bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low frequency of CDKN2 mutation in endometrial carcinomas
Authors: Peiffer Stacia L. , Bartsch Detlef , Whelan Alison J. , Mutch David G. , Herzog Thomas J. , Goodfellow Paul J. 
Published: February 2007

AbstractThe CDKN2 gene on chromosome 9p21 encodes the p16 inhibitor of cyclin D/cyclin‐dependent kinase 4 complexes. Mutations and deletions of CDKN2 have been frequently identified in cell lines, whereas most primary tumors have demonstrated a lower frequency of alteration. To assess the role of CDKN2 in endometrial tumorigenesis, 34 tumor samples were examined for loss of heterozygosity at 9p21 and mutation in CDKN2. To identify tumors that had lost 9p21, samples were genotyped with markers flanking the CDKN2 locus. The frequency of CDKN2 mutation in endometrial carcinomas was determined by single‐strand conformation variant analysis and direct sequencing of variants. Of the 34 tumors examined, three revealed loss of 9p21 sequences. Two samples were characterized by point mutations in CDKN2, one of which also showed loss of 9p21 sequences. © 1995 Wiley‐Liss, Inc.
p53 mutation without allelic loss and absence of mdm‐2 amplification in a transplantable hamster pancreatic ductal adenocarcinoma and derived cell lines but not primary ductal adenocarcinomas in hamsters
Authors: Okita Shunji , Tsutsumi Masahiro , Onji Morikazu , Konishi Yoichi 
Published: February 2007

AbstractAn investigation of p53 gene mutation by single‐stranded conformation polymorphism analysis of polymerase chain reaction products followed by direct sequencing and of murine double minute 2 (mdm‐2) gene amplification by Southern blot analysis was performed, using a series of hamster pancreatic duct adenocarcinomas: 18 primary adenocarcinomas induced by N‐nitrosobis(2‐oxopropyl)amine, a transplantable adenocarcinoma (HPD), and three cell lines derived from HPD (HPD1NR, HPD2NR, and HPD3NR). A mutation in the p53 gene was detected at codon 197, resulting in an amino acid change from leucine to phenylalanine, in both HPD and the three cell lines but in none of the 18 primary adenocarcinomas. In the three HPD cell lines, which were confirmed to contain only cancer cells, a normal p53 gene allele was retained. Immunohistochemical investigation of p53 expression using polyclonal antibody Ab‐7 revealed positive nuclear staining in the HPD and two back‐transplanted tumors derived from HPD1NR and HPD2NR but not in the 18 primary adenocarcinomas. mdm‐2 gene amplification was not detected in 18 primary adenocarcinomas or any of the tumor cell lines. The results suggest that a p53 gene mutation without allelic loss, together with overexpression of p53 protein, may be a genetic alteration involved in the progression stage of multistep pancreatic carcinogenesis in hamsters and that mdm‐2 gene amplification is not important for this process. © 1995 Wiley‐Liss, Inc.
Dietary energy restriction‐induced modulation of protein kinase C ζ isozyme in the hamster pancreas
Authors: Nair Satish C. , Toshkov Ilia A. , Yaktine Ann L. , Barnett Tracy D. , Chaney William G. , Birt Diane F. 
Published: February 2007

AbstractDietary restriction in experimental animals enhances life span, delays disease, inhibits immunological perturbations, and ameliorates cancer. Protein kinase C(a) isozymes mediate signals generated by hormones, growth factors, and neurotransmitters for cell proliferation and differentiation. The results of our study showed that a C‐terminally directed anti‐PKC ζ antibody detected an 81–kDa band in the pancreases of control and energy‐restricted hamsters. Syrian golden hamsters were fed energy‐restricted diets formulated such that the hamsters received 90%(10% energy restriction(a) ), 80%(20% ER), or 60%(40% ER) of the total energy consumed by control hamsters, with the energy reduced proportionally from fat and carbohydrate. ER decreased PKC ζ isozyme levels by 40–75% in hamsters fed 10, 20, and 40% ER diets for 8 wk. PKC ζ isozyme expression was decreased by 75–80% in hamsters fed ER diets for 15 wk. Although ER caused significant decreases in PKC ζ isozyme levels compared with those of control hamsters at both time points, the relative differences in PKC ζ levels between the dietary ER groups(10, 20, and 40%) were small and not significant. A significant decrease in the body weights of ER animals compared with those of controls was observed at both time points. No differences in tomato lectin and phytohemagglutinin reactivity were observed between control animals and animals fed 10, 20, and 40% ER diets. Furthermore, the cellular expression of PKC ζ in the hamster pancreas did not differ among hamsters fed the various ER diets. These observations may be important for understanding not only the role of dietary ER in pancreatic cancers but also PKC ζ signal transduction mechanisms in normal pancreatic physiology.© 1995 Wiley‐Liss, Inc
Effects of genetic background on tumorigenesis in p53‐deficient mice
Authors: Donehower Lawrence A. , Harvey Michele , Vogel Hannes , McArthur Mark J. , Montgomery Charles A. , Park Sang H. , Thompson Timothy , Ford Richard J. , Bradley Allan 
Published: February 2007

AbstractMice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53‐deficient mice(p53+/− and p53−/−) and their wild‐type littermates(p53+/+) of two different genetic backgrounds(129/5v and mixed C57BL/6 × 129/5v) up to 2 yr of age.p53+/− and p53−/− 129/Sv mice show accelerated tumorigenesis rates compared with their p53‐deficient counterparts of mixed C57BL/6 × 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53−/− males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 × 129/Sv mice and never in 129/Sv p53+/− males. In the study reported here, we further characterized the lymphomas that arose in the p53‐nullizygous mice and found that over three‐quarters of the lymphomas were of thymic origin and contained primarily immature(CD4+/CD8+) T‐cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B‐cell type. The high incidence of early‐onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li‐Fraumeni syndrome, a human inherited cancer predisposition.© 1995 Wiley‐Liss, Inc
Molecular genetic basis of renal carcinogenesis in the Eker rat model of tuberous sclerosis(Tsc2)
Authors: Hino Okio , Kobayashi Etsuko , Hirayama Youko , Kobayashi Toshiyuki , Kubo Yoshiaki , Tsuchiya Haruo , Kikuchi Yasushi , Mitani Hiroaki 
Published: February 2007

AbstractWe have recently identified on rat chromosome 10q a germline mutation in the tuberous sclerosis gene(Tsc2), the gene predisposing to renal carcinoma(a) in the Eker rat. The homozygous mutant condition is lethal at around the 13th day of fetal life. In heterozygotes, RCs invariably develop in the first year of life. Histologically, RCs develop through multiple stages from early preneoplastic lesions(i.e., phenotypically altered tubules) to adenomas. The wild‐type allele mutation has been found even in the earliest preneoplastic lesions, fitting Knudson's two‐hit hypothesis and supporting the hypothesis that Tsc2 is a tumor suppressor gene. In this study, homozygous deletion of the Ink4 homologue on rat chromosome 5q was observed in 14 of 24(58%) RC‐derived cell lines. This may represent involvement of a second tumor suppressor gene, contributing to tumor progression. Considering previous results of studies of homozygous deletion of the ifnα gene in five of 24 cases(21%) and the Ifnβ gene in one of 24 cases(4%), the order of the genes may be Ink4–Ifna— Ifnβ Microsatellite instability was not observed in 26 Eker rat tumors.© 1995 Wiley‐Liss, Inc
Predictions of rodent carcinogenicity testing results: Interpretation in light of the lave‐omenn value‐of‐information model
Authors: Omenn Gilbert S. , Stuebbe Seth , Lave Lester B. 
Published: February 2007

AbstractThe recent National Institute of Environmental Health Sciences/National Toxicology Program Carcinogen Prediction Challenge elicited a valuable array of predictions of the carcinogenicity of chemicals tested in the lifetime rodent bioassay. The data warrant additional analyses of the similarities and differences of the predictive methods. We provide here analyses of the sensitivity, specificity, and false‐positive/false‐negative tendencies of the different sets of predictions. Our value‐of‐information model provides guidance to testing agencies and regulatory agencies in determining the social value of additional information and setting up the framework for assessing the social consequences of different test strategies and nontest predictive methods. These considerations deserve attention in the second round of the Carcinogen Prediction Challenge.© 1995 Wiley‐Liss, Inc
Mutational spectra in the lacl gene in skin from 7, 12‐dimethylbenz[a]anthracene‐treated and untreated transgenic mice
Authors: Gorelick Nancy J. , Andrews Julie L. , Gu Marie , Glickman Barry W. 
Published: February 2007

AbstractTransgenic mice carrying the bacterial lacl gene in a lambda shuttle vector were used to isolate and characterize background and 7, 12‐dimethylbenz[a]anthracene(a) ‐induced mutations in skin. Adult male mice were treated once topically with either DMBA or acetone or were left untreated. Seven days later, DMBA treatment had significantly increased the mutant frequency in the skin(mean ± SEM, 36 ± 3 × 10−5) versus in vehicle‐treated(6.4 ± 1.2 × 10−5) and untreated mice(7.1 ± 1.0 × 10−5). At least 10 mutants from each of three DMBA‐treated and three untreated mice were selected for DNA sequence analysis. In each case, the entire 1080‐bp target gene was sequenced. Base‐pair substitutions predominated(86 of 96 mutations), although frameshift and deletion mutations were also detected. Twelve percent of the mutants carried more than one mutation. In controls, the mutations were predominantly GC → AT transitions(26 of 42), and no AT → TA transversions were recovered. In contrast, in the DMBA‐treated mice, AT → TA transversions represented 42% of the mutations(23 of 54) and GC → AT transitions accounted for only 11%. The AT → TA transversions occurred mostly at 5′‐CA sites. This class of mutation has been recovered frequently in ras genes from DMBA‐treated mice and probably represents an early event in carcinogenesis(Nelson MA et al., Proc Natl Acad Sci USA 89:6398–6402, 1992). Our present results are consistent with the types of DNA damage induced by DMBA. The observation of different mutant frequencies and spectra in treated and control mice demonstrates the utility of this approach in the study of mutagenesis in vivo.© 1995 Wiley‐Liss, Inc
Delay of dimethylbenz[a]anthracene‐induced mammary tumorigenesis in transgenic mice by apoptosis induced by an unusual mutant p53 protein
Authors: Li Baolin , Kittrell Frances S. , Medina Daniel , Rosen Jeffrey M. 
Published: February 2007

AbstractMurine p53 containing an Arg → Leu substitution at amino acid 172 possesses many properties characteristic of wild‐type p53, including the ability to induce p21/WAF/Cip1 and apoptosis. To determine if p53–dependent apoptosis plays a critical role in mammary tumorigenesis, transgenic mice were generated in which the expression of this mutant p53 protein was targeted to the mammary gland by using the rat whey acidic protein gene promoter. Mice bearing pituitary isografts were treated with 7,12–dimethylbenz[a]anthracene (a) and examined for mammary tumor development. Mice overexpressing the p53 transgene exhibited a statistically significant increase in apoptosis in the mammary gland and a statistically significant decrease in the incidence of DMBA‐induced mammary tumors. No difference in tumor incidence was observed in mice without pituitary isografts who were treated with DMBA, because the transgene is not overexpressed in the absence of hormone stimulation provided by the pituitary isograft. The unexpected wild‐type properties of the 172Arg→Leu mutant p53, including its ability to stimulate apoptosis, make it a possible candidate for use in gene therapy protocols. ©1995 Wiley‐Liss, Inc.
Frameshift mutation in codon 176 of the p53 gene in rat esophageal epithelial cells transformed by benzo[a]pyrene dihydrodiol
Authors: Wang Dian , You Liang , Sneddon Jeff , Cheng Shu‐Jun , Jamasbi Roubadeh , Stoner Gary D. 
Published: February 2007

AbstractMutations in the p53 tumor suppressor gene have been associated with exposure to environmental chemical carcinogens. Cultured rat esophageal epithelial cells were transformed in vitro by treatment with benzo[a]pyrene dihydrodiol (BP‐DHD). A BP‐DHD‐transformed cell line and control cell lines were analyzed for mutations in the p53 gene and in the Ha‐ras gene by single‐strand conformation polymorphism analysis of polymerase chain reaction‐amplified products and direct DNA sequencing. The deletion of one cytosine in codons 174–176 (TGCCCCCAC → TGCCCCAC) of the p53 gene was found only in the BP‐DHD‐transformed cell line. The BP‐DHD‐transformed cells were highly invasive and tumorigenic when transplanted into syngeneic rats, whereas control lines either were nontumorigenic or formed epithelial cysts. BP‐DHD‐transformed cells and control lines were negative for mutations in the Ha‐ras gene. Our results suggest that the tumorigenic potential of the BP‐DHD‐transformed cell line is associated with a frameshift mutation in codon 176 of the p53 gene but not with mutations in the Ha‐ras gene. The G/C‐rich codons 174–176 in the ratp53 gene may be specific targets for BP‐DHD. ©1995 Wiley‐Liss, Inc.
Expression of c‐myc in altered hepatic foci induced in rats by various single doses of diethylnitrosamine and promotion by 0.05% phenobarbital
Authors: Deguchi Takeshi , Pitot Henry C. 
Published: February 2007

AbstractAmong the proto‐oncogenes examined by northern blot analysis, c‐myc, c‐Ha‐ras, c‐fos, and c‐raf‐1 have been reported to be activated in rat liver cell carcinomas. However, there are relatively few reports on proto‐oncogene expression in altered hepatic foci (a) early during hepatocarcinogenesis in the rat. In this study, diethylnitrosamine (a) at doses ranging from 10 to 200 mg/kg was used to initiate and phenobarbital (0.05%) to promote AHF in rats. AHF were detected by the presence of the marker enzymes glutathione s‐transferase, placental form (GST‐P); γ‐glutamyltranspeptidase (a); glucose‐6‐phosphatase (G6Pase); and canalicular ad‐enosine triphosphatase (a). Proto‐oncogene expression in individual AHF was investigated by in situ hybridization (a). ISH for the mRNAs of c‐Ha‐ras, c‐fos, and c‐raf‐1 revealed little or no expression in AHF. However, the levels of c‐myc mRNA were increased in about 10% of the AHF initiated by the highest dose of DEN (200 mg/kg). Thus, altered expression of proto‐oncogenes was not seen in AHF initiated by nonnecrogenic doses of DEN and promoted by phenobarbital. However, at the necrogenic dose of 200 mg/kg DEN, c‐myc expression was found mostly in AHF in which abnormal expression of GST‐P, GGT, G6Pase, and ATPase was also present, indicating that c‐myc expression is correlated with phenotypically greater complexity of the AHF, a characteristic of malignant hepatic neoplasms in the rat. © 1995 Wiley‐ Liss, Inc.
Distribution of the DNA adducts of 2‐amino‐3–methylimidazo[4,5–f]quinoline and 2–amino‐1–methyl‐6–phenylimidazo[4,5–b]pyridine in the supF gene as determined by polymerase arrest assay
Authors: Endo Hisashi , Schut Herman A. J. , Snyderwine Elizabeth G. 
Published: February 2007

AbstractThe distribution of the adducts of the cooked meat‐derived heterocyclic amines 2–amino‐3–methylimidazo 4,5–flquinoline (a) and 2–amino‐1–methyl‐6–phenylimidazo[4,5–b]pyridine (a) was examined in the supF gene of PSP 189 by a polymerase‐arrest assay using thermal‐cycle sequencing. The reactive N‐acetoxy metabolites of both compounds showed an overwhelming preference for reacting with guanine residues in the supF gene of the shuttle vector pSP189. The distribution of the IQ and PhIP guanine adducts was not random; instead, patterns of adduct hot‐spots and cold‐spots were observed. There was a striking similarity between both compounds in their preferred sites of adduct formation. The finding that IQ and PhIP adducted to guanine concurred with previous results showing that the target sites for IQ and PhIP mutations in supF were also at guanine. However, the adduct hot‐spot sites were not predictive of the known sites of mutation hot‐spots. In addition, despite the similarity in adduct hot‐spots for IQ and PhIP, their reported mutation spectra in the supF gene were different. Factors in addition to adduct location therefore appear to play a role in the mutation spectra induced by the heterocyclic amines in the supF gene. © 1995 Wiley‐ Liss, Inc.
Molecular analysis of a family of cyclin‐dependent kinase inhibitor genes (p15/MTS2/INK4b and p18/INK4c) in non‐small cell lung cancers
Authors: Kawamata Norihiko , Miller Carl W. , Koeffler H. Phillip 
Published: February 2007

AbstractCyclin and cyclin‐dependent kinase (a) complexes play important roles in modulating the cell cycle. The CDK inhibitors (a) inhibit the kinase activities of these complexes and block the cell cycle. The p16/multiple tumor suppressor (MTS) 1/inhibitor of CDK4 (INK4) a/CDKN2 gene, a CDKI, is frequently deleted in a variety of human cancers. Recently another CDKI gene, p15/MTS2/INK4b, was cloned and localized to within 20kb of the p16 gene. Moreover, a third CDKI gene, named p18/INK4c and having a high degree of protein homology to p16, has now been cloned. To elucidate the importance of these CDKI genes in non‐small cell lung cancers (a), we examined DNAs from 34 NSCLC samples for alterations in these genes by Southern blot and polymerase chain reaction (a) ‐single‐strand conformational polymorphism (a) analyses. Matched control normal tissues from the same individuals were also examined. Homozygous deletions of the p15 gene were found in three cases. Furthermore, comparative PCR analysis confirmed these deletions and suggested that one additional case had an abnormality of the p15 gene. Neither rearrangements nor deletions of the p18 gene were detected. By PCR‐SSCP and direct sequencing of the aberrantly migrating bands, we detected only polymorphic nucleotide substitutions in both the p15 and p18 genes. In summary, the frequency of deletions of the p15 gene was 12% (four of 34 cases), and no point mutations in the p15 gene were detected in the NSCLCs. For the p18 gene, no abnormalities were detected. A previous analysis of these NSCLC samples for p16 gene alterations revealed that the three cases with homozygous deletions of the p15 gene also have homozygous deletions of the p16 gene. © 1995 Wiley‐ Liss, Inc.
Infrequent Ha‐ras mutations and absence of Ki‐ras, N‐ras, and p53 mutations in 4‐nitroquinoline 1‐oxide‐induced rat oral lesions
Authors: Suzui Masumi , Yoshimi Naoki , Tanaka Takuji , Mori Hideki 
Published: February 2007

AbstractThe alkylating agent 4‐nitroquinoline 1‐oxide (4‐NQO) is a powerful carcinogen and induces squamous cell hyperplasia, squamous cell dysplasia, papilloma, and squamous cell carcinoma (a) in rat oral epithelia. Oral cancers induced by a single application of 4‐NQO develop through a multistage process in a way similar to the development of this cancer in humans. In this study, mutations in exons 1 and 2 of Ki‐ras, N‐ras, and Ha‐ras and exons 4–7 of p53 were examined by polymerase chain reaction (a) ‐single strand conformation polymorphism (a) analysis, followed by PCR‐direct sequencing for the confirmation of mutations. Samples for the mutation analysis were obtained from dysplasias, papillomas, and SCCs on the tongue epithelia induced in F344 rats by adding 4‐NQO (20 ppm) to their drinking water for 8 wk. The Ha‐ras mutations (61A→T transversions in the second position) were found in five of 29 (17%) samples (one dysplasia and four SCCs). However, no mutations were detected in either Ki‐ras, N‐ras, or p53 under two different conditions of PCR‐SSCP analysis. We suggest that some neoplasms in oral carcinogenesis induced by 4‐NQO may involve Ha‐ras mutations but not mutations in Ki‐ras, N‐ras, or p53. The 4‐NQO‐induced rat oral carcinogenesis model may provide a system for evaluation of the mechanisms of multistage oral carcinogenesis associated with Ha‐ras mutation without Ki‐ras, N‐ras, or p53 mutation. © 1995 Wiley‐ Liss, Inc.
Bladder diary measurements in asymptomatic females: functional bladder capacity, frequency, and 24‐hr volume
Authors: Amundsen Cindy L. , Parsons Matthew , Tissot Bill , Cardozo Linda , Diokno Ananias , Coats Alfred C. 
Published: February 2007

AbstractAimsTo study the effects of age and 24‐h volume (V24) on bladder diary measurements of voiding frequency (F24) and functional bladder capacity (FBC) from an asymptomatic female population. Also, to use these data to develop clinical reference values. (We use FBC as a generic term for bladder diary volume‐per‐void measurements.)Materials and MethodsComputer‐processed 3‐day bladder diaries were collected from 161 females (median age: 46.6 years; range = 19.6–81.8 years) claiming no urological symptoms, previous pelvic surgery and diseases and medications effecting urologic function. Regression analysis was used to investigate relationships among age, FBC and V24.ResultsBoth FBC and F24 increase as V24 increases (P < 0.0005). With aging, F24 increases (P = 0.026) and FBC may decrease slightly (P = 0.02–0.08). There is a concave downward, curvilinear relationship between age and V24. We used multiple regression to generate tables of FBC and F24 “normal limits” adjusted for these simultaneous influences of V24 and age. Removing their relationships to age reduces the variability of FBC and F24 reference values by 50% and 20%, respectively.ConclusionsOur finding, supported by others, that, with increasing V24, FBC increases more than F24 suggests an adaptive mechanism that adjusts FBC to urine production to minimize changes in voiding frequency. We illustrate adjustment of reference values for age and V24 by calculating traditional clinical “normal limits.” However, the probable large overlap between “normal” and “abnormal” suggests that it may be more useful to report bladder diary measurements as reference population percentiles rather than to designate them “normal” or “abnormal”. Neurourol. Urodynam. 26:341–349, 2007. © 2007 Wiley‐Liss, Inc.
Comment on reinterpreting the pollen data from Dos Cabezas
Authors: Reinhard Karl J. , Bryant Vaughn M. , Vinton Sheila Dorsey 
Published: February 2007

AbstractThe published pollen analysis of the Dos Cabezas giants, Geyer et al. (2003), lists a variety of purported dietary pollen types. The paper also hypothesises that the giants were poisoned with plant toxins. We have severe reservations about the pollen evidence of diet and poisoning. We suggest that the analysts made several errors in their interpretation. Firstly, some of the discovered pollen types are not prehistoric endemics to the Dos Cabezas region of coastal Peru. These include the pollen of fava beans (cultivated in the Old World), and specified species of agave and sage. We believe that some or all of the identifications of pollen from arracacha, maca, yuca, oca, potato, peanut, ciruela and tarwi are in error based on the distance they grow from Dos Cabezas and/or their ecological/pollination requirements. We think that it is unlikely that the giants were poisoned because the poisons made from six poisonous plants are not made from the flowers and five of them grow on the opposite side of the Andes from Dos Cabezas. We present an alternative dietary interpretation of the Dos Cabezas giants and suggest methods by which palynological analysis could be improved. Copyright © 2007 John Wiley & Sons, Ltd.