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F X Bosch

Publications and source records attributed to F X Bosch.

At least 127 records · Page 7Linked to original sources
PubMed1991

The early genes E6 and E7 of cancer associated human papilloma viruses as targets of tumor suppression?

We have transplanted HPV 18 positive nontumorigenic hybrid cells and tumorigenic hybrid segregants as well as nontumorigenic and tumorigenic human keratinocytes immortalized by HPV 16-DNA transfection (HPK cells and HPK-ras cells) into nude mice and grown them under in vivo conditions for different periods of time. By analyzing gene expression at the mRNA level of the early viral genes E6/E7 and a number of cytoskeletal cellular genes we wanted to test the hypothesis that the nontumorigenic phenotype of these cells in vivo may be determined by the specific downregulation of expression of the oncogenic E6/E7 genes by the product(s) of tumor suppressor gene(s). The results obtained showed that: 1) The nontumorigenic hybrid cells (in contrast to tumorigenic segregants) stopped to proliferate about 3 days after transplantation. At this time E6/E7 gene expression was already drastically reduced, whereas at day 2 expression was still high. This suppression specifically affected the HPV 18 E6/E7 genes and preceded cell death by at least 10 days. 2) The same specific suppression of HPV E6/E7 gene expression occurred during in vivo growth of the nontumorigenic HPK cells. These cells gave rise to transiently growing cysts, but had retained the in vivo differentiation potential of normal keratinocytes (orderly expression of cytokeratins 1 and 10, involucrin and filaggrin). HPV 16 E6/E7 gene expression was very low and clearly restricted to a small subset of basal cells, thus showing an inverse relationship to terminal differentiation. In contrast, in the tumors induced by HPK-ras cells E6/E7 gene expression extended from the basal cells into suprabasal cells and terminal differentiation was retarded. These results support the hypothesis that during in vivo growth tumor suppressor gene(s) negatively regulated HPV E6/E7 gene expression resulting in the stop of proliferation of the nontumorigenic cells.

Animals↗
PubMed1991

Cytoskeletal gene expression in normal and neoplastic human odontogenic epithelia.

In situ and Northern hybridization was carried out to study cytokeratin (Ck) 1, 4, 8, 18, and 19 and vimentin (Vim) gene expression in 13- to 24-week-old human fetal tooth germs, including overlying oral epithelium and odontogenic tumors (N = 6) of epithelial (ameloblastoma) and epithelial-ectomesenchymal (ameloblastic fibroma) origin. The results were compared with immunocytochemistry using monoclonal antibodies. A relatively strong expression of simple epithelial Ck 19 mRNA, together with low, but significant expression of Ck 8 and 18 mRNAs, was demonstrated in all normal and neoplastic odontogenic epithelia studied. Transcripts for squamous differentiation marker, Ck 4, and for terminal differentiation marker, Ck 1, were detected suprabasally in the fetal oral epithelium, focally in the dental lamina but not in the enamel organ. Ck 4 mRNA was expressed variably in most odontogenic tumors studied, whereas Ck 1 mRNA was detected in one ameloblastoma only. Vim mRNA was not found in the fetal oral epithelia, dental lamina or the enamel organ, but a distinct immunoreactivity with monoclonal antibodies to Vim was seen in the stellate reticulum cells of the enamel organ. The epithelium of most ameloblastomas showed a focal Vim mRNA and polypeptide expression. In addition to Vim, the neoplastic ectomesenchymal cells of ameloblastic fibroma coexpressed low amounts of simple epithelial Cks 8, 18, and 19. The results indicate that the differentiation and cytoskeletal gene expression programs of odontogenic epithelia upon neoplastic transformation are not fully retained. Most ameloblastomas and ameloblastic fibromas show differentiation parameters reminiscent of dental lamina. Ameloblastomas seem to form a heterogenous group of tumors, which may originate from odontogenic epithelial cells at various differentiation levels. The origin of ameloblastic fibroma is more closely related to the tooth germ proper.

Ameloblastoma↗
PubMed1991

Aflatoxins: data on human carcinogenic risk.

Some of the major difficulties in assessing the role of aflatoxin (AF) in the causation of liver cancer are discussed. Firstly, exposure to AF in Africa and parts of Asia and Latin America might begin very early in life and episodically thereafter. The number of episodes and the degree of exposure to AF varies greatly by country and region, by agricultural and crop storage practices, by season and by other factors difficult to control in any questionnaire-based study. Secondly, there is a high geographical correlation between exposure to AF and to hepatitis B virus. Thirdly, long-lasting biological markers for AF are still not available. Epidemiological studies might be enhanced by the incorporation of new biological assays. It is to be hoped that better information will be generated as a result of on-going intervention projects, such as reduction of AF levels and agricultural development programmes, and by monitoring exposure to AF and the incidence of liver cancer in areas where hepatitis B virus vaccination is effectively reducing the prevalence of carriers of the viral surface antigen.

Aflatoxins↗
PubMed1990

Risk factors for hepatocellular carcinoma in Catalonia, Spain.

The influence of hepatitis B virus infection, alcohol consumption, tobacco smoking and use of oral contraceptives on the risk of hepatocellular carcinoma (HCC) was evaluated in a hospital-based case-control study in Catalonia, in the Mediterranean coastal area of north-eastern Spain. A total of 96 HCC cases (86.5% of them with associated liver cirrhosis) and 190 age- and sex-matched controls were studied. The odds ratio of HCC and 95% confidence interval among hepatitis B surface antigen (HBsAg) carriers was 4.9 (1.3-21.9). The OR was not significantly elevated in smokers, and a marginally significant increased risk was found among users of oral contraceptives based on 6 female cases. There was a significant dose-response relationship between alcohol consumption and risk of HCC (chi 2 for trend: 24.3, p less than 0.001). Although hepatitis B infection was strongly associated with HCC, alcohol abuse leading to cirrhosis appears to be one of the main causes of HCC in this region.

Adult↗
PubMed1990

Cancer incidence correlations: genital, urinary and some tobacco-related cancers.

Bivariate correlations between sex-specific age-adjusted incidence rates of 10 genital and urinary tract cancer sites and lung cancer were calculated. The data base used was that published in the 5th edition of the series Cancer incidence in five continents. The purpose of the analyses was to test the consistency of the data with the hypothesis of a common risk factor for genital cancers and other cancers of the urinary tract and for lung and genital cancers. The results indicate that the incidence of cervical cancer is strongly correlated with that of cancer of the penis, of other cancers of the female genital tract and of chorioepithelioma. In countries at low/intermediate risk for cervical cancer (mostly developed Western countries), the incidence of cervical cancer is also correlated with that of lung cancer in males. The incidence of male lung cancer is, moreover, strongly correlated with cancers of the prostate, penis, testis, bladder and other urinary tract cancers. These analyses support the views that: urogenital cancers in both sexes might share (a) common risk factor(s), which may be certain types of human papilloma-virus; and that cigarette smoking is likely to be a risk factor for most of these cancers in countries where the use of tobacco has been widespread for a long time. Other suggestive etiological conclusions about less well-studied cancer sites are also presented.

Age Factors↗
PubMed1990

Two genetically defined trans-acting loci coordinately regulate overlapping sets of liver-specific genes.

Mice homozygous for deletions around the albino locus fail to activate expression of a set of neonatal liver functions and die shortly after birth. This phenotype is thought to result from the loss of a positive transacting factor, denoted alf, in deletion homozygotes. Using differential cDNA screening, we isolated and characterized genes whose cell type-specific transcription is affected by alf and found as a common feature that expression of these genes is induced by glucocorticoids and cAMP. Surprisingly, a subset of these alf-responsive genes is negatively controlled by the tissue-specific extinguisher locus Tse-1. Administration of glucocorticoids and cAMP leads to reversal of Tse-1-mediated extinction of these genes. These results show that two trans-acting factors coordinately regulate expression of overlapping sets of liver-specific genes. We suggest that both the lethal phenotype and the extinguished state result from interference with hormone signal transduction.

Animals↗
PubMed1990

A population-based case-control study of colorectal cancer in Majorca. I. Dietary factors.

A population-based case-control study was conducted between July 1984 and February 1988 in the Spanish island of Majorca; 286 incident colorectal cancer cases, 295 population controls and 203 hospital controls were interviewed using a food frequency questionnaire. In a multivariate analysis, an increased risk of colon cancer was found for high consumption of fresh meats (RR = 2.87) while a high consumption of cruciferous vegetables afforded protection (RR = 0.48). For rectal cancer an increased risk was associated with dairy products (RR = 3.08) while a protection was afforded by consumption of cruciferae (RR = 0.50). For colorectal cancer, the cereal food group also showed an increase in risk (RR = 1.92). When cases were compared to hospital controls, the effects of cruciferae in colon and rectum and those of dairy products in rectal cancer remained. The magnitude of the RR estimates was decreased for most comparisons, although in general terms the direction of the associations was the same. In addition, univariate analyses of food groups also suggested significant increases in risk of colorectal cancer for increasing consumption of cereals, potatoes, pastry, eggs and number of meals per day. An indication was found of a reduction in risk for consumers of coffee. An analysis based on risk scores was also conducted and a 4-fold increase in the risk of colorectal cancer and a highly significant statistical trend was found for high consumption of fresh meat, dairy products and cereals combined with low consumption of cruciferae.

Age Factors↗
PubMed1990

Rescue of the albino phenotype by introduction of a functional tyrosinase gene into mice.

The c-locus of the mouse is thought to encode tyrosinase, the key enzyme for melanin synthesis in melanocytes of the skin and the eye. Recently, a mouse cDNA was isolated and shown to confer tyrosine activity on a cell line which expressed no specialized functions for melanin synthesis. To verify that the isolated tyrosinase gene is encoded at the genetically well characterized c-locus, a minigene was assembled from tyrosinase cDNA and tyrosinase genomic DNA and used for generation of transgenic mice. Following microinjection of this construct into fertilized eggs of an albino mouse strain, transgenic mice were obtained which showed pigmentation in skin and eyes. By in situ hybridization, we show expression of the transgene in melanocytes of the hairbulb and in the pigmented cell layers of the eye. We conclude that we have rescued the albino mutation (c/c) by introduction and expression of a functional tyrosinase gene.

Albinism↗
PubMed1990

Suppression in vivo of human papillomavirus type 18 E6-E7 gene expression in nontumorigenic HeLa X fibroblast hybrid cells.

The E6 and E7 genes of the cancer-associated human papillomavirus (HPV) types 16 (HPV16) and 18 (HPV18) can induce cell immortalization in vitro in normal human keratinocytes. This, however, is not associated with tumorigenicity in vivo. On the other hand, tumorigenicity of HPV18-positive HeLa cervical carcinoma cells can be suppressed by fusion of HeLa cells with normal human keratinocytes or fibroblasts. We have addressed the question of whether suppression of tumorigenicity in HeLa x fibroblast hybrid cells might be due to a reduced ability of these cells to express the HPV18 E6-E7 genes in vivo. Nontumorigenic hybrid cells and tumorigenic hybrid segregants were transplanted as organotypical cultures or injected subcutaneously into immunocompromised mice and were analyzed for HPV18 E6-E7 gene expression by RNA-RNA in situ hybridization. The tumorigenic hybrid cells showed a continuous and invasive growth that was associated with high levels of HPV18 E6-E7 mRNAs at all time points examined. In contrast, the nontumorigenic hybrid cells stopped cell proliferation approximately 3 days after transplantation. At this time they expressed the E6-E7 genes at low levels, whereas at day 2 high expression levels were observed. However, the mRNA levels of the cytoskeletal genes beta-actin and vimentin remained high for at least 14 days, demonstrating that inhibition of growth and of HPV18 E6-E7 gene expression was not due to cell death. These results suggest that growth inhibition of the nontumorigenic HeLa x fibroblast hybrid cells in vivo might be caused by suppression of HPV18 E6-E7 gene expression and are compatible with the idea of an intracellular surveillance mechanism for HPV gene expression existing in nontumorigenic cells.

Blotting, Northern↗
PubMed1990

Multistage theory of carcinogenesis: the epidemiological evidence for liver cancer.

Experimentalists have developed 2 stage carcinogenesis models within which initiation and promotion can be phenomenologically defined. For humans, no comparable sequential exposure situations have been studied, and the concepts of initiation and promotion cannot be defined in the same way that they have been for animal experiments. Nevertheless, there are epidemiological studies of human cancer which provide information on the effect of age at exposure, cessation of exposure and level of exposure on cancer risk which can be used to classify carcinogens according to their apparent mode of action. For the recognized human liver carcinogens, the available epidemiological data are not yet sufficiently detailed to permit clear conclusions about their role in multistage carcinogenesis.

Aflatoxins↗
PubMed1989

Extensive changes in cytokeratin expression patterns in pathologically affected human gingiva.

The stratified squamous epithelium of the oral gingiva and the hard palate is characterized by a tissue architecture and a cytoskeletal composition similar to, although not identical with, that of the epidermis and fundamentally different from that of the adjacent non-masticatory oral mucosa. Using immunocytochemistry with antibodies specific for individual cytokeratins, in situ hybridization and Northern blots of RNA with riboprobes specific for individual cytokeratin mRNAs, and gel electrophoresis of cytoskeletal proteins of microdissected biopsy tissue samples, we show changes in the pattern of expression of cytokeratins and their corresponding mRNAs in pathologically altered oral gingiva. Besides a frequently, although not consistently, observed increase in the number of cells producing cytokeratins 4 and 13 (which are normally found as abundant components in the sulcular epithelium and the alveolar mucosa but not in the oral gingiva) and a reduction in the number of cells producing cytokeratins 1, 10 and 11, the most extensive change was noted for cytokeratin 19, a frequent cytokeratin in diverse one-layered and complex epithelia. While in normal oral gingiva cytokeratin 19 is restricted to certain, sparsely scattered cells of --or near--the basal cell layer, probably neuroendocrine (Merkel) cells, in altered tissue of inflamed samples it can appear in larger regions of the basal cell layer(s) and, in apparently more advanced stages, also in a variable number of suprabasal cells. Specifically, our in situ hybridization experiments show that this altered suprabasal cytokeratin 19 expression is more extended at the mRNA than at the protein level, indicating that cytokeratin 19 mRNA synthesis may be a relatively early event during the alteration. These changes in cytokeratin expression under an external pathological influence are discussed in relation to other factors known to contribute to the expression of certain cytokeratins and with respect to changes occurring during dysplasia and malignant transformation of oral epithelia.

Blotting, Northern↗
PubMed1989

Cytokeratins and cytokeratin filaments in subpopulations of cultured human and rodent cells of nonepithelial origin: modes and patterns of formation.

Using immunofluorescence microscopy, we observed that in several established cell culture lines derived from different nonepithelial tissues and species, cells spontaneously emerge, usually at low frequencies, which contain cytoplasmic structures decorated by antibodies specific for cytokeratins 8 and 18. This phenomenon was further examined at both the protein (gel electrophoreses of cytoskeletal proteins, followed by immunoblotting) and the RNA (Northern blots, "nuclear run-on" analysis, in situ hybridization) level. Positive cell lines included simian virus (SV40)-transformed human fibroblasts (HF-SV80, WI-38 VA13), human astrocytic glioma cells (U333 CG/343MG), rat (RVF-SMC) and hamster (BHK-21/13) cells derived from vascular smooth muscle and murine sarcoma MS-180 cells. In two cell lines (HF-SV80 and BHK-21/13), the frequency of the cytokeratin-containing cells and of the cytokeratin fibril arrays per cell was drastically increased upon treatment with 5-azacytidine. The structural appearance of the cytokeratins was variable in the different cell lines but could also differ among cells of the same culture: While small granular or comma-shaped structures or bizarrely shaped filament arrays prevailed in WI-38, RVF and normally grown BHK-21 cells, most of the other lines revealed extended normal-looking, fibrillar arrays. In one line (MS-180), the appearance of cytokeratins was associated with a morphological change, as it was only found in a subpopulation of cells that had lost their typical elongated and spindle-shaped phenotype and assumed a rounded ("coccoid") shape. Our results show that the expression of the genes encoding cytokeratins 8 and 18 is not necessarily restricted to programs of epithelial differentiation and that factors stochastically effective appear in cultured cell lines that allow the synthesis of these cytoskeletal components. Mechanisms possibly involved in this spontaneous and selective advent of cytokeratins 8 and 18 and implications for tumor diagnosis are discussed.

Animals↗
PubMed1988

Blood, retinol and zinc riboflavin status in relation to precancerous lesions of the esophagus: findings from a vitamin intervention trial in the People's Republic of China.

Data from a double-blind intervention trial in China are reanalyzed to explore auxiliary information. The trial had shown that in a high-risk area for esophageal cancer the dietary supplementation of apparently healthy individuals with a combination of retinol, riboflavin, and zinc did not lead to a different prevalence of precancerous lesions of the esophagus among those receiving the active treatment compared to a placebo group. However, improvement of blood retinol and zinc levels were also observed in the placebo group. The logistic regression analysis presented in this paper illustrates that those individuals who showed large increases in retinol, riboflavin, and zinc blood levels were more likely to have a histologically normal esophagus at the end of the trial. This effect is clearer for retinol than for riboflavin and zinc and it is independent of whether the change was caused by the active treatment or occurred otherwise.

Adult↗
PubMed1988

Molecular characterization and expression of the stratification-related cytokeratins 4 and 15.

A number of human cytokeratins are expressed during the development of stratified epithelia from one-layered polar epithelia and continue to be expressed in several adult epithelial tissues. For studies of the regulation of the synthesis of stratification-related cytokeratins in internal tissues, we have prepared cDNA and genomic clones encoding cytokeratin 4, as a representative of the basic (type II) cytokeratin subfamily and cytokeratin 15, as representative of the acidic (type I) subfamily, and determined their nucleotide sequences. The specific expression of mRNAs encoding these two polypeptides in certain stratified tissues and cultured cell lines is demonstrated by Northern blot hybridization. Hybridization in situ with antisense riboprobes and/or synthetic oligonucleotides shows the presence of cytokeratin 15 mRNA in all layers of esophagus, whereas cytokeratin 4 mRNA tends to be suprabasally enriched, although to degrees varying in different regions. We conclude that the expression of the genes encoding these stratification-related cytokeratins starts already in the basal cell layer and does not depend on vertical differentiation and detachment from the basal lamina. Our results also show that simple epithelial and stratification-related cytokeratins can be coexpressed in basal cell layers of certain stratified epithelia such as esophagus. Implications of these findings for epithelial differentiation and the formation of squamous cell carcinomas are discussed.

Amino Acid Sequence↗
PubMed1988

Expression of simple epithelial type cytokeratins in stratified epithelia as detected by immunolocalization and hybridization in situ.

Multi-layered ("stratified") epithelia differ from one-layered ("simple") polar epithelia by various architectural and functional properties as well as by their cytoskeletal complements, notably a set of cytokeratins characteristic of stratified tissue. The simple epithelial cytokeratins 8 and 18 have so far not been detected in any stratified epithelium. Using specific monoclonal antibodies we have noted, in several but not all samples of stratified epithelia, including esophagus, tongue, exocervix, and vagina, positive immunocytochemical reactions for cytokeratins 8, 18, and 19 which in some regions were selective for the basal cell layer(s) but extended into suprabasal layers in others. In situ hybridization with different probes (riboprobes, synthetic oligonucleotides) for mRNAs of cytokeratin 8 on esophageal epithelium has shown, in extended regions, relatively strong reactivity for cytokeratin 8 mRNA in the basal cell layer. In contrast, probes to cytokeratin 18 have shown much weaker hybridization which, however, was rather evenly spread over basal and suprabasal strata. These results, which emphasize the importance of in situ hybridization in studies of gene expression in complex tissues, show that the genes encoding simple epithelial cytokeratins can be expressed in stratified epithelia. This suggests that continual expression of genes coding for simple epithelial cytokeratins is compatible with the formation of squamous stratified tissues and can occur, at least in basal cell layers, simultaneously with the synthesis of certain stratification-related cytokeratins. We also emphasize differences of expression and immunoreactivity of these cytokeratins between different samples and in different regions of the same stratified epithelium and discuss the results in relation to changes of cytokeratin expression during fetal development of stratified epithelia, in response to environmental factors and during the formation of squamous cell carcinomas.

Antibodies, Monoclonal↗
PubMed1988

Prospects for epidemiological studies on hepatocellular cancer as a model for assessing viral and chemical interactions.

Chronic infection with hepatitis B virus (HBV) accounts for 1-10% of hepatocellular carcinoma (HCC) in low-risk countries and for 56-94% in high-risk populations. However, although HBV is perhaps the second most important human carcinogen so far identified, chronic HBV infection is neither a sufficient nor a necessary cause of HCC. Other factors must be causally related to HCC, and some of them have been identified: aflatoxins, tobacco smoking, and use of alcohol and oral contraceptives. The evidence for an association between these factors and HCC is reviewed, as well as their joint effects. Finally, prospects for epidemiological research on HCC, and specifically the assessment of viral and chemical interactions, are discussed.

Aflatoxins↗