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1.  Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead 
Goodson, William H. | Lowe, Leroy | Carpenter, David O. | Gilbertson, Michael | Manaf Ali, Abdul | Lopez de Cerain Salsamendi, Adela | Lasfar, Ahmed | Carnero, Amancio | Azqueta, Amaya | Amedei, Amedeo | Charles, Amelia K. | Collins, Andrew R. | Ward, Andrew | Salzberg, Anna C. | Colacci, Annamaria | Olsen, Ann-Karin | Berg, Arthur | Barclay, Barry J. | Zhou, Binhua P. | Blanco-Aparicio, Carmen | Baglole, Carolyn J. | Dong, Chenfang | Mondello, Chiara | Hsu, Chia-Wen | Naus, Christian C. | Yedjou, Clement | Curran, Colleen S. | Laird, Dale W. | Koch, Daniel C. | Carlin, Danielle J. | Felsher, Dean W. | Roy, Debasish | Brown, Dustin G. | Ratovitski, Edward | Ryan, Elizabeth P. | Corsini, Emanuela | Rojas, Emilio | Moon, Eun-Yi | Laconi, Ezio | Marongiu, Fabio | Al-Mulla, Fahd | Chiaradonna, Ferdinando | Darroudi, Firouz | Martin, Francis L. | Van Schooten, Frederik J. | Goldberg, Gary S. | Wagemaker, Gerard | Nangami, Gladys | Calaf, Gloria M. | Williams, Graeme | Wolf, Gregory T. | Koppen, Gudrun | Brunborg, Gunnar | Kim Lyerly, H. | Krishnan, Harini | Ab Hamid, Hasiah | Yasaei, Hemad | Sone, Hideko | Kondoh, Hiroshi | Salem, Hosni K. | Hsu, Hsue-Yin | Park, Hyun Ho | Koturbash, Igor | Miousse, Isabelle R. | Scovassi, A.Ivana | Klaunig, James E. | Vondráček, Jan | Raju, Jayadev | Roman, Jesse | Wise, John Pierce | Whitfield, Jonathan R. | Woodrick, Jordan | Christopher, Joseph A. | Ochieng, Josiah | Martinez-Leal, Juan Fernando | Weisz, Judith | Kravchenko, Julia | Sun, Jun | Prudhomme, Kalan R. | Narayanan, Kannan Badri | Cohen-Solal, Karine A. | Moorwood, Kim | Gonzalez, Laetitia | Soucek, Laura | Jian, Le | D’Abronzo, Leandro S. | Lin, Liang-Tzung | Li, Lin | Gulliver, Linda | McCawley, Lisa J. | Memeo, Lorenzo | Vermeulen, Louis | Leyns, Luc | Zhang, Luoping | Valverde, Mahara | Khatami, Mahin | Romano, Maria Fiammetta | Chapellier, Marion | Williams, Marc A. | Wade, Mark | Manjili, Masoud H. | Lleonart, Matilde | Xia, Menghang | Gonzalez, Michael J. | Karamouzis, Michalis V. | Kirsch-Volders, Micheline | Vaccari, Monica | Kuemmerle, Nancy B. | Singh, Neetu | Cruickshanks, Nichola | Kleinstreuer, Nicole | van Larebeke, Nik | Ahmed, Nuzhat | Ogunkua, Olugbemiga | Krishnakumar, P.K. | Vadgama, Pankaj | Marignani, Paola A. | Ghosh, Paramita M. | Ostrosky-Wegman, Patricia | Thompson, Patricia | Dent, Paul | Heneberg, Petr | Darbre, Philippa | Sing Leung, Po | Nangia-Makker, Pratima | Cheng, Qiang (Shawn) | Robey, R.Brooks | Al-Temaimi, Rabeah | Roy, Rabindra | Andrade-Vieira, Rafaela | Sinha, Ranjeet K. | Mehta, Rekha | Vento, Renza | Di Fiore, Riccardo | Ponce-Cusi, Richard | Dornetshuber-Fleiss, Rita | Nahta, Rita | Castellino, Robert C. | Palorini, Roberta | Abd Hamid, Roslida | Langie, Sabine A.S. | Eltom, Sakina | Brooks, Samira A. | Ryeom, Sandra | Wise, Sandra S. | Bay, Sarah N. | Harris, Shelley A. | Papagerakis, Silvana | Romano, Simona | Pavanello, Sofia | Eriksson, Staffan | Forte, Stefano | Casey, Stephanie C. | Luanpitpong, Sudjit | Lee, Tae-Jin | Otsuki, Takemi | Chen, Tao | Massfelder, Thierry | Sanderson, Thomas | Guarnieri, Tiziana | Hultman, Tove | Dormoy, Valérian | Odero-Marah, Valerie | Sabbisetti, Venkata | Maguer-Satta, Veronique | Rathmell, W.Kimryn | Engström, Wilhelm | Decker, William K. | Bisson, William H. | Rojanasakul, Yon | Luqmani, Yunus | Chen, Zhenbang | Hu, Zhiwei
Carcinogenesis  2015;36(Suppl 1):S254-S296.
Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
PMCID: PMC4480130  PMID: 26106142
2.  Human fetal/tumor metakaryotic stem cells: pangenomic homologous pairing and telomeric end-joining of chromatids 
Cancer genetics and cytogenetics  2010;203(2):203-208.
Metakaryotic cells and syncytia with large, hollow, bell shaped nuclei demonstrate symmetrical and asymmetrical amitotic nuclear fissions in microanatomical positions and numbers expected of stem cell lineages in tissues of all three primordial germ layers and their derived tumors. Using fluorescence in situ hybridization mononuclear metakaryotic interphase cells have been found with only 23 centromeric and 23 telomeric staining regions. Syncytial bell shaped nuclei of found in weeks ~5–12 of human gestation display 23 centromeric and either 23 or 46 telomeric staining regions. These images suggest that (a.) homologous chromatids pair at centromeres and telomeres, (b.) all paired telomeres join end-to-end with other paired telomeres in all mononuclear and some syncytial metakaryotic cells and (c.) telomere junctions may open and close during the syncytial phase of development. Twenty-three telomeric joining figures could be accounted by 23 rings of one chromatid pair each, a single pangenomic ring of 23 joined chromatid pairs or any of many possible sets of oligo-chromatid pair rings. As telomeric end-joining may affect peri-telomeric gene expression a programmed sequence of telomeric end-joining associations in metakaryotic stem cells could guide developmental arboration and errors in, or interruptions of, this program could contribute to carcinogenesis.
PMCID: PMC4044826  PMID: 21156234
3.  Metakaryotic stem cell nuclei use pangenomic dsRNA/DNA intermediates in genome replication and segregation 
Organogenesis  2014;10(1):44-52.
Bell shaped nuclei of metakaryotic cells double their DNA content during and after symmetric and asymmetric amitotic fissions rather than in the separate, pre-mitotic S-phase of eukaryotic cells. A parsimonious hypothesis was tested that the two anti-parallel strands of each chromatid DNA helix were first segregated as ssDNA-containing complexes into sister nuclei then copied to recreate a dsDNA genome. Metakaryotic nuclei that were treated during amitosis with RNase A and stained with acridine orange or fluorescent antibody to ssDNA revealed large amounts of ssDNA. Without RNase treatment metakaryotic nuclei in amitosis stained strongly with an antibody complex specific to dsRNA/DNA. Images of amitotic figures co-stained with dsRNA/DNA antibody and DAPI indicated that the entire interphase dsDNA genome (B-form helices) was transformed into two dsRNA/DNA genomes (A-form helices) that were segregated in the daughter cell nuclei then retransformed into dsDNA. As this process segregates DNA strands of opposite polarity in sister cells it hypothetically offers a sequential switching mechanism within the diverging stem cell lineages of development.
PMCID: PMC4049894  PMID: 24418910
amitosis; development; differentiation; dsRNA/DNA; genome replication; metakaryotic; stem cells
4.  Potent cytotoxic effects of Calomeria amaranthoides on ovarian cancers 
Ovarian cancer remains the leading cause of death from gynaecological malignancy. More than 60% of the patients are presenting the disease in stage III or IV. In spite of combination of chemotherapy and surgery the prognosis stays poor for therapy regimen.
The leaves of a plant endemic to Australia, Calomeria amaranthoides, were extracted and then fractionated by column chromatography. In vitro cytotoxicity tests were performed with fractions of the plant extract and later with an isolated compound on ovarian cancer cell lines, as well as normal fibroblasts at concentrations of 1-100 μg/mL (crude extract) and 1-10 μg/mL (compound). Cytotoxicity was measured after 24, 48 and 72 hours by using a non-fluorescent substrate, Alamar blue.
In vivo cytotoxicity was tested on ascites, developed in the abdomen of nude mice after inoculation with human OVCAR3 cells intraperitoneally. The rate of change in abdomen size for the mice was determined by linear regression and statistically evaluated for significance by the unpaired t test.
Two compounds were isolated by chromatographic fractionation and identified by 1H-NMR, 13C-NMR and mass spectrometry analyses, EPD, an α-methylene sesquiterpene lactone of the eremophilanolide subtype, and EPA, an α-methylene carboxylic acid.
Cytotoxicity of EPD for normal fibroblasts at all time points IC50 was greater than 10 μg/mL, whereas, for OVCAR3 cells at 48 hours IC50 was 5.3 μg/mL (95% confidence interval 4.3 to 6.5 μg/mL).
Both, the crude plant extract as well as EPD killed the cancer cells at a final concentration of 10 μg/mL and 5 μg/mL respectively, while in normal cells only 20% cell killing effect was observed. EPA had no cytotoxic effects.
Changes in abdomen size for control versus Cisplatin treated mice were significantly different, P = 0.023, as were control versus EPD treated mice, P = 0.025, whereas, EPD versus Cisplatin treated mice were not significantly different, P = 0.13.
For the first time both crude plant extract from Calomeria amaranthoides and EPD have been shown to have potent anti-cancer effects against ovarian cancer.
PMCID: PMC3068115  PMID: 21401934
5.  Metakaryotic stem cell lineages in organogenesis of humans and other metazoans 
Organogenesis  2009;5(4):191-200.
A non-eukaryotic, metakaryotic cell with large, open mouthed, bell shaped nuclei represents an important stem cell lineage in fetal/juvenile organogenesis in humans and rodents. each human bell shaped nucleus contains the diploid human DNA genome as tested by quantitative Feulgen DNA cytometry and fluorescent in situ hybridization with human pan-telomeric, pan-centromeric and chromosome specific probes. From weeks ∼5–12 of human gestation the bell shaped nuclei are found in organ anlagen enclosed in sarcomeric tubular syncytia. Within syncytia bell shaped nuclear number increases binomially up to 16 or 32 nuclei; clusters of syncytia are regularly dispersed in organ anlagen. Syncytial bell shaped nuclei demonstrate two forms of symmetrical amitoses, facing or “kissing” bells and “stacking” bells resembling separation of two paper cups. Remarkably, DNA increase and nuclear fission occur coordinately. Importantly, syncytial bell shaped nuclei undergo asymmetrical amitoses creating organ specific ensembles of up to eight distinct closed nuclear forms, a characteristic required of a stem cell lineage. Closed nuclei emerging from bell shaped nuclei are eukaryotic as demonstrated by their subsequent increases by extra-syncytial mitoses populating the parenchyma of growing anlagen. From 9–14 weeks syncytia fragment forming single cells with bell shaped nuclei that continue to display both symmetrical and asymmetrical amitoses. These forms persist in the juvenile period and are specifically observed in bases of colonic crypts. Metakaryotic forms are found in organogenesis of humans, rats, mice and the plant Arabidopsis indicating an evolutionary origin prior to the divergence of plants and animals.
PMCID: PMC2878747  PMID: 20539738
metakaryote; human; stem cells; metazoans; metakaryotic cells; stem cell lineage; organogenesis
6.  The Cellular Phenotype of Roberts Syndrome Fibroblasts as Revealed by Ectopic Expression of ESCO2 
PLoS ONE  2009;4(9):e6936.
Cohesion between sister chromatids is essential for faithful chromosome segregation. In budding yeast, the acetyltransferase Eco1/Ctf7 establishes cohesion during DNA replication in S phase and in response to DNA double strand breaks in G2/M phase. In humans two Eco1 orthologs exist: ESCO1 and ESCO2. Both proteins are required for proper sister chromatid cohesion, but their exact function is unclear at present. Since ESCO2 has been identified as the gene defective in the rare autosomal recessive cohesinopathy Roberts syndrome (RBS), cells from RBS patients can be used to elucidate the role of ESCO2. We investigated for the first time RBS cells in comparison to isogenic controls that stably express V5- or GFP-tagged ESCO2. We show that the sister chromatid cohesion defect in the transfected cell lines is rescued and suggest that ESCO2 is regulated by proteasomal degradation in a cell cycle-dependent manner. In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found. The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G), indicating that the acetyltransferase activity of ESCO2 is essential for its function. In contrast to a previous study on cells from patients with Cornelia de Lange syndrome, another cohesinopathy, RBS cells failed to exhibit excessive chromosome aberrations after irradiation in G2 phase of the cell cycle. Our results point at an S phase-specific role for ESCO2 in the maintenance of genome stability.
PMCID: PMC2734174  PMID: 19738907
7.  International study of factors affecting human chromosome translocations 
Mutation research  2008;652(2):112-121.
Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from sixteen laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages vs. a linear relationship (p <0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR) = 1.19, 95% confidence interval (CI), 1.09–1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p<0.001). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes.
PMCID: PMC2696320  PMID: 18337160
chromosome translocations; background frequency; controls; fluorescence in situ hybridization

Results 1-7 (7)