bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholangiocarcinomas in japanese and thai patients: Difference in etiology and incidence of point mutation of the c‐KI‐ras proto‐oncogene
Authors: Tsuda Hitoshi , Satarug Soisungwan , Bhudhisawasdi Vajarabhongsa , Kihana Toshimasa , Sugimura Takashi , Hirohashi Setsuo 
Published: February 2007

AbstractPoint‐mutational activation of the c‐Ki‐ras proto‐oncogene has been shown to be rare in human hepatocellular carcinoma, the most common primary liver cancer and one usually associated with chronic viral infection. To reveal the association of c‐Ki‐ras activation with cholangiocarcinogenesis under different etiological backgrounds, the incidence of point mutation at codons 12 and 13 of the c‐Ki‐ras proto‐oncogene was examined in three groups of human liver cancers with differentiation to biliary epithelial cells: Group 1, cholangiocellular carcinoma in Japanese with normal livers; Group 2, cholangiocellular carcinoma in Thais who had lived in an area where the liver fluke Opisthorchis viverrini is endemic; and Group 3, combined hepatocellular‐cholangiocellular carcinoma, a rare type showing features of both hepatocellular and biliary epithelial differentiation, in Japanese with chronic viral hepatitis with or without cirrhosis. The polymerase chain reaction and direct sequencing of its product were used to detect the mutation. Point mutation at codon 12 of the c‐Ki‐ras gene was detected in five (56%) of nine cases in Group 1. In contrast, the mutation was not detected in any of the cases in Groups 2 and 3. Therefore, point‐mutational activation of c‐Ki‐ras did not seem to be involved in the development of primary liver cancers associated with apparent chronic irritation of liver cells or biliary epithelial cells caused by exogenous liver‐fluke or viral infection. On the other hand, point‐mutational activation of the c‐Ki‐ras proto‐oncogene may be involved in cholangiocarcinogenesis in liver without preexisting liver‐fluke or viral infection. © 1992 Wiley‐Liss, Inc.
Modulation of interleukin‐1α mRNA expression in mouse epidermis by tumor promoters and antagonists
Authors: Lee Wha Young , Fischer Susan M. , Butler Andrew P. , Locniskar Mary F. 
Published: February 2007

AbstractIncreased expression of interleukin‐1 (IL‐1) in skin elicits a variety of responses, including inflammation and epidermal hyperplasia, which are also characteristic events elicited by tumor promoters. The goal of this study was to investigate whether various classes of tumor promoters increase expression of IL‐1α and whether phorbol ester—induced IL‐1α expression can be blocked by antitumor promoters. Northern analysis of mRNA isolated from the dorsal skins of SENCAR mice treated with 1 μg of 4β‐12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) showed that a single application of TPA produced a significant increase in IL‐1α mRNA at 6 h that decreased by 24 h after treatment. Two treatments of TPA at 48‐h intervals induced, at 6 h, twice as much IL‐1α mRNA as one treatment. Of the other promoters tested, anthralin (22.6 μg), mezerein (2 μg), calcium ionophore A23187 (120 μg), and benzoyl peroxide (20 mg) induced IL‐1α mRNA with different kinetics and to different extents. On the other hand, the non‐tumor promoting phorbol ester analogue 4α‐12‐O‐tetradecanoylphorbol‐13‐acetate had little effect on the expression of IL‐1α mRNA. The effects of various antitumor promoters on TPA‐induced IL‐1α mRNA expression were also assessed. Fluocinolone acetonide, mepacrine, and 5,8,11,14‐eicosatetraynoic acid were the most effective inhibitors, and each produced about 80% inhibition. Other antitumor promoters such as retinoic acid, N‐tosyl‐l‐phenylalanine chloromethyl ketone, and butylated hydroxytoluene inhibited approximately 35%, 65%, and 50% of TPA‐induced IL‐1α mRNA expression; respectively. Therefore, this study suggests a possible role of IL‐1α in the promotion stage of skin carcinogenesis.
Localization of a novel chromosome 7 locus that suppresses development of N‐methyl‐N‐nitrosourea—induced murine thymic lymphomas
Authors: Angel Joe M. , Morizot Donald C. , Richie Ellen R. 
Published: February 2007

AbstractN‐Methyl‐N‐nitrosourea (MNU) is a potent carcinogen that causes the development of murine thymic lymphomas. MNU‐induced tumor incidence varies considerably among different inbred mouse strains. In particular, the AKR strain is highly susceptible, whereas the C57L strain is highly resistant to MNU‐induced lymphoma formation. Crosses between AKR and C57L mice were established to investigate the genetic basis for the differential susceptibility of these inbred strains. A strong association between MNU‐induced lymphoma development and coat color was observed in (AKR x C57)F2 and AKR x (AKR x C57)F1 progeny such that albino mice developed a higher tumor incidence than nonalbino animals. These data suggest that a locus on chromosome 7 influences tumor development. Analysis of four additional polymorphic loci (D7Rp2, Fes, Hbb, and Int‐2) on chromosome 7 in AKR x (AKR x C57)F1 backcross mice revealed a significant linkage between high tumor incidence and homozygous inheritance of AKR alleles at the albino (tyrosinase) and Hbb loci. Thus, inheritance of at least one C57L allele at the albino or Hbb loci was associated with protection against MNU‐induced lymphoma development. There was no association between tumor incidence and genotype at the D7Rp2, Fes, or Int‐2 loci. Taken together, the data suggest that whereas C57L mice contain a dominant tumor suppressor gene on chromosome 7, in the AKR strain both alleles at this locus are defective resulting in enhanced susceptibility to MNU‐induced lymphomagenesis.
Carcinogen—induced diploid hepatocytes: Sensitive target cells for transformation by mutated c‐Ha‐ras oncogene
Authors: Höhne Martin W. , Zieroth Siegfried , Veser Ulrich , Kahl Georg F. , Schwarz Leslie R. 
Published: February 2007

AbstractSequential treatment of partially (two‐thirds) hepatectomized rats with diethylnitrosamine and 2‐acetylaminofluorene induces the emergence of diploid hepatocytes in rat liver. These carcinogen‐induced diploid cell populations are thought to contain the progenitors of hepatocellular carcinoma (HCC), i.e., initiated, cells. In the study presented here, we addressed the question of whether putative mutations in carcinogen‐induced diploid hepatocytes can cooperate with activated oncogenes in the process of transformation in vitro. Both carcinogenesis in vivo and transformation in vitro have been shown to be multistep processes requiring at least two independent transforming events. Diploid and polyploid rat hepatocytes were isolated by centrifugal elutriation. The purity of the elutriated fractions was 88 ± 3% in the diploid fraction and 84 ± 3% in the polyploid fraction. Hepatocytes from both the elutriated cell fractions and, for comparison, hepatocytes from untreated rats were transfected by electroporation with oncogene expression vectors containing the mutated human T24 c‐Ha‐ras gene and of the N‐myc gene. Transient expression of transfected DNA was similar in both hepatocyte populations. No cell lines could be established by using the N‐myc vector. In contrast, the carcinogen‐induced diploid hepatocytes, but not polyploid hepatocytes, could be converted by transfection with the ras vector into permanent anchorage‐independent growing cell lines with hepatocyte‐like morphology and differentiation. These cell lines expressed the myc proto‐oncogene and transforming growth factor‐α constitutively. Thus, carcinogeninduced diploid hepatocytes are sensitive to tranformation by the ras oncogene, suggesting cooperation between putative preexisting mutations in the diploid cells and the ras oncogene product in hepatocellular transformation.
Expression of fibroblast growth factors in ultraviolet radiation—induced corneal tumors and corneal tumor cell lines from Monodelphis domestica
Authors: Sabourin Carol L. K. , Kusewitt Donna F. , Applegate Lee A. , Budge Cindy L. , Ley Ronald D. 
Published: February 2007

AbstractChronic exposure of the gray, short‐tailed opossum, Monodelphis domestica, to ultraviolet radiation (UVR) induces highly vascularized mesenchymal tumors of the cornea. Cell lines derived from these UVR‐induced corneal tumors and the corneal tumors themselves were examined for the presence of mRNA coding for basic and acidic fibroblast growth factors (FGF), transforming growth factors‐β and ‐α (TGF‐β and TGF‐α), epidermal growth factor (EGF), and tumor necrosis factor‐α (TNF‐α). Basic FGF was expressed in the cell lines derived from corneal tumors and in the corneal tumors. Expression of basic FGF was high in one corneal tumor. Transcripts for acidic FGF were detected only in the corneal tumor cell lines, not in primary tumors. TGF‐β expression was detected in the corneal tumors and tumor‐derived cell lines. TGF‐α, EGF, and TNF‐α transcripts were not detectable in any opossum material; however, homologous gene sequences for TGF‐α and EGF were detected on Southern blots of opossum genomic DNA. Southern blot analysis revealed no evidence of amplification or rearrangement of the genes for basic FGF or acidic FGF in the UVR‐induced corneal tumor that expressed high levels of basic FGF. Opossum basic FGF, which stimulated the proliferation of fetal bovine heart endothelial cells, was purified by heparin affinity chromatography from a UVR‐induced corneal tumor and a corneal tumor cell line. Immunoblotting of opossum basic FGF from a corneal tumor cell line using antiserum to bovine basic FGF showed two prominent immunoreactive bands of 17.5 and 18.5 kDa. Expression of basic FGF and acidic FGF may play a role in the development and progression of UVR‐induced corneal tumors in M. domestica.
Dinitropyrene metabolism, DNA adduct formation, and DNA amplification in an SV40‐transformed chinese hamster embryo cell line
Authors: Neft Robin E. , Roe Amy L. , Smith Beverly A. , Beland Frederick A. 
Published: February 2007

AbstractThe environmental pollutants 1,6‐dinitropyrene (1,6‐DNP) and 1,8‐dinitropyrene (1,8‐DNP) are strongly carcinogenic in a number of animal models. These DNPs are metabolized by nitroreduction to N‐hydroxy arylamine derivatives that either directly or after acetylation bind to cellular DNA. In the experiments reported here, we examined whether DNA adduct formation by 1,6‐DNP and 1,8‐DNP was associated with amplification of specific DNA sequences, a process that may be causally related to tumorigenesis. CO60 cells, an SV40‐transformed Chinese hamster embryo cell line, were incubated with 2.5 or 50 ng/mL [4,5,9,10‐3H]1,6‐DNP for 5 h. Highpressure liquid chromatographic analysis of organic extracts of the medium indicated the presence of 1‐acetylamino‐6‐nitropyrene, suggesting that these cells are capable of nitroreduction and acetylation. 32P‐Postlabeling analysis of DNA isolated from cells exposed to 1.0 or 2.5 ng/mL 1,6‐DNP revealed dose‐related formation of N‐(deoxyguanosin‐8‐yl)‐1‐amino‐6‐nitropyrene. A similar adduct, presumably N‐(deoxyguanosin‐8‐yl)‐1‐amino‐8‐nitropyrene, was detected after incubations with 1,8‐DNP. DNA isolated from analogous experiments was slot‐blotted onto nylon membranes and hybridized with 32P‐labeled SV40, c‐fos, or β‐actin DNA probes. β‐Actin was not amplified and c‐fos was amplified only a small amount; however, there was dose‐related amplification of SV40 sequences, whose levels were in some instances approximately 20 times that observed in solvent‐treated controls. These data indicate that DNA adduct formation by 1,6‐DNP and 1,8‐DNP is associated with the amplification of certain DNA sequences, a response that may be related to the tumorigenic potential of these compounds.
Negative regulation of mitogen‐stimulated, anchorage‐independent cell growth by a tumor‐suppressor gene function
Authors: Afshari Cynthia A. , Barrett J. Carl 
Published: February 2007

AbstractImmortal, nontumorigenic cell lines of Syrian hamster embryo (SHE) cells with different tumor‐suppressing activity were isolated. Subclones from the parental cells were isolated that either had retained (supB+) or lost (supB−) the ability to suppress tumorigenicity after hybridization with tumor cells. The growth properties of these cells were studied to determine how this tumor‐suppressor gene function influences cell growth. When the cells were grown on plastic, their growth properties were similar, and neither cell type grew in soft agar containing 10% serum, which supported the growth of tumorigenic cells. However, in agar supplemented with growth factors and 10% serum, supB− cells formed colonies whereas supB+ cells did not. Efficient growth (colony‐forming efficiencies greater than 20%) of supB− cells was obtained in agar supplemented with serum and a combination of epidermal growth factor (EGF), platelet‐derived growth factor (PDGF), and insulin (EPI) or with serum and basic fibroblast growth factor (BFGF). The effect of EPI and bFGF together was additive. supB+ cells failed to grow under any of these conditions, suggesting that the suppressor gene function blocked the growth response of the cells to multiple growth factors when the cells were suspended in agar. In SupB− cells, transforming growth factor‐β1 and retinoic acid inhibited anchorage‐independent growth response to EPI but not the growth response to bFGF. These observations are consistent with the hypothesis that bFGF stimulates the growth of supB− cells by a signal transduction pathway that differs from the pathway stimulated by EGF or PDGF. Thus, this suppressor gene function may regulate anchorage‐independent growth at some common point in signal transduction for multiple mitogens.
Detection of p53 gene mutations in rat hepatocellular carcinoma cell lines by denaturing gradient gel electrophoresis
Authors: Fukuda Ikue , Ogawa Katsuhiro 
Published: February 2007

AbstractStructural alterations of the p53 gene were investigated in chemically induced rat hepatocellular carcinomas (HCCs), hyperplastic hepatic nodules (HPNs), and cell lines derived from rat neoplastic and normal liver cells. The mutations were detected by GC‐clamped denaturing gradient gel electrophoresis using DNA that had been amplified from p53 mRNA by the reverse transcriptase—polymerase chain reaction. This method enabled us to find single‐base changes within the p53 gene without using radioisotopes. The presence of mutations was subsequently confirmed by DNA sequencing. No mutations were detected in six primary HCCs and 12 HPNs induced by the Solt and Farber regimen (Nature 236:701–703, 1976), suggesting that p53 gene mutations do not play a major role in rat hepatic carcinogenesis. However, five of seven HCC cell lines and one of two cell lines derived from normal liver cells had the mutated p53 gene and had lost the normal p53 gene. Five cell lines had a G→T transversion at various codons, whereas one line had a 21‐base deletion in exon 5. Therefore, we conclude that p53 gene mutations may occur in vitro during establishment of the cell lines or may be derived from very small populations within the primary tumors.
A sensitive restriction fragment length polymorphism method to detect CAA → AAA mutations at codon 61 of Ha‐ras
Authors: Shinder Gayle A. , Manam Sujata , Nichols Warren W. 
Published: February 2007

AbstractA rapid and sensitive assay was developed to detect CAA → AAA mutations at codon 61 of Ha‐ras. The region surrounding codon 61 was amplified by the polymerase chain reaction (PCR) using one primer containing a mismatch at the second position of codon 60. Using this primer creates an Msel restriction enzyme site if codon 61 carries the C·G → A·T transversion. An aliquot of the second PCR primer was 5′‐end‐labeled with 32P to increase the sensitivity of detection of the PCR product. After cleavage with Msel, DNA was electrophoresed on a nondenaturing polyacrylamide gel, and the products were visualized by autoradiography. The sensitivity of this assay was such that the mutation could be detected when present in only one of 200 alleles. DNA samples from spontaneous Crl:CD‐1(ICR)BR mouse liver tumors were analyzed using this method. Nine of 38 samples contained the mutation, and in one of those nine, the mutation had not been previously detected by either direct sequencing of tumor DNA or by sequencing the DNA from NIH 3T3 cells transfected with the tumor DNA.
ras gene activation and aberrant expression of keratin K13 in ultraviolet B radiation—induced epidermal neoplasias of mouse skin
Authors: Sutter Christian , Winter Hermelita , Schweizer Jürgen , Strickland Paul T. , Mukhtar Hasan , Agarwal Rajesh 
Published: February 2007

AbstractBoth papillomas and squamous cell carcinomas (SCC) induced in mouse epidermis by initiation with 7,12‐dimethylbenz[a]anthracene (DMBA) and promotion with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) exhibit aberrant expression of a type I keratin, K13, that is normally characteristic of terminal differentiation of internal stratified epithelia. There is evidence that the aberrant expression of K13 depends on the presence of an activated ras gene in mouse epidermal keratinocytes (Sutter et al., Mol Carcinog 4:467–476, 1991). To assess the general validity of this hypothesis, we investigated both aberrant K13 expression and activation of each of the three members of the ras gene family in epidermal tumors induced in four different mouse strains (SKH‐1hr, SENCAR, BALB/c, and C3H/He) by chronic irradiation with ultraviolet (UV) B. The tumor collection comprised nine papillomas and 30 well or poorly differentiated SCC. Aberrant K13 expression occurred in only five of 39 tumors and was restricted to SCC of both types. This indicates that aberrant K13 expression in UV‐induced epidermal tumors was intrinsically different from that in chemically induced tumors. Polymerase chain reaction analysis of the tumors for different point mutations in codons 12, 13, and 61 of the Ha‐ras and Ki‐ras genes and in codon 61 of the N‐ras gene revealed that only one of the well differentiated tumors from a SKH‐1hr mouse exhibited a GGA → GAA mutation in codon 12 of the Ha‐ras gene. Although this tumor was also positive for aberrant K13 expression, such a correlation could not be made for the remaining K13‐expressing tumors. This indicates that the activation of one of the members of the ras gene family is not a general prerequisite for the aberrant expression of K13 in mouse epidermal keratinocytes. © 1993 Wiley‐Liss, Inc.
Alterations of the Rb gene and its association with ki‐ras activation and p53 inactivation in endometrial adenocarcinoma
Authors: Enomoto Takayuki , Nomura Taisei , Fujita Masami , Inoue Masaki , Nakazawa‐Miyamoto Aiko , Tanizawa Osamu 
Published: February 2007

AbstractAlterations of the retinoblastoma (Rb) gene were evaluated in nine primary endometrial adenocarcinomas that we had previously analyzed for the presence of Ki‐ras activations and p53 alterations and in three endometrial carcinoma cell lines. Loss of mRNA expression in the Rb gene was detected in two of the 12 tumors. Internal deletions of Rb cDNA were observed in two tumors; one was a deletion of exon 21 in a primary carcinoma, and the other was a deletion of exon 8 in one allele in one cell line. Loss of heterozygosity of the Rb gene, which was detectable by polymorphisms in introns 1 and 17, was analyzed using polymerase chain reaction‐restriction fragment length polymorphism analysis in 29 endometrial carcinomas. Of 13 heterozygous cases, two cases (15%) showed loss of heterozygosity. We therefore suggest that alteration of the Rb gene, as well as activation of the Ki‐ras gene and alterations of the p53 gene, plays a significant role in the etiology of endometrial adenocarcinoma.
Loss of heterozygosity: The most frequent cause of recessive phenotype expression at the heterozygous human adenine phosphoribosyltransferase locus
Authors: Zhu Yuan , Tischfield Jay A. , Stambrook Peter J. 
Published: February 2007

AbstractExpression of a recessive phenotype can occur by a number of different mechanisms, such as chromosomal deletion, recombination, and intragenic frameshift mutation or base substitution. To examine the contribution of different mutational events, we isolated and characterized a human fibroblast cell line heterozygous at the adenine phosphoribosyltransferase (APRT) locus. Cells that subsequently lost APRT activity were selected, cloned, and analyzed for the mechanisms contributing to the loss of APRT activity. Loss of APRT activity occurred at a rate of 7.8 x 10‐5 per allele per cell generation. Molecular analysis of DNA from 21 independent APRT‐ clones demonstrated that 62% of mutants had lost the functional allele and that the rest had incurred intragenic mutations. Loss of the functional allele was frequently accompanied by loss of the proximal marker D16S77 but not the more distant proximal marker D16S4, indicating that a high frequency of mitotic recombination or deletion occurred at the region between D16S77 and D16S4 on chromosome 16. Loss of APRT activity in the remaining 38% of the clones was predominantly due to point mutations. These data demonstrate that the mechanisms for loss of heterozygosity at the APRT locus are similar to those found in retinoblastoma and other tumors. The autosomal location of the APRT gene and the ease with which its phenotype can be selected make this gene useful for modeling mutational events at loci important to carcinogenesis.
Mutagenic specificity of the (+)anti‐diol epoxide of dibenz[a,j]anthracene in the supF gene of an Escherichia coli plasmid
Authors: Gill Rosalynn D. , Digiovanni John , Cortez Cecilia , Harvey Ronald G. , Rodriguez Henry , Loechler Edward L. 
Published: February 2007

AbstractThis study was designed to examine the mutagenic specificity of (+)anti‐dibenz[a,j]anthracene 3,4‐diol‐1,2‐epoxide ((+)anti‐DB[a,j]A‐DE) in SOS‐induced repair‐proficient Escherichia coli ES87 (Δpro‐lac, strA)/F′(pro+, laclQ, laclam26, lacZΔM 15). The plasmid pUB3, which contains the mutation target gene, supF, was modified with (+)anti‐DB[a,j]A‐DE in vitro (two to five adducts/plasmid) and then transformed into bacteria by electroporation. The spontaneous mutation frequency for unmodified pUB3 in uninduced cells was about 2 x 10‐6 and for SOS‐induced cells, about 8 x 10‐6. The spontaneous supF‐ mutations were primarily insertions, deletions, and frameshifts. The mutation frequency for (+)anti‐DB[a,j]A‐DE‐modified pUB3 was about 8 x 10‐6 and about 32 x 10‐6 for uninduced cells and SOS‐induced cells, respectively. (+)anti‐DB[a,j]A‐DE induced primarily point mutations in supF in SOS‐induced cells. GC→ transitions were the major mutations observed in SOS‐induced cells (37%). GC→T́ (21%) and GC→C̀ (8.6%) transversion mutations were also observed, whereas mutations at AT base pairs were rare (1.9%). Furthermore, a large number of tandem GC/GC→Ã/AT transition mutations were also observed (about 15% of all mutations in SOS‐induced cells). Taken together, single and tandem GC→Ã mutations accounted for slightly over half (about 51%) of the mutations observed in SOS‐induced cells. These results demonstrated that (+)anti‐DB[a,j]A‐DE was mutagenic in repair‐proficient E. coli; however, unlike other polycyclic aromatic hydrocarbons that induce primarily transversion mutations, (+)anti‐DB[a,j]A‐DE caused mostly GC→Ã transitions.