Biomedical subjects
L Gissmann
Publications and source records attributed to L Gissmann.
Identification of papillomaviral DNA sequences in hairless mouse tumours induced by ultraviolet irradiation.
Papillomas, carcinomas in situ and squamous cell carcinomas were induced using ultraviolet irradiation in the hairless mouse strain Mus musculus HRA/Skh. DNA extracted from biopsies was examined using Mastomys natalensis papillomaviral DNA as a hybridization probe at reduced stringency. Sequences homologous to the probe were detected in 16 of 24 papillomas, five of five carcinomas in situ and six of 38 squamous cell carcinomas. A number of tumour DNAs (16/33) also hybridized with mixed DNAs of human papillomavirus types 11, 13, 16 and 18 at reduced stringency. This suggests a role for the hairless mouse as a laboratory model for the study of the involvement of papillomaviruses in malignant transformations.
Human papillomavirus type 48.
The cloning and partial characterization of the genome of human papillomavirus (HPV) type 48 is presented. Hybridization and short DNA sequence analyses permitted the alignment of the genome to the HPV genetic map.
Human papillomavirus type 53.
The cloning and partial characterization of the genome of human papillomavirus type 53 is presented. The virus is a distinct type and is most closely related to human papillomavirus type 30.
Immune response to papillomavirus infections.
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Experimental evidence on oncogenicity of papillomaviruses.
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Correlation of modified human papilloma virus early gene expression with altered growth properties in C4-1 cervical carcinoma cells.
In cervical carcinomas and cell lines derived from these tumors the DNA of specific types of human papilloma viruses (HPVs) is integrated into the host cell genome. The two viral open reading frames E6 and E7 are consistently transcribed in tumors and cell lines, and the respective proteins were detected in cells cultured in vitro. As shown here, modulation of HPV 18 E6 and E7 gene expression in C4-1 cervical carcinoma cells is accompanied by an altered cell growth. HPV 18 E6 and E7 expression can be enhanced by glucocorticoid treatment of C4-1 cells, and an increased cell proliferation is observed. In contrast, after introduction of complementary RNA to the HPV 18 E6 and E7 open reading frames, their expression is inhibited, and decreased cell growth is observed. These results support the hypothesis that expression of HPV E6 and E7 open reading frames is directly involved in growth regulation of cervical carcinoma cells.
Human papillomavirus preceding intraepithelial neoplasia in serial cervical smears.
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Detection of individual virus-infected cells by filter in situ hybridization.
The diagnosis of virus infection by nucleic acid hybridization represents an alternative to classical virological diagnostic methods. One special technique termed 'filter in situ hybridization' consists of fixation of intact cells to nitrocellulose filters followed by hybridization with a labelled DNA probe. We demonstrate that filter in situ hybridization can be a simple and sensitive method for the detection of virus infection in cells. In an in vitro model system using a human B-lymphoma cell line infected by the lymphotropic papovavirus (LPV), it is shown that individual virus replicating cells can be detected by this method. Infection can be diagnosed even if only one out of 20,000 cells in a culture contains replicating virus. This assay may be of value as a diagnostic tool in other viral systems.
Subclinical human papillomavirus infections in male sexual partners of female carriers.
The male sexual partners of 156 women with human papillomavirus infection of the cervix uteri were examined. In 120 men (77 per cent) penile lesions were found on examination of the penis via a colposcope (peniscopy) the most common of which were flat acetowhite lesions (53 per cent). Predilection sites of lesions were the urethral meatus and the corona glandis (23 and 19 per cent of the lesions, respectively). Using filter in situ hybridization human papillomavirus-deoxyribonucleic acid was found in penile smears of 61 men (39 per cent). The cancer-associated viral types (human papillomavirus 16 and 18) were identified in 75 per cent of the human papillomavirus positive men. Viral types of sexual partners were identical in 87 per cent. The correlation between infections with human papillomavirus 16 and 18, and the severity of the cervical lesion was significant in corresponding sexual partners. Our results support the hypothesis that male sexual partners represent a risk factor by acting as a reservoir for genital infections with papillomaviruses. The majority of human papillomavirus infections are of subclinical character. They require sensitive diagnostic techniques, such as peniscopy and hybridization for their identification. Detection and treatment of subclinical human papillomavirus infection in men may be important for the prevention of genital cancer in women.
Transcriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer, and by viral E2 trans-activator and repressor gene products: implications for cervical carcinogenesis.
The transcriptional promoter of the candidate E6-E7 transforming gene region of human papillomavirus (HPV)-16 (P97) was active in transiently transfected cervical carcinoma cells when linked to the HSV-1 tk or bacterial cat genes. Sequences 5' to P97 contain a short enhancer element responding to cellular factor(s) in uninfected human foreskin keratinocytes and in cervical carcinoma cells, but not in human or animal fibroblasts. The E2 trans-activator products of HPV-16 or of the related bovine papillomavirus (BPV)-1 further elevated HPV-16-driven transcripts in co-transfections, and required the presence of E2-binding ACC(N)6GGT cores in cis. A 'short E2' C-terminal repressor gene product (sE2) of HPV-16 or the BPV-1 sE2 repressor not only inhibited viral E2 trans-activation, but also suppressed enhancer response to keratinocytic factors. Suppression by the sE2 products was abolished by deletion of the E2-binding cores in cis or by a mutation in the sE2 DNA binding domain. The keratinocyte-dependent enhancer is likely to contribute to the epithelial cell tropism of HPV-16, and may direct persistent E6-E7 gene transcription in response to cellular factors in cervical carcinoma cells in which the viral E2 genes are inactive.
Interferon treatment of human genital papillomavirus infection: importance of viral type.
Eighteen women and 6 of their male sexual partners with lower genital tract infections caused by various human papillomavirus (HPV) types were treated with systemic or topical interferon (IFN) application. All patients with vulvar or penile lesions had a history of podophyllin or surgical treatment. In the female group, 9 patients showed complete response, 8 patients partial response and 1 patient no response. In the male patients complete response was seen in all patients. The response rate appears to depend on the HPV type present. Women with an HPV 16/18 infection showed a lower response rate to IFN treatment (complete response in 5 out of 14 patients), whereas lesions caused by HPV 6(11) showed complete response in all 4 cases. During follow-up examinations (mean 7.5 months) no recurrence of disease was observed. Systemic treatment showed tolerable and temporary side-effects. Topical treatment yielded identical efficacy and no side-effects.
Increased prevalence of human papillomaviruses in the lower genital tract of pregnant women.
In order to evaluate the influence of pregnancy on the presence of human papillomavirus (HPV) in the lower female genital tract, cervical smears of 92 pregnant and 96 non-pregnant women, matched by age, were examined for the presence of HPV-DNA by means of Southern blot hybridization. All patients had negative PAP smears. Twenty-six (28%) of the pregnant women and 12 (12.5%) of the non-pregnant women were positive for HPV. HPV 16 accounted for 42% of all positive pregnant cases and only 25% of the positive non-pregnant cases. Smears of pregnant patients contained more than 10 pg viral DNA in 45% of the cases against 20% in the non-pregnant group. HPV 16 showed the most active replication in both groups. This study demonstrates an increased prevalence of HPV (preferentially of HPV 16) and a higher replication rate of viral DNA during pregnancy.
An amplification unit in human melanoma cells showing partial homology with sequences of human papillomavirus type 9 and with nuclear antigen 1 of the Epstein-Barr virus.
By partial homology with the DNA of human papillomavirus type 9 a cellular amplification unit was detected which is amplified in melanoma cells but not in Epstein-Barr virus-transformed B cells of two melanoma patients. A 2.4-kilobase EcoRI fragment of this amplification unit was cloned and designated mel/HPV9. At the chromosomal level we detected mel/HPV9 in homogeneously staining regions or in abnormally banded regions containing different marker chromosomes of both melanoma cell lines. DNA sequence analysis of a part of mel/HPV 9 revealed homology with the third internal repeat array of Epstein-Barr virus nuclear antigen 1.
Distribution pattern of human papilloma virus 16 genome in cervical neoplasia by molecular in situ hybridization of tissue sections.
Using a highly sensitive method with single-stranded RNA probes, we analyzed the distribution pattern of HPV 16 DNA by in situ hybridization in CIN II (10 cases), CIN III (11 cases) and in invasive cervical carcinoma (17 cases). The technique used detected as little as 20-50 viral genomes per cell. This sensitive technique unmasked HPV 16 genomes in the basal cells of all forms of CIN. In CIN III viral genomes were present throughout the entire thickness of the epithelium. There was a striking difference in the distribution of viral DNA in CIN II compared with CIN III and invasive cancer. Variable viral genome distribution was observed in CIN II with the highest copy number in the area of epithelial differentiation. In contrast, CIN III showed a uniform distribution pattern of HPV genomes reflecting the lack of epithelial maturation. The majority of invasive carcinomas showed the same uniform distribution of the HPV 16 genomes as CIN III.
Sensitivity of the cytologic diagnosis of cervical condyloma in comparison with HPV-DNA hybridization studies.
The cytologic diagnosis of cervical condyloma is based on criteria developed over the last 10 years. It has now become possible to document the presence of human papilloma virus (HPV) DNA directly in cervical swabs by the highly sensitive technique of DNA filter hybridization in situ. The purpose of this article is to evaluate critically the empirically established cytologic criteria of condyloma by comparing them with HPV-DNA hybridization studies in the same material. The results of this study indicate that "classic" koilocytosis and dyskeratocytosis are not highly sensitive criteria for the presence of HPV infection, identifying only 15% of the HPV-DNA-positive cases correctly. In an attempt to improve the sensitivity of the cytologic diagnosis of HPV infections, a panel of nine "nonclassic" criteria was evaluated. The five most valuable signs were "mild koilocytosis," mild dyskeratocytosis," hyperchromatic nuclei, bi- and multinucleation, and cleared cytoplasm. Using these criteria in combination, statistically discriminant analysis could correctly identify 84% of the HPV-positive group.
Analysis of the biological role of human papilloma virus (HPV)-encoded transcripts in cervical carcinoma cells by antisense RNA.
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Chromosomal integration sites of human papillomavirus DNA in three cervical cancer cell lines mapped by in situ hybridization.
Metaphase chromosomes of three cervical cancer cell lines (HeLa, CasKi, SiHa) were subjected to in situ hybridizations with the DNA of human papillomaviruses (HPV) types 16 and 18, respectively. Previous studies have demonstrated multiple copies of HPV 18 DNA in HeLa and of HPV 16 DNA in CasKi cells, but only 1-2 HPV 16 copies in cells of the SiHa line. The viral DNA persists in an integrated state (Schwarz et al 1985). Analysis of the integration sites revealed at least 11 chromosomal sites of HPV 16 integration in CasKi cells. SiHa cells contain integrated HPV 16 DNA in the region q21-q31 of chromosome No. 13. In HeLa cells integration of HPV 18 occurred in chromosome No. 8, band q24. Thus, no evidence was obtained for the existence of preferential chromosomal regions for HPV integration. The data indirectly support a trans-acting function of HPV-mediated cell transformation.