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Retinoblastoma, a primitive neuroectodermal tumor, is the prototypical model for tumor development following genetic damage 1 ; . Observation of its incidence led to the formulation of the two-hit hypothesis 1, 2 ; . Successful therapy for retinoblastoma frequently in 68% of cases; ref. 3 ; requires loss of one or both eyes for cure. Little is known about the risk factors for development of sporadic noninherited ; retinoblastoma. Identifying risk factors for the occurrence of this disease may help target increased surveillance, potentially facilitating earlier diagnosis, and possibly prevention. Retinoblastoma arises as the result of mutations in both alleles of the retinoblastoma gene, RB1. These mutations occur prezygotically in germ cells initial mutation in bilateral disease ; or postzygotically mutation in the second allele in bilateral disease; mutations in both alleles in unilateral disease ; in retinal cells during fetal development or early infancy 2 ; . Although much is understood about the effects of the RB1 mutations underlying the formation of retinoblastoma, little is known about the etiology of these mutations. New germ-line mutations are known to occur preferentially on the paternal allele, suggesting the implication of paternal preconceptional risk factors 4 ; . However, there is no knowledge about the etiology of retinal cell mutations or their time of occurrence. In retinoblastoma, the crucial period for development of mutations in retinal cells is likely to be during retinal formation, which begins between the 4th and 8th week of gestation 5 ; , and continues through early infancy, with macular differentiation occurring at about 6 months 6 ; . The incidence of unilateral retinoblastoma has been reported to be higher in several less affluent regions of the world 7 ; suggesting that environmental factors associated with poverty may increase the risk of mutagenesis in retinal cells. Incidence of retinoblastoma in Mexico City is 15.1 cases per million infants, and 12.2 per million children between the ages of 1 and 4 8 ; . Among children in the United States, incidence per million children under 5 years is 12 in whites and 15 in blacks 9, 10 ; . A study done within the Mexican Institute of Social Security found that incidence of retinoblastoma occurs primarily among children of blue-collar workers and seems higher in Chiapas, the poorest state of Mexico 11 ; . In the United States, a low level of maternal education seems to confer an elevated risk for the development of sporadic retinoblastoma, whereas supplementation with multivitamins seems to be protective 12 ; . We hypothesize that decreased maternal micronutrient intake during retinal formation may contribute to development of sporadic retinoblastoma. In this study, we investigated whether such a decreased intake during pregnancy is associated with development of sporadic retinoblastoma.
Identified in the recommendations of Undergraduate Program Reviews and has been the subject of interest from colleagues across the Faculties. In part, these discussions also arise from the implications of consideration of a health-related Faculty, as well as the increased coordination of graduate and undergraduate planning. As a result, under the leadership of the Vice-President Academic, and in consultation with affected units, the Deans of three undergraduate Faculties Arts, Atkinson, and Science and Engineering ; and the Dean of Graduate Studies have been meeting throughout the year to discuss issues relating to academic structures and coordination within those Faculties. Progress has been made in relation to the administrative movement of the Faculty of Arts program in Mathematics and Statistics to the Faculty of Science and Engineering, and consolidation of Information Technology programs in the Atkinson Faculty in a new School whose name is yet to be confirmed ; through the movement of Arts programs to Atkinson. Collegial discussions are also ongoing in relation to areas such as Natural Science including Science and Technology and Science and Society programs ; , Communications, Public Policy, and Philosophy. These discussions will continue to be a priority in 2005-2006. Changes resulting from these discussions will be brought to Senate and other bodies for approval, as appropriate.
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JACC Vol. 44, No. 11, 2004 December 7, 2004: 224758 Additionally, the SF-36 used by the researchers as an index of quality of life is, like the BDI, comprised of both mood and somatic items. The investigators report a significant correlation between the BDI and the SF-36; thus, they conclude that depression is associated with lower quality of life in HF patients. The overlapping domain items in the BDI and SF-36, however, may potentially confound this correlation, as the statistical association might, at least in part, reflect the degree to which the scales themselves correlate. Depression and quality of life in patients with HF are significant public health issues that clearly warrant further investigation. As scientists, we must successfully grapple with the thorny issues of construct and scale validity within this population e.g., "what is the nature of depression in HF?" "what is a validated measure of depression in HF?" ; if our research is to advance both the science and the standard of care for HF. * Ronald Freudenberger, MD Stacey C. Cahn, PhD Christine Skotzko, MD, FAPM * 125 Paterson Street Suite 6100 New Brunswick, NJ 08903 E-mail: freuders umdnj and medrol
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Scher, H.I., Kelly, W.M., Zhang, Z.F., Ouyang, P., Sun, M., Schwartz, M., Ding, C., Wang, W., Horak, I.D. & Kremer, A.B. 1999 ; . Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer. J Natl Cancer Inst, 91, 244-51 and mefloquine.
Areas, including certain areas in northern China, Iran and South Africa, dietary carcinogen exposure and nutritional deficiencies are major etiological factors 2, 48 ; . Because nitrosamines have been shown to induce esophageal tumors readily in animals, this class of carcinogens have been suspected to be causative agents for this cancer 911 ; . The formation of DNA adducts in the esophagus of nitrosamine-treated rats and in esophageal cancer tissues of humans have been observed 1214 ; . The tobacco-specific nitrosamines, N -nitrosonornicotine NNN ; and 4- methylnitrosamino ; -1- 3-pyridyl ; -1-butanone NNK ; have been suggested to play a role in human tobaccorelated cancers 15, 16 ; . N-Nitrosodimethylamine NDMA ; is present in cigarette smoke, as well as many other sources 17, 18 ; , and induces liver and kidney tumors in animals 11, 19 ; . NNN has been shown to induce esophageal and nasal cavity tumors in rats 15, 16 ; . On the other hand, NNK has been demonstrated to induce lung tumors but not esophageal tumors in all laboratory animals tested 15, 16 ; . In order to exert their carcinogenic effect, nitrosamines need to be metabolically activated by way of -hydroxylation, leading to the formation of diazohydroxides, which can result in DNA alkylation. NNN and NNK share the common pathway leading to the formation of pyridyloxobutylated DNA adducts 15 ; Figure 1 ; . Pyridyloxobutylation of DNA is believed to be important in NNN and NNK carcinogenesis 15, 16, 20 ; . With the pyridyloxobutylating agent 4- acetoxymethylnitrosamino ; 1- 3-pyridyl ; -1-butanone, it was demonstrated that pyridyloxobutylated DNA increased the persistence of O6-methylguanine adducts by inhibiting O6-alkylguanine transferase 21 ; . Although the 5 -hydroxylation pathway of NNN leads to the formation of DNA adducts have not been detected 15, 22 ; . On the other hand, activation of NNK and NDMA, but not NNN, can lead to the methylation of DNA. Studies have suggested that DNA methylation is more important for NNK lung carcinogenesis 23, 24 ; . The molecular events leading to human esophageal carcinogenesis are not known. Cytochrome P450 P450 ; enzymes are involved in the activation of NNN, NNK and NDMA 2530 ; . Recently, heterologously expressed human P450 2A6 has been shown to metabolize NNN to lactol a 5 -hydroxylation product ; and P450 3A4 catalyzed the formation of keto alcohol a 2 hydroxylation product ; 27 ; . Moreover, a low Km enzyme is present in the esophagus of rats that activates NNN 25 ; . However, the specific P450s that are responsible for the activation of NNN in human esophagus are not known. The organ specificity of NNK and NNN may be due to the presence of specific enzymes in the lung and esophagus, respectively, which selectively bioactivates these tobacco-specific nitrosamines. Glutathione S-transferases GST ; exist in multiple forms and are important in the detoxification of xenobiotics. GSTs are grouped into four classes alpha, pi, mu and theta ; based 667.
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However, cross-resistance among alkylating agents in experimental tumors has received only limited study. The presence or absence of cross-resistance among alkylating agents has major therapeutic implications. If mechanisms for selective cytotoxicity and resistance vary among these drugs, then their use in combination, either concurrently or in sequence, represents a rational therapeutic approach. Indeed, it has been demonstrated experimentally that substantial synergism among alkylating agents can occur 3 ; . The above considerations prompted the present study of acquired resistance, including cross-resistance patterns, to three clinically important alkylating agents, HN2 also called mustargen and mechlorethamine hydrochloride ; , N, N'bis 2-chloroethyl ; -N-nitrosourea BCNU ; , and cis-Pt, in two human cell lines, the Burkitt Raji ; lymphoma and a squamous cell carcinoma SCC25 ; of the head and neck. The term "alkylating agent, " as used in this paper, includes cis-Pt and other compounds with metallation activity and megestrol.
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Oge Tascilar, Gldeniz Karadeniz Cakmak, Ali Ugur Emre, Bulent Hamdi Ucan, Oktay Irkorucu, Kemal Karakaya, Mesut Gl, Mustafa Comert, Department of Surgery, Zonguldak Karaelmas University, The School of Medicine, Kozlu-Zonguldak 67600, Turkey Ishak Ozel Tekin, Department of Immunology, Zonguldak Karaelmas University, The School of Medicine, Kozlu-Zonguldak 67600, Turkey Hseyin Blent Engin, Department of Medical Oncology, Zonguldak Karaelmas University, The School of Medicine, KozluZonguldak 67600, Turkey Correspondence to: Dr. Gldeniz Karadeniz Cakmak, Zonguldak Karaelmas Universitesi, Arastirma ve Uygulama Hastanesi Bashekimligi, Kozlu-Zonguldak 67600, Turkey. gkkaradeniz yahoo Telephone: + 90-372-2610169 Fax: + 90-372-2610155 Revised: August 4, 2007 Received: June 29, 2007 Tascilar O, Cakmak GK, Tekin IO, Emre AU, Ucan BH, Irkorucu O, Karakaya K, Gl M, Engin HB, Comert M. Neural cell adhesion molecule-180 expression as a prognostic criterion in colorectal carcinoma: Feasible or not?. World J Gastroenterol 2007; 13 41 ; : 5476-5480 and melphalan.
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Formed by the single DNA strands of the fragile X triplet repeats: structure and biological implications. Proc. Natl Acad. Sci. USA, 92, 51995203. Mitas, M., Yu, A., Dill, J. and Haworth, I.S. 1995 ; The trinucleotide repeat sequence d CGG ; 15 forms a heat-stable hairpin containing Gsyn.Ganti base pairs. Biochemistry, 34, 1280312811. Nadel, Y., Weisman-Shomer, P. and Fry, M. 1995 ; The fragile X syndrome single strand d CGG ; n nucleotide repeats readily fold back to form unimolecular hairpin structures. J. Biol. Chem., 270, 2897028977. Usdin, K. 1998 ; NGG-triplet repeats form similar intrastrand structures: implications for the triplet expansion diseases. Nucleic Acids Res., 26, 40784085. Mariappan, S.V.S., Catasti, P., Chen, X., Ratliff, R., Moyzis, R.K., Bradbury, E.M. and Gupta, G. 1996 ; Solution structures of the individual single strands of the fragile X DNA triplets GCC ; n. GGC ; n. Nucleic Acids Res., 24, 784792. Darlow, J.M. and Leach, D.R.F. 1998 ; Evidence for two preferred hairpin folding patterns in d CGG ; .d CCG ; repeat tracts in vivo. J. Mol. Biol., 275, 1723. Mariappan, S.V., Silks, III, L.A., Bradbury, E.M. and Gupta, G. 1998 ; Fragile X DNA triplet repeats, GCC ; n, form hairpins with single hydrogen-bonded cytosine.cytosine mispairs at the CpG sites: isotopeedited nuclear magnetic resonance spectroscopy on GCC ; n with selective 15N -labeled cytosine bases. J. Mol. Biol., 283, 111120. 4 Zheng, M., Huang, X., Smith, G.K., Yang, X. and Gao, X. 1996 ; Genetically unstable CXG repeats are structurally dynamic and have a high propensity for folding. An NMR and UV spectroscopic study. J. Mol. Biol., 264, 323336. Yu, A., Barron, M.D., Romero, R.M., Christy, M., Gold, B., Dai, J., Gray, D.M., Haworth, I.S. and Mitas, M. 1997 ; At physiological pH, d CCG ; 15 forms a hairpin containing protonated cytosines and a distorted helix. Biochemistry, 36, 36873699. Darlow, J.M. and Leach, D.R.F. 1998 ; Secondary structures in d CGG ; and d CCG ; repeat tracts. J. Mol. Biol., 275, 316. Romero, R.M., Rojsitthisak, P. and Haworth, I.S. 2001 ; DNA Interstrand crosslink formation by mechlorethamine at a cytosine-cytosine mismatch pair: kinetics and sequence dependence. Arch. Biochem. Biophys., 386, 143153. Romero, R.M., Mitas, M. and Haworth, I.S. 1999 ; Anomalous crosslinking by mechlorethamine of DNA duplexes containing C-C mismatch pairs. Biochemistry, 38, 36413648. Rink, S.M., Solomon, M.S., Taylor, M.J., Raja, S.B., McLaughlin, L.W. and Hopkins, P.B. 1993 ; Covalent structure of a nitrogen mustard-induced DNA interstrand cross-link: an N7-to-N7 linkage of deoxyguanosine residues at the duplex sequence 5-d GNC ; . J. Am. Chem. Soc., 115, 25512557 and mechlorethamine.
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