vivo and propose a role for genomic instability during the initiation of neoplastic transformation. PMID:9308243

  10. DUAL ION EXPOSURE VS. SPLIT-DOSE EXPOSURES IN HUMAN CELL NEOPLASTIC TRANSFORMATION.

    SciTech Connect

    BENNETT, P.V.; CUTTER, N.C.; SUTHERLAND, B.M.

    2006-06-05

    Since radiation fields of space contain many-fold more protons than high atomic number, high energy (HZE) particles, cells in astronaut crews will experience on average several proton hits before an HZE hit. Thus radiation regimes of proton exposure before HZE particle exposure simulate space radiation exposure, and measurement of the frequency of neoplastic transformation of human primary cells to anchorage-independent growth simulates in initial step in cancer induction. Previously our group found that exposure to 20 cGy 1 GeV/n protons followed within about 1 hr by a HZE ion (20 cGy 1 GeV/n Fe or Ti ions) hit gave about a 3-fold increase in transformation frequency ([1]). To provide insight into the H-HZE induced increased transformation frequencies, we asked if split doses of the same ion gave similar increased transformation frequencies. However, the data show that the split dose of 20 cGy plus 20 cGy of either H or HZE ions gave about the same effect as the 40 cGy uninterrupted dose, quite different from the effect of the mixed ion H + HZE irradiation. We also asked if lower proton doses than 20 cGy followed 15 minutes later by 20 cGy of HZE ions gave greater than additive transformation frequencies. Substantial increases in transformation levels were observed for all proton doses tested, including 1 cGy. These results point to the signal importance of protons in affecting the effect of space radiation on human cells.

  11. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation

    PubMed Central

    Reshkin, Stephan Joel; Greco, Maria Raffaella; Cardone, Rosa Angela

    2014-01-01

    The change of a normal, healthy cell to a transformed cell is the first step in the evolutionary arc of a cancer. While the role of oncogenes in this ‘passage’ is well known, the role of ion transporters in this critical step is less known and is fundamental to our understanding the early physiological processes of carcinogenesis. Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the normal tissue intracellular to extracellular pH gradient (ΔpHi to ΔpHe). When this perturbation in pH dynamics occurs during carcinogenesis is less clear. Very early studies using the introduction of different oncogene proteins into cells observed a concordance between neoplastic transformation and a cytoplasmic alkalinization occurring concomitantly with a shift towards glycolysis in the presence of oxygen, i.e. ‘Warburg metabolism’. These processes may instigate a vicious cycle that drives later progression towards fully developed cancer where the reversed pH gradient becomes ever more pronounced. This review presents our understanding of the role of pH and the NHE1 in driving transformation, in determining the first appearance of the cancer ‘hallmark’ characteristics and how the use of pharmacological approaches targeting pH/NHE1 may open up new avenues for efficient treatments even during the first steps of cancer development. PMID:24493748

  12. Mechanisms underlying the adaptive response against spontaneous neoplastic transformation induced by low doses of low LET radiation - Final Technical Report

    SciTech Connect

    John Leslie Redpath

    2007-01-17

    The objective of the research was to examine mechanisms underlying the suppressive effects of low doses (<10 cGy) of low-LET radiation on the endpoint of neoplastic transformation in vitro. The findings indicated a role for upregulation of DNA repair but not of antioxidants.

  13. Neoplastic transformation of human breast epithelial cells by estrogens and chemical carcinogens.

    PubMed

    Russo, Jose; Tahin, Quivo; Lareef, M Hasan; Hu, Yun-Fu; Russo, Irma H

    2002-01-01

    Sporadic breast cancer, the most common cancer diagnosed in American and Northern European women, is gradually increasing in incidence in most Western countries. Prevention would be the most efficient way of eradicating this disease. This goal, however, cannot be accomplished until the specific agent(s) or mechanisms that initiate the neoplastic process are identified. Experimental studies have demonstrated that mammary cancer is a hormone-dependent multistep process that can be induced by a variety of compounds and mechanisms, that is, hormones, chemicals, radiation, and viruses, in addition to or in combination with genetic factors. Although estrogens have been shown to play a central role in breast cancer development, their carcinogenicity on human breast epithelial cells (HBECs) has not yet been clearly demonstrated. Breast cancer initiates in the undifferentiated lobules type 1, which are composed of three cell types: highly proliferating cells that are estrogen-receptor negative (ER-), nonproliferating cells that are ER positive (ER+), and very few (<1%) ER+ cells that proliferate. Interestingly, endogenous 17beta-estradiol (E(2)) is metabolized by the cytochrome P450 enzyme isoforms CYP1A1 and CYP1B1, which also activate benzo[a]pyrene (B[a]P), a carcinogen contained in cigarette smoke. We postulate that if estrogens are carcinogenic in HBECs, they should induce the same transformation phenotypes induced by chemical carcinogens and ultimately genomic changes observed in spontaneously developing primary breast cancers. To test this hypothesis we compared the transforming potential of E(2) on the HBEC MCF-10F with that of B[a]P. Both E(2) and B[a]P induced anchorage-independent growth, colony formation in agar methocel, and loss of ductulogenic capacity in collagen gel, all parameters indicative of cell transformation. In addition, the DNA of E(2)-transformed cells expressed LOH in chromosome 11 at 11q23.3, 11q24.2-q25, and LOH at 13q12-q13. B[a]P-induced cell

  14. Neoplastic transformation of rat liver epithelial cells is enhanced by non-transferrin-bound iron

    PubMed Central

    Messner, Donald J; Kowdley, Kris V

    2008-01-01

    Background Iron overload is associated with liver toxicity, cirrhosis, and hepatocellular carcinoma in humans. While most iron circulates in blood as transferrin-bound iron, non-transferrin-bound iron (NTBI) also becomes elevated and contributes to toxicity in the setting of iron overload. The mechanism for iron-related carcinogenesis is not well understood, in part due to a shortage of suitable experimental models. The primary aim of this study was to investigate NTBI-related hepatic carcinogenesis using T51B rat liver epithelial cells, a non-neoplastic cell line previously developed for carcinogenicity and tumor promotion studies. Methods T51B cells were loaded with iron by repeated addition of ferric ammonium citrate (FAC) to the culture medium. Iron internalization was documented by chemical assay, ferritin induction, and loss of calcein fluorescence. Proliferative effects were determined by cell count, toxicity was determined by MTT assay, and neoplastic transformation was assessed by measuring colony formation in soft agar. Cyclin levels were measured by western blot. Results T51B cells readily internalized NTBI given as FAC. Within 1 week of treatment at 200 μM, there were significant but well-tolerated toxic effects including a decrease in cell proliferation (30% decrease, p < 0.01). FAC alone induced little or no colony formation in soft agar. In contrast, FAC addition to cells previously initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) resulted in a concentration dependent increase in colony formation. This was first detected at 12 weeks of FAC treatment and increased at longer times. At 16 weeks, colony formation increased more than 10 fold in cells treated with 200 μM FAC (p < 0.001). The iron chelator desferoxamine reduced both iron uptake and colony formation. Cells cultured with 200 μM FAC showed decreased cyclin D1, decreased cyclin A, and increased cyclin B1. Conclusion These results establish NTBI as a tumor promoter in T51B rat liver

  15. Analysis of the multistage process of neoplastic transformation of human fibroblasts

    SciTech Connect

    McCormick, J.J.

    1994-12-31

    Normal human cells in culture have never been neoplastically transformed by carcinogens. One explanation is that the life span of the cells is too short for them to acquire the necessary changes. To test this, we transfected diploid fibroblasts with a plasmid carrying v-myc gene and a selectable marker. A drug resistant clone expressing v-myc was passaged to the end of its life span. A few cells continued to proliferate and gave rise to a diploid, infinite life span that has normal growth control and in nontumorigenic. Analysis indicated that one more change, in addition to unregulated expression of v-myc, was involved in generating these cells. They spontaneously gave rise to a near-diploid strain with a stable karyotype of 34 chromosomes, including 2 markers. This strain, MSU-1.1, grows more rapidly, is less dependent on growth factors, but does not form large colonies in agar and is not tumorigenic. At least two additional changes were involved in generating this strain. To determine the number and kinds of additional changes required to transform MSU-1.1 cells to oncogenes in vectors engineering for overexpression, and selected for focus-formation. The focus-derived cells were growth factor independent, formed large colonies in agar, and produced sarcomas with a short latency. These malignant cells had acquired two additional changes, but no change in karyotype. Exposure of MSU-1.1 cells to carcinogens and selection for foci also yielded malignant cells. Those analyzed to date show loss of 1 or 2 more chromosomes and of p53 function.

  16. Neoplastic transformation of mouse mammary epithelial cells by in vitro exposure to N-methyl-N-nitrosourea

    SciTech Connect

    Miyamoto, S.; Guzman, R.C.; Osborn, R.C.; Nandi, S.

    1988-01-01

    High-efficiency neoplastic transformation of mouse mammary epithelial cells in primary collagen gel culture was induced by N-methyl-N-nitrosoureau (MNU). Mammary epithelial cells, isolated from virgin BALB/c mice, were embedded within collagen gels and grown in a serum-free medium containing prolactin, progesterone, and linoleic acid. The cells were then treated with MNU on day 3 of culture and subsequently at weekly intervals for up to 4 weeks. Eleven to 14 days after the final carcinogen treatment, the cells were removed from the collagen gels and injected into the cleared mammary fat pads of syngeneic hosts to assay for transformed cell populations. A single exposure or multiple exposures of these cells to MNU was effective in inducing tumorigenic cells that produced palpable tumors as early as 6 weeks after transplantation. Two treatments with MNU were optimal for neoplastic transformation and produced tumors in 79% of the injected fat pads. All the tumors originated at the examination at the site of injection and had extensive central necroses. Histological examination indicated that the tumors were mammary carcinomas. Secondary transplantation of tumor pieces into intact mammary glands produced palpable carcinomas of the same histology within 1-8 weeks. This system provides a distinct means to study the mechanism of mammary neoplastic transformation at cellular and molecular levels.

  17. Althaea rosea Cavanil and Plantago major L. suppress neoplastic cell transformation through the inhibition of epidermal growth factor receptor kinase.

    PubMed

    Choi, Eun-Sun; Cho, Sung-Dae; Shin, Ji-Ae; Kwon, Ki Han; Cho, Nam-Pyo; Shim, Jung-Hyun

    2012-10-01

    For thousands of years in Asia, Althaea rosea Cavanil (ARC) and Plantago major L. (PML) have been used as powerful non-toxic therapeutic agents that inhibit inflammation. However, the anticancer mechanisms and molecular targets of ARC and PML are poorly understood, particularly in epidermal growth factor (EGF)-induced neoplastic cell transformation. The aim of this study was to evaluate the chemopreventive effects and mechanisms of the methanol extracts from ARC (MARC) and PML (MPML) in EGF-induced neoplastic cell transformation of JB6 P+ mouse epidermal cells using an MTS assay, anchorage-independent cell transformation assay and western blotting. Our results showed that MARC and MPML significantly suppressed neoplastic cell transformation by inhibiting the kinase activity of the EGF receptor (EGFR). The activation of EGFR by EGF was suppressed by MARC and MPML treatment in EGFR(+/+) cells, but not in EGFR(-/-) cells. In addition, MARC and MPML inhibited EGF-induced cell proliferation in EGFR-expressing murine embryonic fibroblasts (EGFR(+/+)). These results strongly indicate that EGFR targeting by MARC and MPML may be a good strategy for chemopreventive or chemotherapeutic applications. PMID:22767187

  18. Inhibition of chemically-induced neoplastic transformation by a novel tetrasodium diphosphate astaxanthin derivative.

    PubMed

    Hix, Laura M; Frey, Dean A; McLaws, Mark D; Østerlie, Marianne; Lockwood, Samuel F; Bertram, John S

    2005-09-01

    Carotenoids have been implicated in numerous epidemiological studies as being protective against cancer at many sites, and their chemopreventive properties have been confirmed in laboratory studies. Astaxanthin (AST), primarily a carotenoid of marine origin, responsible for the pink coloration of salmon, shrimp and lobster, has received relatively little attention. As with other carotenoids, its highly lipophilic properties complicate delivery to model systems. To overcome this issue we have synthesized a novel tetrasodium diphosphate astaxanthin (pAST) derivative with aqueous dispersibility of 25.21 mg/ml. pAST was delivered to C3H/10T1/2 cells in an aqueous/ethanol solution and compared with non-esterified AST dissolved in tetrahydrofuran. We show pAST to (i) upregulate connexin 43 (Cx43) protein expression; (ii) increase the formation of Cx43 immunoreactive plaques; (iii) upregulate gap junctional intercellular communication (GJIC); and (iv) cause 100% inhibition of methylcholanthrene-induced neoplastic transformation at 10(-6) M. In all these assays, pAST was superior to non-esterified AST itself; in fact, pAST exceeded the potency of all other previously tested carotenoids in this model system. Cleavage of pAST to non-esterified (free) AST and uptake into cells was also verified by HPLC; however, levels of free AST were approximately 100-fold lower than in cells treated with AST itself, suggesting that pAST possesses intrinsic activity. The dual properties of water dispersibility (enabling parenteral administration in vivo) and increased potency should prove extremely useful in the future development of cancer chemopreventive agents. PMID:15888493

  19. Radiation-resistant B-1 cells: A possible initiating cells of neoplastic transformation.

    PubMed

    Guimarães-Cunha, Caroline Ferreira; Alvares-Saraiva, Anuska Marcelino; de Souza Apostolico, Juliana; Popi, Ana Flavia

    2016-07-01

    The role of B-1 cells in the hyperproliferative hematologic disease has been described. Several reports bring evidences that B-1 cells are the main cell population in the chronic lymphatic leukemia. It is also described that these cells have an important involvement in the lupus erythematous systemic. The murine model used to investigate both disease models is NZB/NZW. Data from literature point that mutation in micro-RNA 15a and 16 are the responsible for the B-1 hyperplasia in these mice. Interestingly, it was demonstrated that NZB/NZW B-1 cells are radioresistant, contrariwise to observe in other mouse lineage derived B-1 cells and B-2 cells. However, some reports bring evidences that a small percentage of B-1 cells in healthy mice are also able to survive to irradiation. Herein, we aim to investigate the malignant potential of ionizing-radiation resistant B-1 cells in vitro. Our main goal is to establish a model that mimics the neoplastic transformation originate to a damage exposure of DNA, and not only related to intrinsic mutations. Data shown here demonstrated that radiation-resistant B-1 cells were able to survive long periods in culture. Further, these cells show proliferation index increase in relation to non-irradiated B-1 cells. In addition, radiation resistant B-1 cells showed hyperploid, morphologic alterations, increased induction of apoptosis after anti-IgM stimulation. Based on these results, we could suggest that radiation resistant B-1 cells showed some modifications in that could be related to induction of malignant potential. PMID:26898918

  20. Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo

    PubMed Central

    2012-01-01

    Background Marek’s Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the non-neoplastic cells (CD30lo) form the majority of population. MD is a unique natural in-vivo model of human CD30hi lymphomas with both natural CD30hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30lo expressing phenotype to CD30hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30lo and CD30hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome. Results Our results show that a) CD30lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis. Conclusions In the context of the MD lymphoma microenvironment (and potentially in other CD30hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor

  1. The Syrian hamster embryo (SHE) cell transformation system: a biologically relevant in vitro model--with carcinogen predicting capabilities--of in vivo multistage neoplastic transformation.

    PubMed

    Isfort, R J; LeBoeuf, R A

    1995-01-01

    Neoplastic transformation is a multistep process that can be modeled in vitro using Syrian hamster embryo (SHE) cells. SHE cells multistage transformation involves several intermediate stages, including morphological transformation, immortality, acquisition of tumorigenicity, and malignant progression. Analysis of the molecular alterations that occur at each stage indicated that morphological transformation results from both carcinogen-induced irreversible chromosomal/genetic mutations and reversible genetic events, including altered DNA methylation. Morphological transformation results from a block in the cellular differentiation of progenitor and determined stem-like cells in the SHE cell population via alternation in the expression of the H19 tumor suppressor gene and other genes. Immortality results from genetic mutations in growth factor responsiveness, including loss of growth suppression by TGF beta and autocrine growth factor production, and genomic stability, resulting in genomic instability and an increased mutation rate. Acquisition of tumorigenicity involves loss of tumor suppressor gene function, altered mitogenic signal transduction, mutation of oncogenes, acquisition of anchorage independent growth, and chromosomal aberrations. Malignant progression is associated with alterations in extracellular matrix growth characteristics, alterations in cytoskeleton structure, elevated fibrinolytic activity, secretion of proteases, and changes in extracellular matrix protein secretion. Together, these changes model the alterations observed during in vivo neoplastic transformation and possibly explain why the SHE assay, as a carcinogen screening tool, is able to identify carcinogens with a 80 to 85% accuracy. PMID:9012585

  2. Different Roles of Negative and Positive Components of the Circadian Clock in Oncogene-induced Neoplastic Transformation.

    PubMed

    Katamune, Chiharu; Koyanagi, Satoru; Shiromizu, Shoya; Matsunaga, Naoya; Shimba, Shigeki; Shibata, Shigenobu; Ohdo, Shigehiro

    2016-05-13

    In mammals, circadian rhythms in physiological function are generated by a molecular oscillator driven by transcriptional-translational feedback loop consisting of negative and positive regulators. Disruption of this circadian clock machinery is thought to increase the risk of cancer development, but the potential contributions of each component of circadian clock to oncogenesis have been little explored. Here we reported that negative and positive transcriptional regulators of circadian feedback loop had different roles in oncogene-induced neoplastic transformation. Mouse embryonic fibroblasts prepared from animals deficient in negative circadian clock regulators, Period2 (Per2) or Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression of H-ras(V12) and SV40 large T antigen (SV40LT). In contrast, mouse embryonic fibroblasts prepared from mice deficient in positive circadian clock regulators, Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence. Although genetic ablation of either negative or positive transcriptional regulators of the circadian clock leads to disrupted rhythms in physiological functions, our findings define their different contributions to neoplastic cellular transformation. PMID:26961881

  3. Increased Frequency of Spontaneous Neoplastic Transformation in Progeny of Bystander Cells from Cultures Exposed to Densely Ionizing Radiation

    PubMed Central

    Buonanno, Manuela; de Toledo, Sonia M.; Azzam, Edouard I.

    2011-01-01

    An increased risk of carcinogenesis caused by exposure to space radiation during prolonged space travel is a limiting factor for human space exploration. Typically, astronauts are exposed to low fluences of ionizing particles that target only a few cells in a tissue at any one time. The propagation of stressful effects from irradiated to neighboring bystander cells and their transmission to progeny cells would be of importance in estimates of the health risks of exposure to space radiation. With relevance to the risk of carcinogenesis, we investigated, in model C3H 10T½ mouse embryo fibroblasts (MEFs), modulation of the spontaneous frequency of neoplastic transformation in the progeny of bystander MEFs that had been in co-culture 10 population doublings earlier with MEFs exposed to moderate doses of densely ionizing iron ions (1 GeV/nucleon) or sparsely ionizing protons (1 GeV). An increase (P<0.05) in neoplastic transformation frequency, likely mediated by intercellular communication through gap junctions, was observed in the progeny of bystander cells that had been in co-culture with cells irradiated with iron ions, but not with protons. PMID:21738697

  4. Autophagy-deficiency in hepatic progenitor cells leads to the defects of stemness and enhances susceptibility to neoplastic transformation.

    PubMed

    Xue, Feng; Hu, Lei; Ge, Ruiliang; Yang, Lixue; Liu, Kai; Li, Yunyun; Sun, Yanfu; Wang, Kui

    2016-02-01

    Autophagy is a highly conserved and lysosome-dependent degradation process which assists in cell survival and tissue homeostasis. Although previous reports have shown that deletion of the essential autophagy gene disturbs stem cell maintenance in some cell types such as hematopoietic and neural cells, it remains unclear how autophagy-deficiency influences hepatic progenitor cells (HPCs). Here we report that Atg5-deficiency in HPCs delays HPC-mediated rat liver regeneration in vivo. In vitro researches further demonstrate that loss of autophagy decreases the abilities of colony and spheroid formations, and disrupts the induction of hepatic differentiation in HPCs. Meanwhile, autophagy-deficiency increases the accumulations of damaged mitochondria and mitochondrial reactive oxygen species (mtROS) and suppresses homologous recombination (HR) pathway of DNA damage repair in HPCs. Moreover, in both diethylnitrosamine (DEN) and CCl4 models, autophagy-deficiency accelerates neoplastic transformation of HPCs. In conclusion, these findings demonstrate that autophagy contributes to stemness maintenance and reduces susceptibility to neoplastic transformation in HPCs. PMID:26607902

  5. Guanidine Alkaloids from the Marine Sponge Monanchora pulchra Show Cytotoxic Properties and Prevent EGF-Induced Neoplastic Transformation in Vitro.

    PubMed

    Dyshlovoy, Sergey A; Tabakmakher, Kseniya M; Hauschild, Jessica; Shchekaleva, Regina K; Otte, Katharina; Guzii, Alla G; Makarieva, Tatyana N; Kudryashova, Ekaterina K; Fedorov, Sergey N; Shubina, Larisa K; Bokemeyer, Carsten; Honecker, Friedemann; Stonik, Valentin A; von Amsberg, Gunhild

    2016-01-01

    Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight rare guanidine alkaloids, recently isolated from the marine sponge Monanchora pulchra, namely: monanchocidin A (1), monanchocidin B (2), monanchomycalin C (3), ptilomycalin A (4), monanchomycalin B (5), normonanchocidin D (6), urupocidin A (7), and pulchranin A (8). All of the compounds induced cell cycle arrest (apart from 8) and programmed death of cancer cells. Ptilomycalin A-like compounds 1-6 activated JNK1/2 and ERK1/2, following AP-1 activation and caused p53-independent programmed cell death. Compound 7 induced p53-independent cell death without activation of AP-1 or caspase-3/7, and the observed JNK1/2 activation did not contribute to the cytotoxic effect of the compound. Alkaloid 8 induced JNK1/2 (but not ERK1/2) activation leading to p53-independent cell death and strong suppression of AP-1 activity. Alkaloids 1-4, 7, and 8 were able to inhibit the EGF-induced neoplastic transformation of JB6 P⁺ Cl41 cells. Our results suggest that investigated guanidine marine alkaloids hold potential to eliminate human cancer cells and prevent cancer cell formation and spreading. PMID:27428983

  6. Guanidine Alkaloids from the Marine Sponge Monanchora pulchra Show Cytotoxic Properties and Prevent EGF-Induced Neoplastic Transformation in Vitro

    PubMed Central

    Dyshlovoy, Sergey A.; Tabakmakher, Kseniya M.; Hauschild, Jessica; Shchekaleva, Regina K.; Otte, Katharina; Guzii, Alla G.; Makarieva, Tatyana N.; Kudryashova, Ekaterina K.; Fedorov, Sergey N.; Shubina, Larisa K.; Bokemeyer, Carsten; Honecker, Friedemann; Stonik, Valentin A.; von Amsberg, Gunhild

    2016-01-01

    Guanidine alkaloids from sponges Monanchora spp. represent diverse bioactive compounds, however, the mechanisms underlying bioactivity are very poorly understood. Here, we report results of studies on cytotoxic action, the ability to inhibit EGF-induced neoplastic transformation, and the effects on MAPK/AP-1 signaling of eight rare guanidine alkaloids, recently isolated from the marine sponge Monanchora pulchra, namely: monanchocidin A (1), monanchocidin B (2), monanchomycalin C (3), ptilomycalin A (4), monanchomycalin B (5), normonanchocidin D (6), urupocidin A (7), and pulchranin A (8). All of the compounds induced cell cycle arrest (apart from 8) and programmed death of cancer cells. Ptilomycalin A-like compounds 1–6 activated JNK1/2 and ERK1/2, following AP-1 activation and caused p53-independent programmed cell death. Compound 7 induced p53-independent cell death without activation of AP-1 or caspase-3/7, and the observed JNK1/2 activation did not contribute to the cytotoxic effect of the compound. Alkaloid 8 induced JNK1/2 (but not ERK1/2) activation leading to p53-independent cell death and strong suppression of AP-1 activity. Alkaloids 1–4, 7, and 8 were able to inhibit the EGF-induced neoplastic transformation of JB6 P+ Cl41 cells. Our results suggest that investigated guanidine marine alkaloids hold potential to eliminate human cancer cells and prevent cancer cell formation and spreading. PMID:27428983

  7. Increased frequency of spontaneous neoplastic transformation in progeny of bystander cells from cultures exposed to densely ionizing radiation.

    PubMed

    Buonanno, Manuela; de Toledo, Sonia M; Azzam, Edouard I

    2011-01-01

    An increased risk of carcinogenesis caused by exposure to space radiation during prolonged space travel is a limiting factor for human space exploration. Typically, astronauts are exposed to low fluences of ionizing particles that target only a few cells in a tissue at any one time. The propagation of stressful effects from irradiated to neighboring bystander cells and their transmission to progeny cells would be of importance in estimates of the health risks of exposure to space radiation. With relevance to the risk of carcinogenesis, we investigated, in model C3H 10T½ mouse embryo fibroblasts (MEFs), modulation of the spontaneous frequency of neoplastic transformation in the progeny of bystander MEFs that had been in co-culture 10 population doublings earlier with MEFs exposed to moderate doses of densely ionizing iron ions (1 GeV/nucleon) or sparsely ionizing protons (1 GeV). An increase (P<0.05) in neoplastic transformation frequency, likely mediated by intercellular communication through gap junctions, was observed in the progeny of bystander cells that had been in co-culture with cells irradiated with iron ions, but not with protons. PMID:21738697

  8. Multistep nature of X-ray-induced neoplastic transformation in golden hamster embryo cells: expression of transformed phenotypes and stepwise changes in karyotypes

    SciTech Connect

    Suzuki, K.; Suzuki, F.; Watanabe, M.; Nikaido, O.

    1989-04-15

    We have examined the expression of transformed phenotypes and genetic changes associated with the expression of each transformed phenotype after X-ray irradiation. Unirradiated cells grown at a constant growth rate until 8 passages (population doubling number, 15) exhibited little morphological change and ceased to divide thereafter. X-irradiated cells escaped from senescence and showed morphological alteration and anchorage independence after a population doubling number of 20. The acquisition of tumorigenicity in nude mice was observed much later (35 population doublings after irradiation). From cytogenetic analysis, all anchorage-independent clones were consistently found to have trisomy of chromosome 7. Furthermore, cells derived from tumors contained three copies of chromosome 9q in addition to the trisomy of chromosome 7. We have not detected any augmented expression of v-Ha-ras- and v-myc-related oncogenes with RNA dot-blot analysis and could not find activation of any type of oncogenes by NIH3T3 transfection experiments. Our studies demonstrated that X-ray-induced neoplastic transformation is a multistep phenomenon and that the numerical change of specific chromosomes may play an important role in the expression of each transformed phenotype. The results suggest that different endogenous oncogenes, other than the ras gene family and myc oncogene, could be responsible for the progressive nature of neoplastic transformation.

  9. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation

    PubMed Central

    Nolan-Stevaux, Olivier; Lau, Janet; Truitt, Morgan L.; Chu, Gerald C.; Hebrok, Matthias; Fernández-Zapico, Martin E.; Hanahan, Douglas

    2009-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh–Ptch–Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh–Ptch–Smo signaling and is regulated by TGF-β and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells. PMID:19136624

  10. Coevolution of neoplastic epithelial cells and multilineage stroma via polyploid giant cells during immortalization and transformation of mullerian epithelial cells

    PubMed Central

    Zhang, Shiwu; Mercado-Uribe, Imelda; Sood, Anil; Bast, Robert C.; Liu, Jinsong

    2016-01-01

    Stromal cells are generally considered to be derived primarily from the host's normal mesenchymal stromal cells or bone marrow. However, the origins of stromal cells have been quite controversial. To determine the role of polyploidy in tumor development, we examined the fate of normal mullerian epithelial cells during the immortalization and transformation process by tracing the expression of SV40 large T antigen. Here we show that immortalized or HRAS-transformed mullerian epithelial cells contain a subpopulation of polyploid giant cells that grow as multicellular spheroids expressing hematopoietic markers in response to treatment with CoCl2. The immortalized or transformed epithelial cells can transdifferentiate into stromal cells when transplanted into nude mice. Immunofluorescent staining revealed expression of stem cell factors OCT4, Nanog, and SOX-2 in spheroid, whereas expression of embryonic stem cell marker SSEA1 was increased in HRAS-transformed cells compared with their immortalized isogenic counterparts. These results suggest that normal mullerian epithelial cells are intrinsically highly plastic, via the formation of polyploid giant cells and activation of embryonic stem-like program, which work together to promote the coevolution of neoplastic epithelial cells and multiple lineage stromal cells. PMID:27382431

  11. Point Mutations in c-Myc Uncouple Neoplastic Transformation from Multiple Other Phenotypes in Rat Fibroblasts

    PubMed Central

    Graves, J. Anthony; Rothermund, Kristi; Wang, Tao; Qian, Wei; Van Houten, Bennett; Prochownik, Edward V.

    2010-01-01

    Deregulation of c-Myc (Myc) occurs in many cancers. In addition to transforming various cell types, Myc also influences additional transformation-associated cellular phenotypes including proliferation, survival, genomic instability, reactive oxygen species production, and metabolism. Although Myc is wild type in most cancers (wtMyc), it occasionally acquires point mutations in certain lymphomas. Some of these mutations confer a survival advantage despite partially attenuating proliferation and transformation. Here, we have evaluated four naturally-occurring or synthetic point mutations of Myc for their ability to affect these phenotypes, as well as to promote genomic instability, to generate reactive oxygen species and to up-regulate aerobic glycolysis and oxidative phosphorylation. Our findings indicate that many of these phenotypes are genetically and functionally independent of one another and are not necessary for transformation. Specifically, the higher rate of glucose metabolism known to be associated with wtMyc deregulation was found to be independent of transformation. One mutation (Q131R) was greatly impaired for nearly all of the studied Myc phenotypes, yet was able to retain some ability to transform. These findings indicate that, while the Myc phenotypes examined here make additive contributions to transformation, none, with the possible exception of increased reliance on extracellular glutamine for survival, are necessary for achieving this state. PMID:21060841

  12. Role of H-Ras/ERK signaling in carbon nanotube-induced neoplastic-like transformation of human mesothelial cells

    PubMed Central

    Lohcharoenkal, Warangkana; Wang, Liying; Stueckle, Todd A.; Park, Jino; Tse, William; Dinu, Cerasela-Zoica; Rojanasakul, Yon

    2014-01-01

    Rapid development and deployment of engineered nanomaterials such as carbon nanotubes (CNTs) in various commercial and biomedical applications have raised concerns about their potential adverse health effects, especially their long-term effects which have not been well addressed. We demonstrated here that prolonged exposure of human mesothelial cells to single-walled CNT (SWCNT) induced neoplastic-like transformation as indicated by anchorage-independent cell growth and increased cell invasiveness. Such transformation was associated with an up-regulation of H-Ras and activation of ERK1/2. Downregulation of H-Ras by siRNA or inactivation of ERK by chemical inhibitor effectively inhibited the aggressive phenotype of SWCNT-exposed cells. Integrin alpha V and cortactin, but not epithelial-mesenchymal transition (EMT) transcriptional regulators, were up-regulated in the SWCNT-exposed cells, suggesting their role in the aggressive phenotype. Cortactin expression was shown to be controlled by the H-Ras/ERK signaling. Thus, our results indicate a novel role of H-Ras/ERK signaling and cortactin in the aggressive transformation of human mesothelial cells by SWCNT. PMID:24971065

  13. Mobile phone base station radiation does not affect neoplastic transformation in BALB/3T3 cells.

    PubMed

    Hirose, H; Suhara, T; Kaji, N; Sakuma, N; Sekijima, M; Nojima, T; Miyakoshi, J

    2008-01-01

    A large-scale in vitro study focusing on low-level radiofrequency (RF) fields from mobile radio base stations employing the International Mobile Telecommunication 2000 (IMT-2000) cellular system was conducted to test the hypothesis that modulated RF fields affect malignant transformation or other cellular stress responses. Our group previously reported that DNA strand breaks were not induced in human cells exposed to 2.1425 GHz Wideband Code Division Multiple Access (W-CDMA) radiation up to 800 mW/kg from mobile radio base stations employing the IMT-2000 cellular system. In the current study, BALB/3T3 cells were continuously exposed to 2.1425 GHz W-CDMA RF fields at specific absorption rates (SARs) of 80 and 800 mW/kg for 6 weeks and malignant cell transformation was assessed. In addition, 3-methylcholanthrene (MCA)-treated cells were exposed to RF fields in a similar fashion, to assess for effects on tumor promotion. Finally, the effect of RF fields on tumor co-promotion was assessed in BALB/3T3 cells initiated with MCA and co-exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA). At the end of the incubation period, transformation dishes were fixed, stained with Giemsa, and scored for morphologically transformed foci. No significant differences in transformation frequency were observed between the test groups exposed to RF signals and the sham-exposed negative controls in the non-, MCA-, or MCA plus TPA-treated cells. Our studies found no evidence to support the hypothesis that RF fields may affect malignant transformation. Our results suggest that exposure to low-level RF radiation of up to 800 mW/kg does not induce cell transformation, which causes tumor formation. PMID:17694516

  14. Inhibition of HMGI-C protein synthesis suppresses retrovirally induced neoplastic transformation of rat thyroid cells.

    PubMed Central

    Berlingieri, M T; Manfioletti, G; Santoro, M; Bandiera, A; Visconti, R; Giancotti, V; Fusco, A

    1995-01-01

    Elevated expression of the three high-mobility group I (HMGI) proteins (HMGI, HMGY, and HMGI-C) has previously been correlated with the presence of a highly malignant phenotype in epithelial and fibroblastic rat thyroid cells and in experimental thyroid, lung, mammary, and skin carcinomas. Northern (RNA) blot and run-on analyses demonstrated that the induction of HMGI genes in transformed thyroid cells occurs at the transcriptional level. An antisense methodology to block HMGI-C protein synthesis was then used to analyze the role of this protein in the process of thyroid cell transformation. Transfection of an antisense construct for the HMGI-C cDNA into normal thyroid cells, followed by infection with transforming myeloproliferative sarcoma virus or Kirsten murine sarcoma virus, generated cell lines that expressed significant levels of the retroviral transforming oncogenes v-mos or v-ras-Ki and removed the dependency on thyroid-stimulating hormones. However, in contrast with untransfected cells or cells transfected with the sense construct, those containing the antisense construct did not demonstrate the appearance of any malignant phenotypic markers (growth in soft agar and tumorigenicity in athymic mice). A great reduction of the HMGI-C protein levels and the absence of the HMGI(Y) proteins was observed in the HMGI-C antisense-transfected, virally infected cells. Therefore, the HMGI-C protein seems to play a key role in the transformation of these thyroid cells. PMID:7862147

  15. A conundrum in molecular toxicology: molecular and biological changes during neoplastic transformation of human cells.

    PubMed

    Milo, G E; Shuler, C F; Lee, H; Casto, B C

    1995-12-01

    The process of multistage carcinogenesis lends itself to the concept that the effects of carcinogens are mediated through dose-related, multi-hit, linear changes. Multiple in vitro model systems have been developed that are designed to examine the cellular changes associated with the progression of cells through the different stages in the process; however, these systems may have inherent limitations due to the cell lines used for these studies, the manner of assessing the effects of the carcinogens, and the subsequent growth and differentiation of the exposed cells. Each of these variables results in increasing levels of uncertainty relative to the correlation of the events with the actual process of human tumor development. Therefore, the prediction of the ultimate effect of any carcinogen is difficult. Moreover, relationships between individual biological endpoints resulting from carcinogen treatment appear at best to be approximations. The presence of an activated carcinogen inside the cell can give rise to multiple outcomes, only some of which may be critical events. For example, site-specific modification of the 12th and 13th codons of H-ras is different than that in the adjacent 14th and 15th codons. It is interesting to speculate what effect these differences might have on a biological outcome, e.g., transformation to anchorage-independent growth. The use of different model systems to examine the effects of activated carcinogens also creates additional problems. Comparisons of in vitro transformed cells with similar cells isolated from human tumors indicate that the culture environment appears to influence the expression of a particular phenotype, in that human tumor cells in culture express many of the same parameters as those found in cells transformed with carcinogens in vitro. If the process of transformation is linear, then less aggressive phenotypes should progress to a more aggressive transformed stage. However, in carcinogen-transformed human cells

  16. Mechanisms underlying the adaptive response against spontaneous neoplastic transformation induced by low doses of low LET radiation, Final Technical Report

    SciTech Connect

    J. Leslie Redpath, Ph.D.

    2006-01-23

    The goal of this project was to investigate mechanisms underlying the adaptive response seen following exposure of HeLa x skin fibroblast human hybrid cells to low doses of low LET radiation. It was proposed to investigate the contributions of three possible mechanisms. These were: 1. Upregulation of cellular antioxidant status. 2. Upregulation of DNA repair. 3. Upregulation of gap junction intracellular communication. We have completed the study of the role of upregulation of reduced glutathione (GSH) as a possible mechanism underlying our observed suppression of transformation frequency at low radiation doses. We have also completed our study of the possible role of upregulation of DNA repair in the observed adaptive response against neoplastic transformation. We concluded that upregulation of DNA repair may be more important in modulating transformation at the higher dose. A manuscript describing the above studies has been submitted published in Carcinogenesis 24:1961-1965, 2003. Finally, we have completed two studies of the possible role of upregulation of gap junction intercellular communication (GJIC) in modulating transformation frequency at low doses of low LET radiation. This research was published in Radiation Research 162:646-654, 2004. In order to optimize the opportunity for GJIC, we then carried out a study where confluent cultures were irradiated. The results indicated, that while the degree of low dose suppression was somewhat reduced compared to that seen for subconfluent cultures, it was not completely absent. This research has been submitted for publication. Our research program was of sufficient interest to generate two invited reviews, and five invited presentations.

  17. Neoplastic transformation of oral lichen: case report and review of the literature

    PubMed Central

    Abbate, G; Foscolo, AM; Gallotti, M; Lancella, A; Mingo, F

    2006-01-01

    Summary Aim of the present investigation was to analyse the possible malignant transformation of oral lichen planus to carcinoma, especially in the atrophic erosive forms and those displaying plaques involving the top of the tongue. A review has been made of the literature, from 1986 to the present day. This search outlines the relationship between oral lichen planus, hepatitis C virus infection, Epstein-Barr virus infection and the importance of periodic follow-up in all patients with oral lichen planus. The case is described of malignant transformation of oral lichen planus to oral cancer in a female presenting asymptomatic hepatitis C virus infection. The clinical history confirms the most important aspects of the relationship between oral lichen planus and oral cancer. Oral lichen planus should be considered as a precancerous lesion, particularly in patients presenting hepatitis C virus infection, requiring follow-up, at close intervals, starting from 3 months after diagnosis. PMID:18383758

  18. [Radiation-induced, irreparable, hereditary changes in cells promoting their neoplastic transformation].

    PubMed

    Kuzin, A M; Vagabova, M E; Iurov, S S

    1988-01-01

    In experiments with model plant tumors (Kalanchoe-ti plasmid Agrobact. tumefaciens C-58D) it was shown that exposure of the recipient plant to low-level gamma-radiation of 2 Gy induced changes in cells that were not repaired over two months promoting tumoral transformations in them. Those changes were shown to persist in the offspring of the exposed somatic cells. PMID:3363091

  19. Neoplastic transformation of rat thyroid cells requires the junB and fra-1 gene induction which is dependent on the HMGI-C gene product.

    PubMed Central

    Vallone, D; Battista, S; Pierantoni, G M; Fedele, M; Casalino, L; Santoro, M; Viglietto, G; Fusco, A; Verde, P

    1997-01-01

    The expression of the high mobility group I (HMGI)-C chromatin component was shown previously to be essential for the establishment of the neoplastic phenotype in retrovirally transformed thyroid cell lines. To identify possible targets of the HMGI-C gene product, we have analyzed the AP-1 complex in normal, fully transformed and antisense HMGI-C-expressing rat thyroid cells. We show that neoplastic transformation is associated with a drastic increase in AP-1 activity, which reflects multiple compositional changes. The strongest effect is represented by the dramatic junB and fra-1 gene induction, which is prevented in cell lines expressing the antisense HMGI-C. These results indicate that the HMGI-C gene product is essential for the junB and fra-1 transcriptional induction associated with neoplastic transformation. The inhibition of Fra-1 protein synthesis by stable transfection with a fra-1 antisense RNA vector significantly reduces the malignant phenotype of the transformed thyroid cells, indicating a pivotal role for the fra-1 gene product in the process of cellular transformation. PMID:9311991

  20. Karyotypic changes with neoplastic conversion in morphologically transformed golden hamster embryo cells induced by X-rays

    SciTech Connect

    Watanabe, M.; Suzuki, K.; Kodama, S. )

    1990-02-01

    Chromosomes from nine morphologically transformed (MT) cell lines (designated MT14 to MT22) of Golden hamster embryo cells induced by X-rays and from tumor-derived cell lines (MT14T to MT22T), obtained after injection of MT cells, were analyzed by the Giemsa banding method. MT cell lines showed a variety of numerical abnormalities. All of the MT cell lines involved trisomy of chromosomes 11 (80 to 100% of cells in each cell line) and 3 (8% of MT22 cells and 100% in other cell lines). Although the latent period for tumor growth differed greatly, eight of nine MT cell lines (MT14 to MT21) produced tumors at the site of injection. All tumor-derived cell lines involved trisomy of chromosome 3 at a 100% rate of incidence. Seven of nine tumor-derived cell lines (MT15T to MT18T, MT20T to MT22T) lost one chromosome 11 from the trisomic condition, resulting in disomy of chromosome 11. These results suggest that trisomies of chromosomes 11 and 3 may play a role in X-ray-induced neoplastic progression.

  1. CDK1 Phosphorylation of YAP Promotes Mitotic Defects and Cell Motility and Is Essential for Neoplastic Transformation

    PubMed Central

    Yang, Shuping; Zhang, Lin; Liu, Miao; Chong, Rong; Ding, Shi-Jian; Chen, Yuanhong; Dong, Jixin

    2013-01-01

    The Yes-associated protein YAP is a downstream effector of the Hippo pathway of cell cycle control which plays important roles in tumorigenesis. Hippo-mediated phosphorylation YAP, mainly at S127, inactivates YAP function. In this study, we define a mechanism for positive regulation of YAP activity that is critical for its oncogenic function. Specifically, we found that YAP is phosphorylated in vitro and in vivo by the cell cycle kinase CDK1 at T119, S289, and S367 during G2/M phase of the cell cycle. We also found that ectopic expression of a phosphomimetic YAP mutant (YAP3D, harboring T119D/S289D/S367D) was sufficient to induce mitotic defects in immortalized epithelial cells, including centrosome amplification, multipolar spindles and chromosome missegregation. Finally, we documented that mitotic phosphorylation of YAP was sufficient to promote cell migration and invasion in a manner essential for neoplastic cell transformation. In support of our findings, CDK1 inhibitors largely suppressed cell motility mediated by activated YAP-S127A but not the phosphomimetic mutant YAP3D. Collectively, our results reveal a previously unrecognized mechanism for controlling the activity of YAP that is crucial for its oncogenic function mediated by mitotic dysregulation. PMID:24101154

  2. Metastasis suppressors Nm23H1 and Nm23H2 differentially regulate neoplastic transformation and tumorigenesis.

    PubMed

    Tong, Yao; Yung, Lisa Y; Wong, Yung H

    2015-06-01

    Nm23H1 and H2 are prototypical metastasis suppressors with diverse functions, but recent studies suggest that they may also regulate tumorigenesis. Here, we employed both cellular and in vivo assays to examine the effect of Nm23H1 and H2 on tumorigenesis induced by oncogenic Ras and/or p53 deficiency. Co-expression of Nm23H1 but not H2 in NIH3T3 cells effectively suppressed neoplastic transformation and tumorigenesis induced by the oncogenic H-Ras G12V mutant. Overexpression of Nm23H1 but not H2 also inhibited tumorigenesis by human cervical cancer HeLa cells with p53 deficiency. However, in human non-small-cell lung carcinoma H1299 cells harboring N-Ras Q61K oncogenic mutation and p53 deletion, overexpression of Nm23H1 did not affect tumorigenesis in nude mice assays, while overexpression of Nm23H2 enhanced tumor growth with elevated expression of the c-Myc proto-oncogene. Collectively, these results suggest that Nm23H1 and H2 have differential abilities to modulate tumorigenesis. PMID:25748386

  3. Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells

    PubMed Central

    Wang, Liying; Stueckle, Todd A.; Mishra, Anurag; Derk, Raymond; Meighan, Terence; Castranova, Vincent; Rojanasakul, Yon

    2015-01-01

    Accumulating evidence indicates that carbon nanotubes (CNTs) are biopersistent and can cause lung damage. With similar fibrous morphology and mode of exposure to asbestos, a known human carcinogen, growing concern has arisen for elevated risk of CNT-induced lung carcinogenesis; however, relatively little is known about the long-term carcinogenic effect of CNT. Neoplastic transformation is a key early event leading to carcinogenesis. We studied the ability of single- and multi-walled CNTs to induce neoplastic transformation of human lung epithelial cells compared to asbestos. Long-term (6-month) exposure of the cells to occupationally relevant concentrations of CNT in culture caused a neoplastic-like transformation phenotype as demonstrated by increased cell proliferation, anchorage-independent growth, invasion and angiogenesis. Whole-genome expression signature and protein expression analyses showed that single- and multi-walled CNTs shared similar signaling signatures which were distinct from asbestos. These results provide novel toxicogenomic information and suggest distinct particle-associated mechanisms of neoplasia promotion induced by CNTs and asbestos. PMID:23634900

  4. Neoplastic transformation and tumorigenesis associated with overexpression of imup-1 and imup-2 genes in cultured NIH/3T3 mouse fibroblasts

    SciTech Connect

    Ryoo, Zae Young . E-mail: jaewoong64@hanmail.net; Jung, Boo Kyoung; Lee, Sang Ryeul; Kim, Myoung Ok; Kim, Sung Hyun; Kim, Hyo Jin; Ahn, Jung Yong; Lee, Tae-Hoon; Cho, Youl Hee; Park, Jae Hak; Kim, Jin Kyeoung

    2006-10-27

    Immortalization-upregulated protein 1 (IMUP-1) and immortalization-upregulated protein 2 (IMUP-2) genes have been recently cloned and are known to be involved in SV40-mediated immortalization. IMUP-1 and IMUP-2 genes were strongly expressed in various cancer cell lines and tumors, suggesting the possibility that they might be involved in tumorigenicity. To directly elucidate the functional role of IMUP-1 and IMUP-2 on neoplastic transformation and tumorigenicity, we stably transfected IMUP-1 and IMUP-2 into NIH/3T3 mouse fibroblast cells. Cellular characteristics of the neoplastic transformation were assessed by transformation foci, growth in soft agar, and tumor development in nude mice. We found that IMUP-1 and IMUP-2 overexpressing cells showed altered growth properties, anchorage-independent growth in soft agar and inducing tumor in nude mice. Furthermore, IMUP-1 and IMUP-2 transformants proliferated in reduced serum and shortened cell cycle. These results suggest that ectopic overexpression of IMUP-1 and IMUP-2 may play an important role in acquiring a transformed phenotype, tumorigenicity in vivo, and be related to cellular proliferation.

  5. Focus formation and neoplastic transformation by herpes simplex virus type 2 inactivated intracellularly by 5-bromo-2'-deoxyuridine and near UV light

    SciTech Connect

    Manak, M.M.; Aurelian, L.; Ts'o, P.O.

    1981-01-01

    The induction of focus formation in low serum and of neoplastic transformation of Syrian hamster embryo cells was examined after the expression of herpes simplex virus type 2 functions. Syrian hamster embryo cells infected at a high multiplicity (5 PFU/cell) with 5-bromo-2'-deoxyuridine-labeled herpes simplex virus type 2 (11% substitution of thymidine residues) were exposed to near UV light irradiation at various times postinfection. This procedure specifically inactivated the viral genome, while having little, if any, effect on the unlabeled cellular DNA. Focus formation in 1% serum and neoplastic transformation were observed in cells exposed to virus inactivated before infection, but the frequency was enhanced (15- to 27-fold) in cells in which the virus was inactivated at 4 to 8 h postinfection. Only 2 to 45 independently isolated foci were capable of establishing tumorigenic lines. The established lines exhibited phenotypic alterations characteristic of a transformed state, including reduced serum requirement, anchorage-independent growth, and tumorigenicity. They retained viral DNA sequences and, even at relatively late passage, expressed viral antigens, including ICP 10.

  6. A panel of in vitro tests to evaluate genotoxic and morphological neoplastic transformation potential on Balb/3T3 cells by pristine and remediated titania and zirconia nanoparticles.

    PubMed

    Stoccoro, Andrea; Di Bucchianico, Sebastiano; Uboldi, Chiara; Coppedè, Fabio; Ponti, Jessica; Placidi, Claudia; Blosi, Magda; Ortelli, Simona; Costa, Anna Luisa; Migliore, Lucia

    2016-09-01

    The FP7 Sanowork project was aimed to minimise occupational hazard and exposure to engineered nanomaterials (ENM) through the surface modification in order to prevent possible health effects. In this frame, a number of nanoparticles (NP) have been selected, among which zirconium (ZrO2) and titanium (TiO2) dioxide. In this study, we tested ZrO2 NP and TiO2 NP either in their pristine (uncoated) form, or modified with citrate and/or silica on their surface. As benchmark material, Aeroxide® P25 was used. We assessed cytotoxicity, genotoxicity and induction of morphological neoplastic transformation of NP by using a panel of in vitro assays in an established mammalian cell line of murine origin (Balb/3T3). Cell viability was evaluated by means of colony-forming efficiency assay (CFE). Genotoxicity was investigated by cytokinesis-block micronucleus cytome assay (CBMN cyt) and comet assay, and by the use of the restriction enzymes EndoIII and Fpg, oxidatively damaged DNA was detected; finally, the morphological neoplastic transformation of NP was assayed in vitro by cell transformation assay (CTA). Our results show that the surface remediation has not been effective in modifying cyto- and genotoxic properties of the nanomaterials tested; indeed, in the case of remediation of zirconia and titania with citrate, there is a tendency to emphasise the toxic effects. The use of a panel of assays, such as those we have employed, allowing the evaluation of multiple endpoints, including cell transformation, seems particularly advisable especially in the case of long-term exposure effects in the same cell type. PMID:27056944

  7. Dr. Josef Steiner Cancer Research Prize Lecture: the role of physiological cell death in neoplastic transformation and in anti-cancer therapy.

    PubMed

    Strasser, A

    1999-05-17

    Cell death is a physiological process which is required for normal development and existence of multi-cellular organisms. Physiological cell death, or apoptosis, is controlled by an evolutionarily conserved mechanism. Abnormalities in this process are implicated as a cause or contributing factor in a variety of diseases. Inhibition of apoptosis can promote neoplastic transformation, particularly in combination with dysregulated cell-cycle control, and can influence the response of tumour cells to anti-cancer therapy. Molecular biological and biochemical approaches are used to find missing cell-death regulators and to define signalling cascades, while experiments in genetically modified mice will identify the essential function of these molecules. Discoveries from cell death research should provide clues for designing therapies for a variety of diseases, including degenerative disorders, auto-immunity and cancer. PMID:10225436

  8. Rat Protein Tyrosine Phosphatase η Suppresses the Neoplastic Phenotype of Retrovirally Transformed Thyroid Cells through the Stabilization of p27Kip1

    PubMed Central

    Trapasso, Francesco; Iuliano, Rodolfo; Boccia, Angelo; Stella, Antonella; Visconti, Roberta; Bruni, Paola; Baldassarre, Gustavo; Santoro, Massimo; Viglietto, Giuseppe; Fusco, Alfredo

    2000-01-01

    The r-PTPη gene encodes a rat receptor-type protein tyrosine phosphatase whose expression is negatively regulated by neoplastic cell transformation. Here we first demonstrate a dramatic reduction in DEP-1/HPTPη (the human homolog of r-PTPη) expression in a panel of human thyroid carcinomas. Subsequently, we show that the reexpression of the r-PTPη gene in highly malignant rat thyroid cells transformed by retroviruses carrying the v-mos and v-ras-Ki oncogenes suppresses their malignant phenotype. Cell cycle analysis demonstrated that r-PTPη caused G1 growth arrest and increased the cyclin-dependent kinase inhibitor p27Kip1 protein level by reducing the proteasome-dependent degradation rate. We propose that the r-PTPη tumor suppressor activity is mediated by p27Kip1 protein stabilization, because suppression of p27Kip1 protein synthesis using p27-specific antisense oligonucleotides blocked the growth-inhibitory effect induced by r-PTPη. Furthermore, we provide evidence that in v-mos- or v-ras-Ki-transformed thyroid cells, the p27Kip1 protein level was regulated by the mitogen-activated protein (MAP) kinase pathway and that r-PTPη regulated p27Kip1 stability by preventing v-mos- or v-ras-Ki-induced MAP kinase activation. PMID:11094075

  9. Nuclear Factor kappa B is central to Marek’s Disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Marek’s Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the n...

  10. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    SciTech Connect

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-06-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a 6 month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. Highlights: ► Chronic As{sub 2}O

  11. Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells

    PubMed Central

    Stueckle, Todd A.; Lu, Yongju; Davis, Mary E.; Wang, Liying; Jiang, Bing-Hua; Holaskova, Ida; Schafer, Rosana; Barnett, John B.; Rojanasakul, Yon

    2012-01-01

    Chronic arsenic exposure remains a human health risk; however a clear mode of action to understand gene signaling-driven arsenic carcinogenesis is currently lacking. This study chronically exposed human lung epithelial BEAS-2B cells to low-dose arsenic trioxide to elucidate cancer promoting gene signaling networks associated with arsenic-transformed (B-As) cells. Following a six month exposure, exposed cells were assessed for enhanced cell proliferation, colony formation, invasion ability and in vivo tumor formation compared to control cell lines. Collected mRNA was subjected to whole genome expression microarray profiling followed by in silico Ingenuity Pathway Analysis (IPA) to identify lung carcinogenesis modes of action. B-As cells displayed significant increases in proliferation, colony formation and invasion ability compared to BEAS-2B cells. B-As injections into nude mice resulted in development of primary and secondary metastatic tumors. Arsenic exposure resulted in widespread up-regulation of genes associated with mitochondrial metabolism and increased reactive oxygen species protection suggesting mitochondrial dysfunction. Carcinogenic initiation via reactive oxygen species and epigenetic mechanisms was further supported by altered DNA repair, histone, and ROS-sensitive signaling. NF-κB, MAPK and NCOR1 signaling disrupted PPARα/δ-mediated lipid homeostasis. A ‘pro-cancer’ gene signaling network identified increased survival, proliferation, inflammation, metabolism, anti-apoptosis and mobility signaling. IPA-ranked signaling networks identified altered p21, EF1α, Akt, MAPK, and NF-κB signaling networks promoting genetic disorder, altered cell cycle, cancer and changes in nucleic acid and energy metabolism. In conclusion, transformed B-As cells with their whole genome expression profile provide an in vitro arsenic model for future lung cancer signaling research and data for chronic arsenic exposure risk assessment. PMID:22521957

  12. Regulation of the pituitary tumor transforming gene by insulin-like-growth factor-I and insulin differs between malignant and non-neoplastic astrocytes

    SciTech Connect

    Chamaon, Kathrin; Kirches, Elmar; Kanakis, Dimitrios; Braeuninger, Stefan; Dietzmann, Knut; Mawrin, Christian . E-mail: christian.mawrin@medizin.uni-magdeburg.de

    2005-05-27

    The reasons for overexpression of the oncogene pituitary tumor transforming gene (PTTG) in tumors are still not fully understood. A possible influence of the insulin-like growth factor I (Igf-I) may be of interest, since enhanced Igf-I signalling was reported in various human tumors. We examined the influence of Igf-I and insulin on PTTG expression in human astrocytoma cells in comparison to proliferating non-neoplastic rat embryonal astrocytes. PTTG mRNA expression and protein levels were increased in malignant astrocytes treated with Igf-I or insulin, whereas in rat embryonic astrocytes PTTG expression and protein levels increased only when cells were exposed to Igf-I. Enhanced transcription did not occur after treatment with inhibitors of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), blocking the two basic signalling pathways of Igf-I and insulin. In addition to this transcriptional regulation, both kinases directly bind to PTTG, suggesting a second regulatory route by phosphorylation. However, the interaction of endogenous PTTG with MAPK and PI3K, as well as PTTG phosphorylation were independent from Igf-I or insulin. The latter results were also found in human testis, which contains high PTTG levels as well as in nonneoplastic astrocytes. This suggest, that PI3K and MAPK signalling is involved in PTTG regulation not only in malignant astrocytomas but also in non-tumorous cells.

  13. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha.

    PubMed Central

    Santoni-Rugiu, E.; Nagy, P.; Jensen, M. R.; Factor, V. M.; Thorgeirsson, S. S.

    1996-01-01

    We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in major enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we describe in detail the progression from liver cell dysplasia to hepatocellular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the sequence of events between the two transgenic lines, the dramatic acceleration, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice clearly demonstrated the synergistic effects of this transgenic combination. Although c-myc/TGF-alpha and c-myc females displayed longer latency and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc and TGF-alpha and, most frequently, unchanged or decreased epidermal growth factor receptor, further indicating the collaborative role of c-myc and TGF-alpha in providing a selective growth advantage to tumor cells independently of the epidermal growth factor receptor levels. To identify possible tumor precursors, we focused particularly on the dysplastic changes preceding and accompanying the appearance of preneoplastic and neoplastic lesions in the double-transgenic mice. Early on, these changes were characterized by the appearance of large dysplastic hepatocytes, mostly pericentrally, expressing high levels of TGF-alpha and uPA, as well as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent apoptotic cell death while preneoplastic and neoplastic lesions were forming. The peritumorous tissues also

  14. PDZ-binding kinase/T-LAK cell-originated protein kinase is a target of the fucoidan from brown alga Fucus evanescens in the prevention of EGF-induced neoplastic cell transformation and colon cancer growth

    PubMed Central

    Wang, Zhe; Ermakova, Svetlana P.; Xiao, JuanJuan; Lu, Tao; Xue, PeiPei; Zvyagintseva, Tatyana N.; Xiong, Hua; Shao, Chen; Yan, Wei; Duan, Qiuhong; Zhu, Feng

    2016-01-01

    The fucoidan with high anticancer activity was isolated from brown alga Fucus evanescens. The compound effectively prevented EGF-induced neoplastic cell transformation through inhibition of TOPK/ERK1/2/MSK 1 signaling axis. In vitro studies showed that the fucoidan attenuated mitogen-activated protein kinases downstream signaling in a colon cancer cells with different expression level of TOPK, resulting in growth inhibition. The fucoidan exerts its effects by directly interacting with TOPK kinase in vitro and ex vivo and inhibits its kinase activity. In xenograft animal model, oral administration of the fucoidan suppressed HCT 116 colon tumor growth. The phosphorylation of TOPK downstream signaling molecules in tumor tissues was also inhibited by the fucoidan. Taken together, our findings support the cancer preventive efficacy of the fucoidan through its targeting of TOPK for the prevention of neoplastic cell transformation and progression of colon carcinomas in vitro and ex vivo. PMID:26936995

  15. Enhanced neoplastic transformation by mammography X rays relative to 200 kVp X rays: indication for a strong dependence on photon energy of the RBE(M) for various end points.

    PubMed

    Frankenberg, D; Kelnhofer, K; Bär, K; Frankenberg-Schwager, M

    2002-01-01

    The fundamental assumption implicit in the use of the atomic bomb survivor data to derive risk estimates is that the gamma rays of Hiroshima and Nagasaki are considered to have biological efficiencies equal to those of other low-LET radiations up to 10 keV/microm, including mammography X rays. Microdosimetric and radiobiological data contradict this assumption. It is therefore of scientific and public interest to evaluate the efficiency of mammography X rays (25-30 kVp) to induce cancer. In this study, the efficiency of mammography X rays relative to 200 kVp X rays to induce neoplastic cell transformation was evaluated using cells of a human hybrid cell line (CGL1). For both radiations, a linear-quadratic dose-effect relationship was observed for neoplastic transformation of CGL1 cells; there was a strong linear component for the 29 kVp X rays. The RBE(M) of mammography X rays relative to 200 kVp X rays was determined to be about 4 for doses < or = 0.5 Gy. A comparison of the electron fluences for both X rays provides strong evidence that electrons with energies of < or = 15 keV can induce neoplastic transformation of CGL1 cells. Both the data available in the literature and the results of the present study strongly suggest an increase of RBE(M) for carcinogenesis in animals, neoplastic cell transformation, and clastogenic effects with decreasing photon energy or increasing LET to an RBE(M) approximately 8 for mammography X rays relative to 60Co gamma rays. PMID:11754647

  16. Fluorescence Spectroscopy of Neoplastic and Non-Neoplastic Tissues

    PubMed Central

    Ramanujam, Nirmala

    2000-01-01

    Abstract Fast and non-invasive, diagnostic techniques based on fluorescence spectroscopy have the potential to link the biochemical and morphologic properties of tissues to individual patient care. One of the most widely explored applications of fluorescence spectroscopy is the detection of endoscopically invisible, early neoplastic growth in epithelial tissue sites. Currently, there are no effective diagnostic techniques for these early tissue transformations. If fluorescence spectroscopy can be applied successfully as a diagnostic technique in this clinical context, it may increase the potential for curative treatment, and thus, reduce complications and health care costs. Steady-state, fluorescence measurements from small tissue regions as well as relatively large tissue fields have been performed. To a much lesser extent, time-resolved, fluorescence measurements have also been explored for tissue characterization. Furthermore, sources of both intrinsic (endogenous fluorophores) and extrinsic fluorescence (exogenous fluorophores) have been considered. The goal of the current report is to provide a comprehensive review on steady-state and time-resolved, fluorescence measurements of neoplastic and non-neoplastic, biologic systems of varying degrees of complexity. First, the principles and methodology of fluorescence spectroscopy are discussed. Next, the endogenous fluorescence properties of cells, frozen tissue sections and excised and intact bulk tissues are presented; fluorescence measurements from both animal and human tissue models are discussed. This is concluded with future perspectives. PMID:10933071

  17. Interval process model and non-random vibration analysis

    NASA Astrophysics Data System (ADS)

    Jiang, C.; Ni, B. Y.; Liu, N. Y.; Han, X.; Liu, J.

    2016-07-01

    This paper develops an interval process model for time-varying or dynamic uncertainty analysis when information of the uncertain parameter is inadequate. By using the interval process model to describe a time-varying uncertain parameter, only its upper and lower bounds are required at each time point rather than its precise probability distribution, which is quite different from the traditional stochastic process model. A correlation function is defined for quantification of correlation between the uncertain-but-bounded variables at different times, and a matrix-decomposition-based method is presented to transform the original dependent interval process into an independent one for convenience of subsequent uncertainty analysis. More importantly, based on the interval process model, a non-random vibration analysis method is proposed for response computation of structures subjected to time-varying uncertain external excitations or loads. The structural dynamic responses thus can be derived in the form of upper and lower bounds, providing an important guidance for practical safety analysis and reliability design of structures. Finally, two numerical examples and one engineering application are investigated to demonstrate the feasibility of the interval process model and corresponding non-random vibration analysis method.

  18. Neoplastic diseases of marine bivalves.

    PubMed

    Carballal, María J; Barber, Bruce J; Iglesias, David; Villalba, Antonio

    2015-10-01

    Two types of prevalent neoplastic diseases have been described in marine bivalves of commercial interest: disseminated neoplasia (DN) and gonadal neoplasia. The first involves the excessive proliferation of abnormal cells with unknown origin (probably of hemic source in some cases/species), disseminating through the circulatory system and infiltrating the connective tissue of various organs; the second consists of an abnormal proliferation of undifferentiated germinal cells of the gonad. These two types of bivalve neoplasia fit the criteria of malignant tumors: pleomorphic and undifferentiated cells, rapid and invasive growth, abundance of mitotic figures, metastasis and progressive development often resulting in the death of the affected individual. Different causes have been suggested regarding etiology: genetic alterations, virus, retrotranspons, and contaminants, although it could depend on the mollusk species; evidence of horizontal transmission of clonal cancer cells as the cause of DN spreading in clam Mya arenaria populations has been recently reported. In some species and populations, the neoplastic disorders affect only a few individuals, but in others reach high prevalence. Among the diagnostic methods, DN has been detected by histology and cytologic examination of hemolymph, and with developed specific antibodies. Recently, flow cytometry has also been applied, allowing detecting DNA quantity alteration. Several studies reported many genes and pathways critically involved in neoplastic transformation in Mya arenaria, Mytilus spp. and Ostrea edulis. These genetic studies will allow the development of diagnosis by PCR which can be used in biomonitoring studies. PMID:26146225

  19. Non-random patterns in viral diversity

    PubMed Central

    Anthony, Simon J.; Islam, Ariful; Johnson, Christine; Navarrete-Macias, Isamara; Liang, Eliza; Jain, Komal; Hitchens, Peta L.; Che, Xiaoyu; Soloyvov, Alexander; Hicks, Allison L.; Ojeda-Flores, Rafael; Zambrana-Torrelio, Carlos; Ulrich, Werner; Rostal, Melinda K.; Petrosov, Alexandra; Garcia, Joel; Haider, Najmul; Wolfe, Nathan; Goldstein, Tracey; Morse, Stephen S.; Rahman, Mahmudur; Epstein, Jonathan H.; Mazet, Jonna K.; Daszak, Peter; Lipkin, W. Ian

    2015-01-01

    It is currently unclear whether changes in viral communities will ever be predictable. Here we investigate whether viral communities in wildlife are inherently structured (inferring predictability) by looking at whether communities are assembled through deterministic (often predictable) or stochastic (not predictable) processes. We sample macaque faeces across nine sites in Bangladesh and use consensus PCR and sequencing to discover 184 viruses from 14 viral families. We then use network modelling and statistical null-hypothesis testing to show the presence of non-random deterministic patterns at different scales, between sites and within individuals. We show that the effects of determinism are not absolute however, as stochastic patterns are also observed. In showing that determinism is an important process in viral community assembly we conclude that it should be possible to forecast changes to some portion of a viral community, however there will always be some portion for which prediction will be unlikely. PMID:26391192

  20. Snail Family Members Unequally Trigger EMT and Thereby Differ in Their Ability to Promote the Neoplastic Transformation of Mammary Epithelial Cells

    PubMed Central

    Wierinckx, Anne; Lamblot, Christelle; Fauvet, Frédérique; Lachuer, Joël; Puisieux, Alain; Ansieau, Stéphane

    2014-01-01

    By fostering cell commitment to the epithelial-to-mesenchymal transition (EMT), SNAIL proteins endow cells with motility, thereby favoring the metastatic spread of tumor cells. Whether the phenotypic change additionally facilitates tumor initiation has never been addressed. Here we demonstrate that when a SNAIL protein is ectopically produced in non-transformed mammary epithelial cells, the cells are protected from anoikis and proliferate under low-adherence conditions: a hallmark of cancer cells. The three SNAIL proteins show unequal oncogenic potential, strictly correlating with their ability to promote EMT. SNAIL3 especially behaves as a poor EMT-inducer comforting the concept that the transcription factor functionally diverges from its two related proteins. PMID:24638100

  1. Glyoxalase I drives epithelial-to-mesenchymal transition via argpyrimidine-modified Hsp70, miR-21 and SMAD signalling in human bronchial cells BEAS-2B chronically exposed to crystalline silica Min-U-Sil 5: Transformation into a neoplastic-like phenotype.

    PubMed

    Antognelli, Cinzia; Gambelunghe, Angela; Muzi, Giacomo; Talesa, Vincenzo Nicola

    2016-03-01

    Glyoxalase I (Glo1) is the main scavenging enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). AGEs are known to control multiple biological processes, including epithelial to mesenchymal transition (EMT), a multistep phenomenon associated with cell transformation, playing a major role in a variety of diseases, including cancer. Crystalline silica is a well-known occupational health hazard, responsible for a great number of human pulmonary diseases, such as silicosis. There is still much debate concerning the carcinogenic role of crystalline silica, mainly due to the lack of a causal demonstration between silica exposure and carcinogenesis. It has been suggested that EMT might play a role in crystalline silica-induced lung neoplastic transformation. The aim of this study was to investigate whether, and by means of which mechanism, the antiglycation defence Glo1 is involved in Min-U-Sil 5 (MS5) crystalline silica-induced EMT in BEAS-2B human bronchial epithelial cells chronically exposed, and whether this is associated with the beginning of a neoplastic-like transformation process. By using gene silencing/overexpression and scavenging/inhibitory agents, we demonstrated that MS5 induced hydrogen peroxide-mediated c-Jun-dependent Glo1 up-regulation which resulted in a decrease in the Argpyrimidine-modified Hsp70 protein level which triggered EMT in a novel mechanism involving miR-21 and SMAD signalling. The observed EMT was associated with a neoplastic-like phenotype. The results obtained provide a causal in vitro demonstration of the MS5 pro-carcinogenic transforming role and more importantly they provide new insights into the mechanisms involved in this process, thus opening new paths in research concerning the in vivo study of the carcinogenic potential of crystalline silica. PMID:26784015

  2. [Tongue paralysis of neoplastic origin].

    PubMed

    Marco, M; Dalmau, J; Aguilar, M

    1989-10-01

    Tongue paralysis are often underestimated, particularly when isolated or having a chronic course. Sometimes, its early recognition may lead to the diagnosis of a tumor process, favorably modifying its course. We have retrospectively analyzed 13 cases of tongue paralysis of neoplastic etiology. In a woman, the paralysis was due to a lesion of the corticobulbar pathway whereas in the remaining 12, the alteration occurred in the hypoglossal nerve, particularly at extrabulbar intracranial and cranial base tract (10 cases). The clinical picture was due to the primary tumor in 9 patients, and due to bone or leptomeningeal metastases in the remaining four cases. In five cases, the lesion of the XII cranial nerve was essential for the diagnosis of the neoplasm or the neoplastic recurrence and in four cases, it was the only affected cranial nerve. PMID:2637769

  3. Non-random DNA fragmentation in next-generation sequencing

    PubMed Central

    Poptsova, Maria S.; Il'icheva, Irina A.; Nechipurenko, Dmitry Yu.; Panchenko, Larisa A.; Khodikov, Mingian V.; Oparina, Nina Y.; Polozov, Robert V.; Nechipurenko, Yury D.; Grokhovsky, Sergei L.

    2014-01-01

    Next Generation Sequencing (NGS) technology is based on cutting DNA into small fragments, and their massive parallel sequencing. The multiple overlapping segments termed “reads” are assembled into a contiguous sequence. To reduce sequencing errors, every genome region should be sequenced several dozen times. This sequencing approach is based on the assumption that genomic DNA breaks are random and sequence-independent. However, previously we showed that for the sonicated restriction DNA fragments the rates of double-stranded breaks depend on the nucleotide sequence. In this work we analyzed genomic reads from NGS data and discovered that fragmentation methods based on the action of the hydrodynamic forces on DNA, produce similar bias. Consideration of this non-random DNA fragmentation may allow one to unravel what factors and to what extent influence the non-uniform coverage of various genomic regions. PMID:24681819

  4. Non-random DNA fragmentation in next-generation sequencing

    NASA Astrophysics Data System (ADS)

    Poptsova, Maria S.; Il'Icheva, Irina A.; Nechipurenko, Dmitry Yu.; Panchenko, Larisa A.; Khodikov, Mingian V.; Oparina, Nina Y.; Polozov, Robert V.; Nechipurenko, Yury D.; Grokhovsky, Sergei L.

    2014-03-01

    Next Generation Sequencing (NGS) technology is based on cutting DNA into small fragments, and their massive parallel sequencing. The multiple overlapping segments termed ``reads'' are assembled into a contiguous sequence. To reduce sequencing errors, every genome region should be sequenced several dozen times. This sequencing approach is based on the assumption that genomic DNA breaks are random and sequence-independent. However, previously we showed that for the sonicated restriction DNA fragments the rates of double-stranded breaks depend on the nucleotide sequence. In this work we analyzed genomic reads from NGS data and discovered that fragmentation methods based on the action of the hydrodynamic forces on DNA, produce similar bias. Consideration of this non-random DNA fragmentation may allow one to unravel what factors and to what extent influence the non-uniform coverage of various genomic regions.

  5. Vulvovaginal reconstruction for neoplastic disease.

    PubMed

    Höckel, Michael; Dornhöfer, Nadja

    2008-06-01

    Current treatment of neoplastic disease that involves the external female genitalia aims to achieve local disease control, but not to restore form and function of these organs. Despite a growing trend to reduce the extent of surgical resection, impaired quality of life after surgery due to severe sexual dysfunction and disturbed body image is common. We postulate that the integration of surgical techniques for vulvar and vaginal reconstruction into primary treatment would improve aesthetic and functional results and therefore quality of life. We systematically searched the literature for surgical procedures designed and validated for vulvovaginal reconstruction. Various skin flaps, both with random vascularisation and those based on vascular territories (ie, axial pattern, fasciocutaneous, musculocutaneous, and bowel flaps), can restore important parts of vulvovaginal form and function with acceptable morbidity at the donor and recipient sites. Appropriate vulvovaginal reconstruction cannot be achieved by doing a few standardised procedures; rather, it necessitates specialists who are familiar with general principles of reconstructive surgery to master many techniques to select the optimum procedure for the individual patient. Vulvovaginal reconstructive surgery has limitations, particularly achievement of functional restoration in irradiated tissue. Physicians who treat women with neoplastic disease of the external genitalia should be aware of the current state of vulvovaginal reconstructive surgery. Prospective controlled clinical trials are warranted to assess the effect of vulvovaginal reconstruction on morbidity and quality of life after treatment. PMID:18510987

  6. Reducing bias in survival under non-random temporary emigration

    USGS Publications Warehouse

    Peñaloza, Claudia L.; Kendall, William L.; Langtimm, Catherine Ann

    2014-01-01

    Despite intensive monitoring, temporary emigration from the sampling area can induce bias severe enough for managers to discard life-history parameter estimates toward the terminus of the times series (terminal bias). Under random temporary emigration unbiased parameters can be estimated with CJS models. However, unmodeled Markovian temporary emigration causes bias in parameter estimates and an unobservable state is required to model this type of emigration. The robust design is most flexible when modeling temporary emigration, and partial solutions to mitigate bias have been identified, nonetheless there are conditions were terminal bias prevails. Long-lived species with high adult survival and highly variable non-random temporary emigration present terminal bias in survival estimates, despite being modeled with the robust design and suggested constraints. Because this bias is due to uncertainty about the fate of individuals that are undetected toward the end of the time series, solutions should involve using additional information on survival status or location of these individuals at that time. Using simulation, we evaluated the performance of models that jointly analyze robust design data and an additional source of ancillary data (predictive covariate on temporary emigration, telemetry, dead recovery, or auxiliary resightings) in reducing terminal bias in survival estimates. The auxiliary resighting and predictive covariate models reduced terminal bias the most. Additional telemetry data was effective at reducing terminal bias only when individuals were tracked for a minimum of two years. High adult survival of long-lived species made the joint model with recovery data ineffective at reducing terminal bias because of small-sample bias. The naïve constraint model (last and penultimate temporary emigration parameters made equal), was the least efficient, though still able to reduce terminal bias when compared to an unconstrained model. Joint analysis of several

  7. PNA: a marker of neoplastic progression and differentiation in the gastro-intestinal tract.

    PubMed

    Grigolato, P; Benetti, A; Berenzi, A; Villanacci, V; Tardanico, R

    1990-01-01

    We examined 35 cases of stomach carcinoma and 40 cases of colonic carcinoma with PNA associated with peroxidase (peanut agglutinin, lectin which binds to the terminal disaccharide galactose beta (1,3)-N-acetil-galacto-samine). In this way evaluation of the functional aspects of the normal-neoplastic sequence was undertaken. This method was carried out for histological and ultrastructural investigations. The results obtained in both cases showed a different reactivity in the evolution of neoplastic disease: in fact, positivity in dysplasia is finely granular intracytoplasmic, whereas in well-differentiated neoplastic transformation such a reactivity is preferentially localized along the cellular membranes, with restoration of gross positivity in the cytoplasm for the poorly-differentiated neoplasm. We therefore believe PNA to be a marker not only of neoplastic progression but of differentiation as well: we also hypothesize it to reveal glycoprotein groups with possible antigenic power, involved in immunologic interactions between tumor and host. PMID:2283482

  8. Does homeobox-related "positional" genomic information contribute to implantation of metastatic cancer cells at non-random sites?

    PubMed

    Anderson, K M; Darweesh, M; Jajah, A; Tsui, P; Guinan, P; Rubenstein, M

    2007-01-01

    Reasons for the lodgment of metastases from several types of solid cancer at apparently non-random sites have not been established. Recently, a group of genes expressed in human fibroblasts obtained from different anatomic locations was implicated in "positional" genomic information. Essentially, a Cartesian coordinate system identifying fibroblasts originally resident at anterior or more posterior, proximal or distal and dermal or non-dermal (heart, lung, etc.) locations was proposed. The determinants used for these identifications included HOX genes, central to embryonic segmental development, some of which are expressed in differentiated, post-embryonic cells. To the extent that HOX or other homeobox genes are expressed in ectodermal, mesodermal or endodermally-derived, malignantly transformed cells, they might contribute "positional" information to nidation of specific malignant clones at non-random sites. As understood in the past, interdiction of HOX or homeobox-related gene expression might reduce the probability of cancer cell implantation or alter their destinations in complex ways. Ideally, by interfering with HOX or other homeobox gene-related expression of antigenic determinants potentially contributing to their "homing" and nidation, reduced implantation of circulating cancer cells could render them more susceptible to systemic chemotherapy or immunotherapy, as demonstrated in mice. Furthermore, HOX or other homeobox genes or their products could provide novel intra- or extracellular targets for therapy. PMID:17695497

  9. TRANSFORMATION

    SciTech Connect

    LACKS,S.A.

    2003-10-09

    Transformation, which alters the genetic makeup of an individual, is a concept that intrigues the human imagination. In Streptococcus pneumoniae such transformation was first demonstrated. Perhaps our fascination with genetics derived from our ancestors observing their own progeny, with its retention and assortment of parental traits, but such interest must have been accelerated after the dawn of agriculture. It was in pea plants that Gregor Mendel in the late 1800s examined inherited traits and found them to be determined by physical elements, or genes, passed from parents to progeny. In our day, the material basis of these genetic determinants was revealed to be DNA by the lowly bacteria, in particular, the pneumococcus. For this species, transformation by free DNA is a sexual process that enables cells to sport new combinations of genes and traits. Genetic transformation of the type found in S. pneumoniae occurs naturally in many species of bacteria (70), but, initially only a few other transformable species were found, namely, Haemophilus influenzae, Neisseria meningitides, Neisseria gonorrheae, and Bacillus subtilis (96). Natural transformation, which requires a set of genes evolved for the purpose, contrasts with artificial transformation, which is accomplished by shocking cells either electrically, as in electroporation, or by ionic and temperature shifts. Although such artificial treatments can introduce very small amounts of DNA into virtually any type of cell, the amounts introduced by natural transformation are a million-fold greater, and S. pneumoniae can take up as much as 10% of its cellular DNA content (40).

  10. TRANSFORMER

    DOEpatents

    Baker, W.R.

    1959-08-25

    Transformers of a type adapted for use with extreme high power vacuum tubes where current requirements may be of the order of 2,000 to 200,000 amperes are described. The transformer casing has the form of a re-entrant section being extended through an opening in one end of the cylinder to form a coaxial terminal arrangement. A toroidal multi-turn primary winding is disposed within the casing in coaxial relationship therein. In a second embodiment, means are provided for forming the casing as a multi-turn secondary. The transformer is characterized by minimized resistance heating, minimized external magnetic flux, and an economical construction.

  11. Non-random structures in universal compression and the Fermi paradox

    NASA Astrophysics Data System (ADS)

    Gurzadyan, A. V.; Allahverdyan, A. E.

    2016-02-01

    We study the hypothesis of information panspermia assigned recently among possible solutions of the Fermi paradox ("where are the aliens?"). It suggests that the expenses of alien signaling can be significantly reduced, if their messages contained compressed information. To this end we consider universal compression and decoding mechanisms ( e.g. the Lempel-Ziv-Welch algorithm) that can reveal non-random structures in compressed bit strings. The efficiency of the Kolmogorov stochasticity parameter for detection of non-randomness is illustrated, along with the Zipf's law. The universality of these methods, i.e. independence from data details, can be principal in searching for intelligent messages.

  12. The potential influence of radiation-induced microenvironments in neoplastic progression

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Ionizing radiation is a complete carcinogen, able both to initiate and promote neoplastic progression and is a known carcinogen of human and murine mammary gland. Tissue response to radiation is a composite of genetic damage, cell death and induction of new gene expression patterns. Although DNA damage is believed to initiate carcinogenesis, the contribution of these other aspects of radiation response are beginning to be explored. Our studies demonstrate that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. We postulate that radiation-induced microenvironments may affect epithelial cells neoplastic transformation by altering their number or susceptibility. Alternatively, radiation induced microenvironments may exert a selective force on initiated cells and/or be conducive to progression. A key impetus for these studies is the possibility that blocking these events could be a strategy to interrupt neoplastic progression.

  13. The quality of control groups in non-randomized studies published in Journal of Hand Surgery

    PubMed Central

    Johnson, Shepard P.; Malay, Sunitha; Chung, Kevin C.

    2016-01-01

    Purpose To evaluate control group selection in non-randomized studies published in the Journal of Hand Surgery American (JHS). Methods We reviewed all papers published in JHS in 2013 to identify studies that used non-randomized control groups. Data collected included type of study design and control group characteristics. We then appraised studies to determine if authors discussed confounding and selection bias and how they controlled for confounding. Results Thirty-seven non-randomized studies were published in JHS in 2013. The source of control was either the same institution as the study group, a different institution, a database, or not provided in the manuscript. Twenty-nine (78%) studies statistically compared key characteristics between control and study group. Confounding was controlled with matching, exclusion criteria, or regression analysis. Twenty-two (59%) papers explicitly discussed the threat of confounding and 18(49%) identified sources of selection bias. Conclusions In our review of non-randomized studies published in JHS, papers had well-defined controls that were similar to the study group, allowing for reasonable comparisons. However, we identified substantial confounding and bias that were not addressed as explicit limitations, which might lead the reader to overestimate the scientific validity of the data. Clinical relevance Incorporating a brief discussion of control group selection in scientific manuscripts should help readers interpret the study more appropriately. Authors, reviewers, and editors should strive to address this component of clinical importance. PMID:25447000

  14. 42 CFR 421.505 - Termination and extension of non-random prepayment complex medical review.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... complex medical review if a provider or supplier stops billing the code under review, shifts billing to... medical records, or engages in any other improper claims or billing-related activity to avoid non-random... complex medical review. 421.505 Section 421.505 Public Health CENTERS FOR MEDICARE & MEDICAID...

  15. 42 CFR 421.505 - Termination and extension of non-random prepayment complex medical review.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... prepayment complex medical review if a provider or supplier stops billing the code under review, shifts... requests for medical records, or engages in any other improper claims or billing-related activity to avoid... billing error are no longer suspended for non-random prepayment complex medical review. (d) Periodic...

  16. 42 CFR 421.505 - Termination and extension of non-random prepayment complex medical review.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... complex medical review if a provider or supplier stops billing the code under review, shifts billing to... medical records, or engages in any other improper claims or billing-related activity to avoid non-random... complex medical review. 421.505 Section 421.505 Public Health CENTERS FOR MEDICARE & MEDICAID...

  17. Bayesian hierarchical modeling for a non-randomized, longitudinal fall prevention trial with spatially correlated observations

    PubMed Central

    Murphy, T. E.; Allore, H. G.; Leo-Summers, L.; Carlin, B. P.

    2012-01-01

    Because randomization of participants is often not feasible in community-based health interventions, non-randomized designs are commonly employed. Non-randomized designs may have experimental units that are spatial in nature, such as zip codes that are characterized by aggregate statistics from sources like the U.S. census and the Centers for Medicare and Medicaid Services. A perennial concern with non-randomized designs is that even after careful balancing of influential covariates, bias may arise from unmeasured factors. In addition to facilitating the analysis of interventional designs based on spatial units, Bayesian hierarchical modeling can quantify unmeasured variability with spatially correlated residual terms. Graphical analysis of these spatial residuals demonstrates whether variability from unmeasured covariates is likely to bias the estimates of interventional effect. The Connecticut Collaboration for Fall Prevention is the first large-scale longitudinal trial of a community-wide healthcare intervention designed to prevent injurious falls in older adults. Over a two-year evaluation phase, this trial demonstrated a rate of fall-related utilization at hospitals and emergency departments by persons 70 years and older in the intervention area that was 11 per cent less than that of the usual care area, and a 9 per cent lower rate of utilization from serious injuries. We describe the Bayesian hierarchical analysis of this non-randomized intervention with emphasis on its spatial and longitudinal characteristics. We also compare several models, using posterior predictive simulations and maps of spatial residuals. PMID:21294148

  18. Organoids as Models for Neoplastic Transformation | Office of Cancer Genomics

    Cancer.gov

    Cancer models strive to recapitulate the incredible diversity inherent in human tumors. A key challenge in accurate tumor modeling lies in capturing the panoply of homo- and heterotypic cellular interactions within the context of a three-dimensional tissue microenvironment. To address this challenge, researchers have developed organotypic cancer models (organoids) that combine the 3D architecture of in vivo tissues with the experimental facility of 2D cell lines.

  19. Somatic mutation and cell differentiation in neoplastic transformation

    SciTech Connect

    Huberman, E.; Collart, F.R.

    1987-01-01

    In brief, the authors suggest that tumor formation may result from continuous expression of growth facilitating genes that, as a result of irreversible changes during the initiation step, are placed under the control of genes expressed during normal differentiation. Thus, to understand carcinogenesis, we must decipher the processes that lead to the acquisition of a mature phenotype in both normal and tumor cells and characterize the growth dependency of tumor cells to inducers of cell differentiation. Furthermore, the growth of a variety of tumors may be controlled through the use of inducers of maturation that activate genes located beyond the gene that is altered during tumor initiation. 22 refs., 3 figs.

  20. Human papilloma virus in neoplastic and non-neoplastic conditions of the external eye

    PubMed Central

    Karcioglu, Z.; Issa, T.

    1997-01-01

    AIM—Human papilloma virus (HPV) types 16 and 18 have been associated with neoplastic conditions of the conjunctiva. However, the presence of this virus has not been reported in non-neoplastic disorders of the external eye nor has it been studied in normal conjunctival tissues.
METHODS—Ninety six paraffin embedded tissue specimens with neoplastic and non-neoplastic lesions and 19 conjunctiva samples free from overt disease were studied for HPV types 16 and 18 positivity with the polymerase chain reaction.
RESULTS—HPV types 16 and 18 DNA were identified in 57% of in situ squamous cell carcinoma, in 55% of invasive squamous cell carcinoma, in 20% of climatic droplet keratopathy, in 35% of scarred corneas, and in 32% of normal conjunctival tissue obtained during routine cataract extractions.
CONCLUSION—These findings indicate that HPV types 16 and 18 are detectable with the polymerase chain reaction not only in epithelial neoplasms of the ocular mucous membrane but also in non-neoplastic lesions as well as in apparently healthy conjunctiva.

 PMID:9290377

  1. Identification of non-neoplastic and neoplastic gastric polyps using multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Jiang, Shanghai; Kang, Deyong; Xu, Meifang; Zhu, Xiaoqin; Zhuo, Shuangmu; Chen, Jianxin

    2012-12-01

    Gastric polyps can be broadly defined as luminal lesions projecting above the plane of the mucosal surface. They are generally divided into non-neoplastic and neoplastic polyps. Accurate diagnosis of neoplastic polyps is important because of their well-known relationship with gastric cancer. Multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) is one of the most important recent inventions in biological imaging. In this study, we used MPM to image the microstructure of gastric polyps, including fundic gland polyps, hyperplastic polyps, inflammatory fibroid polyps and adenomas, then compared with gold-standard hematoxylin- eosin(H-E)-stained histopathology. MPM images showed that different gastric polyps have different gland architecture and cell morphology. Dilated, elongated or branch-like hyperplastic polyps are arranged by columnar epithelial cells. Inflammatory fibroid polyps are composed of small, thin-walled blood vessels surrounded by short spindle cells. Fundic glands polyps are lined by parietal cells and chief cells, admixed with normal glands. Gastric adenomas are generally composed of tubules or villi of dysplastic epithelium, which usually show some degree of intestinal-type differentiation toward absorptive cells, goblet cells, endocrine cells. Our results demonstrated that MPM can be used to identify non- neoplastic and neoplastic gastric polyps without the need of any staining procedure.

  2. Neoplastic Reprogramming of Patient-Derived Adipose Stem Cells by Prostate Cancer Cell-Associated Exosomes

    PubMed Central

    Abd Elmageed, Zakaria Y.; Yang, Yijun; Thomas, Raju; Ranjan, Manish; Mondal, Debasis; Moroz, Krzysztof; Fang, Zhide; Rezk, Bashir M.; Moparty, Krishnarao; Sikka, Suresh C.; Sartor, Oliver; Abdel-Mageed, Asim B.

    2014-01-01

    Emerging evidence suggests that mesenchymal stem cells (MSCs) are often recruited to tumor sites but their functional significance in tumor growth and disease progression remains elusive. Herein we report that prostate cancer (PC) cell microenvironment subverts PC patient adipose-derived stem cells (pASCs) to undergo neoplastic transformation. Unlike normal ASCs, the pASCs primed with PC cell conditioned media (CM) formed prostate-like neoplastic lesions in vivo and reproduced aggressive tumors in secondary recipients. The pASC tumors acquired cytogenetic aberrations and mesenchymal-to-epithelial transition (MET) and expressed epithelial, neoplastic, and vasculogenic markers reminiscent of molecular features of PC tumor xenografts. Our mechanistic studies revealed that PC cell-derived exosomes are sufficient to recapitulate formation of prostate tumorigenic mimicry generated by CM-primed pASCs in vivo. In addition to down-regulation of the large tumor suppressor homolog2 (Lats2) and the programmed cell death protein 4 (PDCD4), a neoplastic transformation inhibitor, the tumorigenic reprogramming of pASCs was associated with trafficking by PC cell-derived exosomes of oncogenic factors, including H-ras and K-ras transcripts, oncomiRNAs miR-125b, miR-130b, and miR-155 as well as the Ras superfamily of GTPases Rab1a, Rab1b, and Rab11a. Our findings implicate a new role for PC cell-derived exosomes in clonal expansion of tumors through neoplastic reprogramming of tumor tropic ASCs in cancer patients. PMID:24715691

  3. CD44 and the adhesion of neoplastic cells.

    PubMed Central

    Rudzki, Z; Jothy, S

    1997-01-01

    and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation. Images PMID:9231152

  4. [Non-neoplastic lesions of the mediastinum].

    PubMed

    Tzankov, A

    2016-09-01

    The mediastinum is a complex body region of limited space but containing numerous organs of different embryonic origins. A variety of lesions that are difficult to distinguish from each other can occur here. Non-neoplastic lesions of the mediastinum represent important differential diagnostic pitfalls to mediastinal tumors, clinically, radiologically and histopathologically. It is important to bear these lesions in mind and to adequately verify or exclude them before starting further differential diagnostic considerations on mediastinal neoplasms. The most common non-neoplastic lesions in this region include cysts and lymphadenopathies. Mediastinal cysts result from abnormal events in the branching of the tracheobronchial tree, the pharyngeal pouches, the primary intestines, the pleuropericardial membranes and the brain meninges or are complications of inflammatory and hydrostatic processes. The histogenesis of the lining epithelium and the cyst wall structure are decisive for the exact classification. The histopathologically most prevalent patterns of mediastinal lymphadenopathies are those accompanied by increased histiocytes and Castleman's disease. Sclerosis is a non-specific reaction pattern of the mediastinum and can be associated with many processes; therefore, when establishing the diagnosis of sclerosing mediastinitis, several differential diagnoses have to be excluded. Simple thymic hyperplasia can be accompanied by considerable increase in organ size with severe local symptoms, while follicular thymic hyperplasia is often associated with myasthenia gravis and represents the most common findings in non-thymoma thymectomy specimens. PMID:27465275

  5. Non-neoplastic salivary gland diseases.

    PubMed

    Arduino, P G; Carrozzo, M; Pentenero, M; Bertolusso, G; Gandolfo, S

    2006-05-01

    A wide range of non neoplastic disorders can affect the salivary glands, although the more common are: mumps, acute suppurative sialadenitis, Sjögren's syndrome and drug-induced xerostomia. Salivary dysfunction is not a normal consequence of old age, and can be due to systemic diseases, medications or head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, followed by a cautious examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Health-care professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventive and interventive techniques that will help to preserving a person's health, function, and quality of life. The present work provides an overview of most of the non neoplastic disorders of the salivary glands, in which the general presentation, pathology, and treatments are discussed. PMID:16688102

  6. Regulatory Considerations Of Waste Emplacement Within The WIPP Repository: Random Versus Non-Random Distribution

    SciTech Connect

    Casey, S. C.; Patterson, R. L.; Gross, M.; Lickliter, K.; Stein, J. S.

    2003-02-25

    The U.S. Department of Energy (DOE) is responsible for disposing of transuranic waste in the Waste Isolation Pilot Plant (WIPP) in southeastern New Mexico. As part of that responsibility, DOE must comply with the U.S. Environmental Protection Agency's (EPA) radiation protection standards in Title 40 Code of Federal Regulations (CFR), Parts 191 and 194. This paper addresses compliance with the criteria of 40 CFR Section 194.24(d) and 194.24(f) that require DOE to either provide a waste loading scheme for the WIPP repository or to assume random emplacement in the mandated performance and compliance assessments. The DOE established a position on waste loading schemes during the process of obtaining the EPA's initial Certification in 1998. The justification for utilizing a random waste emplacement distribution within the WIPP repository was provided to the EPA. During the EPA rulemaking process for the initial certification, the EPA questioned DOE on whether waste would be loaded randomly as modeled in long-term performance assessment (PA) and the impact, if any, of nonrandom loading. In response, DOE conducted an impact assessment for non-random waste loading. The results of this assessment supported the contention that it does not matter whether random or non-random waste loading is assumed for the PA. The EPA determined that a waste loading plan was unnecessary because DOE had assumed random waste loading and evaluated the potential consequences of non-random loading for a very high activity waste stream. In other words, the EPA determined that DOE was not required to provide a waste loading scheme because compliance is not affected by the actual distribution of waste containers in the WIPP.

  7. Non-Random Mating, Parent-of-Origin, and Maternal-Fetal Incompatibility Effects in Schizophrenia

    PubMed Central

    Kim, Yunjung; Ripke, Stephan; Kirov, George; Sklar, Pamela; Purcell, Shaun; Owen, Michael; O’Donovan, Michael C.; Sullivan, Patrick F.

    2014-01-01

    Although the association of common genetic variation in the extended MHC region with schizophrenia is the most significant yet discovered, the MHC region is one of the more complex regions of the human genome, with unusually high gene density and long-range linkage disequilibrium. The statistical test on which the MHC association is based is a relatively simple, additive model which uses logistic regression of SNP genotypes to predict case-control status. However, it is plausible that more complex models underlie this association. Using a well-characterized sample of trios, we evaluated more complex models by looking for evidence for: (a) non-random mating for HLA alleles, schizophrenia risk profiles, and ancestry; (b) parent-of-origin effects for HLA alleles; and (c) maternal-fetal genotype incompatibility in the HLA. We found no evidence for non-random mating in the parents of individuals with schizophrenia in terms of MHC genotypes or schizophrenia risk profile scores. However, there was evidence of non-random mating that appeared mostly to be driven by ancestry. We did not detect over-transmission of HLA alleles to affected offspring via the general TDT test (without regard to parent of origin) or preferential transmission via paternal or maternal inheritance. We evaluated the hypothesis that maternal-fetal HLA incompatibility may increase risk for schizophrenia using eight classical HLA loci. The most significant alleles were in HLA-B, HLA-C, HLA-DQB1, and HLA-DRB1 but none was significant after accounting for multiple comparisons. We did not find evidence to support more complex models of gene action, but statistical power may have been limiting. PMID:23177929

  8. Non-random biodiversity loss underlies predictable increases in viral disease prevalence

    PubMed Central

    Lacroix, Christelle; Jolles, Anna; Seabloom, Eric W.; Power, Alison G.; Mitchell, Charles E.; Borer, Elizabeth T.

    2014-01-01

    Disease dilution (reduced disease prevalence with increasing biodiversity) has been described for many different pathogens. Although the mechanisms causing this phenomenon remain unclear, the disassembly of communities to predictable subsets of species, which can be caused by changing climate, land use or invasive species, underlies one important hypothesis. In this case, infection prevalence could reflect the competence of the remaining hosts. To test this hypothesis, we measured local host species abundance and prevalence of four generalist aphid-vectored pathogens (barley and cereal yellow dwarf viruses) in a ubiquitous annual grass host at 10 sites spanning 2000 km along the North American West Coast. In laboratory and field trials, we measured viral infection as well as aphid fecundity and feeding preference on several host species. Virus prevalence increased as local host richness declined. Community disassembly was non-random: ubiquitous hosts dominating species-poor assemblages were among the most competent for vector production and virus transmission. This suggests that non-random biodiversity loss led to increased virus prevalence. Because diversity loss is occurring globally in response to anthropogenic changes, such work can inform medical, agricultural and veterinary disease research by providing insights into the dynamics of pathogens nested within a complex web of environmental forces. PMID:24352672

  9. How does non-random spontaneous activity contribute to brain development?

    PubMed

    Thivierge, Jean-Philippe

    2009-09-01

    Highly non-random forms of spontaneous activity are proposed to play an instrumental role in the early development of the visual system. However, both the fundamental properties of spontaneous activity required to drive map formation, as well as the exact role of this information remain largely unknown. Here, a realistic computational model of spontaneous retinal waves is employed to demonstrate that both the amplitude and frequency of waves may play determining roles in retinocollicular map formation. Furthermore, results obtained with different learning rules show that spike precision in the order of milliseconds may be instrumental to neural development: a rule based on precise spike interactions (spike-timing-dependent plasticity) reduced the density of aberrant projections to the SC to a markedly greater extent than a rule based on interactions at much broader time-scale (correlation-based plasticity). Taken together, these results argue for an important role of spontaneous yet highly non-random activity, along with temporally precise learning rules, in the formation of neural circuits. PMID:19196491

  10. Pharmacological reactivity of neoplastic and non-neoplastic associated neovasculature to vasoconstrictors.

    PubMed

    Andrade, S P; Beraldo, W T

    1998-12-01

    Angiogenesis and the pharmacological responses of the tumour and non-tumour associated neovasculature have been investigated. Cannulated sponge discs in mice were used to host the angiogenic stimulators, while 133Xe washout was employed to assess local blood flow. Enhancement of blood flow was detected in implants bearing B16 cells, 3T3 cells and angiotensin II (AII)-treated at day 7. The responses of non-neoplastic associated neovasculature at day 14 post sponge implantation to the vasoconstrictors used endothelin-1 (Et-1), AII, platelet activating factor (PAF) and 5-hydroxytryptamine (5-HT) were dose-dependent. By contrast, the newly formed blood vessels induced by tumour cells were markedly insensitive to the vasoconstrictors agonists Et-1 and AII, while fully responsive to PAF and 5-HT. The vessels resulting from neoplastic stimulus exhibited altered pharmacological reactivity, suggesting that the characteristics of the neovasculature are dependent on the nature of the angiogenic stimuli. PMID:10319023

  11. Non-neoplastic salivary gland lesions: a 15-year study.

    PubMed

    Mohan, Harsh; Tahlan, Anita; Mundi, Irneet; Punia, R P S; Dass, Arjun

    2011-08-01

    The spectrum of salivary gland lesions is wide and the relative incidence of neoplastic versus non-neoplastic lesions is variable in different studies. A series of non-neoplastic salivary gland lesions is reviewed to analyze their spectrum and their relative frequency. This is a retrospective study of salivary gland excisions and biopsies received in our department from January 1994 to December 2008. Routine hematoxylin and eosin-stained sections of all the salivary gland excisions and biopsies received were analyzed. Of the 393 salivary gland excisions and biopsies received, 216 cases were reported as non-neoplastic (55%) and formed our study group; 177 (45%) were neoplastic. Non-neoplastic lesions were more frequent in major salivary glands (65.7%) and submandibular gland was the most commonly involved (66.2%). Lip was the most frequent site (81.7%) for minor salivary gland lesions. Inflammation was the predominant pathological finding (49.5%), of which non-specific chronic sialadenitis constituted the majority (86.9%). Sialolithiasis was present in 22 cases (20.6%); all of these cases were of non-specific chronic sialadenitis. Cysts were second in frequency (36.6%), of which mucocele was the most common (54.5%). There were 5.6% cases of benign lympho-epithelial lesions, while normal salivary gland tissue was seen in 6.5% cases. Non-neoplastic salivary gland diseases are more common than neoplastic diseases and have a wide disease spectrum. PMID:21170719

  12. Expression of Cytokeratin-19 and Thyroperoxidase in Relation to Morphological Features in Non-Neoplastic and Neoplastic Lesions of Thyroid

    PubMed Central

    Rajamani, Revathishree; Noorunnisa, Naseen; Durairaj, Manimaran

    2016-01-01

    Introduction Thyroperoxidase (TPO) is a protein involved in thyroid hormone synthesis. TPO gene suppression and mutation were involved in thyroid tumours. CK-19 plays important role in the structural integrity of epithelial cells. Reduced TPO expression with increased CK-19 immunoreactivity has been implicated as a marker for differentiating non neoplastic and neoplastic thyroid lesions. Aim To study the histopathological features of thyroid lesions and to evaluate the diagnostic role of thyroperoxidase and CK-19 in non-neoplastic and neoplastic thyroid lesions. Materials and Methods Prospective observational study of 65 thyroid specimens was studied for detailed histopathological examination and Expression of Immunohistochemical Markers Cytokeratin-19 (CK-19) and Thyroperoxidase. Results TPO IHC marker was expressed by non-neoplastic and benign lesions of thyroid but not in malignancy. CK-19 was expressed 100% in papillary carcinoma of thyroid and its variants, focal and weak staining noted in goitre and hyperplastic areas. Conclusion Most of the non-neoplastic and neoplastic lesions were diagnosed based on histopathological features. When the histopathological diagnosis are equivocal, immunohistochemical markers aids in diagnosing malignancy. Diffuse and strong TPO expression indicates non-neoplastic thyroid lesions whereas diffused and strong CK-19 expression indicates thyroid malignancy. PMID:27504290

  13. Non-random mating in classical lekking grouse species: seasonal and diurnal trends

    NASA Astrophysics Data System (ADS)

    Tsuji, L. J. S.; DeIuliis, G.; Hansell, R. I. C.; Kozlovic, D. R.; Sokolowski, M. B.

    This paper is the first to integrate both field and theoretical approaches to demonstrate that fertility benefits can be a direct benefit to females mating on the classical lek. Field data collected for male sharp-tailed grouse (Tympanuchus phasianellus), a classical lekking species, revealed potential fertility benefits for selective females. Adult males and individuals occupying centrally located territories on the lek were found to have significantly larger testes than juveniles and peripheral individuals. Further, using empirical data from previously published studies of classical lekking grouse species, time-series analysis was employed to illustrate that female mating patterns, seasonal and daily, were non-random. We are the first to show that these patterns coincide with times when male fertility is at its peak.

  14. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age

    PubMed Central

    Khuong-Quang, Dong-Anh; Bechet, Denise; Gayden, Tenzin; Kool, Marcel; De Jay, Nicolas; Jacob, Karine; Gerges, Noha; Hutter, Barbara; Şeker-Cin, Huriye; Witt, Hendrik; Montpetit, Alexandre; Brunet, Sébastien; Lepage, Pierre; Bourret, Geneviève; Klekner, Almos; Bognár, László; Hauser, Peter; Garami, Miklós; Farmer, Jean-Pierre; Montes, Jose-Luis; Atkinson, Jeffrey; Lambert, Sally; Kwan, Tony; Korshunov, Andrey; Tabori, Uri; Collins, V. Peter; Albrecht, Steffen; Faury, Damien; Pfister, Stefan M.; Paulus, Werner; Hasselblatt, Martin; Jones, David T.W.; Jabado, Nada

    2015-01-01

    Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor. PMID:26378811

  15. Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age.

    PubMed

    Fontebasso, Adam M; Shirinian, Margret; Khuong-Quang, Dong-Anh; Bechet, Denise; Gayden, Tenzin; Kool, Marcel; De Jay, Nicolas; Jacob, Karine; Gerges, Noha; Hutter, Barbara; Şeker-Cin, Huriye; Witt, Hendrik; Montpetit, Alexandre; Brunet, Sébastien; Lepage, Pierre; Bourret, Geneviève; Klekner, Almos; Bognár, László; Hauser, Peter; Garami, Miklós; Farmer, Jean-Pierre; Montes, Jose-Luis; Atkinson, Jeffrey; Lambert, Sally; Kwan, Tony; Korshunov, Andrey; Tabori, Uri; Collins, V Peter; Albrecht, Steffen; Faury, Damien; Pfister, Stefan M; Paulus, Werner; Hasselblatt, Martin; Jones, David T W; Jabado, Nada

    2015-10-13

    Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor. PMID:26378811

  16. Cancer related fatigue syndrome in neoplastic diseases.

    PubMed

    Franc, Magdalena; Michalski, Bogdan; Kuczerawy, Ilona; Szuta, Justyna; Skrzypulec-Plinta, Violetta

    2014-12-01

    Fatigue is one of the most important factors which has a considerable influence on treatment and the life quality of oncological patients. The fatigue syndrome is often diagnosed during cancer treatment and this syndrome is not related to the physical effort. Cancer related fatigue is a patient's subjective, psychologically, physically and emotionally based feeling. It is disproportionate to patient's daily activity. The pathogenesis of this syndrome remains still unknown. However, on the basis of various questionnaires, it is possible to test the disease's complex nature. Cancer related fatigue causes deterioration of patient's life along with lower motivation to struggle with the disease. It is thought that the factor which increases the incidence of cancer related fatigue is a long-term use of drugs such as opioids, benzodiazepine, and medicines containing codeine, tranquilizers, anxiolytics and antidepressants. On the basis of the results, one can choose an appropriate treatment method for cancer related fatigue such as rehabilitation, psychotherapy or public assistance. A great number of patients consider excessive fatigue a typical concomitant symptom in neoplastic disease; therefore, they do not report it. It is of a paramount importance to make patients aware of the fact that cancer related fatigue is a serious disease which can be treated. PMID:26327879

  17. Cancer related fatigue syndrome in neoplastic diseases

    PubMed Central

    Michalski, Bogdan; Kuczerawy, Ilona; Szuta, Justyna; Skrzypulec-Plinta, Violetta

    2014-01-01

    Fatigue is one of the most important factors which has a considerable influence on treatment and the life quality of oncological patients. The fatigue syndrome is often diagnosed during cancer treatment and this syndrome is not related to the physical effort. Cancer related fatigue is a patient's subjective, psychologically, physically and emotionally based feeling. It is disproportionate to patient's daily activity. The pathogenesis of this syndrome remains still unknown. However, on the basis of various questionnaires, it is possible to test the disease's complex nature. Cancer related fatigue causes deterioration of patient's life along with lower motivation to struggle with the disease. It is thought that the factor which increases the incidence of cancer related fatigue is a long-term use of drugs such as opioids, benzodiazepine, and medicines containing codeine, tranquilizers, anxiolytics and antidepressants. On the basis of the results, one can choose an appropriate treatment method for cancer related fatigue such as rehabilitation, psychotherapy or public assistance. A great number of patients consider excessive fatigue a typical concomitant symptom in neoplastic disease; therefore, they do not report it. It is of a paramount importance to make patients aware of the fact that cancer related fatigue is a serious disease which can be treated. PMID:26327879

  18. Matrix Metalloproteinases in Non-Neoplastic Disorders

    PubMed Central

    Tokito, Akinori; Jougasaki, Michihisa

    2016-01-01

    The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. PMID:27455234

  19. The Mitochondrial Chaperone TRAP1 Promotes Neoplastic Growth by Inhibiting Succinate Dehydrogenase

    PubMed Central

    Sciacovelli, Marco; Guzzo, Giulia; Morello, Virginia; Frezza, Christian; Zheng, Liang; Nannini, Nazarena; Calabrese, Fiorella; Laudiero, Gabriella; Esposito, Franca; Landriscina, Matteo; Defilippi, Paola; Bernardi, Paolo; Rasola, Andrea

    2013-01-01

    Summary We report that the mitochondrial chaperone TRAP1, which is induced in most tumor types, is required for neoplastic growth and confers transforming potential to noncancerous cells. TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex II of the respiratory chain. The respiratory downregulation elicited by TRAP1 interaction with SDH promotes tumorigenesis by priming the succinate-dependent stabilization of the proneoplastic transcription factor HIF1α independently of hypoxic conditions. These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target. PMID:23747254

  20. The neoplastic potential of rat tracheal epithelial cell lines induced by dibenzo(a, i)pyrene and 1-nitropyrene

    SciTech Connect

    Xiang, M.; Ong, T. |; Nath, J.

    1997-10-01

    The rat tracheal epithelial (RTE) cell transformation system is an important short-term assay for respiratory carcinogenesis. In our laboratories, studies have been performed using this assay system to determine the carcinogenic potential of dibenzo(a,i)pyrene (DBP) and 1-nitropyrene (1-NP), two compounds commonly contaminating occupational and environmental settings. RTE cells were exposed in vivo to DBP or 1-NP by intertracheal instillation. RTE cells were then isolated and plated on a medium for determination of cloning and transformation frequencies. Cell lines established from transformed cells induced by DBP and 1-NP were analyzed for their neoplastic potential with the soft agar cloning and the athymic nude mouse tumorigenicity assays. Results showed that: (1) incidence of transformed foci in cultures treated with DBP or 1-NP in vivo was significantly higher than that in the control cultures; (2) 8 and 25 cell lines were established from 28 and 48 transformed foci induced by DBP and 1-NP, respectively; (3) 3 of 5 cell lines from DBP and 5 anchorage independent growth in soft agar; (4) some of the cell lines from DBP and 1-NP induced transformed foci formed tumors after cells were injected in athymic nude mice. These results indicate that in vivo exposure to DBP and 1-NP can induce RTE cell transformation and that transformed cells induced by DBP and 1-NP may have neoplastic potential.

  1. Human promoter genomic composition demonstrates non-random groupings that reflect general cellular function

    PubMed Central

    McNutt, Markey C; Tongbai, Ron; Cui, Wenwu; Collins, Irene; Freebern, Wendy J; Montano, Idalia; Haggerty, Cynthia M; Chandramouli, GVR; Gardner, Kevin

    2005-01-01

    Background The purpose of this study is to determine whether or not there exists nonrandom grouping of cis-regulatory elements within gene promoters that can be perceived independent of gene expression data and whether or not there is any correlation between this grouping and the biological function of the gene. Results Using ProSpector, a web-based promoter search and annotation tool, we have applied an unbiased approach to analyze the transcription factor binding site frequencies of 1400 base pair genomic segments positioned at 1200 base pairs upstream and 200 base pairs downstream of the transcriptional start site of 7298 commonly studied human genes. Partitional clustering of the transcription factor binding site composition within these promoter segments reveals a small number of gene groups that are selectively enriched for gene ontology terms consistent with distinct aspects of cellular function. Significance ranking of the class-determining transcription factor binding sites within these clusters show substantial overlap between the gene ontology terms of the transcriptions factors associated with the binding sites and the gene ontology terms of the regulated genes within each group. Conclusion Thus, gene sorting by promoter composition alone produces partitions in which the "regulated" and the "regulators" cosegregate into similar functional classes. These findings demonstrate that the transcription factor binding site composition is non-randomly distributed between gene promoters in a manner that reflects and partially defines general gene class function. PMID:16232321

  2. Non-random nectar unloading interactions between foragers and their receivers in the honeybee hive

    NASA Astrophysics Data System (ADS)

    Goyret, Joaquín; Farina, Walter M.

    2005-09-01

    Nectar acquisition in the honeybee Apis mellifera is a partitioned task in which foragers gather nectar and bring it to the hive, where nest mates unload via trophallaxis (i.e. mouth-to-mouth transfer) the collected food for further storage. Because forager mates exploit different feeding places simultaneously, this study addresses the question of whether nectar unloading interactions between foragers and hive-bees are established randomly, as it is commonly assumed. Two groups of foragers were trained to exploit a different scented food source for 5 days. We recorded their trophallaxes with hive-mates, marking the latter ones according to the forager group they were unloading. We found non-random probabilities for the occurrence of trophallaxes between experimental foragers and hive-bees, instead, we found that trophallactic interactions were more likely to involve groups of individuals which had formerly interacted orally. We propose that olfactory cues present in the transferred nectar promoted the observed bias, and we discuss this bias in the context of the organization of nectar acquisition: a partitioned task carried out in a decentralized insect society.

  3. Random and non-random mating populations: Evolutionary dynamics in meiotic drive.

    PubMed

    Sarkar, Bijan

    2016-01-01

    Game theoretic tools are utilized to analyze a one-locus continuous selection model of sex-specific meiotic drive by considering nonequivalence of the viabilities of reciprocal heterozygotes that might be noticed at an imprinted locus. The model draws attention to the role of viability selections of different types to examine the stable nature of polymorphic equilibrium. A bridge between population genetics and evolutionary game theory has been built up by applying the concept of the Fundamental Theorem of Natural Selection. In addition to pointing out the influences of male and female segregation ratios on selection, configuration structure reveals some noted results, e.g., Hardy-Weinberg frequencies hold in replicator dynamics, occurrence of faster evolution at the maximized variance fitness, existence of mixed Evolutionarily Stable Strategy (ESS) in asymmetric games, the tending evolution to follow not only a 1:1 sex ratio but also a 1:1 different alleles ratio at particular gene locus. Through construction of replicator dynamics in the group selection framework, our selection model introduces a redefining bases of game theory to incorporate non-random mating where a mating parameter associated with population structure is dependent on the social structure. Also, the model exposes the fact that the number of polymorphic equilibria will depend on the algebraic expression of population structure. PMID:26524140

  4. Non random usage of T cell receptor alpha gene expression in atopy using anchored PCR.

    PubMed

    Mansur, A H; Gelder, C M; Holland, D; Campell, D A; Griffin, A; Cunliffe, W; Markham, A F; Morrison, J F

    1996-01-01

    The T cell receptor (TCR) alpha beta heterodimer recognises antigenic peptide fragments presented by Class II MHC. This interaction initiates T cell activation and cytokine release with subsequent recruitment of inflammatory cells. Previous work from our group suggests a qualitative difference in variable alpha gene expression in atopy as compared to non atopic controls. In this study we examine TCR alpha repertoire using anchored PCR to provide a quantitative assessment of the V alpha and J alpha repertoire. One atopic (DRB1*0701,DRB1*15: DRB4*0101, DRB5*01: DQB1* 0303, DQB1*601/2) and one non-atopic (DRB1*0701,DRB1*03011/2: DRB4*01, DRB3*0x: DQB1* 0303, DQB1*0201/2) control were studied. Variable gene usage was markedly limited in the atopic individual. V alpha 1, 3, 8 accounted for 60% and J alpha 12, 31 30% of the gene usage. There was evidence of preferential V alpha-J alpha gene pairing and clonal expansion. We conclude that there is a marked non random TCR alpha gene distribution in atopy using both V alpha family and anchored PCR. This may be due in part to antigen driven clonal expansion. PMID:9095269

  5. Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring

    PubMed Central

    Miner, Daniel; Triesch, Jochen

    2016-01-01

    Understanding the structure and dynamics of cortical connectivity is vital to understanding cortical function. Experimental data strongly suggest that local recurrent connectivity in the cortex is significantly non-random, exhibiting, for example, above-chance bidirectionality and an overrepresentation of certain triangular motifs. Additional evidence suggests a significant distance dependency to connectivity over a local scale of a few hundred microns, and particular patterns of synaptic turnover dynamics, including a heavy-tailed distribution of synaptic efficacies, a power law distribution of synaptic lifetimes, and a tendency for stronger synapses to be more stable over time. Understanding how many of these non-random features simultaneously arise would provide valuable insights into the development and function of the cortex. While previous work has modeled some of the individual features of local cortical wiring, there is no model that begins to comprehensively account for all of them. We present a spiking network model of a rodent Layer 5 cortical slice which, via the interactions of a few simple biologically motivated intrinsic, synaptic, and structural plasticity mechanisms, qualitatively reproduces these non-random effects when combined with simple topological constraints. Our model suggests that mechanisms of self-organization arising from a small number of plasticity rules provide a parsimonious explanation for numerous experimentally observed non-random features of recurrent cortical wiring. Interestingly, similar mechanisms have been shown to endow recurrent networks with powerful learning abilities, suggesting that these mechanism are central to understanding both structure and function of cortical synaptic wiring. PMID:26866369

  6. Plasticity-Driven Self-Organization under Topological Constraints Accounts for Non-random Features of Cortical Synaptic Wiring.

    PubMed

    Miner, Daniel; Triesch, Jochen

    2016-02-01

    Understanding the structure and dynamics of cortical connectivity is vital to understanding cortical function. Experimental data strongly suggest that local recurrent connectivity in the cortex is significantly non-random, exhibiting, for example, above-chance bidirectionality and an overrepresentation of certain triangular motifs. Additional evidence suggests a significant distance dependency to connectivity over a local scale of a few hundred microns, and particular patterns of synaptic turnover dynamics, including a heavy-tailed distribution of synaptic efficacies, a power law distribution of synaptic lifetimes, and a tendency for stronger synapses to be more stable over time. Understanding how many of these non-random features simultaneously arise would provide valuable insights into the development and function of the cortex. While previous work has modeled some of the individual features of local cortical wiring, there is no model that begins to comprehensively account for all of them. We present a spiking network model of a rodent Layer 5 cortical slice which, via the interactions of a few simple biologically motivated intrinsic, synaptic, and structural plasticity mechanisms, qualitatively reproduces these non-random effects when combined with simple topological constraints. Our model suggests that mechanisms of self-organization arising from a small number of plasticity rules provide a parsimonious explanation for numerous experimentally observed non-random features of recurrent cortical wiring. Interestingly, similar mechanisms have been shown to endow recurrent networks with powerful learning abilities, suggesting that these mechanism are central to understanding both structure and function of cortical synaptic wiring. PMID:26866369

  7. A Novel Role of E-Cadherin-Based Adherens Junctions in Neoplastic Cell Dissemination

    PubMed Central

    Gloushankova, Natalya A.

    2015-01-01

    Using confocal microscopy, we analyzed the behavior of IAR-6-1, IAR1170, and IAR1162 transformed epithelial cells seeded onto the confluent monolayer of normal IAR-2 epithelial cells. Live-cell imaging of neoplastic cells stably expressing EGFP and of normal epithelial cells stably expressing mKate2 showed that transformed cells retaining expression of E-cadherin were able to migrate over the IAR-2 epithelial monolayer and invade the monolayer. Transformed IAR cells invaded the IAR-2 monolayer at the boundaries between normal cells. Studying interactions of IAR-6-1 transformed cells stably expressing GFP-E-cadherin with the IAR-2 epithelial monolayer, we found that IAR-6-1 cells established E-cadherin-based adhesions with normal epithelial cells: dot-like dynamic E-cadherin-based adhesions in protrusions and large adherens junctions at the cell sides and rear. A comparative study of a panel of transformed IAR cells that differ by their ability to form E-cadherin-based AJs, either through loss of E-cadherin expression or through expression of a dominant negative E-cadherin mutant, demonstrated that E-cadherin-based AJs are key mediators of the interactions between neoplastic and normal epithelial cells. IAR-6-1DNE cells expressing a dominant-negative mutant form of E-cadherin with the mutation in the first extracellular domain practically lost the ability to adhere to IAR-2 cells and invade the IAR-2 epithelial monolayer. The ability of cancer cells to form E-cadherin-based AJs with the surrounding normal epithelial cells may play an important role in driving cancer cell dissemination in the body. PMID:26207916

  8. MGMT promoter methylation in non-neoplastic brain.

    PubMed

    Hsu, Chih-Yi; Ho, Hsiang-Ling; Chang-Chien, Yi-Chun; Chang, Yi-Wen; Ho, Donald Ming-Tak

    2015-02-01

    O(6)-methylguanine-DNA-methyltransferase (MGMT) is mainly regulated by cytosine-guanine island promoter methylation that is believed to occur only in neoplastic tissue. The present study was undertaken to investigate whether methylation occurs also in non-neoplastic brains by collecting 45 non-neoplastic brains from autopsies and 56 lobectomy specimens from epileptic surgeries. The promoter methylation status of MGMT was studied by methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ), while protein expression was studied by immunohistochemical stain (IHC). The methylation rates, as determined by MSP and PSQ, were 3.0 % (3/101) and 2.9 % (2/69), respectively. Of note, no case had positive result concomitantly from both MSP and PSQ (3 were MSP+/PSQ- and 2 were MSP-/PSQ+), and all the positive samples were further confirmed by cloning and Sanger sequencing. All the methylated cases, except for those having indeterminate IHC results from autopsy specimens, revealed no loss of MGMT protein expression and similar staining pattern to that of the unmethylated cases. In conclusion, the current study demonstrated that MGMT promoter methylation could occur in a low percentage of non-neoplastic brains but did not affect the status of protein expression, which could be regarded as a normal variation in non-neoplastic brains. PMID:25391970

  9. Non-random fragmentation patterns in circulating cell-free DNA reflect epigenetic regulation

    PubMed Central

    2015-01-01

    Background The assessment of cell-free circulating DNA fragments, also known as a "liquid biopsy" of the patient's plasma, is an important source for the discovery and subsequent non-invasive monitoring of cancer and other pathological conditions. Although the nucleosome-guided fragmentation patterns of cell-free DNA (cfDNA) have not yet been studied in detail, non-random representation of cfDNA sequencies may reflect chromatin features in the tissue of origin at gene-regulation level. Results In this study, we investigated the association between epigenetic landscapes of human tissues evident in the patterns of cfDNA in plasma by deep sequencing of human cfDNA samples. We have demonstrated that baseline characteristics of cfDNA fragmentation pattern are in concordance with the ones corresponding to cell lines-derived. To identify the loci differentially represented in cfDNA fragment, we mapped the transcription start sites within the sequenced cfDNA fragments and tested for association of these genomic coordinates with the relative strength and the patterns of gene expressions. Preselected sets of house-keeping and tissue specific genes were used as models for actively expressed and silenced genes. Developed measure of gene regulation was able to differentiate these two sets based on sequencing coverage near gene transcription start site. Conclusion Experimental outcomes suggest that cfDNA retains characteristics previously noted in genome-wide analysis of chromatin structure, in particular, in MNase-seq assays. Thus far the analysis of the DNA fragmentation pattern may aid further developing of cfDNA based biomarkers for a variety of human conditions. PMID:26693644

  10. Functional Redundancy Patterns Reveal Non-Random Assembly Rules in a Species-Rich Marine Assemblage

    PubMed Central

    Guillemot, Nicolas; Kulbicki, Michel; Chabanet, Pascale; Vigliola, Laurent

    2011-01-01

    The relationship between species and the functional diversity of assemblages is fundamental in ecology because it contains key information on functional redundancy, and functionally redundant ecosystems are thought to be more resilient, resistant and stable. However, this relationship is poorly understood and undocumented for species-rich coastal marine ecosystems. Here, we used underwater visual censuses to examine the patterns of functional redundancy for one of the most diverse vertebrate assemblages, the coral reef fishes of New Caledonia, South Pacific. First, we found that the relationship between functional and species diversity displayed a non-asymptotic power-shaped curve, implying that rare functions and species mainly occur in highly diverse assemblages. Second, we showed that the distribution of species amongst possible functions was significantly different from a random distribution up to a threshold of ∼90 species/transect. Redundancy patterns for each function further revealed that some functions displayed fast rates of increase in redundancy at low species diversity, whereas others were only becoming redundant past a certain threshold. This suggested non-random assembly rules and the existence of some primordial functions that would need to be fulfilled in priority so that coral reef fish assemblages can gain a basic ecological structure. Last, we found little effect of habitat on the shape of the functional-species diversity relationship and on the redundancy of functions, although habitat is known to largely determine assemblage characteristics such as species composition, biomass, and abundance. Our study shows that low functional redundancy is characteristic of this highly diverse fish assemblage, and, therefore, that even species-rich ecosystems such as coral reefs may be vulnerable to the removal of a few keystone species. PMID:22039543

  11. Intrauterine synechiae after myomectomy; laparotomy versus laparoscopy: Non-randomized interventional trial

    PubMed Central

    Asgari, Zahra; Hafizi, Leili; Hosseini, Rayhaneh; Javaheri, Atiyeh; Rastad, Hathis

    2015-01-01

    Background: Leiomyomata is the most frequent gynecological neoplasm. One of the major complications of myomectomy is intrauterine adhesion (synechiae). Objective: To evaluate and compare the rate and severity of synechiae formation after myomectomy by laparotomy and laparoscopy. Materials and Methods: In this non-randomized interventional trial, hysteroscopy was performed in all married fertile women who had undergone myomectomy (type 3-6 interamural and subserosal fibroids) via laparotomy and laparoscopy in Tehran’s Arash Hospital from 2010 to 2013. Three months after the operation, the occurrence rate and severity of intrauterine synechiae, and its relationship with type, number and location of myomas were investigated and compared in both groups. Results: Forty patients (19 laparoscopy and 21 laparotomy cases) were studied. Both groups were similar regarding the size, type (subserosal or intramural), number and location of myoma. The occurrence rate of synechiae in the laparoscopy and laparotomy group was 21% and 19%, respectively; showing no significant difference (p=0.99). Among all patients, no significant relationship was found between the endometrial opening (p=0.92), location (p=0.14) and type of myoma (p=0.08) with the occurrence rate of synechiae. However, a significant relationship was observed between myoma’s size (p=0.01) and the location of the largest myoma with the occurrence of synechiae (p=0.02). Conclusion: With favorable suturing methods, the outcome of intrauterine synechiae formation after myomectomy, either performed by laparotomy or laparoscopy, is similar. In all cases of myomectomy in reproductive-aged women, postoperative hysteroscopy is highly recommended to better screen intrauterine synechiae. PMID:26000007

  12. Non-random correlation structures and dimensionality reduction in multivariate climate data

    NASA Astrophysics Data System (ADS)

    Vejmelka, Martin; Pokorná, Lucie; Hlinka, Jaroslav; Hartman, David; Jajcay, Nikola; Paluš, Milan

    2015-05-01

    It is well established that the global climate is a complex phenomenon with dynamics driven by the interaction of a multitude of identifiable but intertwined subsystems. The identification, at some level, of these subsystems is an important step towards understanding climate dynamics. We present a method to determine the number of principal components representing non-random correlation structures in climate data, or components that cannot be generated by a surrogate model of independent stochastic processes replicating the auto-correlation structure of each time series. The purpose of the method is to automatically reduce the dimensionality of large climate datasets into spatially localised components suitable for further interpretation or, for example, for use as nodes in a complex network analysis of large-scale climate dynamics. We apply the method to two 2.5° resolution NCEP/NCAR reanalysis global datasets of monthly means: the sea level pressure (SLP) and the surface air temperature (SAT), and extract 60 components explaining 87 % variance and 68 components explaining 72 % variance, respectively. The obtained components are in agreement with previous results in that they recover many well-known climate modes previously identified using other approaches including regionally constrained principal component analysis. Selected SLP components are discussed in more detail with respect to their correlation with important climate indices and their relationship to other SLP and SAT components. Finally, we consider a subset of the obtained components that have not yet been explicitly identified by other authors but seem plausible in the context of regional climate observations discussed in literature.

  13. In vivo diagnostic accuracy of high resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study

    PubMed Central

    Parikh, Neil; Perl, Daniel; Lee, Michelle H.; Shah, Brijen; Young, Yuki; Chang, Shannon S.; Shukla, Richa; Polydorides, Alexandros D.; Moshier, Erin; Godbold, James; Zhou, Elinor; Mitchaml, Josephine; Richards-Kortum, Rebecca; Anandasabapathy, Sharmila

    2013-01-01

    High-resolution microendoscopy (HRME) is a low-cost, “optical biopsy” technology that allows for subcellular imaging. The purpose of this study was to determine the in vivo diagnostic accuracy of the HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps and compare it to that of high-definition white-light endoscopy (WLE) with histopathology as the gold standard. Three endoscopists prospectively detected a total of 171 polyps from 94 patients that were then imaged by HRME and classified in real-time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). HRME had a significantly higher accuracy (94%), specificity (95%), and positive predictive value (87%) for the determination of neoplastic colorectal polyps compared to WLE (65%, 39%, and 55%, respectively). When looking at small colorectal polyps (less than 10 mm), HRME continued to significantly outperform WLE in terms of accuracy (95% vs. 64%), specificity (98% vs. 40%) and positive predictive value (92% vs. 55%). These trends continued when evaluating diminutive polyps (less than 5 mm) as HRME's accuracy (95%), specificity (98%), and positive predictive value (93%) were all significantly greater than their WLE counterparts (62%, 41%, and 53%, respectively). In conclusion, this in vivo study demonstrates that HRME can be a very effective modality in the differentiation of neoplastic and non-neoplastic colorectal polyps. A combination of standard white-light colonoscopy for polyp detection and HRME for polyp classification has the potential to truly allow the endoscopist to selectively determine which lesions can be left in situ, which lesions can simply be discarded, and which lesions need formal histopathologic analysis. PMID:24296752

  14. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis.

    PubMed

    Verstovsek, Srdan; Manshouri, Taghi; Pilling, Darrell; Bueso-Ramos, Carlos E; Newberry, Kate J; Prijic, Sanja; Knez, Liza; Bozinovic, Ksenija; Harris, David M; Spaeth, Erika L; Post, Sean M; Multani, Asha S; Rampal, Raajit K; Ahn, Jihae; Levine, Ross L; Creighton, Chad J; Kantarjian, Hagop M; Estrov, Zeev

    2016-08-22

    Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process. PMID:27481130

  15. Plastic bronchitis caused by neoplastic infiltrates in a child.

    PubMed

    Kuperman, Tamar; Wexler, Isaiah D; Shoseyov, David; Weintraub, Michael; Revel-Vilk, Shoshana; Kerem, Eitan

    2006-09-01

    We report on a case of a 7-year-old girl admitted for pneumonia not responding to oral antibiotics. During hospitalization, her pulmonary status deteriorated as a result of significant atelectasis. An extensive workup revealed an anaplastic large-cell lymphoma with neoplastic cells, found in both a biopsied lymph node and pleural fluid aspirate. Bronchoscopic examination showed nearly complete obstruction of the left side by bronchial casts composed of tumor cells, fibrin, and necrotic material, consistent with plastic bronchitis. Neoplastic infiltration of the bronchi should be considered in the differential diagnosis of disease entities causing plastic bronchitis in children. PMID:16779857

  16. Non-random distribution of DNA double-strand breaks induced by particle irradiation

    NASA Technical Reports Server (NTRS)

    Lobrich, M.; Cooper, P. K.; Rydberg, B.; Chatterjee, A. (Principal Investigator)

    1996-01-01

    Induction of DNA double-strand breaks (dsbs) in mammalian cells is dependent on the spatial distribution of energy deposition from the ionizing radiation. For high LET particle radiations the primary ionization sites occur in a correlated manner along the track of the particles, while for X-rays these sites are much more randomly distributed throughout the volume of the cell. It can therefore be expected that the distribution of dsbs linearly along the DNA molecule also varies with the type of radiation and the ionization density. Using pulsed-field gel and conventional gel techniques, we measured the size distribution of DNA molecules from irradiated human fibroblasts in the total range of 0.1 kbp-10 Mbp for X-rays and high LET particles (N ions, 97 keV/microns and Fe ions, 150 keV/microns). On a mega base pair scale we applied conventional pulsed-field gel electrophoresis techniques such as measurement of the fraction of DNA released from the well (FAR) and measurement of breakage within a specific NotI restriction fragment (hybridization assay). The induction rate for widely spaced breaks was found to decrease with LET. However, when the entire distribution of radiation-induced fragments was analysed, we detected an excess of fragments with sizes below about 200 kbp for the particles compared with X-irradiation. X-rays are thus more effective than high LET radiations in producing large DNA fragments but less effective in the production of smaller fragments. We determined the total induction rate of dsbs for the three radiations based on a quantitative analysis of all the measured radiation-induced fragments and found that the high LET particles were more efficient than X-rays at inducing dsbs, indicating an increasing total efficiency with LET. Conventional assays that are based only on the measurement of large fragments are therefore misleading when determining total dsb induction rates of high LET particles. The possible biological significance of this non-randomness

  17. Cell adhesion geometry regulates non-random DNA segregation and asymmetric cell fates in mouse skeletal muscle stem cells.

    PubMed

    Yennek, Siham; Burute, Mithila; Théry, Manuel; Tajbakhsh, Shahragim

    2014-05-22

    Cells of several metazoan species have been shown to non-randomly segregate their DNA such that older template DNA strands segregate to one daughter cell. The mechanisms that regulate this asymmetry remain undefined. Determinants of cell fate are polarized during mitosis and partitioned asymmetrically as the spindle pole orients during cell division. Chromatids align along the pole axis; therefore, it is unclear whether extrinsic cues that determine spindle pole position also promote non-random DNA segregation. To mimic the asymmetric divisions seen in the mouse skeletal stem cell niche, we used micropatterns coated with extracellular matrix in asymmetric and symmetric motifs. We show that the frequency of non-random DNA segregation and transcription factor asymmetry correlates with the shape of the motif and that these events can be uncoupled. Furthermore, regulation of DNA segregation by cell adhesion occurs within a defined time interval. Thus, cell adhesion cues have a major impact on determining both DNA segregation patterns and cell fates. PMID:24836002

  18. Radiation injury of the normal and neoplastic prostate

    SciTech Connect

    Bostwick, D.G.; Egbert, B.M.; Fajardo, L.F.

    1982-09-01

    Tissue samples from 40 patients with prostatic adenocarcinoma treated by radiation therapy were evaluated simultaneously by three observers to establish criteria for distinguishing residual tumor from radiation-induced atypia. Sections from 10 patients irradiated for nonprostatic pelvic neoplasms served as controls in addition to pretreatment biopsies from the determinate group. Patients had been treated by external x-irradiation, the majority receiving 6200-7400 rad to the prostate and pelvis over 7 to 8 weeks. Positive (tumor) biopsy incidence in the determinate group was 80% at 18 months, 40% at 36 months, and 43% in later samples. The following features were characteristic of radiation injury in the prostate: decreased ratio of the number of tumor glands to stroma, atrophy and squamous-like metaplasia of non-neoplastic glands with or without atypia, stromal fibrosis, arterial lumenal narrowing due to myointimal proliferation, foam cells within vessel walls, and fibrosis and atrophy of seminal vesicles. Criteria not useful for diagnosing radiation injury included architectural pattern or differentiation of tumor, cytologic features of tumor cells, inflammatory infiltrate, and ratio of normal glands to stroma. Ionizing radiation produced characteristic lesions in neoplastic and non-neoplastic prostatic glands, stroma, and blood vessels, and the sum of these changes was a reliable indicator of prior radiotherapy. An understanding of the morphologic effects of radiation injury of the prostate allowed distinction between residual prostatic adenocarcinoma and radiation-induced atypia of non-neoplastic glands.

  19. The post-pollination ethylene burst and the continuation of floral advertisement are harbingers of non-random mate selection in Nicotiana attenuata.

    PubMed

    Bhattacharya, Samik; Baldwin, Ian T

    2012-08-01

    The self-compatible plant Nicotiana attenuata grows in genetically diverse populations after fires, and produces flowers that remain open for 3 days and are visited by assorted pollinators. To determine whether and when post-pollination non-random mate selection occurs among self and non-self pollen, seed paternity and semi-in vivo pollen tube growth were determined in controlled single/mixed pollinations. Despite all pollen sources being equally proficient in siring seeds in single-genotype pollinations, self pollen was consistently selected in mixed pollinations, irrespective of maternal genotype. However, clear patterns of mate discrimination occurred amongst non-self pollen when mixed pollinations were performed soon after corollas open, including selection against hygromycin B resistance (transformation selectable marker) in wild-type styles and for it in transformed styles. However, mate choice among pollen genotypes was completely shut down in plants transformed to be unable to produce (irACO) or perceive (ETR1) ethylene. The post-pollination ethylene burst, which originates primarily from the stigma and upper style, was strongly correlated with mate selection in single and mixed hand-pollinations using eight pollen donors in two maternal ecotypes. The post-pollination ethylene burst was also negatively correlated with the continuation of emission of benzylacetone, the most abundant pollinator-attracting corolla-derived floral volatile. We conclude that ethylene signaling plays a pivotal role in mate choice, and the post-pollination ethylene burst and the termination of benzylacetone release are accurate predictors, both qualitatively and quantitatively, of pre-zygotic mate selection and seed paternity. PMID:22458597

  20. Micro-Raman spectroscopy Detects Individual Neoplastic and Normal Hematopoietic Cells

    SciTech Connect

    Chan, J W; Taylor, D; Zwerdling, T; Lane, S M; Ihara, K; Huser, T

    2005-01-18

    Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often non-specific, slow, biologically perturbing, or a combination, thereof. Here, we show that single-cell micro-Raman spectroscopy averts these shortcomings and can be used to discriminate between unfixed normal human lymphocytes and transformed Jurkat and Raji lymphocyte cell lines based on their biomolecular Raman signatures. We demonstrate that single-cell Raman spectra provide a highly reproducible biomolecular fingerprint of each cell type. Characteristic peaks, mostly due to different DNA and protein concentrations, allow for discerning normal lymphocytes from transformed lymphocytes with high confidence (p << 0.05). Spectra are also compared and analyzed by principal component analysis (PCA) to demonstrate that normal and transformed cells form distinct clusters that can be defined using just two principal components. The method is shown to have a sensitivity of 98.3% for cancer detection, with 97.2% of the cells being correctly classified as belonging to the normal or transformed type. These results demonstrate the potential application of confocal micro-Raman spectroscopy as a clinical tool for single cell cancer detection based on intrinsic biomolecular signatures, therefore eliminating the need for exogenous fluorescent labeling.

  1. Microbial growth tests in anti-neoplastic injectable solutions.

    PubMed

    Paris, Isabelle; Paci, Angelo; Rey, Jean-Baptiste; Bourget, Philippe

    2005-03-01

    The Institut Gustave-Roussy (IGR) Department of Clinical Pharmacy (DCP) ensures the annual preparation of about 30 000 therapeutic batches of anti-neoplastic agents. High performance thin-layer chromatography (HPTLC) allows postproduction quality control of these batches. Although the centralized chemotherapy manufacturing unit has been recently ISO 9001:2000 certified, it was considered to improve the quality level of manufactured batches even further. The viability of micro-organisms (bacteria and fungi) in appropriate sterile media containing various anti-neoplastic agents at therapeutic concentration was assessed to demonstrate the lack of contamination during our manufacturing process in the isolator. After 14 days of incubation in these media, the results show the absence of contamination of the manufactured batches. This leads us to conclude that using sterile drugs and sterile medical devices in a sterile isolator allows the manufacture of sterile therapeutic batches with excellent confidence. PMID:16460598

  2. Gonadotropin-Dependent Precocious Puberty: Neoplastic Causes and Endocrine Considerations

    PubMed Central

    2011-01-01

    Premature activation of the hypothalamic-pituitary-gonadal (HPG) axis manifests as gonadotropin-dependent precocious puberty. The mechanisms behind HPG activation are complex and a clear etiology for early activation is often not elucidated. Though collectively uncommon, the neoplastic and developmental causes of gonadotropin-dependent precocious puberty are very important to consider, as a delay in diagnosis may lead to adverse patient outcomes. The intent of the current paper is to review the neoplastic and developmental causes of gonadotropin-dependent precocious puberty. We discuss the common CNS lesions and human chorionic gonadotropin-secreting tumors that cause sexual precocity, review the relationship between therapeutic radiation and gonadotropin-dependent precocious puberty, and finally, provide an overview of the therapies available for height preservation in this unique patient population. PMID:21603196

  3. CD1a Reactivity in Non-neoplastic Adenohypophysis.

    PubMed

    Pisapia, David J; Rosenblum, Marc K; Lavi, Ehud

    2016-06-01

    Within the differential diagnosis of patients presenting with sellar or suprasellar lesions is Langerhans cell histiocytosis (LCH). CD1a staining is frequently used to identify the presence of an abnormal proliferation of Langerhans cells on histologic sections and contributes to the diagnosis of LCH. Here, we report that the MTB-1 monoclonal antibody against the CD1a antigen reacts to native adenohypophyseal epithelial cells. We show that immunohistochemistry for CD1a exhibits strong positivity in all autopsy and surgically resected non-neoplastic adenohypophysis tested. Thus, CD1a positivity by itself should be interpreted with caution, and we recommend the routine use of a panel of stains including CD1a, Langerin, and synaptophysin in conjunction with morphologic analysis before a diagnosis of LCH is rendered. In addition, we find that pituitary adenomas fail to stain for CD1a prompting consideration of the utility of this stain as a marker for non-neoplastic gland. PMID:26999501

  4. Neoplastic Meningitis from Solid Tumors: New Diagnostic and Therapeutic Approaches

    PubMed Central

    Zustovich, Fable; Farina, Patrizia; Della Puppa, Alessandro; Manara, Renzo; Cecchin, Diego; Brunello, Antonella; Cappetta, Alessandro; Zagonel, Vittorina

    2011-01-01

    Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%–15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography–computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches. PMID:21795431

  5. A mosaic genetic screen for Drosophila neoplastic tumor suppressor genes based on defective pupation.

    PubMed

    Menut, Laurent; Vaccari, Thomas; Dionne, Heather; Hill, Joseph; Wu, Geena; Bilder, David

    2007-11-01

    The Drosophila neoplastic tumor suppressor genes (TSGs) coordinately control cell polarity and proliferation in epithelial and neuronal tissues. While a small group of neoplastic TSG mutations have been isolated and their corresponding genes cloned, the regulatory pathways that normally prevent inappropriate growth remain unclear. Identification of additional neoplastic TSGs may provide insight into this question. We report here the design of an efficient screen for isolating neoplastic TSG mutations utilizing genetically mosaic larvae. This screen is based on a defective pupation phenotype seen when a single pair of imaginal discs is homozygous for a neoplastic TSG mutation, which suggests that continuously proliferating cells can interfere with metamorphosis. Execution of this screen on two chromosome arms led to the identification of mutations in at least seven new neoplastic TSGs. The isolation of additional loci that affect hyperplastic as well as neoplastic growth indicates the utility of this screening strategy for studying epithelial growth control. PMID:17947427

  6. Seminal plasma induces the expression of IL-1α in normal and neoplastic cervical cells via EP2/EGFR/PI3K/AKT pathway

    PubMed Central

    2014-01-01

    Background Cervical cancer is a chronic inflammatory disease of multifactorial etiology usually presenting in sexually active women. Exposure of neoplastic cervical epithelial cells to seminal plasma (SP) has been shown to promote the growth of cancer cells in vitro and tumors in vivo by inducing the expression of inflammatory mediators including pro-inflammatory cytokines. IL-1α is a pleotropic pro-inflammatory cytokine induced in several human cancers and has been associated with virulent tumor phenotype and poorer prognosis. Here we investigated the expression of IL-1α in cervical cancer, the role of SP in the regulation of IL-1α in neoplastic cervical epithelial cells and the molecular mechanism underlying this regulation. Methods and results Real-time quantitative RT-PCR confirmed the elevated expression of IL-1α mRNA in cervical squamous cell carcinoma and adenocarcinoma tissue explants, compared with normal cervix. Using immunohistochemistry, IL-1α was localized to the neoplastically transformed squamous, columnar and glandular epithelium in all cases of squamous cell carcinoma and adenocarcinomas explants studied. We found that SP induced the expression of IL-α in both normal and neoplastic cervical tissue explants. Employing HeLa (adenocarcinoma) cell line as a model system we identified PGE2 and EGF as possible ligands responsible for SP-mediated induction of IL-1α in these neoplastic cells. In addition, we showed that SP activates EP2/EGFR/PI3kinase-Akt signaling to induce IL-1α mRNA and protein expression. Furthermore, we demonstrate that in normal cervical tissue explants the induction of IL-1α by SP is via the activation of EP2/EGFR/PI3 kinase-Akt signaling. Conclusion SP-mediated induction of IL-1α in normal and neoplastic cervical epithelial cells suggests that SP may promote cervical inflammation as well as progression of cervical cancer in sexually active women. PMID:25237386

  7. Identification of non-random sequence properties in groups of signature peptides obtained in random sequence peptide microarray experiments.

    PubMed

    Kuznetsov, Igor B

    2016-05-01

    Immunosignaturing is an emerging experimental technique that uses random sequence peptide microarrays to detect antibodies produced by the immune system in response to a particular disease. Two important questions regarding immunosignaturing are "Do microarray peptides that exhibit a strong affinity to a given type of antibodies share common sequence properties?" and "If so, what are those properties?" In this work, three statistical tests designed to detect non-random patterns in the amino acid makeup of a group of microarray peptides are presented. One test detects patterns of significantly biased amino acid usage, whereas the other two detect patterns of significant bias in the biochemical properties. These tests do not require a large number of peptides per group. The tests were applied to analyze 19 groups of peptides identified in immunosignaturing experiments as being specific for antibodies produced in response to various types of cancer and other diseases. The positional distribution of the biochemical properties of the amino acids in these 19 peptide groups was also studied. Remarkably, despite the random nature of the sequence libraries used to design the microarrays, a unique group-specific non-random pattern was identified in the majority of the peptide groups studied. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 318-329, 2016. PMID:27037995

  8. Differential expression of immune-modulatory molecule HLA-E in non-neoplastic and neoplastic lesions of the thyroid.

    PubMed

    Zanetti, B R; Carvalho-Galano, D F; Feitosa, N L F; Hassumi-Fukasawa, M K; Miranda-Camargo, F A; Maciel, L M Z; Ribeiro-Silva, A; Soares, E G

    2013-01-01

    Human leukocyte antigen (HLA)–E is a non-classical molecule of the histocompatibility complex that functions as one of the main ligands of the Natural Killer (NK) cell inhibitory receptor CD94/NKG2A and inhibits its potent cytotoxic activity. Due to the important role of NK cells in combating neoplasm, we hypothesized that the differential expression of HLA-E could favor the progression of heterogeneous thyroid tumors.Using an immunohistochemistry technique in 143 biopsies of thyroid tumors, including benign and malignant neoplasms and goiters, we evaluated the expression of HLA-E among various tumor types and its association with the clinicopathological factors of diseases. We verified high HLA-E expression in all types of neoplastic tumors, although no significant differences between the groups were found. Low expression was observed in 95 percent of the goiter samples, showing significant differences between neoplastic and non-neoplastic lesions. Furthermore, a significant result was found with regard to the tumor size, with high HLA-E expression being related to smaller tumors. Therefore, our data suggest that an increase in HLA-E may be associated with the establishment of thyroid neoplasms, with either benign or malignant features. PMID:24355224

  9. Cell culture systems to study glial transformation

    SciTech Connect

    Bressler, J.P.; Cole, R.; de Vellis, J.

    1980-01-01

    The transformation of two different types of glial cells has been studied using an in vivo-/in vitro model and a complete in vitro model. The purpose of the study and to define in vitro model systems is to study the the neoplastic transformation of pure populations of glial cells. Data are presented to demonstrate that the transformed cells are glial and tumorigenic. (ACR)

  10. The Origin of Aging: Imperfectness-Driven Non-Random Damage Defines the Aging Process and Control of Lifespan

    PubMed Central

    Gladyshev, Vadim N.

    2013-01-01

    Physico-chemical properties preclude ideal biomolecules and perfect biological functions. This inherent imperfectness leads to the generation of damage by every biological process, at all levels, from small molecules to cells. The damage is too numerous to be repaired, is partially invisible to natural selection and manifests as aging. I propose that it is the inherent imperfectness of biological systems that is the true root of the aging process. As each biomolecule generates specific forms of damage, the cumulative damage is largely non-random and is indirectly encoded in the genome. I consider this concept in light of other proposed theories of aging and integrate these disparate ideas into a single model. I also discuss the evolutionary significance of damage accumulation and strategies for reducing damage. Finally, I suggest ways to test this integrated model of aging. PMID:23769208

  11. Methodological issues in observational studies and non-randomized controlled trials in oncology in the era of big data.

    PubMed

    Tanaka, Shiro; Tanaka, Sachiko; Kawakami, Koji

    2015-04-01

    Non-randomized controlled trials, cohort studies and database studies are appealing study designs when there are urgent needs for safety data, outcomes of interest are rare, generalizability is a matter of concern, or randomization is not feasible. This paper reviews four typical case studies from methodological viewpoints and clarifies how to minimize bias in observational studies in oncology. In summary, researchers planning observational studies should be cautious of selection of appropriate databases, validity of algorithms for identifying outcomes, comparison with incident users or self-control, rigorous collection of information on potential confounders and reporting details of subject selection. Further, a careful study protocol and statistical analysis plan are also necessary. PMID:25589456

  12. Immunohistochemical expression of SOX9 protein in immature, mature, and neoplastic canine Sertoli cells.

    PubMed

    Banco, Barbara; Palmieri, Chiara; Sironi, Giuseppe; Fantinato, Eleonora; Veronesi, Maria C; Groppetti, Debora; Giudice, Chiara; Martignoni, Benedetta; Grieco, Valeria

    2016-05-01

    Sex-determining region Y box9 gene (SOX9) protein plays a pivotal role in male sexual development. It regulates the transcription of the anti-Müllerian hormone gene promoting development of testis cords, multiplication, and maturation of Sertoli cells (SCs) and maintenance of spermatogenesis in adult testis. The immunohistochemical expression of SOX9 in normal testes has been reported in humans, mice, and rats. The present study aimed to investigate the expression of SOX9 in canine SCs during testicular maturation and neoplastic transformation. Canine testicular samples derived from three fetuses, four newborns, four prepubertal puppies, five adult dogs, 31 Sertoli cell tumors (SCTs) (one metastasizing), and five Leydig cell tumors (LCTs) were selected from departmental archive and tested immunohistochemically with a polyclonal antibody against SOX9 (1:150). All SCs from fetal, neonatal, and adult testes had a strong and exclusively nuclear labeling for SOX9. In SCs from prepubertal testes, SOX9 staining was highly variable with one negative sample (one of four), two samples with exclusively nuclear staining (two of four), and one with both nuclear and cytoplasmic labeling (one of four). Leydig cells (LCs) and LCTs were always negative. All 31 SCTs were positive for SOX9. The expression of SOX9 was nuclear, nuclear and cytoplasmic, and exclusively cytoplasmic in 18 of 31, 11 of 31, and two of 31 SCTs, respectively. This first report on the immunohistochemical expression of SOX9 in canine testes reports that in normal SCs from fetal, neonatal, and adult testes SOX9 labeled the nucleus, as in humans and laboratory animals. The cytoplasmic labeling observed in one prepubertal pairs of testes and in 11 SCTs could reflect SC immaturity or dedifferentiation, paralleling results observed in rat testes. The expression of SOX9 in SCs and SCTs and its absence in LCs and LCTs suggests that SOX9 is a reliable diagnostic marker for both normal and neoplastic SCs. PMID:26777558

  13. De-misty-fying the mesentery: an algorithmic approach to neoplastic and non-neoplastic mesenteric abnormalities.

    PubMed

    Taffel, Myles T; Khati, Nadia J; Hai, Nabila; Yaghmai, Vahid; Nikolaidis, Paul

    2014-08-01

    Mesenteric abnormalities are often incidentally discovered on cross-sectional imaging performed during daily clinical practice. Findings can range from the vague "misty mesentery" to solid masses, and the possible etiologic causes encompass a wide spectrum of underlying pathologies including infectious, inflammatory, and neoplastic processes. Unfortunately, the clinical and imaging findings are often non-specific and may overlap. This article discusses the various diseases that result in mesenteric abnormalities. It provides a framework to non-invasively differentiate these entities, when possible. PMID:24633598

  14. Multifunctional CD40L: pro- and anti-neoplastic activity.

    PubMed

    Korniluk, Aleksandra; Kemona, Halina; Dymicka-Piekarska, Violetta

    2014-10-01

    The CD40 ligand is a type I transmembrane protein that belongs to a tumor necrosis factor (TNF) superfamily. It is present not only on the surface of activated CD4+ T cells, B cells, blood platelets, monocytes, and natural killer (NK) cells but also on cancer cells. The receptor for ligand is constitutively expressed on cells, TNF family protein: CD40. The role of the CD40/CD40L pathway in the induction of body immunity, in inflammation, or in hemostasis has been well documented, whereas its involvement in neoplastic disease is still under investigation. CD40L ligand may potentiate apoptosis of tumor cells by activation of nuclear factor-κB (NF-κB), AP-1, CD95, or caspase-depended pathways and stimulate host immunity to defend against cancer. Although CD40L has a major contribution to anti-cancer activity, many reports point at its ambivalent nature. CD40L enhance release of strongly pro-angiogenic factor, vascular endothelial growth factor (VEGF), and activator of coagulation, TF, the level of which is correlated with tumor metastasis. CD40L involvement in the inhibition of tumor progression has led to the emergence of not only therapy using recombinant forms of the ligand and vaccines in the treatment of cancer but also therapy consisting of inhibiting platelets-main source of CD40L. This article is a review of studies on the ambivalent role of CD40L in neoplastic diseases. PMID:25117071

  15. Cancer: The Transforming Power of Cell Competition.

    PubMed

    Gil, Jesus; Rodriguez, Tristan

    2016-02-22

    The tumour-host microenvironment plays key roles in cancer, but the mechanisms involved are not fully understood. Two new studies provide insight into this problem by showing that through cell competition, a fitness-sensing process that usually eliminates defective cells, pre-cancerous lesions signal the death of surrounding tissue that in turn promotes their neoplastic transformation. PMID:26906487

  16. Role of Peroxisome Proliferator-Activated Receptor γ and Its Ligands in Non-Neoplastic and Neoplastic Human Urothelial Cells

    PubMed Central

    Nakashiro, Koh-ichi; Hayashi, Yoshiki; Kita, Akiyo; Tamatani, Tetsuya; Chlenski, Alexandre; Usuda, Nobuteru; Hattori, Kazunori; Reddy, Janardan K.; Oyasu, Ryoichi

    2001-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and is expressed in several types of tissue. Although PPARγ reportedly is expressed in normal urothelium, its function is unknown. We examined the expression of PPARγ in normal urothelium and bladder cancer in an attempt to assess its functional role. Immunohistochemical staining revealed normal urothelium to express PPARγ uniformly. All low-grade carcinomas were positive either diffusely or focally, whereas staining was primarily focal or absent in high-grade carcinomas. A nonneoplastic urothelial cell line (1T-1), a low-grade (RT4) carcinoma cell line, and two high-grade (T24 and 253J) carcinoma cell lines in culture expressed PPARγ mRNA and protein. Luciferase assay indicated that PPARγ was functional. PPARγ ligands (15-deoxy-Δ12,14-prostaglandin J2, troglitazone and pioglitazone) suppressed the growth of nonneoplastic and neoplastic urothelial cells in a dose-dependent manner. However, neoplastic cells were more resistant than were nonneoplastic cells. Failure to express PPARγ or ineffective transcriptional activity may be some of the mechanisms responsible for resistance to the inhibitory action of PPARγ ligands. PMID:11485917

  17. Risk factors for neoplastic progression in Barrett’s esophagus

    PubMed Central

    Wiseman, Elizabeth F; Ang, Yeng S

    2011-01-01

    Barrett’s esophagus (BE) confers a significant increased risk for development of esophageal adenocarcinoma (EAC), with the pathogenesis appearing to progress through a “metaplasia-dysplasia-carcinoma” (MDC) sequence. Many of the genetic insults driving this MDC sequence have recently been characterized, providing targets for candidate biomarkers with potential clinical utility to stratify risk in individual patients. Many clinical risk factors have been investigated, and associations with a variety of genetic, specific gastrointestinal and other modifiable factors have been proposed in the literature. This review summarizes the current understanding of the mechanisms involved in neoplastic progression of BE to EAC and critically appraises the relative roles and contributions of these putative risk factors from the published evidence currently available. PMID:21990948

  18. Neoplastic cauda equina syndrome: a neuroimaging-based review.

    PubMed

    Bennett, Shelby J; Katzman, Gregory L; Roos, Raymond P; Mehta, Amar S; Ali, Saad

    2016-02-01

    Cauda equina syndrome refers to dysfunction of the cauda equina, the collection of ventral and dorsal lumbar, sacral and coccygeal nerve roots that surround the filum terminale. This most commonly occurs as a result of compression by a herniated lumbosacral disc. However, the syndrome may also complicate metastatic cancer or a primary neoplasm within or infiltrating the spinal canal. An accurate and timely diagnosis is critical to avoid irreversible loss of neurological function. The clinician and radiologist must therefore be aware of the many possible causes to guide timely management. Here we review the diverse neoplastic causes affecting the cauda equina nerve roots from a neuroimaging-based perspective. We divide them by location into intramedullary neoplasms at the conus (such as astrocytoma), intradural-extramedullary neoplasms (such as schwannoma and leptomeningeal metastases) and extradural neoplasms (such as spinal metastases from systemic neoplasms). We also discuss the clinical features associated with cauda equina tumours, with special focus on cauda equina syndrome. PMID:26442520

  19. Guidelines for genomic array analysis in acquired haematological neoplastic disorders.

    PubMed

    Schoumans, Jacqueline; Suela, Javier; Hastings, Ros; Muehlematter, Dominique; Rack, Katrina; van den Berg, Eva; Berna Beverloo, H; Stevens-Kroef, Marian

    2016-05-01

    Genetic profiling is important for disease evaluation and prediction of prognosis or responsiveness to therapy in neoplasia. Microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism-detecting arrays, have in recent years been introduced into the diagnostic setting for specific types of haematological malignancies and solid tumours. It can be used as a complementary test or depending on the neoplasia investigated, also as a standalone test. However, comprehensive and readable presentation of frequently identified complex genomic profiles remains challenging. To assist diagnostic laboratories, standardization and minimum criteria for clinical interpretation and reporting of acquired genomic abnormalities detected through arrays in neoplastic disorders are presented. © 2016 Wiley Periodicals, Inc. PMID:26774012

  20. Nuclear Division Index may Predict Neoplastic Colorectal Lesions

    PubMed Central

    IONESCU, Mirela E.; CIOCIRLAN, Mihai; BECHEANU, Gabriel; NICOLAIE, Tudor; DITESCU, Cristina; TEIUSANU, Adriana G.; GOLOGAN, Serban I.; ARBANAS, Tudor; DICULESCU, Mircea M.

    2011-01-01

    ABSTRACT Background: Colorectal cancer (CRC) develops by accumulation of multiple genetic damages leading to genetic instability that can be evaluated by cytogenetic methods. In the current study we used Cytokinesis-Blocked Micronucleus Assay (CBMN) technique to assess the behavior of Nuclear Division Index(NDI) in peripheral lymphocytes of patients with CRC and polyps versus patients with normal colonoscopy. Methods: Blood samples were collected from patients after informed consent. By CBMN technique we assessed the proportion of mono-nucleated, bi-nucleated, tri-nucleated and tetra-nucleated cells/500 cells, to calculate NDI. Data were statistically analyzed using the SPSS 11.0 package. Results: 45 patients were available for analysis, 23 men and 22 women, with a mean age of 58.7±13.5. 17 had normal colonoscopy, 17 colonic polyps and 11 CRC. The mean NDI values were significantly smaller for patients with CRC or polyps than in patients with normal colonoscopy (1.57 vs 1.73, p=0.013). The difference persisted for patients with neoplastic lesions (adenomas and carcinomas) when compared with patients with normal colonoscopy or non neoplastic (hyperplastic) polyps (1.56 vs.1.71, p=0.018). The NDI cut-off value to predict the presence of adenomas or carcinomas was equal to 1.55 with a 54.2% sensitivity and 81% specificity of lower values (p=0.019). The NDI cut off value to predict the presence of advanced adenomas or cancer was 1.525 for a sensitivity of 56.3% and a specificity of 82.8% (p=0.048). Conclusion: NDI may be useful in screening strategies for colorectal cancer as simple, noninvasive, inexpensive cytogenetic biomarker. PMID:22368693

  1. Non-random cation distribution in hexagonal Al 0.5Ga 0.5PO 4

    NASA Astrophysics Data System (ADS)

    Kulshreshtha, S. K.; Jayakumar, O. D.; Sudarsan, V.

    2010-05-01

    Based on powder X-ray diffraction and 31P Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) investigations of mixed phosphate Al 0.5Ga 0.5PO 4, prepared by co-precipitation method followed by annealing at 900 °C for 24 h, it is shown that Al 0.5Ga 0.5PO 4 phase crystallizes in hexagonal form with lattice parameter a=0.491(2) and c=1.106(4) nm. This hexagonal phase of Al 0.5Ga 0.5PO 4 is similar to that of pure GaPO 4. The 31P MAS NMR spectrum of the mixed phosphate sample consists of five peaks with systematic variation of their chemical shift values and is arising due to existence of P structural units having varying number of the Al 3+/Ga 3+ cations as the next nearest neighbors in the solid solution. Based on the intensity analysis of the component NMR spectra of Al 0.5Ga 0.5PO 4, it is inferred that the distribution of Al 3+ and Ga 3+ cations is non-random for the hexagonal Al 0.5Ga 0.5PO 4 sample although XRD patterns showed a well-defined solid solution formation.

  2. Co-occurrence analyses show that non-random community structure is disrupted by fire in two groups of soil arthropods (Isopoda Oniscidea and Collembola)

    NASA Astrophysics Data System (ADS)

    Pitzalis, Monica; Luiselli, Luca; Bologna, Marco A.

    2010-01-01

    In this paper, we tested the hypothesis that natural catastrophes may destroy non-random community structure in natural assemblages of organisms. As a study system, we selected fire as the catastrophic event, and two groups of soil arthropods (Collembola and Isopoda Oniscidea) as target organisms. By co-occurrence analyses and Monte Carlo simulations of niche overlap analysis (C-score, with fixed-equiprobable model; RA2 and RA3 algorithms) we evaluated whether the community structure of these two groups were random/non-random at three unburnt sites and at three neighbour burnt sites that were devastated by a large-scale fire in summer 2000. Both taxa experienced a remarkable reduction in the number of species sampled in burnt versus unburnt sites, but the difference among sites was not statistically significant for Oniscidea. We determined that community structure was clearly non-random at the unburnt sites for both Collembola (according to RA3 algorithm) and Isopoda Oniscidea (according to co-occurrence analysis) and that, as predicted by theory, the catastrophic event did deeply alter the community structure by removing the non-random organization of the species interactions. We also observed a shift from segregation to aggregation/randomness in soil arthropods communities affected by fire, a pattern that was similar to that observed in natural communities of organisms perturbed by the introduction of alien species, thus indicating that this pattern may be generalizable when alteration of communities may occur.

  3. Growth factors, their receptor expression and markers for proliferation of endothelial and neoplastic cells in human osteosarcoma.

    PubMed

    Bianchi, E; Artico, M; Di Cristofano, C; Leopizzi, M; Taurone, S; Pucci, M; Gobbi, P; Mignini, F; Petrozza, V; Pindinello, I; Conconi, M T; Della Rocca, C

    2013-01-01

    Osteosarcoma is the most common primary malignant tumour of the bone. Although new therapies continue to be reported, osteosarcoma-related morbidity and mortality remain high. Modern medicine has greatly increased knowledge of the physiopathology of this neoplasm. Novel targets for drug development may be identified through an understanding of the normal molecular processes that are deeply modified in pathological conditions. The aim of the present study is to investigate, by immunohistochemistry, the localisation of different growth factors and of the proliferative marker Ki-67 in order to determine whether these factors are involved in the transformation of osteogenic cells and in the development of human osteosarcoma. We observed a general positivity for NGF - TrKA - NT3 - TrKC - VEGF in the cytoplasm of neoplastic cells and a strong expression for NT4 in the nuclear compartment. TGF-beta was strongly expressed in the extracellular matrix and vascular endothelium. BDNF and TrKB showed a strong immunolabeling in the extracellular matrix. Ki-67/MIB-1 was moderately expressed in the nucleus of neoplastic cells. We believe that these growth factors may be considered potential therapeutic targets in the treatment of osteosarcoma, although proof of this hypothesis requires further investigation. PMID:24067459

  4. Lectin histochemistry of normal and neoplastic peripheral nerve sheath. 2. Lectin binding patterns of schwannoma and neurofibroma.

    PubMed

    Matsumura, K; Nakasu, S; Nioka, H; Handa, J

    1993-01-01

    Lectin binding patterns of 31 schwannomas and 6 neurofibromas were examined using 12 lectins, and the results were compared with those of normal peripheral nerves. Tumors obtained from 10 cases of neurofibromatosis and 4 recurrent schwannomas were included. Changes of glycoconjugates were observed in association with a neoplastic transformation of Schwann cells; Arachis hypogaea (PNA) staining after neuraminidase treatment seen in normal Schwann cells was reduced in schwannoma of Antoni type A, and bindings with Glycine max (SBA) and Helix pomatia (HPA) after sialic acid removal, which were not seen in normal Schwann cells, appeared in schwannoma cells. Intensities of staining of tumor cells with each lectin were higher in Antoni type B than those in Antoni type A. No differences in lectin binding patterns were observed between schwannomas in patients with neurofibromatosis or recurrent schwannomas and ordinary, primary schwannomas in patients without stigmata of neurofibromatosis. Lectin binding patterns of Schwann cells and perineurial cells in neurofibroma were almost similar to those in normal peripheral nerves with an exception of faint stain of Schwann cells with HPA after neuraminidase pretreatment. This result suggests differences in extent of differentiation between schwannoma cells and neoplastic Schwann cells in neurofibroma. Specific PNA binding to perineurial cells in neurofibroma indicates the significance of this lectin as a marker of these cells. PMID:8310811

  5. ADAPTIVE RESPONSE AGAINST SPONTANEOUS NEOPLASTIC TRANSFORMATION IN VITRO INDUCED BY IONIZING RADIATION

    EPA Science Inventory

    The following paragraphs outline a project which addresses the area "Understanding biological responses to radiation and endogeneous damage". The proposed research addresses the following key question: (a) "How much do low doses of radiation protect against subsequent low doses ...

  6. LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation

    PubMed Central

    Lee, Chia-Huei; Pan, Kao-Lu; Tang, Ya-Chu; Tsai, Ming-Hsien; Cheng, Ann-Joy; Shen, Mei-Ya; Cheng, Ying-Min; Huang, Tze-Ta; Lin, Pinpin

    2015-01-01

    Previously, we identified global epigenetic aberrations in smoking-associated oral squamous cell carcinoma (OSCC). We hypothesized that cigarette exposure triggers OSCC through alteration of the methylome of oral cells. Here we report that cigarette smoke condensate (CSC) significantly changes the genomic 5-methyldeoxycytidine content and nuclear accumulation of DNA methyltransferase 1 (DNMT1) and DNMT3A in human untransformed oral cells. By using integrated analysis of cDNA and methylation arrays of the smoking-associated dysplastic oral cell line and OSCC tumors, respectively, we identified four epigenetic targets—UCHL1, GPX3, LXN, and LDOC1—which may be silenced by cigarette. Results of quantitative methylation-specific PCR showed that among these four genes, LDOC1 promoter was the most sensitive to CSC. LDOC1 promoter hypermethylation and gene silencing followed 3 weeks of CSC treatment. LDOC1 knockdown led to a proliferative response and acquired clonogenicity of untransformed oral cells. Immunohistochemistry showed that LDOC1 was downregulated in 53.3% (8/15) and 57.1% (20/35) of premalignant oral tissues and early stage OSCCs, respectively, whereas 76.5% (13/17) of normal oral tissues showed high LDOC1 expression. Furthermore, the microarray data showed that LDOC1 expression had decreased in the lung tissues of current smokers compared with that in those of never smokers and had significantly decreased in the lung tumors of smokers compared with that in normal lung tissues. Our data suggest that CSC-induced promoter methylation may contribute to LDOC1 downregulation, thereby conferring oncogenic features to oral cells. These findings also imply a tumor suppressor role of LDOC1 in smoking-related malignancies such as OSCC and lung cancer. PMID:26317789

  7. ULTRAVIOLET RADIATION-INDUCED NEOPLASTIC TRANSFORMATION OF NORMAL HUMAN CELLS, IN VITRO

    EPA Science Inventory

    Human foreskin cell cultures in schedules DNA synthesis (S phase) of the cell cycle were exposed to UV irradiation at a dose of 10 J.sq. m. in the presence of insulin. These treated cell populations, when selectively passaged in a high amino acid supplemented complete growth medi...

  8. Complementary approaches to understanding the role of proteases and their natural inhibitors in neoplastic development: retrospect and prospect.

    PubMed

    Rubin, Harry

    2003-05-01

    A great deal of evidence has accumulated in recent years for an important but complex role for proteases in tumor development. However, attempts to treat cancer in humans with anti-proteases have been disappointing, and it has been suggested that more basic groundwork is needed before anti-proteases can be effectively applied. Considerable basic information comes from the recognition that earlier results on transformation of chicken embryo fibroblasts (CEF) by the Bryan strain of Rous sarcoma virus (B-RSV) can be explained in terms of proteases and their inhibitors. In particular, the full but reversible normalization of discrete transformed foci by appropriate concentrations of fetal bovine or of calf serum implies a causal role for multiple proteases in transformation, and the efficacy of treatment with a physiological balance of their natural inhibitors. Addition of certain proteases to contact-inhibited normal cultures was then found to stimulate their proliferation. The toxicity of medium produced by CEF heavily transformed with B-RSV suggests that cachexia and other systemic effects of human cancer may result from vascular dissemination of peptides from pericellular proteolysis within tumors. Comprehensive studies revealed significant increases of plasminogen activator and matrix metalloproteinases (MMPs) after infection of CEF with other strains of RSV, and correlation of the proteases with aspects of transformation. A similar role for proteases is indicated in the transformation of mammalian cells by chemical and physical agents. The information gained from functional experiments on cell transformation in culture is complementary to that obtained from the molecular identification of proteases and their inhibitors in all stages of tumor development. The speed, quantification and easy manipulation of the RSV-CEF transformation assay can be combined with current methods of characterizing proteases and anti-proteases to further enrich our basic knowledge of

  9. A school intervention for mental health literacy in adolescents: effects of a non-randomized cluster controlled trial

    PubMed Central

    2013-01-01

    Background “Mental health for everyone” is a school program for mental health literacy and prevention aimed at secondary schools (13–15 yrs). The main aim was to investigate whether mental health literacy, could be improved by a 3-days universal education programme by: a) improving naming of symptom profiles of mental disorder, b) reducing prejudiced beliefs, and c) improving knowledge about where to seek help for mental health problems. A secondary aim was to investigate whether adolescent sex and age influenced the above mentioned variables. A third aim was to investigate whether prejudiced beliefs influenced knowledge about available help. Method This non-randomized cluster controlled trial included 1070 adolescents (53.9% boys, M age14 yrs) from three schools in a Norwegian town. One school (n = 520) received the intervention, and two schools (n = 550) formed the control group. Pre-test and follow-up were three months apart. Linear mixed models and generalized estimating equations models were employed for analysis. Results Mental health literacy improved contingent on the intervention, and there was a shift towards suggesting primary health care as a place to seek help. Those with more prejudiced beleifs did not suggest places to seek help for mental health problems. Generally, girls and older adolescents recognized symptom profiles better and had lower levels of prejudiced beliefs. Conclusions A low cost general school program may improve mental health literacy in adolescents. Gender specific programs and attention to the age and maturity of the students should be considered when mental health literacy programmes are designed and tried out. Prejudice should be addressed before imparting information about mental health issues. PMID:24053381

  10. Telomere Disruption Results in Non-Random Formation of De Novo Dicentric Chromosomes Involving Acrocentric Human Chromosomes

    PubMed Central

    Stimpson, Kaitlin M.; Song, Ihn Young; Jauch, Anna; Holtgreve-Grez, Heidi; Hayden, Karen E.; Bridger, Joanna M.; Sullivan, Beth A.

    2010-01-01

    Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the α-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extra-chromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same α-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment. PMID:20711355

  11. Detecting neoplastic development in the hamster cheek pouch using Fourier domain low coherence interferometry

    NASA Astrophysics Data System (ADS)

    Graf, Robert N.; Robles, Francisco; Chen, Xiaoxin; Wax, Adam

    2009-02-01

    Fourier Domain Low Coherence Interferometry (fLCI) is an optical technique that recovers depth-resolved spectroscopic information about scatterers. The current fLCI system utilizes a white light Xe arc lamp source, a 4-f interferometer, and an imaging spectrometer at the detection plane to acquire spectra from 256 adjacent spatial points. This configuration permits the acquisition of ultrahigh depth resolution Fourier domain OCT images without the need for any beam scanning. fLCI has traditionally obtained depth-resolved spectral information by performing a short-time Fourier transform (STFT) on the detected spectra, similar to the processing techniques of spectroscopic OCT. We now employ a dual Gaussian window processing method which simultaneously obtains high spectral and temporal resolution, thus avoiding the resolution trade-off normally associated with the STFT. Wavelength dependent variations in scattering intensity are analyzed as a function of depth to obtain structural information about the probed scatterers. We now verify fLCI's ability to distinguish between normal and dysplastic epithelial tissue using the hamster cheek pouch model. Thirty hamsters will have one cheek pouch treated with the known carcinogen DMBA. At the conclusion of the 24 week treatment period the animals will be anesthetized and the cheek pouches will be extracted. We will use the fLCI optical system to measure the neoplastic transformation of the in situ subsurface tissue layers in both the normal and DMBA-treated cheek pouches. Traditional histological analysis will be used to verify the fLCI measurements. Our results will further establish fLCI as an effective method for distinguishing between normal and dysplastic epithelial tissues.

  12. Uroplakin Gene Expression by Normal and Neoplastic Human Urothelium

    PubMed Central

    Lobban, E. Dawn; Smith, Barbara A.; Hall, Geoffrey D.; Harnden, Patricia; Roberts, Paul; Selby, Peter J.; Trejdosiewicz, Ludwik K.; Southgate, Jennifer

    1998-01-01

    cDNA sequences for human uroplakins UPIa, UPIb, UPII, and UPIII were cloned and used to investigate uroplakin transcription by normal and neoplastic urothelial cells. Normal urothelium expressed mRNA for all four uroplakins, although UPIII could be detected only by ribonuclease protection assay. By in situ hybridization, UPIa and UPII were confined to superficial cells and UPIb was also expressed by intermediate cells. Cultured normal human urothelial cells showed a proliferative basal/intermediate cell phenotype and constitutive expression of UPIb only. Uroplakin expression by transitional cell carcinoma cell lines was related to their differentiated phenotype in vitro. RT4 cells expressed all uroplakins, VM-CUB-3 expressed three uroplakins, RT112 and HT1376 cells expressed only UPIb in high abundance, and COLO232, KK47, and EJ cells had no detectable expression. These results correlated with patterns of uroplakin expression in tumors. UPIa and UPII were detected superficially only in well differentiated transitional cell carcinoma papillae. UPIb was positive in seven of nine and overexpressed in five of nine noninvasive transitional cell carcinomas and was also present in four of eight invasive transitional cell carcinomas. Lymph node metastases retained the same pattern of UPIb expression as the primary tumor. Unlike the three differentiation-regulated uroplakins, UPIb may have an alternative role in urothelial cell/tissue processes. PMID:9846985

  13. Uroplakin gene expression by normal and neoplastic human urothelium.

    PubMed

    Lobban, E D; Smith, B A; Hall, G D; Harnden, P; Roberts, P; Selby, P J; Trejdosiewicz, L K; Southgate, J

    1998-12-01

    cDNA sequences for human uroplakins UPIa, UPIb, UPII, and UPIII were cloned and used to investigate uroplakin transcription by normal and neoplastic urothelial cells. Normal urothelium expressed mRNA for all four uroplakins, although UPIII could be detected only by ribonuclease protection assay. By in situ hybridization, UPIa and UPII were confined to superficial cells and UPIb was also expressed by intermediate cells. Cultured normal human urothelial cells showed a proliferative basal/intermediate cell phenotype and constitutive expression of UPIb only. Uroplakin expression by transitional cell carcinoma cell lines was related to their differentiated phenotype in vitro. RT4 cells expressed all uroplakins, VM-CUB-3 expressed three uroplakins, RT112 and HT1376 cells expressed only UPIb in high abundance, and COLO232, KK47, and EJ cells had no detectable expression. These results correlated with patterns of uroplakin expression in tumors. UPIa and UPII were detected superficially only in well differentiated transitional cell carcinoma papillae. UPIb was positive in seven of nine and overexpressed in five of nine noninvasive transitional cell carcinomas and was also present in four of eight invasive transitional cell carcinomas. Lymph node metastases retained the same pattern of UPIb expression as the primary tumor. Unlike the three differentiation-regulated uroplakins, UPIb may have an alternative role in urothelial cell/tissue processes. PMID:9846985

  14. Microfluorometric comparisons of heat-induced nuclear acridine orange metachromasia between normal cells and neoplastic cells from primary tumors of diverse origin.

    PubMed

    Alvarez, M R

    1975-01-01

    Nuclear fluorescence metachromasia of heated fixed cells subsequently stained with acridine orange was compared in smears and isolated nuclei of various types of primary tumors and normal cells from the tissues that gave rise to the tumors. The ratios of fluorescence emission at 590 and 530 nm reflect the thermal stability of chromatin in situ. The results show that the mean thermal stability of the chromatin in neoplastic cells was lower than the stability of their normal counterparts in all cases. This was found in both spontaneous and chemically induced tumors as divergent in type as a dog vaginal tumor and murine lymphocytic leukemia. These data, together with our previous observations in other neoplastic systems, indicate that reduced chromatin thermal stability may be a general characteristic of cells that have undergone neoplastic transformation and is not confined to rapidly growing tumors. The present investigation identifies the sources of variability encountered in measuring fluorescence metachromasia in slide preparations, and methods of minimizing this variability for potential cytodiagnostic application are discussed. PMID:45893

  15. Effectiveness of a 'Global Postural Reeducation' program for persistent Low Back Pain: a non-randomized controlled trial

    PubMed Central

    2010-01-01

    Background The aim of this non-randomized controlled trial was to evaluate the effectiveness of a Global Postural Reeducation (GPR) program as compared to a Stabilization Exercise (SE) program in subjects with persistent low back pain (LBP) at short- and mid-term follow-up (ie. 3 and 6 months). Methods According to inclusion and exclusion criteria, 100 patients with a primary complaint of persistent LBP were enrolled in the study: 50 were allocated to the GPR group and 50 to the SE group. Primary outcome measures were Roland and Morris Disability Questionnaire (RMDQ) and Oswestry Disability Index (ODI). Secondary outcome measures were lumbar Visual Analogue Scale (VAS) and Fingertip-to-floor test (FFT). Data were collected at baseline and at 3/6 months by health care professionals unaware of the study. An intention to treat approach was used to analyze participants according to the group to which they were originally assigned. Results Of the 100 patients initially included in the study, 78 patients completed the study: 42 in the GPR group and 36 in the SE group. At baseline, the two groups did not differ significantly with respect to gender, age, BMI and outcome measures. Comparing the differences between groups at short- and mid-term follow-up, the GPR group revealed a significant reduction (from baseline) in all outcome measures with respect to the SE group. The ordered logistic regression model showed an increased likelihood of definitive improvement (reduction from baseline of at least 30% in RMDQ and VAS scores) for the GPR group compared to the SE group (OR 3.9, 95% CI 2.7 to 5.7). Conclusions Our findings suggest that a GPR intervention in subjects with persistent LBP induces a greater improvement on pain and disability as compared to a SE program. These results must be confirmed by further studies with higher methodological standards, including randomization, larger sample size, longer follow-up and subgrouping of the LBP subjects. Trial registration NCT

  16. Terminal deoxynucleotidyltransferase distribution in neoplastic and hematopoietic cells.

    PubMed

    Greenwood, M F; Coleman, M S; Hutton, J J; Lampkin, B; Krill, C; Bolium, F J; Holland, P

    1977-05-01

    In the present study, terminal deoxynucleotidyltransferase was examined in the peripheral blood and (or) bone marrow of 115 children with a variety of neoplastic, hematologic, and other unrelated disorders. Terminal deoxynucleotidyltransferase activity was present at 4.08+/-0.74 U/108 cells in 23 morphologicall normal bone marrow samples from childhood controls. Terminal transferase was present at greater than 23 U/108 nucleated cells and at greater than31 U/108 blasts in the bone marrow of all children with acute lymphoblastic leukemia studied at initial diagnosis and at disease relapse. Terminal deoxynucleotidyltransferase was detectable at low levels, less than 7.5 U/108 cells, in all remission marrow smaples. Bone marrow terminal transferase activity was markedly elevated in all untreated acute lymphoblastic leukemia patients, whereas low levels which were difficult to interpret were present in the peripheral blood samples of two patients at diagnosis and six patients at relapse who had low absolute lymphoblast counts. Because of greater variation in the lymphoblast content of peripheral blood, bone marrow assays are more reliable in detecting disease activity. Marrow terminal deoxynucleotidyltransferase values obtained during the active phase of acute lymphoblastic leukemia were significantly greater than those found in other types of leukemia, bone marrow malignancies, and hematologic disorders. Terminal transferase determinations in blast cells of two patients with leukemic conversion of non-Hodgkin's lymphoma and in tumor cells from one patient with Burkitt's lymphoma were within the control range. These dat further define the usefulness of terminal deoxynucleotidyltrnasferase assay in the differentiation and classication of hematologic malignancies. PMID:265945

  17. Immunohistochemical characterization of neoplastic cells of breast origin

    PubMed Central

    2012-01-01

    Background After skin cancer, breast cancer is the most common malignancy in women. Tumors of unknown origin account for 5-15% of malignant neoplasms, with 1.5% being breast cancer. An immunohistochemical panel with conventional and newer markers, such as mammaglobin, was selected for the detection of neoplastic cells of breast origin. The specific objectives are: 1) to determine the sensitivity and specificity of the panel, with a special emphasis on the inclusion of the mammaglobin marker, and 2) to compare immunohistochemistry performed on whole tissue sections and on Tissue Micro-Array. Methods Twenty-nine metastatic breast tumors were included and assumed as tumors of unknown origin. Other 48 biopsies of diverse tissues were selected and assumed as negative controls. Tissue Micro-Array was performed. Immunohistochemistry for mammaglobin, gross cystic disease fluid protein-15, estrogen receptor, progesterone receptor and cytokeratin 7 was done. Results Mammaglobin positive staining was observed in 10/29 cases, in 13/29 cases for gross cystic disease fluid protein-15, in 20/29 cases for estrogen receptor, in 9/29 cases for progesterone receptor, and in 25/29 cases for cytokeratin 7. Among the negative controls, mammaglobin was positive in 2/48, and gross cystic disease fluid protein-15 in 4/48. Conclusions The inclusion of MAG antibody in the immunohistochemical panel for the detection of tumors of unknown origin contributed to the detection of metastasis of breast cancer. The diagnostic strategy with the highest positive predictive value (88%) included hormone receptors and mammaglobin in serial manner. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1366310812718988 PMID:22726568

  18. Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression.

    PubMed Central

    Rieger, K. M.; Little, A. F.; Swart, J. M.; Kastrinakis, W. V.; Fitzgerald, J. M.; Hess, D. T.; Libertino, J. A.; Summerhayes, I. C.

    1995-01-01

    Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes (p53, MDM2, Rb, E-cadherin, APC) within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 (PSI, HT1197) in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 (TCCSUP, SCaBER, 5637, HT1376, J82) cell lines. Absence of E-cadherin was recorded in 5/15 cell lines (TCCSUP, EJ, KK47, UM-UC-3, J82) with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:7669581

  19. Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence

    PubMed Central

    2014-01-01

    Background Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would also appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. Methods A retrospective series of 78 adenomas were collected and classified as low (35) or high-risk (43) for recurrence according to National Comprehensive Cancer Network guidelines. Methylation alterations were analyzed by the methylation-specific multiplex ligation probe assay (MS-MLPA) which is capable of quantifying methylation levels simultaneously in 24 different gene promoters. MS-MLPA results were confirmed by pyrosequencing and immunohistochemistry. Results Higher levels of methylation were associated with disease recurrence. In particular, MLH1, ATM and FHIT gene promoters were found to be significantly hypermethylated in recurring adenomas. Unconditional logistic regression analysis used to evaluate the relative risk (RR) of recurrence showed that FHIT and MLH1 were independent variables with an RR of 35.30 (95% CI 4.15-300.06, P = 0.001) and 17.68 (95% CI 1.91-163.54, P = 0.011), respectively. Conclusions Histopathological classification does not permit an accurate evaluation of the risk of recurrence of colorectal lesions. Conversely, results from our methylation analysis suggest that a classification based on molecular parameters could help to define the mechanisms involved in carcinogenesis and prove an effective method for identifying patients at high risk of recurrence. PMID:25091577

  20. Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells

    PubMed Central

    Dingwall, Steve; Lee, Jung Bok; Guezguez, Borhane; Fiebig, Aline; McNicol, Jamie; Boreham, Douglas; Collins, Tony J.; Bhatia, Mick

    2015-01-01

    Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs. PMID:26082437

  1. Recovery of uncommon bacteria from blood: association with neoplastic disease.

    PubMed Central

    Beebe, J L; Koneman, E W

    1995-01-01

    bloodstream infections of Salmonella typhimurium and Capno-cytophaga canimorsus in Hodgkin's disease patients seems likely due to a particular mechanism which infection by these species is favored. The specific nature of these mechanisms remains to be determined. The recovery of any unusual bacterium from blood should warrant a careful consideration of the possibility of underlying disease, especially cancer. Microbiologists should advise clinicians of the unusual nature of the identified organism and provide the counsel that certain neoplastic processes, often accompanied by neutropenia, render the human host susceptible to invasion by almost any bacterium. The recovery of such organisms as C. septicum or S. bovis should prompt the clinician to aggressively seek to identify an occult neoplasm if one has not yet been diagnosed. PMID:7553569

  2. Cell surface oligosaccharide modulation during differentiation: VI. The effect of biomodulation on the senescent and neoplastic cell phenotype.

    PubMed

    Mann, P L; Busse, S C; Griffey, R H; Laubscher, K

    1992-01-01

    These investigations test the hypothesis developed previously, that there are biomolecules which control and integrate cellular differentiation. Our specific interest in cellular differentiation lies in the area of what we refer to as basal or primitive cellular differentiation mechanisms. These mechanisms are common to all cells, and are required for simple recognition and growth regulation. We have investigated two models, the IMR-90 human fetal lung fibroblast model as a representative of normal growth control, and the CG model, canine glioma cells, a transplantable growth transformed cell line. These two models represent normal, and aberrant cellular differentiation control. In previous studies we have shown that the arrangement of the cell surface oligosaccharide structure on these cell types are predictive of phenotypic transition. We have developed, and partially characterized a series of BIOMODULATORS (BM) which delay the onset of display of neoplastic cells. Three classes of BIOMODULATOR have been explored; (1) a large molecular weight natural product (25-35 kDa), PokeWeed Mitogen (PWM); (2) a small molecular weight natural product (500 Da) Cellular Activator and Differentiator (CAD) and a number of natural and synthetic analogs; and (3) an indolizidine alkaloid natural product, Swainsonine (Sw) which has a known cellular target (oligosaccharide biosynthesis). Preliminary data is presented which structurally links some of these BIOMODULATORS in terms of their effective stereochemistry. These BIOMODULATORS, when used before PDL 38, prevent the cell surface oligosaccharide display changes typical of morphological senescence and delay their onset to PDL 100 or more. These BIOMODULATORS also appear to have regulatory effects on the neoplastic cell models. This re-regulation results in increases in generation time and an increase in the ability of these cells to be recognized by cytotoxic lymphocytes. Proton NMR linewidth measurements of the fraction of 'bound

  3. Proliferating cell nuclear antigen (PCNA) activity in hepatocellular carcinoma, benign peri-neoplastic and normal liver.

    PubMed

    Mun, Kein-Seong; Cheah, Phaik-Leng; Baharudin, Nurul Bahiyah; Looi, Lai-Meng

    2006-12-01

    Hepatocellular carcinoma (HCC) is among the ten most common cancers in Malaysian males. As cellular proliferation is an important feature of malignant transformation, we studied the proliferation pattern of normal and benign perineoplastic liver versus hepatocellular carcinoma in an attempt to further understand the tumour transformation process. 39 HCC (21 with accompanying and 18 without cirrhosis) histologically diagnosed at the Department of Pathology, University of Malaya Medical Centre between January 1992 and December 2003 were immunohistochemically studied using a monoclonal antibody to PCNA (Clone PC10: Dako). 20 livers from cases who had succumbed to traumatic injuries served as normal liver controls (NL). PCNA labeling index (PCNA-LI) was determined by counting the number of immunopositive cells in 1000 contiguous HCC, benign cirrhotic perineoplastic liver (BLC), benign perineoplastic non-cirrhotic (BLNC) and NL cells and conversion to a percentage. The PCNA-LI was also expressed as Ojanguren et al's grades. PCNA was expressed in 10% NL, 38.9% BLNC, 76.2% BLC and 71.8% HCC with BLNC, BLC and HCC showing significantly increased (p < 0.05) number of cases which expressed PCNA compared with NL. The number of BLC which expressed PCNA was also significantly increased compared with BLNC. PCNA-LI ranged from 0-2.0% (mean = 0.2%) in NL, 0-2.0% (mean = 0.3%) in BLNC, 0-3.6% (mean = 0.7%) in BLC and 0-53.8% (mean = 7.6%) in HCC with PCNA-LI significantly increased (p < 0.05) only in HCC compared with BLC, BLNC and NL. Accordingly, all NL, BLC and BLNC showed minimal (<5% cells being immunopositive) immunoreactivity on Ojanguren et al's grading system and only HCC demonstrated immunoreactivity which ranged up to grade 3 (75% of cells). From this study, there appears to be a generally increasing trend of proliferative activity from NL to BLNC to BLC and HCC. Nonetheless, BLNC and BLC, like NL, retained low PCNA-LI and only HCC had a significantly increased PCNA

  4. The absorption of ultraviolet light by cell nuclei. A technique for identifying neoplastic change

    SciTech Connect

    Baisden, C.R.; Booker, D.; Wright, R.D. )

    1989-11-01

    A technique for measuring the absorption of 260-nm ultraviolet light by cell nuclei is described. The results of such measurements of normal thyroid epithelial cells and benign and malignant thyroid neoplastic cells demonstrate a progressive increase in absorbance that correlates with the histologic appearance of neoplasia. The possible theoretic basis for this phenomenon is explored. The increased nuclear absorbance observed in neoplastic cells is hypothesized to result from the disruption of hydrogen bonds between the DNA base pairs, which allows unwinding of the double helix and loss of the normal control of mitosis.

  5. Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis

    PubMed Central

    de Sá, V.K.; Rocha, T.P.; Moreira, AL.; Soares, F.A.; Takagaki, T.; Carvalho, L.; Nicholson, A.G.; Capelozzi, V.L.

    2015-01-01

    We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and −3, and hyaluronan synthases (HAS)-1, −2, and −3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and −3 and HAS-1, −2, and −3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic

  6. Hyaluronidases and hyaluronan synthases expression is inversely correlated with malignancy in lung/bronchial pre-neoplastic and neoplastic lesions, affecting prognosis.

    PubMed

    Sá, V K de; Rocha, T P; Moreira, Al; Soares, F A; Takagaki, T; Carvalho, L; Nicholson, A G; Capelozzi, V L

    2015-11-01

    We collected a series of 136 lung/bronchial and 56 matched lung parenchyma tissue samples from patients who underwent lung/bronchial biopsies and presented invasive carcinoma after lung surgery. The lung/bronchial samples included basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma. Matched lung parenchyma tissue samples included 25 squamous cell carcinomas and 31 adenocarcinomas. Immunohistochemistry was performed to analyze for the distribution of hyaluronidase (Hyal)-1 and -3, and hyaluronan synthases (HAS)-1, -2, and -3. Hyal-1 showed significantly higher expression in basal cell hyperplasia than in moderate dysplasia (P=0.01), atypical adenomatous hyperplasia (P=0.0001), or severe dysplasia (P=0.03). Lower expression of Hyal-3 was found in atypical adenomatous hyperplasia than in basal cell hyperplasia (P=0.01) or moderate dysplasia (P=0.02). HAS-2 was significantly higher in severe dysplasia (P=0.002) and in squamous metaplasia (P=0.04) compared with basal cell hyperplasia. HAS-3 was significantly expressed in basal cell hyperplasia compared with atypical adenomatous hyperplasia (P=0.05) and severe dysplasia (P=0.02). Lower expression of HAS-3 was found in severe dysplasia compared with squamous metaplasia (P=0.01) and moderate dysplasia (P=0.01). Epithelial Hyal-1 and -3 and HAS-1, -2, and -3 expressions were significantly higher in pre-neoplastic lesions than in neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04). We concluded that localization of Hyal and HAS in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, which implied that visualizing these factors could be a useful diagnostic procedure for

  7. Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine.

    PubMed

    Provinciali, M; Di Stefano, G; Raffaeli, W; Pari, G; Desiderio, F; Fabris, N

    1991-07-01

    The cytotoxic activity of Natural Killer (NK) and Lymphokine Activated Killer (LAK) cells in neoplastic patients with or without antalgic treatment was studied. NK cell activity was found reduced in untreated neoplastic patients when compared to healthy subjects. The atalgic treatment with morphine (orally or intrathecally administered) was able to significantly reduce the mean values of NK cell activity found in cancer patients. In three patients the cytotoxicity of NK cells significantly decreased during transfer from oral to intrathecal administration of morphine. In contrast to the NK cell function, the development of LAK cell activity significantly increased in neoplastic patients when compared to healthy controls. Further increments were obtained during treatment with morphine. The oral treatment with morphine was able to determine a higher induction of LAK cells than the intrathecal administration of the drug. Besides providing new knowledge on the effect of morphine on immune system our findings suggest that, in order to include neoplastic patients in clinical trials of adoptive immunotherapy with LAK cells and interleukin-2 (IL-2), the antalgic therapy with oral administration of morphine may represent a better solution than the intrathecal administration of the drug. PMID:1774133

  8. 78 FR 76507 - Revised Medical Criteria for Evaluating Cancer (Malignant Neoplastic Diseases)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-17

    ...We propose to revise the criteria in parts A and B of the Listing of Impairments (listings) that we use to evaluate cases involving cancer (malignant neoplastic diseases) in adults and children under titles II and XVI of the Social Security Act (Act). These proposed revisions reflect our adjudicative experience, advances in medical knowledge, and recommendations from medical experts we......

  9. Interferons as Therapy for Viral and Neoplastic Diseases: From Panacea to Pariah to Paragon

    PubMed Central

    Friedman, Robert M.; Contente, Sara

    2009-01-01

    For more than 20 years after the excitement engendered by their discovery in 1957 as antiviral agents, there were no significant clinical uses of interferons; however, following their cloning they have been employed as effective treatment for several viral, autoimmune, and neoplastic diseases.

  10. Vital-dye-enhanced multimodal imaging of neoplastic progression in a mouse model of oral carcinogenesis

    NASA Astrophysics Data System (ADS)

    Hellebust, Anne; Rosbach, Kelsey; Wu, Jessica Keren; Nguyen, Jennifer; Gillenwater, Ann; Vigneswaran, Nadarajah; Richards-Kortum, Rebecca

    2013-12-01

    In this longitudinal study, a mouse model of 4-nitroquinoline 1-oxide chemically induced tongue carcinogenesis was used to assess the ability of optical imaging with exogenous and endogenous contrast to detect neoplastic lesions in a heterogeneous mucosal surface. Widefield autofluorescence and fluorescence images of intact 2-NBDG-stained and proflavine-stained tissues were acquired at multiple time points in the carcinogenesis process. Confocal fluorescence images of transverse fresh tissue slices from the same specimens were acquired to investigate how changes in tissue microarchitecture affect widefield fluorescence images of intact tissue. Widefield images were analyzed to develop and evaluate an algorithm to delineate areas of dysplasia and cancer. A classification algorithm for the presence of neoplasia based on the mean fluorescence intensity of 2-NBDG staining and the standard deviation of the fluorescence intensity of proflavine staining was found to separate moderate dysplasia, severe dysplasia, and cancer from non-neoplastic regions of interest with 91% sensitivity and specificity. Results suggest this combination of noninvasive optical imaging modalities can be used in vivo to discriminate non-neoplastic from neoplastic tissue in this model with the potential to translate this technology to the clinic.

  11. EFFECTS OF PHOSGENE EXPOSURE ON BACTERIAL VIRAL AND NEOPLASTIC LUNG DISEASE SUSCEPTIBILITY IN MICE

    EPA Science Inventory

    The effects of phosgene inhalation exposure on host resistance models representative of bacterial, viral, and neoplastic lung diseases were assessed. ingle 4 h exposure to concentrations of phosgene of 0.025 ppm and above significantly enhanced mortality due to aerosol infection ...

  12. Liposomal cytarabine (DepoCyte) for the treatment of neoplastic meningitis.

    PubMed

    Rueda Domínguez, Antonio; Olmos Hidalgo, David; Viciana Garrido, Ruth; Torres Sánchez, Esperanza

    2005-07-01

    Neoplastic meningitis is a feared complication in cancer patients, the median survival ranging from some weeks to a few months. Management is palliative and aims to provide symptoms relief while delaying neurological deterioration. Intrathecal methotrexate and/or cytarabine is the most widely used treatment in such clinical situations. These drugs are administered 2 or 3 times a week--a circumstance that is both bothersome for the patient and time-costly for the medical personnel. Liposomal cytarabine is a sustained-release cytarabine formulation specifically developed for the treatment of neoplastic meningitis. Its administration on a twice-weekly basis ensures sustained cytotoxic drug concentrations in cerebrospinal fluid. Controlled clinical trials have shown liposomal cytarabine to be equally or more effective than the classical treatment for neoplastic meningitis. In lymphomatous meningitis, liposomal cytarabine offers superior response rates, improved patient quality of life, and a prolongation of the time to neurological progression. When the cause of meningitis is a solid tumor, liposomal cytarabine prolongs the time to neurological progression and improves quality of life. These observations indicate that DepoCyte is a convenient treatment for patients with neoplastic meningitis, due to its efficacy and easy of administration characteristics. PMID:16131445

  13. Cell cannibalism by malignant neoplastic cells: three cases in dogs and a literature review.

    PubMed

    Meléndez-Lazo, Antonio; Cazzini, Paola; Camus, Melinda; Doria-Torra, Georgina; Marco Valle, Alberto Jesús; Solano-Gallego, Laia; Pastor, Josep

    2015-06-01

    Cell cannibalism refers to the engulfment of cells by nonprofessional phagocytic cells. Studies in human medicine have demonstrated a relationship between the presence of cell cannibalism by neoplastic cells and a poor outcome, and have shown a positive correlation with the presence of metastasis at the time of diagnosis. The biologic significance of cell cannibalism is unknown, but it is proposed that it may represent a novel mechanism of tumor immune evasion as a survival strategy in cases of unfavorable microenvironmental conditions. This report describes clinical and morphologic features of 3 cases of dogs with malignant neoplasia in which the presence of cellular cannibalism was observed in cytologic and histologic specimens. In the 1(st) case, a dog with a primary tonsillar squamous cell carcinoma with metastasis to retropharyngeal lymph nodes had neoplastic epithelial cells engulfing neutrophils noted in cytologic examination of the lymph nodes. In the 2(nd) case, neoplastic epithelial cells were seen engulfing each other in fine-needle aspirates from a primary mammary carcinoma with lung metastasis. In the 3(rd) case, poorly differentiated neoplastic mast cells from a recurrent, metastatic grade III mast cell tumor were observed cannibalizing eosinophils. A brief review of the literature describing known cell-into-cell relationships and the possible biologic significance and mechanisms involved in this phenomenon is provided. The relationship between cell cannibalism and distant metastasis should be explored in further studies, as it may prove to be a criterion of malignancy, as it is proposed in human medicine. PMID:25688652

  14. CONCURRENT NEOPLASTIC AND PROTISTAN DISORDERS IN THE AMERICAN OYSTER (CRASSOSTREA VIRGINICA)

    EPA Science Inventory

    One of 373 oysters examined as part of a histological survey of oysters from Apalachicola Bay, Florida, USA, had a concurrent blood cell proliferative disorder and a protistan infection. The neoplastic blood cells (leukocytes) were found throughout the vesicular connective tissue...

  15. Generation and Quantitative Analysis of Pulsed Low Frequency Ultrasound to Determine the Sonic Sensitivity of Untreated and Treated Neoplastic Cells

    PubMed Central

    Trendowski, Matthew; Christen, Timothy D.; Zoino, Joseph N.; Acquafondata, Christopher; Fondy, Thomas P.

    2015-01-01

    Low frequency ultrasound in the 20 to 60 kHz range is a novel physical modality by which to induce selective cell lysis and death in neoplastic cells. In addition, this method can be used in combination with specialized agents known as sonosensitizers to increase the extent of preferential damage exerted by ultrasound against neoplastic cells, an approach referred to as sonodynamic therapy (SDT). The methodology for generating and applying low frequency ultrasound in a preclinical in vitro setting is presented to demonstrate that reproducible cell destruction can be attained in order to examine and compare the effects of sonication on neoplastic and normal cells. This offers a means by which to reliably sonicate neoplastic cells at a level of consistency required for preclinical therapeutic assessment. In addition, the effects of cholesterol-depleting and cytoskeletal-directed agents on potentiating ultrasonic sensitivity in neoplastic cells are discussed in order to elaborate on mechanisms of action conducive to sonochemotherapeutic approaches. PMID:26274053

  16. Galectin-1 is a useful marker for detecting neoplastic squamous cells in oral cytology smears.

    PubMed

    Noda, Yuri; Kondo, Yuko; Sakai, Manabu; Sato, Sunao; Kishino, Mitsunobu

    2016-06-01

    Cytologic diagnoses in the oral region are very difficult due to the small amount of cells in smears, which are also exposed to many stimulating factors and often show atypical changes. Galectin-1 (Gal1) is a β-galactoside binding protein that modulates tumor progression. Gal1 is very weakly expressed in normal cells, but is often overexpressed in neoplastic lesions. The aim of the present study was to determine whether it is possible to differentiate reactive changes from neoplastic changes in oral cytology smears based on the expression of Gal1. A total of 155 tissue biopsy specimens and 61 liquid-based cytology specimens were immunostained by an anti-Gal1 antibody, and Gal1 expression levels were subsequently evaluated. These samples consisted of oral squamous cell carcinomas, epithelial dysplasia, and oral mucosal diseases. The positive and negative expressions of Gal1 were examined in 37 specimens collected by scalpel and cytobrush biopsy. The sensitivity, specificity, and positive predictive value of Gal1 were also evaluated in smears. In tissue sections, the positive ratio of Gal1 in neoplastic lesions was high (72.3%). In cytology specimens, the positive ratio of Gal1 was higher in neoplastic lesions (79.0%) than in those negative for intraepithelial lesion or malignancy (22.2%). A correlation was found between immunocytochemical Gal1 expression and immunohistochemical Gal1 expression (P < .001). The sensitivity (75.0%), specificity (75.0%), and positive predictive value (91.3%) of Gal1 were also high in smears. In conclusion, Gal1 may be a useful marker for determining whether morphologic changes in cells are reactive or neoplastic. PMID:26980012

  17. Identifying Baseline Covariates for Use in Propensity Scores: A Novel Approach Illustrated for a Non-randomized Study of Recovery High Schools

    PubMed Central

    Tanner-Smith, Emily E.; Lipsey, Mark W.

    2014-01-01

    There are many situations where random assignment of participants to treatment and comparison conditions may be unethical or impractical. This article provides an overview of propensity score techniques that can be used for estimating treatment effects in non-randomized quasi-experimental studies. After reviewing the logic of propensity score methods, we call attention to the importance of the strong ignorability assumption and its implications. We then discuss the importance of identifying and measuring a sufficient set of baseline covariates upon which to base the propensity scores and illustrate approaches to that task in the design of a study of recovery high schools for adolescents treated for substance abuse. One novel approach for identifying important covariates that we suggest and demonstrate is to draw on the predictor-outcome correlations compiled in meta-analyses of prospective longitudinal correlations. PMID:25071297

  18. Expression of keratin and vimentin intermediate filaments in rabbit bladder epithelial cells at different stages of benzo(a)pyrene-induced neoplastic progression

    SciTech Connect

    Summerhayes, I.C.; Cheng, Y.S.E.; Sun, T.T.; Chen, L.B.

    1981-07-01

    Rabbit bladder epithelium, grown on collagen gels and exposed to the chemical carcinogen benzo(a)pyrene, produced nontumorigenic altered foci as well as tumorigenic epithelial cell lines during 120 to 180 d in culture. Immunofluorescence studies revealed extensive keratin filaments in both primary epithelial cells and benzo(a)pyrene-induced altered epithelial foci but showed no detectable vimentin filaments. The absence of vimentin expression in these cells was confirmed by two-dimensional gel electrophoresis. In contrast, immunofluorescence staining of the cloned benzo(a)pyrene-transformed rabbit bladder epithelial cell line, RBC-1, revealed a reduction in filamentous keratin concomitant with the expression of vimentin filaments. The epithelial nature of this cell line was established by the observation that cells injected into nude mice formed well-differentiated adenocarcinomas. Frozen sections of such tumors showed strong staining with antikeratins antibodies, but no detectable staining with antivimentin antibodies. These results demonstrated a differential expression of intermediate filament type in cells at different stages of neoplastic progression and in cells maintained in different growth environments. It is apparent that the expression of intermediate filaments throughout neoplastic progression is best studied by use of an in vivo model system in parallel with culture studies.

  19. In vitro and in vivo studies on potentiation of cytotoxic effects of anticancer drugs or cobalt 60 gamma ray by interferon on human neoplastic cells

    SciTech Connect

    Namba, M.; Yamamoto, S.; Tanaka, H.; Kanamori, T.; Nobuhara, M.; Kimoto, T.

    1984-11-15

    A possibility that interferon may potentiate the cytotoxic effects of anticancer drugs or /sup 60/Co gamma ray on human neoplastic cells was studied by in vitro and in vivo experimental procedures. The human neoplastic cells used were HeLa (uterine cervical cancer) and WI-38 CT-1 (embryonic lung fibroblasts transformed in culture by /sup 60/Co gamma ray) cells. As normal human cells, WI-38 cells were used. Interferon was a preparation of beta-type produced by human fibroblasts. The cytotoxicity was determined by colony formation for in vitro experiments and by tumor growth for animal experiments. Of 17 anticancer drugs, the cytotoxic effects of six drugs, namely, peplomycin, bleomycin, aclacinomycin, cisplatin, 5-fluorouracil (5-FU), and Adriamycin (doxorubicin) were potentiated by concomitant application of interferon. The cytolethal effects of /sup 60/Co gamma ray were also enhanced by interferon. The growth of tumor induced by transplantation of HeLa cells into a nude mouse was remarkably reduced by combination therapy of interferon and 5-FU. The current results indicate a possibility that combined therapy of certain types of anticancer drugs or /sup 60/Co gamma ray with interferon may be effective in treatment of cancer patients.

  20. A 4-Mb deletion in the region Xq27.3-q28 is associated with non-random inactivation of the non-mutant X chromosome

    SciTech Connect

    Clarke, J.T.R.; Han, L.P.; Michalickova, K.

    1994-09-01

    A girl with severe Hunter disease was found to have a submicroscopic deletion distrupting the IDS locus in the region Xq27.3-q28 together with non-random inactivation of the non-mutant X chromosome. Southern analysis of DNA from the parents and from hamster-patient somatic cell hybrids containing only the mutant X chromosome revealed that the deletion represented a de novo mutation involving the paternal X chromosome. Methylation-sensitive RFLP analysis of DNA from maternal fibroblasts and lymphocytes showed methylation patterns consistent with random X-inactivation, indicating that the non-random X-inactivation in the patient was not inherited and was likely a direct result of the Xq27.3-q28 deletion. A 15 kb EcoRI junction fragment, identified in patient DNA using IDS cDNA probes, was cloned from a size-selected patient DNA library. Clones containing the deletion junction were restriction mapped and fragments were subcloned and used to isolate normal sequence on either side of the deletion from normal X chromosome libraries. Comparison of the sequences from normal and mutant X chromosome clones straddling the deletion breakpoint showed that the mutation had occurred by recombination between Alu repeats. Screening of YAC contigs containing normal X chromosome sequence from the region of the mutation, using probes from either side of the deletion breakpoint, showed that the deletion was approximately 4 Mb in size. Probing of mutant DNA with 16 STSs distributed throughout the region of the deletion confirmed that the mutation is a simple deletion with no complex rearrangements of islands of retained DNA. A search for sequences at Xq27.3-q28 involved in X chromosome inactivation is in progress.

  1. Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization.

    PubMed

    Meseure, Didier; Drak Alsibai, Kinan; Nicolas, Andre

    2014-12-01

    Reciprocal interactions between neoplastic cells and their microenvironment are crucial events in carcinogenesis and tumor progression. Pervasive stromal reprogramming and remodeling that transform a normal to a tumorigenic microenvironment modify numerous stromal cells functions, status redox, oxidative stress, pH, ECM stiffness and energy metabolism. These environmental factors allow selection of more aggressive cancer cells that develop important adaptive strategies. Subpopulations of cancer cells acquire new properties associating plasticity, stem-like phenotype, unfolded protein response, metabolic reprogramming and autophagy, production of exosomes, survival to anoikis, invasion, immunosuppression and therapeutic resistance. Moreover, by inducing vascular transdifferentiation of cancer cells and recruiting endothelial cells and pericytes, the tumorigenic microenvironment induces development of tumor-associated vessels that allow invasive cells to gain access to the tumor vessels and to intravasate. Circulating cancer cells can survive in the blood stream by interacting with the intravascular microenvironment, extravasate through the microvasculature and interact with the metastatic microenvironment of target organs. In this review, we will focus on many recent paradigms involved in the field of tumor progression. PMID:25523234

  2. P16(INK4a) expression as a potential prognostic marker in cervical pre-neoplastic and neoplastic lesions.

    PubMed

    Queiroz, Conceição; Silva, Tânia Correia; Alves, Venâncio A F; Villa, Luisa L; Costa, Maria Cecília; Travassos, Ana Gabriela; Filho, José Bouzas Araújo; Studart, Eduardo; Cheto, Tatiana; de Freitas, Luiz Antonio R

    2006-01-01

    An immunohistochemical analysis with monoclonal antibody p16(INK4a) was performed in formalin-fixed, paraffin-embedded samples of 60 cases. The aim was to investigate in biopsies the expression of p16(INK4a) of normal uterine cervical tissue, pre-cancerous and cancerous lesions, and their relation with human papilloma virus (HPV) and HIV status. Three parameters were evaluated: percentage of p16(INK4a) positive cells, reaction intensity, and cell staining pattern. All of these parameters were statistically different when compared among different histological groups. However, logistic regression model showed that the reaction intensity was the best indicator of the expression of p16(INK4a). This expression increases from normal to invasive squamous carcinoma. Sixty-six percent of the patients with CIN grade 1 (CIN1) expressed p16(INK4a) (all these cases were infected with high risk HPV). Our study supports the hypothesis that p16(INK4a) expression in pre-cancerous lesions and cancers can be used to identify HPV-transformed cells. Of great interest for routine diagnostic use is the fact that immunohistochemical testing for p16(INK4a) seems to be capable of identifying HPV-positive cells and potentially recognizing those lesions with an increased risk of progression to high-grade lesions. PMID:16376485

  3. Prognostic significance of neoplastic cell proliferation parameters in human haematological malignancies.

    PubMed

    Kotelnikov, V M

    1990-01-01

    High percentage of neoplastic cells in S, G2 and M phases of cell cycle is unfavourable prognostic sign in human haematological malignancies. In chronic leukaemias (CML and CLL) it is true for peripheral blood leukaemic cells, in non-Hodgkin lymphomas--for lymph node cells, in multiple myeloma--for bone marrow plasma cells. In acute leukaemia results are controversial: some authors found a correlation between proliferation parameters of bone marrow blast cells while others did not. These parameters correlate positively with the rate of complete remission and negatively with its duration. It is concluded that proliferation parameters of neoplastic cells may be used for individual prognosis in patients with haematological tumours especially in combination with other biological and clinical prognostic markers. PMID:1703108

  4. Immunohistological recognition of cyclin D1 expression by non-lymphoid cells among lymphoid neoplastic cells.

    PubMed

    Abdulla, Zainalabideen; Turley, Helen; Gatter, Kevin; Pezzella, Francesco

    2014-03-01

    Cyclin D1 immunostaining of non-neoplastic cells has been a source of diagnostic confusion especially in lymphoproliferative lesions. This study has reviewed these in two hundred and thirty-one haematopathological samples stained for cyclin D1. Most cases were formalin-fixed except for a few bone marrow trephines, which were B-5 fixed, and EDTA decalcified. Overall, 94% (216/231) of cases showed one or more types of non-neoplastic cells expressing Cyclin D1 of variable intensity. Endothelial cells and histiocytes were the most commonly identified Cyclin D1 positive cells being positive in 92% (214/231) of cases. Other normal cell types identified included fat cells, stromal fibroblasts, glial cells, spermatocytes, smooth muscle cells, osteoblasts and where present epithelial cells. Many normal cell types can express cyclinD1. Knowledge of these is useful to prevent misinterpretation of cyclin D1 positive tumours. PMID:23758159

  5. Prevalence of Neoplastic Diseases in Pet Birds Referred for Surgical Procedures.

    PubMed

    Castro, Patrícia F; Fantoni, Denise T; Miranda, Bruna C; Matera, Julia M

    2016-01-01

    Neoplastic disease is common in pet birds, particularly in psittacines, and treatment should be primarily aimed at tumor eradication. Nineteen cases of pet birds submitted to diagnostic and/or therapeutic surgical procedures due to neoplastic disease characterized by the presence of visible masses were retrospectively analyzed; affected species, types of neoplasms and respective locations, and outcomes of surgical procedures were determined. All birds undergoing surgery belonged to the order Psittaciformes; the Blue-fronted parrot (Amazona aestiva) was the prevalent species. Lipoma was the most frequent neoplasm in the sample studied. Most neoplasms affected the integumentary system, particularly the pericloacal area. Tumor resection was the most common surgical procedure performed, with high resolution and low recurrence rates. PMID:26981315

  6. Prevalence of Neoplastic Diseases in Pet Birds Referred for Surgical Procedures

    PubMed Central

    Castro, Patrícia F.; Fantoni, Denise T.; Miranda, Bruna C.; Matera, Julia M.

    2016-01-01

    Neoplastic disease is common in pet birds, particularly in psittacines, and treatment should be primarily aimed at tumor eradication. Nineteen cases of pet birds submitted to diagnostic and/or therapeutic surgical procedures due to neoplastic disease characterized by the presence of visible masses were retrospectively analyzed; affected species, types of neoplasms and respective locations, and outcomes of surgical procedures were determined. All birds undergoing surgery belonged to the order Psittaciformes; the Blue-fronted parrot (Amazona aestiva) was the prevalent species. Lipoma was the most frequent neoplasm in the sample studied. Most neoplasms affected the integumentary system, particularly the pericloacal area. Tumor resection was the most common surgical procedure performed, with high resolution and low recurrence rates. PMID:26981315

  7. Neoplastic pericardial disease: Old and current strategies for diagnosis and management

    PubMed Central

    Lestuzzi, Chiara

    2010-01-01

    The prevalence of neoplastic pericardial diseases has changed over time and varies according to diagnostic methods. The diagnostic factor is usually the detection of neoplastic cells within the pericardial fluid or in specimens of pericardium, but the diagnosis may be difficult. Accurate sampling and cytopreparatory techniques, together with ancillary studies, including immunohistochemical tests and neoplastic marker dosage, are essential to obtain a reliable diagnosis. The goals of treatment may be simply to relieve symptoms (cardiac tamponade or dyspnea), to prevent recurrent effusion for a long-term symptomatic benefit, or to treat the local neoplastic disease with the aim of prolonging survival. Immediate relief of symptoms may be obtained with percutaneous drainage or with a surgical approach. For long term prevention of recurrences, various approaches have been proposed: extended drainage, pericardial window (surgical or percutaneous balloon pericardiostomy), sclerosing local therapy, local and/or systemic chemotherapy or radiation therapy (RT) (external or with intrapericardial radionuclides). The outcomes of various therapeutic approaches vary for different tumor types. Lymphoma and leukemias can be successfully treated with systemic chemotherapy; for solid tumors, percutaneous drainage and the use of systemic and/or local sclerosing and antineoplastic therapy seems to offer the best chance of success. The use of “pure” sclerosing agents has been replaced by agents with both sclerosing and antineoplastic activity (bleomycin or thiotepa), which seems to be quite effective in breast cancer, at least when associated with systemic chemotherapy. Local chemotherapy with platinum, mitoxantrone and other agents may lead to good local control of the disease, but the addition of systemic chemotherapy is probably relevant in order to prolong survival. The surgical approach (creation of a pericardial window, even with the mini-invasive method of balloon

  8. Selective binding of lectins to normal and neoplastic urothelium in rat and mouse bladder carcinogenesis models.

    PubMed

    Zupančič, Daša; Kreft, Mateja Erdani; Romih, Rok

    2014-01-01

    Bladder cancer adjuvant intravesical therapy could be optimized by more selective targeting of neoplastic tissue via specific binding of lectins to plasma membrane carbohydrates. Our aim was to establish rat and mouse models of bladder carcinogenesis to investigate in vivo and ex vivo binding of selected lectins to the luminal surface of normal and neoplastic urothelium. Male rats and mice were treated with 0.05 % N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water and used for ex vivo and in vivo lectin binding experiments. Urinary bladder samples were also used for paraffin embedding, scanning electron microscopy and immunofluorescence labelling of uroplakins. During carcinogenesis, the structure of the urinary bladder luminal surface changed from microridges to microvilli and ropy ridges and the expression of urothelial-specific glycoproteins uroplakins was decreased. Ex vivo and in vivo lectin binding experiments gave comparable results. Jacalin (lectin from Artocarpus integrifolia) exhibited the highest selectivity for neoplastic compared to normal urothelium of rats and mice. The binding of lectin from Amaranthus caudatus decreased in rat model and increased in mouse carcinogenesis model, indicating interspecies variations of plasma membrane glycosylation. Lectin from Datura stramonium showed higher affinity for neoplastic urothelium compared to the normal in rat and mouse model. The BBN-induced animal models of bladder carcinogenesis offer a promising approach for lectin binding experiments and further lectin-mediated targeted drug delivery research. Moreover, in vivo lectin binding experiments are comparable to ex vivo experiments, which should be considered when planning and optimizing future research. PMID:23828036

  9. Temperature dependence of 1H NMR relaxation time, T2, for intact and neoplastic plant tissues

    NASA Astrophysics Data System (ADS)

    Lewa, Czesław J.; Lewa, Maria

    Temperature dependences of the spin-spin proton relaxation time, T2, have been shown for normal and tumorous tissues collected from kalus culture Nicotiana tabacum and from the plant Kalanchoe daigremontiana. For neoplastic plant tissues, time T2 was increased compared to that for intact plants, a finding similar to that for animal and human tissues. The temperature dependences obtained were compared to analogous relations observed with animal tissues.

  10. Human colon tissue in organ culture: preservation of normal and neoplastic characteristics

    PubMed Central

    Bhagavathula, Narasimharao; Mankey, Cohra; DaSilva, Marissa; Paruchuri, Tejaswi; Aslam, Muhammad Nadeem; Varani, James

    2009-01-01

    Normal and neoplastic human colon tissue obtained at surgery was used to establish conditions for organ culture. Optimal conditions included an atmosphere of 5% CO2 and 95% O2; tissue partially submerged with mucosa at the gas interface; and serum-free medium with 1.5 mM Ca2+ and a number of growth supplements. Histological, histochemical, and immunohistochemical features that distinguish normal and neoplastic tissue were preserved over a 2-d period. With normal tissue, this included the presence of elongated crypts with small, densely packed cells at the crypt base and mucin-containing goblet cells in the upper portion. Ki67 staining, for proliferating cells, was confined to the lower third of the crypt, while expression of extracellular calcium-sensing receptor was seen in the upper third and surface epithelium. E-cadherin and β-catenin were expressed throughout the epithelium and confined to the cell surface. In tumor tissue, the same disorganized, abnormal glandular structures seen at time zero were present after 2 d. The majority of cells in these structures were mucin-poor, but occasional goblet cells were seen and mucin staining was present. Ki67 staining was seen throughout the abnormal epithelium and calcium-sensing receptor expression was weak and variable. E-cadherin was seen at the cell surface (similar to normal tissue), but in some places, there was diffuse cytoplasmic staining. Finally, intense cytoplasmic and nuclear β-catenin staining was observed in cultured neoplastic tissue. PMID:19915935

  11. [Use of BICAP by endoscopic route in the palliative treatment of neoplastic stenosis of the esophagus].

    PubMed

    Pantuso, G; Bottino, A; Cipolla, C; Gitto, C; Farro, G; Talarico, F; Latteri, M; Florena, M

    1990-12-01

    Over the years the palliative treatment of neoplastic stenosis of the esophagus in patients who cannot be operated has seen a variation of endoscopic methods which aimed to reopen the alimentary canal either using simple dilatation, or the insertion of endoprostheses, or sclerosing injection or antiblastic therapy, or lastly using disobstructive laser therapy. In particular, the use of Neodymium YAG laser in endoscopic therapy for the deobstruction of neoplastic esophageal stenosis is currently widely used. More recently deobstruction of the stenosis may also be achieved using bipolar diathermocoagulation with BICAP following esophageal dilatation. Recent comparative studies of the use of BICAP and laser therapy in the treatment of neoplastic esophageal stenosis have tended to reveal the complementary characteristics of the two techniques. The present paper reports the Authors' experience in this respect which has been satisfactory with regard to both methods, in line with the findings of other studies. In the study of two groups of 8 patients treated with BICAP and laser therapy respectively, recanalisation was obtained in 100% of cases with good functional results in 75% of patients treated with BICAP and 87.5% of those receiving laser therapy. The time interval between one treatment session and the next in relation to the efficacy of the therapy was similar in both methods and ranged from a minimum of 4 weeks to a maximum of 12 weeks. Complications were scarce in both groups. PMID:1708116

  12. Dialysis disequilibrium syndrome induced by neoplastic meningitis in a patient receiving maintenance hemodialysis

    PubMed Central

    2013-01-01

    Background Dialysis disequilibrium syndrome is characterized by neurological symptoms resulting from cerebral edema, which occurs as a consequence of hemodialysis. Dialysis disequilibrium syndrome most often occurs in patients who have just started hemodialysis, during hemodialysis, or soon after hemodialysis; although it may also occur in patients who are under maintenance hemodialysis with pre-existing neurological disease. Case presentation A 70-year-old woman, who had been receiving maintenance hemodialysis for one year, was diagnosed with ovarian cancer by ascites cytological examination. Two years later, she reported severe headache and nausea during hemodialysis and was diagnosed with dialysis disequilibrium syndrome. Although brain images revealed mild hydrocephalus without any mass lesions, poorly differentiated adenocarcinoma cells were detected in her cerebrospinal fluid. These findings indicated that DDS was induced by neoplastic meningitis due to ovarian cancer metastasis. Conclusion Neoplastic meningitis should be considered and excluded in hemodialysis patients with dialysis disequilibrium syndrome and malignancy by cytological examination of the cerebrospinal fluid even if cerebral imaging shows no obvious lesions. This is the first reported case of dialysis disequilibrium syndrome induced by neoplastic meningitis in a patient receiving maintenance hemodialysis. PMID:24238645

  13. Selected aspects of palliative care and quality of life at the terminal stage of neoplastic disease.

    PubMed

    Farbicka, Paulina; Nowicki, Andrzej

    2012-01-01

    Neoplastic diseases are among the most common causes of death. The quality of life in neoplastic disease depends on the type of neoplasm, level of progression, location, treatment possibilities and prognosis. Cancer reduces the quality of life at the advanced stage of disease. At this time patients feel pain and suffering. Palliative care is used in the terminal phase of neoplastic disease. It includes overall care of an incurable patient and her/his family. The main objective of palliative care is meeting somatic and psycho-social requirements. Recently, more and more physicians dealing with oncological patients are moving away from treatment of the patient like an object. They pay attention to a subjective approach to treatment outcomes that are felt by the patient. The model of medicine is becoming a holistic one and during examination physicians pay attention to the patient's physical and mental state, economic condition, social situation, feelings or lack of complaints more often. Research on quality of life is becoming a vital part of medical examination. PMID:23788936

  14. A comparative study of the major glycoprotein isolated from normal and neoplastic gastric mucosa.

    PubMed

    Schrager, J; Oates, M D

    1973-04-01

    The isolation and composition of glycoproteins from mucosae of normal stomachs, of stomachs with gastric ulcer, and of stomachs with carcinoma is described. The glycoproteins from the mucosae of normal stomachs and with gastric ulcer showed virtually the same carbohydrate and amino acid content as the principal gastric glycoprotein isolated from gastric aspirates. They all revealed a common basic carbohydrate composition: galactose, fucose, glucosamine, and galactosamine were present in approximate molar ratios of 4:3:3:1. THE RESULTS SUGGEST THAT THE GLYCOPROTEINS ISOLATED FROM GASTRIC ASPIRATES FROM NORMAL AND NEOPLASTIC GASTRIC MUCOSAE SHARE A NUMBER OF STRUCTURAL FEATURES: (1) a protein core with a characteristic amino acid composition; (2) the range of sugars forming the carbohydrate side chains; (3) galactosamine approximately equimolar with the sum of threonine and serine; (4) galactose approximately equimolar with the sum of glucosamine and galactosamine; (5) absence of mannose; (6) a high carbohydrate content (80-85%); and (7) blood group activity. The neoplastic glycoproteins differed from the normal glycoproteins in that the quantitative relationships of the carbohydrate components of the neoplastic glycoproteins showed variations dividing the extracts investigated into groups, each group with a distinctive and constant carbohydrate composition. The blood group specificity of 15 out of 24 cases investigated differed from that of the hosts' red cells. PMID:4706916

  15. Neoplastic lesions in CADASIL syndrome: report of an autopsied Japanese case

    PubMed Central

    Hassan, Wael Abdo; Udaka, Naoka; Ueda, Akihiko; Ando, Yukio; Ito, Takaaki

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common heritable causes of stroke and dementia in adults. The gene involved in the pathogenesis of CADASIL is Notch3; in which mutations affect the number of cysteine residues in its extracellular domain, causing its accumulation in small arteries and arterioles of the affected individuals. Besides the usual neurological and vascular findings that have been well-documented in CADASIL patients, this paper additionally reports multiple neoplastic lesions that were observed in an autopsy case of CADASIL patient; that could be related to Notch3 mutation. The patient was a 62 years old male, presented with a past history of neurological manifestations, including gait disturbance and frequent convulsive attacks. He was diagnosed as CADASIL syndrome with Notch3 Arg133Cys mutation. He eventually developed hemiplegia and died of systemic convulsions. Autopsy examination revealed-besides the vascular and neurological lesions characteristic of CADASIL- multiple neoplastic lesions in the body; carcinoid tumorlet and diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia (DIPNECH) in the lungs, renal cell carcinoma (RCC), prostatic adenocarcinoma (ADC) and adenomatoid tumor of the epididymis. This report describes a spectrum of neoplastic lesions that were found in a case of CADASIL patient that could be related to Notch3 gene mutations. PMID:26261665

  16. Targeting neoplastic B cells and harnessing microenvironment: the "double face" of ibrutinib and idelalisib.

    PubMed

    Maffei, Rossana; Fiorcari, Stefania; Martinelli, Silvia; Potenza, Leonardo; Luppi, Mario; Marasca, Roberto

    2015-01-01

    Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements. PMID:26022368

  17. Selected aspects of palliative care and quality of life at the terminal stage of neoplastic disease

    PubMed Central

    Farbicka, Paulina

    2013-01-01

    Neoplastic diseases are among the most common causes of death. The quality of life in neoplastic disease depends on the type of neoplasm, level of progression, location, treatment possibilities and prognosis. Cancer reduces the quality of life at the advanced stage of disease. At this time patients feel pain and suffering. Palliative care is used in the terminal phase of neoplastic disease. It includes overall care of an incurable patient and her/his family. The main objective of palliative care is meeting somatic and psycho-social requirements. Recently, more and more physicians dealing with oncological patients are moving away from treatment of the patient like an object. They pay attention to a subjective approach to treatment outcomes that are felt by the patient. The model of medicine is becoming a holistic one and during examination physicians pay attention to the patient's physical and mental state, economic condition, social situation, feelings or lack of complaints more often. Research on quality of life is becoming a vital part of medical examination. PMID:23788936

  18. Multiphoton microscopy and microspectroscopy for diagnostics of inflammatory and neoplastic lung

    NASA Astrophysics Data System (ADS)

    Pavlova, Ina; Hume, Kelly R.; Yazinski, Stephanie A.; Flanders, James; Southard, Teresa L.; Weiss, Robert S.; Webb, Watt W.

    2012-03-01

    Limitations of current medical procedures for detecting early lung cancers inspire the need for new diagnostic imaging modalities for the direct microscopic visualization of lung nodules. Multiphoton microscopy (MPM) provides for subcellular resolution imaging of intrinsic fluorescence from unprocessed tissue with minimal optical attenuation and photodamage. We demonstrate that MPM detects morphological and spectral features of lung tissue and differentiates between normal, inflammatory and neoplastic lung. Ex vivo MPM imaging of intrinsic two-photon excited fluorescence was performed on mouse and canine neoplastic, inflammatory and tumor-free lung sites. Results showed that MPM detected microanatomical differences between tumor-free and neoplastic lung tissue similar to standard histopathology but without the need for tissue processing. Furthermore, inflammatory sites displayed a distinct red-shifted fluorescence compared to neoplasms in both mouse and canine lung, and adenocarcinomas displayed a less pronounced fluorescence emission in the 500 to 550 nm region compared to adenomas in mouse models of lung cancer. These spectral distinctions were also confirmed by two-photon excited fluorescence microspectroscopy. We demonstrate the feasibility of applying MPM imaging of intrinsic fluorescence for the differentiation of lung neoplasms, inflammatory and tumor-free lung, which motivates the application of multiphoton endoscopy for the in situ imaging of lung nodules.

  19. Estimating fitness consequences of dispersal: a road to 'know-where'? Non-random dispersal and the underestimation of dispersers' fitness.

    PubMed

    Doligez, Blandine; Pärt, Tomas

    2008-11-01

    philopatric and dispersing individuals, others, based on adult and juvenile survival, are open to the alternative explanation of biased fitness estimates. 6. We list three potential ways of reducing the risk of making wrong inferences on biased fitness estimates due to such non-random dispersal behaviour between dispersing and philopatric individuals: (a) diagnosing effects of non-random dispersal, (b) reducing the effects of spatially limited study area and (c) performing controlled experiments. PMID:18808435

  20. Immunohistochemical detection of Ca antigen in normal, dysplastic and neoplastic squamous epithelia of the human uterine cervix.

    PubMed Central

    Lloyd, J M; O'Dowd, T; Driver, M; Tee, D E

    1984-01-01

    Immunohistochemical staining was performed on biopsies and cytological samples from normal, dysplastic and neoplastic squamous epithelia using the monoclonal Ca 1 antibody. The results of staining 92 biopsies and 20 cytological samples are described and it is reported that positive staining with Ca 1 antibody was detected in normal, dysplastic and neoplastic epithelia. The role of the Ca 1 antibody in the study of cervical cancer is discussed. Images PMID:6368596

  1. Feasibility and effectiveness of a combined individual and psychoeducational group intervention in psychiatric residential facilities: A controlled, non-randomized study.

    PubMed

    Magliano, Lorenza; Puviani, Marta; Rega, Sonia; Marchesini, Nadia; Rossetti, Marisa; Starace, Fabrizio

    2016-01-30

    This controlled, non-randomized study explored the feasibility of introducing a Combined Individual and Group Intervention (CIGI) for users with mental disorders in residential facilities, and tested whether users who received the CIGI had better functioning than users who received the Treatment-As-Usual (TAU), at two-year follow up. In the CIGI, a structured cognitivebehavioral approach called VADO (in English, Skills Assessment and Definition of Goals) was used to set specific goals with each user, while Falloon's psychoeducational treatment was applied with the users as a group. Thirty-one professionals attended a training course in CIGI, open to users' voluntary participation, and applied it for two years with all users living in 8 residential facilities of the Mental Health Department of Modena, Italy. In the same department, 5 other residential facilities providing TAU were used as controls. ANOVA for repeated measures showed a significant interaction effect between users' functioning at baseline and follow up assessments, and the intervention. In particular, change in global functioning was higher in the 55 CIGI users than in the 44 TAU users. These results suggest that CIGI can be successfully introduced in residential facilities and may be useful to improve functioning in users with severe mental disorders. PMID:26723137

  2. Novel gene arrangement in the mitochondrial genome of Bothus myriaster (Pleuronectiformes: Bothidae): evidence for the Dimer-Mitogenome and Non-random Loss model.

    PubMed

    Gong, Li; Shi, Wei; Yang, Min; Li, Donghe; Kong, Xiaoyu

    2016-09-01

    In the present study, the complete mitochondrial genome of the oval flounder Bothus myriaster was determined and a novel gene rearrangement was discovered. A striking finding was that eight genes encoded by the L-strand (ND6 and tRNA-Q, A, C, Y, S1, E, and P genes) were translocated to a position between tRNA-T and tRNA-F. Simultaneously, the original order of the rearranged genes Q-A-C-Y-S1-ND6-E-P was maintained. Thus, the genes with identical transcriptional polarities were clustered in the genome with one exception that tRNA-N gene is located in the original position. The other rearrangement was the H-strand-encoded tRNA-D that translocated from its typical location between COI and COII to a position between S1 and ND6. The Dimer-Mitogenome and Non-random Loss model (DMNL)was adopted to account for the novel rearrangement in B. myriaster mitogenome, which provides evidence to support the hypothesis of the DMNL model. PMID:25629499

  3. Design and Baseline Findings of a Multi-site Non-randomized Evaluation of the Effect of a Health Programme on Microfinance Clients in India

    PubMed Central

    Saha, Somen

    2014-01-01

    Microfinance is the provision of financial services for the poor. Health program through microfinance has the potential to address several access barriers to health. We report the design and baseline findings of a multi-site non-randomized evaluation of the effect of a health program on the members of two microfinance organizations from Karnataka and Gujarat states of India. Villages identified for roll-out of health services with microfinance were pair-matched with microfinance only villages. A quantitative survey at inception and twelve months post health intervention compare the primary outcome (incidence of childhood diarrhea), and secondary outcome (place of last delivery, toilet at home, and out-of-pocket expenditure on treatment). At baseline, the intervention and comparison communities were similar except for out-of-pocket expenditure on health. Low reported use of toilet at home indicates the areas are heading towards a sanitation crisis. This should be an area of program priority for the microfinance organizations. While respondents primarily rely on their savings for meeting treatment expenditure, borrowing from friends, relatives, and money-lenders remains other important source of meeting treatment expenditure in the community. Programs need to prioritize steps to ensure awareness about national health insurance schemes, entitlement to increase service utilization, and developing additional health financing safety nets for financing outpatient care, that are responsible for majority of health-debt. Finally we discuss implications of such programs for national policy makers. PMID:24373263

  4. A non-randomized confirmatory study regarding selection of fertility-sparing surgery for patients with epithelial ovarian cancer: Japan Clinical Oncology Group Study (JCOG1203).

    PubMed

    Satoh, Toyomi; Tsuda, Hitoshi; Kanato, Keisuke; Nakamura, Kenichi; Shibata, Taro; Takano, Masashi; Baba, Tsukasa; Ishikawa, Mitsuya; Ushijima, Kimio; Yaegashi, Nobuo; Yoshikawa, Hiroyuki

    2015-06-01

    Fertility-sparing treatment has been accepted as a standard treatment for epithelial ovarian cancer in stage IA non-clear cell histology grade 1/grade 2. In order to expand an indication of fertility-sparing treatment, we have started a non-randomized confirmatory trial for stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The protocol-defined fertility-sparing surgery is optimal staging laparotomy including unilateral salpingo-oophorectomy, omentectomy, peritoneal cytology and pelvic and para-aortic lymph node dissection or biopsy. After fertility-sparing surgery, four to six cycles of adjuvant chemotherapy with paclitaxel and carboplatin are administered. We plan to enroll 250 patients with an indication of fertility-sparing surgery, and then the primary analysis is to be conducted for 63 operated patients with pathologically confirmed stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The primary endpoint is 5-year overall survival. Secondary endpoints are other survival endpoints and factors related to reproduction. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000013380. PMID:26059697

  5. Links between fear of humans, stress and survival support a non-random distribution of birds among urban and rural habitats.

    PubMed

    Rebolo-Ifrán, Natalia; Carrete, Martina; Sanz-Aguilar, Ana; Rodríguez-Martínez, Sol; Cabezas, Sonia; Marchant, Tracy A; Bortolotti, Gary R; Tella, José L

    2015-01-01

    Urban endocrine ecology aims to understand how organisms cope with new sources of stress and maintain allostatic load to thrive in an increasingly urbanized world. Recent research efforts have yielded controversial results based on short-term measures of stress, without exploring its fitness effects. We measured feather corticosterone (CORTf, reflecting the duration and amplitude of glucocorticoid secretion over several weeks) and subsequent annual survival in urban and rural burrowing owls. This species shows high individual consistency in fear of humans (i.e., flight initiation distance, FID), allowing us to hypothesize that individuals distribute among habitats according to their tolerance to human disturbance. FIDs were shorter in urban than in rural birds, but CORTf levels did not differ, nor were correlated to FIDs. Survival was twice as high in urban as in rural birds and links with CORTf varied between habitats: while a quadratic relationship supports stabilizing selection in urban birds, high predation rates may have masked CORTf-survival relationship in rural ones. These results evidence that urban life does not constitute an additional source of stress for urban individuals, as shown by their near identical CORTf values compared with rural conspecifics supporting the non-random distribution of individuals among habitats according to their behavioural phenotypes. PMID:26348294

  6. Links between fear of humans, stress and survival support a non-random distribution of birds among urban and rural habitats

    PubMed Central

    Rebolo-Ifrán, Natalia; Carrete, Martina; Sanz-Aguilar, Ana; Rodríguez-Martínez, Sol; Cabezas, Sonia; Marchant, Tracy A.; Bortolotti, Gary R.; Tella, José L.

    2015-01-01

    Urban endocrine ecology aims to understand how organisms cope with new sources of stress and maintain allostatic load to thrive in an increasingly urbanized world. Recent research efforts have yielded controversial results based on short-term measures of stress, without exploring its fitness effects. We measured feather corticosterone (CORTf, reflecting the duration and amplitude of glucocorticoid secretion over several weeks) and subsequent annual survival in urban and rural burrowing owls. This species shows high individual consistency in fear of humans (i.e., flight initiation distance, FID), allowing us to hypothesize that individuals distribute among habitats according to their tolerance to human disturbance. FIDs were shorter in urban than in rural birds, but CORTf levels did not differ, nor were correlated to FIDs. Survival was twice as high in urban as in rural birds and links with CORTf varied between habitats: while a quadratic relationship supports stabilizing selection in urban birds, high predation rates may have masked CORTf-survival relationship in rural ones. These results evidence that urban life does not constitute an additional source of stress for urban individuals, as shown by their near identical CORTf values compared with rural conspecifics supporting the non-random distribution of individuals among habitats according to their behavioural phenotypes. PMID:26348294

  7. Radiogenic cell transformation and carcinogenesis

    NASA Technical Reports Server (NTRS)

    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

  8. Localization of collagen modifying enzymes on fibroblastic reticular cells and follicular dendritic cells in non-neoplastic and neoplastic lymphoid tissues

    PubMed Central

    Ohe, Rintaro; Aung, Naing Ye; Meng, Hongxue; Kabasawa, Takanobu; Suto, Aya; Tamazawa, Nobuyuki; Yang, Suran; Kato, Tomoya; Yamakawa, Mitsunori

    2016-01-01

    Abstract The aim of this study was to evaluate the localization of collagen modifying enzymes (CMEs) on fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) in non-neoplastic lymphoid tissues and various malignant lymphomas. The expression of prolyl 4-hydroxylase 1 (P4H1), lysyl hydroxylase 3 (LH3), and protein disulfide isomerase (PDI) was frequently observed on FRCs and FDCs in the germinal center (GC), except for the mantle zone. The expression of CMEs was lower in most lymphomas than in their respective postulated normal counterparts. The ratio of transglutaminase II+ FRCs/CD35+ FDCs was also lower in follicular lymphomas (FL) than in other lymphomas. The mRNAs of some CMEs (P4H1, prolyl 4-hydroxylase 3, LH3, and heat shock protein 47) were confirmed in almost all lymphomas. These results indicate that lymphoma cell proliferation suppresses/decreases the number of CMEs expressing FRCs and FDCs in most lymphomas. PMID:26700650

  9. Localization of collagen modifying enzymes on fibroblastic reticular cells and follicular dendritic cells in non-neoplastic and neoplastic lymphoid tissues.

    PubMed

    Ohe, Rintaro; Aung, Naing Ye; Meng, Hongxue; Kabasawa, Takanobu; Suto, Aya; Tamazawa, Nobuyuki; Yang, Suran; Kato, Tomoya; Yamakawa, Mitsunori

    2016-07-01

    The aim of this study was to evaluate the localization of collagen modifying enzymes (CMEs) on fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) in non-neoplastic lymphoid tissues and various malignant lymphomas. The expression of prolyl 4-hydroxylase 1 (P4H1), lysyl hydroxylase 3 (LH3), and protein disulfide isomerase (PDI) was frequently observed on FRCs and FDCs in the germinal center (GC), except for the mantle zone. The expression of CMEs was lower in most lymphomas than in their respective postulated normal counterparts. The ratio of transglutaminase II(+) FRCs/CD35(+) FDCs was also lower in follicular lymphomas (FL) than in other lymphomas. The mRNAs of some CMEs (P4H1, prolyl 4-hydroxylase 3, LH3, and heat shock protein 47) were confirmed in almost all lymphomas. These results indicate that lymphoma cell proliferation suppresses/decreases the number of CMEs expressing FRCs and FDCs in most lymphomas. PMID:26700650

  10. Involvement of epigenetics and EMT related miRNA in arsenic induced neoplastic transformation and their potential clinical use

    PubMed Central

    Michailidi, Christina; Hayashi, Masamichi; Datta, Sayantan; Sen, Tanusree; Zenner, Kaitlyn; Oladeru, Oluwadamilola; Brait, Mariana; Izumchenko, Evgeny; Baras, Alexander; VandenBussche, Christopher; Argos, Maria; Bivalacqua, Trinity J; Ahsan, Habibul; Hahn, Noah M.; Netto, George J.; Sidransky, David; Hoque, Mohammad O.

    2015-01-01

    Exposure to toxicants leads to cumulative molecular changes that overtime increase a subject’s risk of developing urothelial carcinoma (UC). To assess the impact of arsenic exposure at a time progressive manner, we developed and characterized a cell culture model and tested a panel of miRNAs in urine samples from arsenic exposed subjects, UC patients and controls. To prepare an in vitro model, we chronically exposed an immortalized normal human bladder cell line (HUC1) to arsenic. Growth of the HUC1 cells was increased in a time dependent manner after arsenic treatment and cellular morphology was changed. In soft agar assay, colonies were observed only in arsenic treated cells and the number of colonies gradually increased with longer periods of treatment. Similarly, invaded cells in invasion assay were observed only in arsenic treated cells. Withdrawal of arsenic treatment for 2.5 months did not reverse the tumorigenic properties of arsenic treated cells. Western blot analysis demonstrated decreased PTEN and increased AKT and mTOR in arsenic treated HUC1 cells. Levels of miR-200a, miR-200b, and miR-200c were down-regulated in arsenic exposed HUC1 cells by quantitative RT-PCR. Furthermore, in human urine, miR-200c and miR-205 were inversely associated with arsenic exposure (P=0.005 and 0.009, respectively). Expression of miR-205 discriminated cancer cases from controls with high sensitivity and specificity (AUC=0.845). Our study suggests that exposure to arsenic rapidly induces a multifaceted dedifferentiation program and miR-205 has potential to be used as a marker of arsenic exposure as well as a maker of early UC detection. PMID:25586904

  11. Role of Vitamin D receptor gene in radiation-induced neoplastic transformation of human breast epithelial cell.

    PubMed

    Roy, Debasish; Calaf, Gloria; Hei, Tom K

    2003-09-01

    1 Alpha,25-(OH)(2)-Vitamin D(3), the physiologically active metabolite of Vitamin D is known for its pro-differentiating and antiproliferative activity on various cancer cell lines. It exerts its growth-regulatory effects through binding to the Vitamin D recepter (VDR), a member of the steroid/thyroid/retinoic acid receptor family, which functions as a ligand-dependent transcription factor. There is accumulating evidence that Vitamin D may be an important determinant of both the occurrence and progression of breast cancer. Since radiation is an important etiological factor for breast cancer progression, it is important to study the role of VDR gene in radiation-induced breast carcinogenesis. This study is focused on a human breast tumor model developed by irradiating the spontaneously immortalized MCF-10F cell line with graded doses of high-linear energy transfer (LET) radiation followed by treatment with estrogen. Study of VDR gene by restriction digestion with ApaI, BsmI and TaqI detected no polymorphism but direct sequencing analyses identified few single-base mutations within intron 8 and exon 9 of the gene. Over-expression of the VDR gene was noticed in irradiated and tumorigenic cell lines compared with control. Likewise, immunohistochemical data indicated a significant increase in VDR intensity in irradiated and tumorigenic cell lines. Considering all these evidence, it is likely that VDR can be used as a prognostic marker of tumor progression in radiation- and estrogen-induced breast carcinogenesis. PMID:12957667

  12. Low plasma selenium concentration is associated with elevated risk to neoplastic polyps of the colon

    SciTech Connect

    Clark, L.C.; Hixson, L.G.; Sampliner, R.E. ); Combs, G.F. Jr. )

    1991-03-11

    A cross-sectional study was conducted to examine the relationship of selenium (Se) status and polyps incidence in a sequential series of 100 patients undergoing outpatient colonoscopies at the Tucson VA Hospital. Se was measured in plasma samples by electrothermal atomic absorption spectrophotometry with Zeeman background correction using a reduced palladium matrix modified. The activities of the Se-dependent enzyme glutathione peroxidase (SeGSHpx) were measured using H{sub 2}O{sub 2} as substrate in all plasma samples and in colonic mucosal biopsies obtained from some patients. The mean plasma Se concentration of patients without polyps was 134 ng/ml. Mean plasma Se levels of patients with only diminutive or large polyps were 127 ng/ml and 125 ng/ml; while patients with polyps of both sizes had a mean plasma Se level of 121 ng/ml. Patients with no reported history of cancer, neoplastic polyps or prior colonoscopy, showed an inverse association of plasma Se level and risk of benign colonic neoplasms. The age-adjusted odds ratio for neoplastic polyps was 3.8 for patients with plasma Se levels below vs. above the median value. This association was stronger for patients under 68 yrs of age than for older patients. Activities of SeGSHpx in plasma or colonic mucosa were not related to plasma Se level; however, smokers showed greater SeGSHpx activities than non-smokers. This study is the first to detect an association of Se status and risk to neoplastic polyps of the colon.

  13. Evaluation of the Efficacy and Safety of Short-Course Deep Sedation Therapy for the Treatment of Intracerebral Hemorrhage After Surgery: A Non-Randomized Control Study.

    PubMed

    Hou, Dapeng; Liu, Beibei; Zhang, Juan; Wang, Qiushi; Zheng, Wei

    2016-01-01

    BACKGROUND While mild and moderate sedation have been widely used to reduce sudden agitation in intracerebral hemorrhage (ICH) patients after surgery, agitation is still a frequent problem, which may cause postoperative blood pressure fluctuation. The present study aimed to evaluate the efficacy and safety of short-course deep sedation for the treatment of ICH after surgery. MATERIAL AND METHODS A total of 41 ICH patients who received surgery, including traditional craniotomy hematoma removal and decompressive craniectomy, were including in this non-randomized control study. Patients in the deep sedation group received continuous postoperative sedation with a target course for ≤12 hours and reached SAS scores of 1~2. Patients in the traditional sedition group received continuous light sedation and reached SAS scores of 3~4. Additional therapeutic interventions included antihypertensive treatment, mechanical ventilation, tracheotomy, and re-operation. RESULTS Patients in the deep sedation group had deeper sedation degree, and lower systolic blood pressure (SBP) and diastolic blood pressure (DBP). Residual hematoma after surgery in patients in the deep sedation group were smaller on the second, seventh, and fourteenth day after surgery (p=0.023, 0.003, 0.004, respectively). The 3-month mortality and quality of life of patients in the deep sedation group were lower and better than that of patients in the traditional sedation group, respectively (p=0.044, p<0.01). No significant difference in the incidence of ventilator-associated pneumonia (VAP) and ICU days were observed between the two groups. CONCLUSIONS Short-course deep sedation therapy in ICH patients after surgery is efficient in controlling postoperative blood pressure, reducing re-bleeding, and improving clinical prognosis. PMID:27466863

  14. Effectiveness of a peer-led HIV prevention intervention in secondary schools in Rwanda: results from a non-randomized controlled trial

    PubMed Central

    2012-01-01

    Background While the HIV epidemic is levelling off in sub-Saharan Africa, it remains at an unacceptably high level. Young people aged 15-24 years remain particularly vulnerable, resulting in a regional HIV prevalence of 1.4% in young men and 3.3% in young women. This study assesses the effectiveness of a peer-led HIV prevention intervention in secondary schools in Rwanda on young people’s sexual behavior, HIV knowledge and attitudes. Methods In a non-randomized longitudinal controlled trial, fourteen schools were selected in two neighboring districts in Rwanda Bugesera (intervention) and Rwamagana (control). Students (n = 1950) in eight intervention and six control schools participated in three surveys (baseline, six and twelve months in the intervention). Analysis was done using linear and logistic regression using generalized estimation equations adjusted for propensity score. Results The overall retention rate was 72%. Time trends in sexual risk behavior (being sexually active, sex in last six months, condom use at last sex) were not significantly different in students from intervention and control schools, nor was the intervention associated with increased knowledge, perceived severity or perceived susceptibility. It did significantly reduce reported stigma. Conclusions Analyzing this and other interventions, we identified several reasons for the observed limited effectiveness of peer education: 1) intervention activities (spreading information) are not tuned to objectives (changing behavior); 2) young people prefer receiving HIV information from other sources than peers; 3) outcome indicators are not adequate and the context of the relationship in which sex occurs and the context in which sex occurs is ignored. Effectiveness of peer education may increase through integration in holistic interventions and redefining peer educators’ role as focal points for sensitization and referral to experts and services. Finally, we argue that a narrow focus on

  15. Rock magnetic evidence of non-random raw material selection criteria in Cerro Toledo Obsidian Artifacts from Valles Caldera, New Mexico

    NASA Astrophysics Data System (ADS)

    Gregovich, A.; Feinberg, J. M.; Steffen, A.; Sternberg, R. S.

    2014-12-01

    Stone tools are one of the most enduring forms of ancient human behavior available to anthropologists. The geologic materials that comprise stone tools are a reflection of the rocks that were available locally or through trade, as are the intended use of the tools and the knapping technology needed to produce them. Investigation of the rock magnetic and geochemical characteristics of the artifacts and the geological source materials provides a baseline to explore these past behaviors. This study uses rock magnetic properties to explore the raw material selection criteria involved in the production of obsidian tools in the region around Valles Caldera in northern New Mexico. Obsidian is locally abundant and was traded by tribes across the central United States. Here we compare the rock magnetic properties of a sample of obsidian projectile points (N =25) that have been geochemically sourced to the Cerro Toledo obsidian flow with geological samples collected from four sites within the same flow (N =135). This collection of archaeological artifacts, albeit small, contains representatives of at least 8 different point styles that were used over 6000 years from the Archaic into the Late Prehistoric. Bulk rock hysteresis parameters (Mr, Ms, Bc, and Bcr) and low-field susceptibility (Χ) measurements show that the projectile points generally contain a lower concentration of magnetic minerals than the geologic samples. For example, the artifacts' median Ms value is 2.9 x 10-3 Am2kg-1, while that of the geological samples is 6.5 x 10-3 Am2kg-1. The concentration of magnetic minerals in obsidian is a proxy for the concentration of microlites in general, and this relationship suggests that although obsidian was locally abundant, toolmakers employed non-random selection criteria resulting in generally lower concentrations of microlites in their obsidian tools.

  16. Evaluation of the Efficacy and Safety of Short-Course Deep Sedation Therapy for the Treatment of Intracerebral Hemorrhage After Surgery: A Non-Randomized Control Study

    PubMed Central

    Hou, Dapeng; Liu, Beibei; Zhang, Juan; Wang, Qiushi; Zheng, Wei

    2016-01-01

    Background While mild and moderate sedation have been widely used to reduce sudden agitation in intracerebral hemorrhage (ICH) patients after surgery, agitation is still a frequent problem, which may cause postoperative blood pressure fluctuation. The present study aimed to evaluate the efficacy and safety of short-course deep sedation for the treatment of ICH after surgery. Material/Methods A total of 41 ICH patients who received surgery, including traditional craniotomy hematoma removal and decompressive craniectomy, were including in this non-randomized control study. Patients in the deep sedation group received continuous postoperative sedation with a target course for ≤12 hours and reached SAS scores of 1~2. Patients in the traditional sedition group received continuous light sedation and reached SAS scores of 3~4. Additional therapeutic interventions included antihypertensive treatment, mechanical ventilation, tracheotomy, and re-operation. Results Patients in the deep sedation group had deeper sedation degree, and lower systolic blood pressure (SBP) and diastolic blood pressure (DBP). Residual hematoma after surgery in patients in the deep sedation group were smaller on the second, seventh, and fourteenth day after surgery (p=0.023, 0.003, 0.004, respectively). The 3-month mortality and quality of life of patients in the deep sedation group were lower and better than that of patients in the traditional sedation group, respectively (p=0.044, p<0.01). No significant difference in the incidence of ventilator-associated pneumonia (VAP) and ICU days were observed between the two groups. Conclusions Short-course deep sedation therapy in ICH patients after surgery is efficient in controlling postoperative blood pressure, reducing re-bleeding, and improving clinical prognosis. PMID:27466863

  17. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V.

    PubMed

    Gleixner, Karoline V; Peter, Barbara; Blatt, Katharina; Suppan, Verena; Reiter, Andreas; Radia, Deepti; Hadzijusufovic, Emir; Valent, Peter

    2013-09-01

    Patients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and investigated whether ponatinib acts synergistically with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V(+)) and HMC-1.2 cells (KIT G560V(+)/KIT D816V(+)) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells. PMID:23539538

  18. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V

    PubMed Central

    Gleixner, Karoline V.; Peter, Barbara; Blatt, Katharina; Suppan, Verena; Reiter, Andreas; Radia, Deepti; Hadzijusufovic, Emir; Valent, Peter

    2013-01-01

    Patients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and investigated whether ponatinib acts synergistically with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V+) and HMC-1.2 cells (KIT G560V+/KIT D816V+) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V than in those lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells. PMID:23539538

  19. Mediastinal sarcoidosis mimicking lymph malignancy recurrence after anti-neoplastic therapy.

    PubMed

    El Hammoumi, Massine; El Marjany, Mohamed; Moussaoui, Driss; Doudouh, Aberahim; Mansouri, Hamid; Kabiri, El Hassane

    2015-07-01

    The aim of our work is to promote the awareness about the development of sarcoidosis after antineoplastic therapy in order to avoid diagnostic errors with FDG-PET/CT findings. We report the observation of three women with breast, cervix and stomach treated cancers who developed a sarcoidosis after the end of anti-neoplastic therapy. The utility of FDG-PET/CT is in pinpointing the organs candidates for diagnostic biopsy and not distinguishing between the malignancy and granulomatous or inflammatory diseases. PMID:25294405

  20. Uptake and distribution of fluorescently labeled cobalamin in neoplastic and healthy breast tissue

    NASA Astrophysics Data System (ADS)

    Cannon, Michelle J.; McGreevy, James M.; Holden, Joseph A.; West, Frederick G.; Grissom, Charles B.

    2000-05-01

    Fluorescent analogs of cobalamin (vitamin B12) have been developed as diagnostic markers of cancer cells. These compounds are recognized by transcobalamin, a cobalamin transport protein, with high affinity, as shown by surface plasmon resonance. The cellular sequestration and gross distribution of fluorescent cobalamin bioconjugates in breast tissue is being examined by epifluorescence microscopy. The distribution of each compound is being evaluated in proliferative and non-proliferative tissue, i.e. normal tissue and breast carcinoma. The results of preliminary studies suggest that fluorescent analogs of cobalamin may be a useful tool in therapeutic breast operations to define tumor margins and to distinguish neoplastic breast tissue from healthy breast tissue.

  1. MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer.

    PubMed

    Mao, Jenny T; Xue, Bingye; Smoake, Jane; Lu, Qing-Yi; Park, Heesung; Henning, Susanne M; Burns, Windie; Bernabei, Alvise; Elashoff, David; Serio, Kenneth J; Massie, Larry

    2016-08-01

    Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032-0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer. PMID:27289489

  2. Interobserver agreement for the spine instability neoplastic score varies according to the experience of the evaluator

    PubMed Central

    Teixeira, William Gemio Jacobsen; de Mesquita Coutinho, Pedro Ricardo; Marchese, Luiz Delboni; Narazaki, Douglas Kenji; Cristante, Alexandre Fogaça; Teixeira, Manoel Jacobsen; de Barros Filho, Tarcísio Eloy Pessoa; de Camargo, Olavo Pires

    2013-01-01

    OBJECTIVES: To evaluate the interobserver agreement for the Neoplastic Spine Instability Score (SINS) among spine surgeons with or without experience in vertebral metastasis treatment and physicians in other specialties. METHODS: Case descriptions were produced based on the medical records of 40 patients with vertebral metastases. The descriptions were then published online. Physicians were invited to evaluate the descriptions by answering questions according to the Neoplastic Spine Instability Score (SINS). The agreement among physicians was calculated using the kappa coefficient. RESULTS: Seventeen physicians agreed to participate: three highly experienced spine surgeons, seven less-experienced spine surgeons, three surgeons of other specialties, and four general practitioners (n = 17). The agreement for the final SINS score among all participants was fair, and it varied according to the SINS component. The agreement was substantial for the spine location only. The agreement was higher among experienced surgeons. The agreement was nearly perfect for spinal location among the spine surgeons who were highly experienced in vertebral metastases. CONCLUSIONS: This study demonstrates that the experience of the evaluator has an impact on SINS scale classification. The interobserver agreement was only fair among physicians who were not spine surgeons and among spine surgeons who were not experienced in the treatment of vertebral metastases, which may limit the use of the SINS scale for the screening of unstable lesions by less-experienced evaluators. PMID:23525318

  3. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.

    PubMed

    Granger, D L; Lehninger, A L

    1982-11-01

    Previous work has shown that injury of neoplastic cells by cytotoxic macrophages (CM) in cell culture is accompanied by inhibition of mitochondrial respiration. We have investigated the nature of this inhibition by studying mitochondrial respiration in CM-injured leukemia L1210 cells permeabilized with digitonin. CM-induced injury affects the mitochondrial respiratory chain proper. Complex I (NADH-coenzyme Q reductase) and complex II (succinate-coenzyme Q reductase) are markedly inhibited. In addition a minor inhibition of cytochrome oxidase was found. Electron transport from alpha-glycerophosphate through the respiratory chain to oxygen is unaffected and permeabilized CM-injured L1210 cells oxidizing this substrate exhibit acceptor control. However, glycerophosphate shuttle activity was found not to occur within CM-injured or uninjured L1210 cells in culture hence, alpha-glycerophosphate is apparently unavailable for mitochondrial oxidation in the intact cell. It is concluded that the failure of respiration of intact neoplastic cells injured by CM is caused by the nearly complete inhibition of complexes I and II of the mitochondrial electron transport chain. The time courses of CM-induced electron transport inhibition and arrest of L1210 cell division are examined and the possible relationship between these phenomena is discussed. PMID:6292238

  4. Hypercobalaminaemia is associated with hepatic and neoplastic disease in cats: a cross sectional study

    PubMed Central

    2014-01-01

    Background When increased serum cobalamin concentrations are encountered clinically they are usually attributed to parenteral supplementation, dietary factors, or otherwise ignored. However, recently, hypercobalaminaemia has been associated with numerous diseases in humans, most notably neoplastic and hepatic disorders. The aim of this retrospective, observational, cross-sectional study was to determine the significance of increased cobalamin in cats. Results In total, 237 records were retrieved and 174 cats, of various ages and sexes met the inclusion criteria. A total of 42 cats had increased serum cobalamin concentration, and had not received prior supplementation. Multiple logistic regression analysis revealed that increased serum cobalamin concentration was positively related to pedigree breed (pedigree breeds more likely to have increased cobalamin concentration, odds ratio [OR] 4.24, 95% CI 1.78-10.15, P = 0.001), to having liver disease (OR 9.91, 95% CI 3.54-27.68), and to having a solid neoplasm (OR 8.54, 95% CI 1.10-66.45). Conclusions The results of the current study suggest that increased serum cobalamin concentrations should not be ignored in cats with no history of supplementation, and investigation for underlying hepatic or neoplastic disease is warranted. PMID:25103858

  5. Evaluation of impact of immunocytochemical techniques in cytological diagnosis of neoplastic effusions.

    PubMed Central

    Linari, A; Bussolati, G

    1989-01-01

    A prospective study (1984-87) on the immunocytochemical identification of cancer cells in effusions using HMFG2 monoclonal antibody, and in addition, monoclonal anti-CEA and B72.3 antibodies in cases of suspected mesothelioma, was undertaken. On the basis of cytology alone, of a total of 2362 pleural, peritoneal, and pericardial effusions, 525 cases were diagnosed as positive and 1485 as negative for neoplastic cells, while in 352 (15%) specimens from 307 patients the diagnosis was doubtful. Sections of the embedded sediment of doubtful cases were tested with HMFG2 antibody and proved positive in 215 cases, negative in 108, and inconclusive in 29. The results were checked by following the clinical outcome of the cases. The method was specific in identifying cancer cells in cases at best diagnosed as suspicious on the basis of cytology alone; this represents a clear diagnostic gain. Sensitivity of the test, however, was relatively low (41%). Combined cytological and immunocytochemical characteristics (CEA negative and only some of the neoplastic cells positive with HMFG2 and B72.3 monoclonal antibodies) permitted diagnosis on the effusions of most cases of mesothelioma. The impact of the diagnosis on the progress of the disease was not appreciable as no difference in outcome was noted, irrespective of whether cancer cells had been recognised. The occurrence of an effusion remains an ominous sign in most patients treated for cancer. Images PMID:2685053

  6. Neoplastic meningitis resulting from hematological malignancies: pharmacokinetic considerations and maximizing outcome

    PubMed Central

    Grewal, Jai; Saria, Marlon; Grewal, Harpreet K; Kesari, Santosh

    2012-01-01

    Neoplastic meningitis, also known as leptomeningeal metastases, is a complication of various types of cancer that occurs when tumor cells enter the cerebrospinal fluid (CSF), travel along CSF pathways and grow. Treatment options include drug delivery directly into the CNS or systemic administration for targeted action in the CNS. CNS drug delivery is limited by the blood–brain barrier and the blood–CSF barrier. It may be possible to partially overcome this by using high-dose systemic therapy; however, this is done at the possible expense of increased systemic toxicity. Intra-CSF drug delivery bypasses the blood–brain barrier and allows direct access of the chemotherapeutic agent to the CSF. Because neoplastic meningitis occurs in an increasingly large percentage of all cancer patients, it is imperative to optimize drug delivery to the CSF and meninges. Both the pharmacokinetic profile of the chemotherapeutic agent and the site of administration influence therapeutic efficacy. Achieving prolonged therapeutic cytotoxic drug concentrations and even distribution in the CSF will improve efficacy. In this article we summarize data on the efficacy, safety and outcome of high-dose systemic and intra-CSF treatments. PMID:22396850

  7. Taurolidine: a novel anti-neoplastic agent induces apoptosis of osteosarcoma cell lines.

    PubMed

    Walters, Denise K; Muff, Roman; Langsam, Bettina; Gruber, Philipp; Born, Walter; Fuchs, Bruno

    2007-08-01

    Taurolidine, the active agent of Taurolin, is a broad spectrum anti-biotic that has been used for over 15 years for the treatment of severe surgical infections. Recently, taurolidine has been shown to possess anti-neoplastic properties in vitro and in vivo against a variety of cancers including ovarian, colon and prostate. In this study we assessed the cytotoxic activity of taurolidine against human osteosarcoma (OS) cell lines and normal human bone cells. Treatment with taurolidine inhibited the growth of all ten osteosarcoma cell lines tested and taurolidine was equally potent against cell lines with and without distinct genetic defects (i.e. p53, Rb). Moreover, taurolidine-induced growth inhibition was found to be associated with a dose dependent increase in the number of apoptotic cells and apoptosis was shown to be caspase-dependent. Taurolidine treatment was also found to inhibit adhesion of OS cell lines. Compared to OS cell lines, normal bone cells in primary culture were found to be less sensitive to the cytotoxic and anti-adhesive effects of taurolidine. These data indicate that taurolidine possesses potent anti-neoplastic activity against osteosarcoma cell lines and may have potential as a novel OS chemotherapeutic agent. PMID:17458504

  8. A core of kinase-regulated interactomes defines the neoplastic MDSC lineage

    PubMed Central

    Zudaire, Isabel; Liechtenstein, Therese; Arasanz, Hugo; Lozano, Teresa; Casares, Noelia; Chaikuad, Apirat; Knapp, Stefan; Guerrero-Setas, David; Escors, David; Kochan, Grazyna; Santamaría, Enrique

    2015-01-01

    Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a “kinase signature” and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells. PMID:26320174

  9. The treatment of snoring by radiofrequency-assisted uvulopalatoplasty and results after one-session protocol: a prospective, longitudinal, non-randomized study.

    PubMed

    Chiesa Estomba, Carlos Miguel; Rivera Schmitz, Teresa; Ossa Echeverri, Carla Cristina; Betances Reinoso, Frank Alberto; Fariña Conde, José; Alonso Parraga, Dionisio

    2015-10-01

    Snoring is usually caused by the vibration of walls of the soft palate at the pharyngeal level. Its worldwide prevalence is estimated to range between 2 and 85% depending on age, gender or population group. The aim of this study is to determine the degree of improvement that can be subjectively evident in patients treated by snoring with radiofrequency-assisted uvulopalatoplasty based on a one-session protocol. This is a prospective, longitudinal, non-randomized study. Patients of both sexes, aged 18 years, who attended to the ENT consultation in a tertiary hospital with snoring during the period of July 2012-July 2013 were included. Age, body mass index, Epworth sleepiness scale were calculated. The volume of snoring of each subject was assessed using a visual analog scale. A total of 27 patients were included in the study; the average age of the sample was 49 years (±8.7; min 36/max 74); of these 22 (81.5%) were male and 5 (18.5%) females. The average BMI was 27.07 ± 2.5 (min 23.15/max 29.39) before the test and after 1 year was 26.75 ± 2.32 (min 23.11/max 29.56) with no statistically significant differences in BMI before and after surgery (p = 0.407). Preoperative snoring intensity was 8.10 ± 0.93 according to VAS. We found a statistically significant difference in the post-operative intensity at 3 months of 3.93 ± 0.88 (p ≤ 0.05) at 6 months of 4.41 ± 1.08 (p ≤ 0.05), and after 1 year 4.90 ± 0.77 (p ≤ 0.05). The average rate of ESS was significantly higher preoperatively than post-operative, being 8.76 ± 3.1 preoperative and 6.93 ± 1.68 post-operative (p ≤ 0.05). We conclude that the use of radiofrequency in simple snorers with an apnea/hypopnea index <15 events per hour and a BMI < 30 kg/m(2) in whom clinically proven that the source of snoring is the soft palate, can be treated by one-session protocol, being possible to obtain an improvement of snoring up to 70% of cases by a short follow-up period. PMID:25837987

  10. Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions.

    PubMed

    Schünemann, Holger J; Tugwell, Peter; Reeves, Barnaby C; Akl, Elie A; Santesso, Nancy; Spencer, Frederick A; Shea, Beverley; Wells, George; Helfand, Mark

    2013-03-01

    The terms applicability, generalizability, external validity and transferability are related, sometimes used interchangeably and have in common that they lack a clear and consistent definition in the classic epidemiological literature. However, all of these terms generally describe one overarching theme: whether or not available research evidence can be directly utilized to answer the healthcare questions at hand, ideally supported by a judgment about the degree of confidence for this utilization. This concept has been called directness. The objectives of this paper were to delineate how non-randomized studies (NRS) inform judgments in relation to directness and the concepts that it encompasses in the context of systematic reviews. We will briefly review what is known and describe the theoretical and practical issues as well as offer guidance to those tackling the challenges of judging directness and using research evidence to answer healthcare questions with evidence from NRS. In particular, we suggest a framework in which authors can use NRS as a complement, sequence or replacement for randomized controlled trials (RCTs) by focusing on judgments about the population, intervention, comparison and outcomes. Authors of systematic reviews will use NRS to complement judgments about the inconsistencies, the rationale and credibility of subgroup analysis, the baseline risk estimates for the determination of absolute benefits and downsides, and the directness of surrogate outcomes. This evidence includes contextual or supplementary evidence. Authors of systematic review and other summaries of the evidence use NRS as sequential evidence to provide evidence when insufficient evidence is available for an outcome from RCTs, but NRS evidence is available (e.g., long-term harms). Use of evidence from NRS may also serve to replace RCT evidence when NRS provide equivalent (or potentially higher) confidence in the evidence (i.e. quality) compared to indirect evidence from RCTs