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51.
Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints 总被引:2,自引:0,他引:2
Lovett BD Strumberg D Blair IA Pang S Burden DA Megonigal MD Rappaport EF Rebbeck TR Osheroff N Pommier YG Felix CA 《Biochemistry》2001,40(5):1159-1170
Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis of leukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint cluster region in a DNA topoisomerase II-dependent manner like the parent drug and the nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1) among the unique sites, which differs from the parent drug. Cleavage at most sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained within the substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays using the same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may be relevant to translocations. 相似文献
52.
Background
Investigation of bioheat transfer problems requires the evaluation of temporal and spatial distributions of temperature. This class of problems has been traditionally addressed using the Pennes bioheat equation. Transport of heat by conduction, and by temperature-dependent, spatially heterogeneous blood perfusion is modeled here using a transport lattice approach. 相似文献53.
Joanne T. Emerman Eveline E. Fiedler Anthony W. Tolcher Patricia M. Rebbeck 《In vitro cellular & developmental biology. Plant》1987,23(2):134-140
Summary We compared the effects of defined medium, fetal bovine serum (FBS) and human serum (HuS) on the growth and responses to chemotherapeutic
agents of human breast cancer cells in primary culture. Normal and tumor tissues were dissociated to small aggregates and
single cells and seeded onto collagen-gel-coated wells in defined medium or medium supplemented with 5% FBS or 5% HuS. In
all cases examined, defined medium and medium containing HuS were superior to medium containing FBS in supporting growth of
both normal and tumor cell cultures. However, cultures in defined medium showed an initial cell loss. Cells from the same
tumor cultured in different media varied in their responses to chemotherapeutic agents. In light of these results, medium
supplemented with HuS, which promoted attachment of these cells in culture and stimulated their growth, should be the most
appropriate nutrient environment for determining the effects of therapeutic agents on cells as it most closely resembles the
in vivo situation. Because there were also variations in growth rates and chemosensitivities of tumor cells cultured in different
human serum samples, we suggest that optimal conditions in which to culture these cells include the serum of the patient whose
tumor is removed. This serum may provide host factors that influence cell growth and interact with exogenous factors.
This work was supported by a grant from the National Cancer Institute of Canada and funds contributed by Mr. B. T. Wharton
in memory of his wife, Nadia. J. T. Emerman is a research scholar of the National Cancer Institute of Canada. 相似文献
54.
T. R. Rebbeck F. J. Couch J. Kant K. Calzone M. DeShano Y. Peng K. Chen J. E. Garber B. L. Weber 《American journal of human genetics》1996,59(3):547-553
The common hereditary forms of breast cancer have been largely attributed to the inheritance of mutations in the BRCA1 or BRCA2 genes. However, it is not yet clear what proportion of hereditary breast cancer is explained by BRCA1 and BRCA2 or by some other unidentified susceptibility gene(s). We describe the proportion of hereditary breast cancer explained by BRCA1 or BRCA2 in a sample of North American hereditary breast cancers and assess the evidence for additional susceptibility genes that may confer hereditary breast or ovarian cancer risk. Twenty-three families were identified through two high-risk breast cancer research programs. Genetic analysis was undertaken to establish linkage between the breast or ovarian cancer cases and markers on chromosomes 17q (BRCA1) and 13q (BRCA2). Mutation analysis in the BRCA1 and BRCA2 genes was also undertaken in all families. The pattern of hereditary cancer in 14 (61%) of the 23 families studied was attributed to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. Five families (22%) provided evidence against linkage to both BRCA1 and BRCA2. No BRCA1 or BRCA2 mutations were detected in these five families. The BRCA1 or BRCA2 status of four families (17%) could not be determined. BRCA1 and BRCA2 probably explain the majority of hereditary breast cancer that exists in the North American population. However, one or more additional genes may yet be found that explain some proportion of hereditary breast cancer. 相似文献
55.
Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat 总被引:16,自引:0,他引:16
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Rebbeck TR Kantoff PW Krithivas K Neuhausen S Blackwood MA Godwin AK Daly MB Narod SA Garber JE Lynch HT Weber BL Brown M 《American journal of human genetics》1999,64(5):1371-1377
Compared with the general population, women who have inherited a germline mutation in the BRCA1 gene have a greatly increased risk of developing breast cancer. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1 mutation carriers. We hypothesize that other genes, particularly those involved in endocrine signaling, may modify the BRCA1-associated age-specific breast cancer risk. We studied the effect of the CAG repeat-length polymorphism found in exon 1 of the androgen-receptor (AR) gene (AR-CAG). AR alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Using a sample of women who inherited germline BRCA1 mutations, we compared AR-CAG repeat length in 165 women with and 139 women without breast cancer. We found that women were at significantly increased risk of breast cancer if they carried at least one AR allele with >/=28 CAG repeats. Women who carried an AR-CAG allele of >/=28, >/=29, or >/=30 repeats were given a diagnosis 0.8, 1.8, or 6.3 years earlier than women who did not carry at least one such allele. All 11 women in our sample who carried at least one AR-CAG allele with >/=29 repeats had breast cancer. Our results support the hypothesis that age at breast cancer diagnosis is earlier among BRCA1 mutation carriers who carry very long AR-CAG repeats. These results suggest that pathways involving androgen signaling may affect the risk of BRCA1-associated breast cancer. 相似文献
56.
Phylogenetic relationships of bolitoglossine salamanders: a demonstration of the effects of combining morphological and molecular data sets 总被引:2,自引:0,他引:2
We analyzed sequence data for 555 bp of the mitochondrial gene cytochrome b
in plethodontid salamanders, taken from 18 ingroup (tribe Bolitoglossini)
and 4 outgroup (tribe Plethodontini) taxa. There were 257 variable sites,
of which 219 were phylogenetically informative. Sequence differences among
taxa exceeded 20%, and there were up to 15% amino acid differences among
the sequences. We also analyzed 37 morphological (including karyological)
characters, taken from the literature. Data were analyzed separately and
then combined using parsimony and likelihood approaches. There is little
conflict between the morphological and DNA data, and that which occurs is
at nodes that are weakly supported by one or both of the data sets. Treated
separately, the morphological and DNA data provide strong support for some
nodes but not for others. The combined data act synergistically so that
good support is obtained for nearly all of the nodes in the tree. Recent
divergences are supported by silent transitions, and older divergences are
supported by a combination of morphological, karyological, DNA
transversion, and amino acid changes. Eliminating silent changes from the
DNA data improves the consistency index and improves some bootstrap and
decay index values for several deeper branches in the tree. However, the
combined data set with all characters included provides a better supported
tree overall. Maximum likelihood and parsimony with all of the data give
not only the same topology but also remarkably similar branch lengths.
Results of this analysis support the monopoly of the supergenera
Hydromantes and Batrachoseps, and of a sister group relationship of
Batrachoseps and the supergenus Bolitoglossa (represented in this study one
species of the genus Bolitoglossa).
相似文献
57.
Lurie G Gaudet MM Spurdle AB Carney ME Wilkens LR Yang HP Weiss NS Webb PM Thompson PJ Terada K Setiawan VW Rebbeck TR Prescott J Orlow I O'Mara T Olson SH Narod SA Matsuno RK Lissowska J Liang X Levine DA Le Marchand L Kolonel LN Henderson BE Garcia-Closas M Doherty JA De Vivo I Chen C Brinton LA Akbari MR;Australian National Endometrial Cancer Study Group;Epidemiology of Endometrial Cancer Consortium 《PloS one》2011,6(2):e16756
Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis. 相似文献
58.
Depending on geographical location, plants are exposed to variable amounts of UVB radiation and herbivore attack. Because the role(s) of UVB in the priming and/or accumulation of plant defence metabolites against herbivores are not well understood, we used field‐grown Nicotiana attenuata plants to explore the effects of UVB on herbivore performance. Consistent with previous reports, UVB‐exposed plants accumulated higher levels of ultraviolet (UV)‐absorbing compounds (rutin, chlorogenic acid, crypto‐chlorogenic acid and dicaffeoylspermidine). Furthermore, UVB increased the accumulation of jasmonic acid, jasmonoyl‐L‐isoleucine and abscisic acid, all phytohormones which regulate plant defence against biotic and abiotic stress. In herbivore bioassays, N. attenuata plants experimentally protected from UVB were more infested by mirids in three consecutive field seasons. Among defence metabolites measured, 17‐hydroxygeranyllinalool diterpene glycosides (HGL‐DTGs) showed strongly altered accumulation patterns. While constitutive HGL‐DTGs levels were higher under UVB, N. attenuata plants exposed to mirid bugs (Tupiocoris notatus) had still more HGL‐DTGs under UVB, and mirids preferred to feed on HGL‐DTGs‐silenced plants when other UVB protecting factors were eliminated by UVB filters. We conclude that UVB exposure not only stimulates UV protective screens but also affects plant defence mechanisms, such as HGL‐DTGs accumulation, and modulates ecological interactions of N. attenuata with its herbivores in nature. 相似文献
59.
Phenotypic variability in X-linked ocular albinism: relationship to linkage genotypes. 总被引:3,自引:1,他引:2
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R. E. Schnur P. A. Wick C. Bailey T. Rebbeck R. G. Weleber J. Wagstaff A. W. Grix R. A. Pagon A. Hockey M. J. Edwards 《American journal of human genetics》1994,55(3):484-496
One hundred nineteen individuals from 11 families with X-linked ocular albinism (OA1) were studied with respect to both their clinical phenotypes and their linkage genotypes. In a four-generation Australian family, two affected males and an obligatory carrier lacked cutaneous melanin macroglobules (MMGs); ocular features were identical to those of Nettleship-Falls OA1. Four other families had more unusual phenotypic features in addition to OA1. All OA1 families were genotyped at DXS16, DXS85, DXS143, STS, and DXS452 and for a CA-repeat polymorphism at the Kallmann syndrome locus (KAL). Separate two-point linkage analyses were performed for the following: group A, six families with biopsy-proved MMGs in at least one affected male; group B, four families whose biopsy status was not known; and group C, OA-9 only (16 samples), the family without MMGs. At the set of loci closest to OA1, there is no clear evidence in our data set for locus heterogeneity between groups A and C or among the four other families with complex phenotypes. Combined multipoint analysis (LINKMAP) in the 11 families and analysis of individual recombination events confirms that the major locus for OA1 resides within the DXS85-DXS143 interval. We suggest that more detailed clinical evaluations of OA1 individuals and families should be performed for future correlation with specific mutations in candidate OA1 genes. 相似文献
60.
Joan E. Pellegrino Roberta A. V. George Jacquelyn Biegel Martin R. Farlow Kathy Gardner Judy Caress Mark J. Brown Timothy R. Rebbeck Thomas D. Bird P. F. Chance 《Human genetics》1997,101(3):277-283
Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder on chromosome 17q, associated with recurrent,
episodic, painful brachial plexus neuropathy. Dysmorphic features, including hypotelorism, long nasal bridge and facial asymmetry,
are frequently associated with HNA. To assess genetic homogeneity, determine the cytogenetic location, and identify flanking
markers for the HNA locus, six pedigrees were studied with multiple DNA markers from distal chromosome 17q. The results in
all pedigrees supported linkage of the HNA locus to chromosome 17. A maximum combined lod score (Ζ = 10.94, £ = 0.05) was obtained with marker D17S939 and the maximum multipoint lod score was 22.768 in the interval defined
by D17S802– D17S939. An analysis of crossovers placed the HNA locus within an approximate 4.0-cM interval flanked by D17S1603
and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid with linked markers suggests that band 17q25 harbors the
HNA locus. These results support genetic homogeneity within HNA and define a specific interval and a precise cytogenetic location
in chromosome 17q25 for this disorder.
Received: 24 June 1997 / Accepted: 21 August 1997 相似文献