bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of calcium‐dependent protein kinase C isoforms in the early stages of diethylnitrosamine‐induced rat hepatocarcinogenesis
Authors: Perletti Gian Paolo , Piccinini Francesco , La Porta Caterina A. M. , Comolli Roberto 
Published: February 2007

AbstractThe profiles of the calcium‐dependent protein kinase C (PKC) isozymes α, β, and γ were examined in subcellular fractions from Fischer 344 rat liver during the early stages (48 h, 96 h, 7 d, and 60 d) of diethylnitrosamine (DEN)‐induced carcinogenesis, using the Solt‐Farber “resistant hepatocyte” model (DEN‐2‐acetylaminofluorenepartial hepatectomy; DEN‐AAF‐PH), and then related to the presence of focal or nodular m̀‐glutamyl transpeptidase (GGT)—positive morphologic changes in the liver. After DEAE and hydroxyapatite column chromatograaphy, two peaks, immunologically identified as PKC‐α and ‐β isoforms, were detected in the liver of normal (α/β ratio=4.0) and treated rats. In DEN‐AAF‐PH hepatocarcinogenesis an increase in PKC‐α expression was found after PH ( + 43 ± 19% at 48 h, α/β ratio=5.1; + 125 ± 25% at 96 h, α/β ratio=4.8), whereas the PKC‐β isoform appeared less significantly modified (+ 11 ± 3% at 48 h and + 89 ± 17% at 96 h). Seven and 60 days after PH, a marked increase in the PKC‐α ( + 96 ± 20% and + 150 ± 48%, respectively) and PKC‐β isoforms (+ 158 ± 41%, α/β ratio=3.1 and + 130 ± 26%, α/β ratio=4.4, respectively), occurred along with the appearance of GGT‐positive altered hepatic foci and nodules in the liver sections. Sham hepatectomy caused PKC‐α and ‐β isoform activities similar to those of normal controls. In contrast, saline‐AAF‐PH‐treated rats had downregulation of PKC‐α after PH (α/β ratio=1.8 at 96 h), possibly due to the mitoinhibitory effect of the carcinogen AAF on normal uninitiated hepatocytes. Immunohistochemical analysis with monoclonal antibodies to PKC‐α and ‐β revealed diffuse positive cytoplasmic signals in GGT‐positive foci and nodules in rat liver. Taken together, these preliminary results, using the Solt‐Farber model of liver carcinogenesis, suggest a role for PKC in tumor promotion. They also suggest that the PKC‐α isoform may play a specific role in clonal expansion of DEN‐initiated hepatocytes after PH.
Mutations and expression of the p53 gene in rat bladder carcinomas and cell lines
Authors: Asamoto Makoto , Mann Angela M. , Macatee Timothy L. , Cohen Samuel M. 
Published: February 2007

AbstractAbnormalities of the p53 gene are frequently observed in human tumors, including urinary bladder carcinoma, suggesting that p53 plays an important role in human carcinogenesis. However, its role in rat bladder carcinogenesis is unclear. We investigated p53 gene mutations and expression in rat urinary bladder carcinogenesis in vivo and in Vitro. Fifteen urothelial cell lines, including six untransformed (nontumorigenic) ones, six transformed (tumorigenic) in vitro, and three derived from tumors induced in vivo, were examined for p53 expression by immunochemical analysis and for p53 mutations; in addition, 81 rat bladders were analyzed immunohistochemically for p53 expression, and 23 rat bladder tumors were analyzed for p53 mutations. Four cell lines had mutations in the p53 gene. Two of these were missense point mutations, and the other two were splicing mutations. On the other hand, no mutations were found in the bladder tumors induced in rats. By immunoprecipitation with PAb240, which is supposed to be specific for mutant p53, we detected mutations in three of the cell lines; PAb240 did not react with wild‐type p53. However, in all cell lines and in growing populations of primary cultured bladder urothelial cells, p53 expression was detected immunohistochemically or by western blotting using PAb240 or PAb 421 monoclonal antibodies. In a high percentage of transitional cell carcinomas, wild‐type p53 expression was detected by immunohistochemical analysis with PAb240. These results suggest that p53 gene mutations may not occur frequently in rat bladder carcinogenesis in vivo but may occur in vitro and that p53 overexpression detected immunohistochemically is common and may be related to cell proliferation rather than to the presence of mutations in rat bladder carcinogenesis. © 1994 Wiley‐Liss, Inc.
Association of elevated levels of protein kinase C‐ζ mrna and protein with murine B‐lymphocytic neoplasia
Authors: Goodnight Joanne , Mischak Harald , Mushinski J. Frederic 
Published: February 2007

AbstractExpression of mRNA for protein kinase C(PKC)‐α, ‐β, ‐γ, ‐δ, ‐ϵ, ‐ζ, and ‐η has been shown, by polymerase chain reaction‐generated isozyme‐specific probes, to be cell‐type‐ and differentiation‐stage‐specific in mouse hemopoietic cells. Recently, we cloned a 2.2‐kb mouse PKC‐ζ cDNA. In this study, we used the nearly full‐length cDNA PKC‐ζ probe to demonstrate that expression of PKC‐ζ was significantly elevated in lymphocytic neoplasms at both the mRNA and protein levels. Normal brain, kidney, and liver contain 2.4‐ and 4.4‐kb mRNAs, whereas normal lymphoid organs (spleen, thymus, and lymph nodes) express barely detectable amounts of PKC‐ζ. These vanishingly small levels of PKC‐ζ mRNA did not increase when polyclonal spleen B‐cell proliferation and differentiation were induced in vivo with anti—immunoglobulin D antiserum or in vitro with lipopolysaccharide. In contrast, 2.4‐kb transcripts of PKC‐ζ are abundant in virtually all neoplastic B‐lymphocytic cell lines. Furthermore, additional transcripts of a novel size, about 7 and 8 kb, were found in several mature B‐cell lymphomas and plasma cell tumors. Western blot analysis of protein extracts from normal B cells and hemopoietic tumors confirmed that these quantitative differences in PKC‐ζ mRNA also exist at the protein level. That is, only trace amounts of PKC‐ζ protein were detectable in pro‐B cells and pre‐B cells, but abundant amounts of this isoform were found in protein extracts from most B‐cell lymphomas and plasma cell tumors. These findings suggest that this atypical member of the PKC multigene family participates in the multistep process of malignant transformation of lymphocytes.
Lack of concordant p53 mutations in some paired primary and metastatic mouse squamous cell carcinomas induced by chemical carcinogenesis
Authors: Zhang Shi‐Yu , Bauer Brett , Mitsunaga Shin‐Ichiro , Goodrow Tamra L. , Klein‐Szanto Andres J. P. 
Published: February 2007

AbstractWe studied the frequency and pattern of p53 mutations in 16 mouse skin primary squamous carcinomas induced by chemical carcinogens and their 19 matched metastases. The molecular changes were analyzed by polymerase chain reaction‐single‐strand conformation polymorphism and subsequent direct sequencing analysis. Eleven mutations of the p53 gene were detected in a total of eight primary tumors, and 10 mutations were detected in nine metastases. Only four pairs had identical mutations in primary and paired metastatic tumors. Eight mutations in six pairs were detected in primary tumors but not in their metastases, and four mutations from three matched pairs were detected in metastases but not in primary tumors. The four pairs that contained the same mutations in both the primary and secondary tumors had lymph‐node metastases, and all mutations occurred in exon 8. Conversely, five of six pairs with p53 mutations only in primary tumors had lung metastases and only one of the mutations occurred in exon 8. None of the mutations found only in metastases were located in exon 8. These data indicate that p53 mutations are prevalent in lymph‐node metastases and infrequent in lung metastases of mouse skin tumors and that primary tumors with exon 8 mutations may be more likely to metastasize to the lymph nodes. © 1995 Wiley‐Liss Inc.
Differential mutagenicity and cytotoxicity of (±)‐benzo[a]pyrene‐trans‐7,8‐dihydrodiol and (±)‐anti‐benzo[a]pyrene‐trans‐7,8‐dihydrodiol‐9, 10‐epoxide in genetically engineered human fibroblasts
Authors: Quan Taihao , Reiners John J. , Culp Sandra J. , Richter Patricia , States J. Christopher 
Published: February 2007

AbstractDNA repair–deficient (xeroderma pigmentosum group A (XPA)) and DNA repair‐proficient (normal) human skin fibroblasts were genetically engineered by transformation with a controllable human cytochrome P450 (CYP)1A1 expression vector. Induction of CYP1A1 enabled these cells to metabolize (±)‐benzo[a]pyrene‐trans‐7,8‐dihydrodiol (BPD) into a potent cytotoxicant and mutagen. The XPA cells were more susceptible than the normal cells to the cytotoxic effects of both CYP1A1‐metabolized BPD and exogenously supplied (±)‐antibenzo[a]pyrene‐trans‐7,8‐dihydrodiol‐9, 10‐epoxide (BPDE). Furthermore, the differential cytotoxicity between XPA and normal cells induced by CYP1A1‐metabolized BPD was 8.4‐fold greater than that induced by exogenously supplied BPDE. The two cell lines had similar CYP1A1 activities, suggesting that a difference in metabolic potential was not the cause of the differential response to BPD. At comparable cytotoxicity in both XPA and normal cells, BPD treatment induced more mutants and more DNA adducts than BPDE treatment did. At similar levels of DNA adducts in XPA cells, the levels of cytotoxicity induced by CYP1A1‐metabolized BPD and exogenously supplied BPDE were similar, but CYP1A1‐metabolized BPD induced a threefold higher hypoxanthine phosphoribosyltransferase mutation frequency. In contrast, at similar levels of adducts in CYP1A1‐expressing normal cells, BPD induced less cytotoxicity and a lower mutation frequency. DNA adducts were identified and quantified by 32P‐postlabeling analyses. The principal adduct formed by both CYP1A1‐metabolized BPD and exogenously supplied BPDE was 10‐β‐(deoxyguanosin‐N2‐yl)‐7β,8α,9α‐trihydroxy‐7,8,9,10‐tetrahydrobenzo[a]pyrene, indicating that the differential effects of BPD‐ and BPDE‐induced adducts were not due to a difference in the types of adducts formed. The results of these studies suggest that CYP1A1‐metabolized BPD may form adducts preferentially in transcriptionally active genes or that the intracellular concentration of BPDE may influence the balance between cytotoxicity and mutagenicity (or both). © 1995 Wiley‐Liss Inc.
Expression of β1 integrin receptors in transformed mouse epidermal keratinocytes: Upregulation of α5β1 in spindle carcinoma cells
Authors: Gomez Manuel , Cano Amparo 
Published: February 2007

AbstractThe adhesive properties and the expression of extracellular matrix receptors of the β1‐integrin subfamily were analyzed in transformed epidermal keratinocyte cell lines of different stages of mouse skin carcinogenesis. One‐ and two‐dimensional analyses of the immunoprecipitates obtained with anti‐β1‐ and specific anti‐α‐integrin subunits showed qualitative and quantitative changes in the expression of β1 integrins by the different cell lines. The polyvalent α3β1 integrin was expressed by all analyzed cell lines, although the levels detected in undifferentiated spindle CarC cells were lower than those present in the rest of keratinocyte cell lines. In contrast, spindle cells expressed high levels of the specific fibronectin receptor α5β1, whereas this integrin was absent or expressed at very reduced levels in the other epithelial cell lines. Expression of α5β1 integrin in spindle cells appeared organized in cell‐substratum contact areas on spread cells. In addition, high and homogenous expression of α5β1 was detected in fully undifferentiated tumors induced in nude mice by three independent spindle cell lines. These results suggest that the expression of α5β1 integrin is upregulated during the development of spindle cell carcinomas that occur in the last stages of mouse skin carcinogenesis and can be associated with the acquisition of the fibroblastoid phenotype of spindle cells. On the other hand, expression of the collagen receptor α2β1 was demonstrated in a transformed cell line (PDV), and it was apparently also expressed in two other malignant keratinocyte cell lines (PDVC57 and HaCa4). The expression of α2β1 was correlated with the increased adhesion to collagen type I and Collagen type IV exhibited by the tumorigenic cell lines. © 1995 Wiley‐Liss Inc.
Contribution of O6‐methylguanine‐DNA methyltransferase to monofunctional alkylating‐agent resistance in human brain tumor—derived cell lines
Authors: Bobola Michael S. , Blank A. , Berger Mitchel S. , Silber John R. 
Published: February 2007

AbstractThe DNA repair protein O6‐methylguanine‐DNA methyltransferase (MGMT) has been implicated in resistance of human brain tumors to alkylating agents. We observed that 14 human medulloblastoma‐ and gliomaderived cell lines differ in sensitivity to the methylating agent N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG), as shown by their 28‐fold range in 10% survival dose (LD10). By using the substrate analogue inhibitor O6‐benzylguanine (O6‐BG), we showed that the contribution of MGMT to resistance varies widely, as evidenced by 3‐ to 30‐fold reductions in LD10 among the lines, and varies up to 20‐fold among subpopulations of individual lines. Importantly, variability in resistance, manifested as a 20‐fold range in LD10, persists after measurable MGMT is eliminated, disclosing differential contributions of other resistance mechanisms to survival. Cells exposed to MNNG while suspended in growth medium are more resistant than cells alkylated as subconfluent monolayers, and MGMT accounts for a smaller proportion of their resistance. Notably, the MGMT content of the lines is not statistically correlated with MNNG resistance or with potentiation of killing by O6‐BG, even though MGMT is a biochemically demonstrated determinant of resistance. In contrast, the same lines vary less in resistance to the ethylating agent N‐ethylnitrosourea (ENU), and MGMT makes only a small contribution to resistance. Our results strongly indicate that resistance to both MNNG and ENU is multifactorial. © 1995 Wiley‐Liss, Inc.
Analysis of v‐Ha‐ras and v‐fos oncogene transduction into a mouse epidermal cell line with “initiated” phenotype in culture but normal skin phenotype in vivo
Authors: Ueda Masato , Kawamura Hideki , Sutter Christian , Glick Adam , Yuspa Stuart H. , Strickland James E. 
Published: February 2007

AbstractCell line SCR722 was derived from adult SENCAR mouse epidermal cells initiated in culture by treatment with the carcinogen N‐methyl‐N′‐nitro‐N‐nitrosoguanidine and selection for foci proliferating in medium with calcium levels that induce terminal differentiation in normal cells. Expansion of one of these foci and two additional cell clonings produced cell line SCR722, which was near‐tetraploid and formed normal skin when grafted to athymic nude mouse hosts. However, unlike normal keratinocytes, SCR722 cells fail to suppress papilloma formation when grafted along with papilloma cell line SP‐1. For optimum growth in culture, SCR722 cells required fibroblast‐conditioned medium and 0.5 mM Ca2+. SCR722 cells had a wild‐type c‐Ha‐ras gene but had lost their requirement for conditioned medium in culture and produced dysplastic papillomas in grafts when transduced with the v‐Ha‐ras gene. SCR722 cells stably expressing the v‐fos gene produced normal epidermis in grafts, but when these cells were transduced with the v‐Ha‐ras gene, they produced carcinomas. Clones with greater expression of the transfected v‐fos gene had a more invasive phenotype in vivo. These results indicate that carcinogen treatment of epithelial cells can result in an altered but nontumorigenic phenotype that may be at risk for becoming a more advanced neoplastic state with additional genetic alterations. © 1995 Wiley‐Liss. Inc.
Overexpression of MDM‐2 mRNA and mutation of the p53 tumor suppressor gene in bladder carcinoma cell lines
Authors: Cheng Ya‐Tse , Li Yu‐Ling , Wu Jeng Dau , Long Shih‐Bin , Tzai Tzong‐Shin , Tzeng Ching‐Cherng , Lai Ming‐Derg 
Published: February 2007

AbstractTo investigate the importance of oncogenes and tumor suppressor genes in bladder carcinogenesis, we determined the status of the expression of the MDM‐2 and p53 genes and genetic alterations in the p53 gene in five bladder carcinoma cell lines and one kidney urothelial carcinoma cell line. Overexpression of MDM‐2 mRNA was observed in three bladder carcinoma cell lines, J82, SCaBER, and BFTC‐905. Amplification of the MDM‐2 gene was not detected in any of the six cell lines by Southern analysis. The deletion in the p53 gene was observed in J82, and point mutation was detected in J82 and BFTC‐909, the kidney urothelial carcinoma cell line. In contrast, no mutations were found in codons 12, 13, and 61 in the Ha‐ras and Ki‐ras genes in these six cell lines. These results indicate that alterations in the p53‐regulated pathway are important in bladder carcinogenesis. © 1995 Wiley‐Liss, Inc.
p53 gene mutational spectra in hepatocellular carcinomas induced by 2‐acetylaminofluorene and N‐nitroso‐2‐acetylaminofluorene in rats
Authors: Ho Yuan‐Soon , Cheng Hui‐Teng , Wang Ying‐Jan , Lin Jen‐Kun 
Published: February 2007

AbstractIn this study, the mutation frequencies of the p53 gene in rat hepatocellular carcinomas (HCCs) induced by N‐nitroso‐2‐acetylaminofluorene (NO‐AAF) and 2‐acetylaminofluorene (AAF) were 19.23% (20 of 104) and 31.1% (33 of 106), respectively. Four noteworthy features of the mutation spectrums of the p53 gene in HCCs induced by both NO‐AAF and AAF were observed: (i) There was preferential clustering of mutations at exons 5–8 in both the NO‐AAF or AAF groups, (ii) Nearly all the mutations (98%) induced by NO‐AAF and AAF were point mutations, (iii) A high frequency of the p53 mutations were transition mutations, and the ratios of transition to transversion in the NO‐AAF and the AAF group were 13:6 and 21:12, respectively. Almost all the mutations were G→A transitions and guanosine was the major target base. (iv) The frequency and base location of p53 mutations were significantly associated with cancer cell differentiation. In poorly differentiated HCCs (58 individual tumor samples), mutations were detected in 24 of 58 samples (41.1%) and clustered mostly in exons 7 and 8 (19 of 24 samples), whereas in well‐differentiated HCCs (105 individual tumor samples), the incidence of mutations was low (one of 10 in the AAF group, 17 of 95 in the NO‐AAF group), and the mutations were located in exon 5 (11 of 18). The biological significance of these different mutational spectra among p53 genes deserves further investigation. © 1995 Wiley‐Liss, Inc.
Environmental health science research and human risk assessment
Authors: Olden Kenneth , Klein Jean‐Louis 
Published: February 2007

AbstractEnvironmental health science research, with its focus on fundamental science and disease prevention, is important for the development of rational and cost‐effective public health and regulatory policies related to environmental protection. Environmentally related diseases are preventable, yet they impose a major burden on society in terms of human suffering and costs related to health care. Similarly, the expenditure of hundreds of billions of dollars for regulatory compliance is a major economic concern. There is considerable debate regarding current regulatory risk assessment practices for environmental agents. Implicit in all risk assessment schemes is the need to extrapolate from high‐exposure studies to low‐exposure situations and from known risks in rodents to probable risks in people. Both extrapolations are fraught with uncertainties. These uncertainties are accommodated in risk‐assessment schemes by the incorporation of arbitrary “safety factors” and other default approaches. Since these factors are not derived experimentally, they may overestimate or under estimate actual risks. Risk‐assessment methodology, its relevance to the human condition, and its use in protecting human health will greatly improve when our expanding knowledge of the basic biology of environmental effects is incorporated into toxicological testing and risk‐assessment schemes. Moreover, exciting opportunities now exist to advance our understanding of the environmental and genetic bases of many common diseases and to design effective prevention and interventi on strategies to combat their development. This report discusses some of the current opportunities and challenges.© 1995 Wiley‐Liss, Inc
Strain‐dependent differences in DNA synthesis and gene expression in the regenerating livers of C57BL/6J and C3H/HeJ mice
Authors: Bennett L. Michelle , Farnham Peggy J. , Drinkwater Norman R. 
Published: February 2007

AbstractC3H/HeJ(C3H) mice are approximately 50‐fold more susceptible to liver‐tumor induction than C57BL/6J(B6) mice. This difference in susceptibility is a consequence of allelic differences in hepatocarcinogen sensitivity(Hcs) genes that control the growth of preneoplastic lesions in the liver. We have shown previously that these two strains differ in their responses to partial hepatectomy, which acts as a promoter of hepatocarcinogenesis in B6 mice but not in C3H mice. To determine whether there are also strain‐specific differences in normal regulation of hepatic growth, we compared liver regeneration in C3H and B6 mice at the levels of DNA synthesis and gene expression. Partial hepatectomy induced a cascade of controlled events resulting in the regeneration of the liver to its original mass 11 d after surgery. We observed a two‐fold greater level of DNA synthesis in C3H mice relative to B6 mice during the first peak of DNA synthesis, which occurred 35 h after hepatectomy in both strains. While the c‐fos transcript was readily induced in both strains, there was a reduction in the expression of the late response genes E2F1 and dihydrofolate reductase in the livers of B6 mice when compared with the expression of these transcripts in the livers of C3H mice. The differential regulation of E2F1 between B6 and C3H mice may indicate that the Hcs genes and E2F1 function in the same signal‐transduction pathway of normal growth control.© 1995 Wiley‐Liss, Inc
Integrated capacity, demand, and production planning with subcontracting and overtime options
Authors: Merzifonluoğlu Yasemin , Geunes Joseph , Romeijn H.E. 
Published: February 2007

AbstractModels for integrated production and demand planning decisions can serve to improve a producer's ability to effectively match demand requirements with production capabilities. In contexts with price‐sensitive demands, economies of scale in production, and multiple capacity options, such integrated planning problems can quickly become complex. To address these complexities, this paper provides profit‐maximizing production planning models for determining optimal demand and internal production capacity levels under price‐sensitive deterministic demands, with subcontracting and overtime options. The models determine a producer's optimal price, production, inventory, subcontracting, overtime, and internal capacity levels, while accounting for production economies of scale and capacity costs through concave cost functions. We use polyhedral properties and dynamic programming techniques to provide polynomial‐time solution approaches for obtaining an optimal solution for this class of problems when the internal capacity level is time‐invariant. © 2007 Wiley Periodicals, Inc. Naval Research Logistics, 2007