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Biomedical subjects

G Orth

Publications and source records attributed to G Orth.

At least 73 records · Page 4Linked to original sources
PubMed1991

Genetic heterogeneity among human papillomaviruses (HPV) associated with epidermodysplasia verruciformis: evidence for multiple allelic forms of HPV5 and HPV8 E6 genes.

In order to get some insight into modifications of human papillomavirus (HPV) genomes which could play a role in tumor progression in epidermodysplasia verruciformis (EV), we studied three EV patients infected by HPV5 and one by HPV8, with cancers containing mostly or only episomal viral genomes with a deletion. The mutants were compared with the full-length genomes present in the benign lesions of each patient. Deletions affected the L1 and/or L2 open reading frames (ORFs), and extended in the 5' end of the long control region in two cancers. The isolates studied showed a polymorphism of restriction endonuclease cleavage sites and variations in the nucleotide sequence of the E6 ORF and the regions flanking the deletions. However, except for one patient infected by two distinct HPV5 variants, no difference was observed in the nucleotide sequence of isolates cloned from the benign lesions and the cancer of the same patient. This may suggest that point mutations are not involved in tumor progression. Comparison of nucleotide sequence data revealed an unexpectedly high number of nucleotide substitutions among the four HPV5 variants and the HPV8 variant, as compared with HPV5 and HPV8 published sequences. Changes involved 49 of the 457 nucleotides of HPV5 E6 ORF and 14 of the 465 nucleotides of HPV8 E6 ORF. This corresponds to amino acid substitutions affecting 17 of the 157 amino acids of HPV5 E6 proteins and 7 of the 155 amino acids of HPV8 E6 proteins. Half of the substitutions represent nonconservative changes. The variants showing the highest degree of sequence variation were detected in additional EV patients by PCR. This points to the existence of a set of HPV5 and HPV8 stable variants, encoding for multiple allelic forms of the transforming E6 gene.

Alleles↗
PubMed1991

TGF beta-1 and TNF alpha expression in the epidermis of patients with epidermodysplasia verruciformis.

In epidermodysplasia verruciformis (EV), the infection with specific human papillomaviruses (HPV) might be under control of the local immunosurveillance mechanisms related to cytokines produced by epidermal cells. We have investigated by in situ hybridization the expression of mRNA coding for TGF beta-1 and TNF alpha in the skin of patients with EV (n = 4) as compared to the skin lesions of patients with other premalignant (actinic keratosis; n = 5) or malignant (squamous cell carcinoma; n = 4) skin lesions, and to the skin of healthy individuals (n = 5). The expression of TGF beta-1 and TNF alpha mRNA was higher in the epidermis of EV patients as compared to the control skin from healthy individuals. The increased expression of mRNA for both cytokines was confirmed by northern blot analysis of RNA isolated from the skin lesions of the patient with EV. No specific signals for TGF beta-1 and TNF alpha were detected in actinic keratosis, and in cases of squamous cell carcinomas only single neoplastic cells were positive for TGF beta-1. It is conceivable that in EV TGF beta-1 and TNF alpha can be involved in the regulation of the growth and differentiation of HPV-infected keratinocytes and in the persistence of HPV-induced skin lesions.

Adult↗
PubMed1991

Characterization of human papillomavirus type 66 from an invasive carcinoma of the uterine cervix.

Human papillomavirus (HPV) DNA sequences coexisting with HPV16 and HPV45 were cloned from an invasive cervical carcinoma. The cloned HPV was shown to be a novel type, named HPV66, and is related to HPV56 (an HPV detected in cervical cancer). After screening 160 anogenital biopsies, four specimens exhibited histological features of intraepithelial neoplasia and contained HPV66 sequences. Of these, three were found to be associated with another HPV type.

Amino Acid Sequence↗
PubMed1991

Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogene expression.

DNA sequences of specific human papillomavirus (HPV) types are found integrated in the cell genome in most invasive genital carcinomas. We have determined the chromosomal localization of integrated HPV type 16 (HPV-16) or HPV-18 genomes in genital cancers by in situ hybridization experiments. In three cancers, HPV sequences were localized in chromosome band 8q24.1, in which the c-myc gene is mapped, and in one cancer HPV sequences were localized in chromosome band 2p24, which contains the N-myc gene. In three of the four cases, the proto-oncogene located near integrated viral sequences was found to be structurally altered and/or overexpressed. These data indicate that HPV genomes are preferentially integrated near myc genes in invasive genital cancers and support the hypothesis that integration plays a part in tumor progression via an activation of cellular oncogenes.

Blotting, Northern↗
PubMed1990

Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA.

Human papilloma virus (HPV) DNA sequences (HPV types 16, 18, 33, 35 or uncharacterized) were detected by Southern blot hybridisation and polymerase chain reaction in 84% of 106 early-stage invasive carcinomas of the uterine cervix. Among HPV-positive patients, the risk of overall relapse did not differ with individual HPV types. Compared with HPV-positive patients, those with no detectable HPV DNA had a 2.6 times higher risk of overall relapse (p less than 0.05) and 4.5 times higher risk of distant metastases (p less than 0.01). The 24-month relapse-free survival rate in HPV-positive patients was significantly higher than that in HPV-negative patients (77% vs 40%), and the difference was similar (91% vs 56%) among those who were node-negative. These data indicate that HPV-negative cervical carcinomas may represent a biologically distinct subset of tumours that carry a poorer prognosis than do HPV-positive cancers.

Adenocarcinoma↗
PubMed1990

Two new human papillomavirus types (HPV54 and 55) characterized from genital tumours illustrate the plurality of genital HPVs.

The genomes of two new human papillomavirus (HPV) types, named HPV54 and HPV55, were cloned from penile lesions of 2 patients. HPV54 was isolated from a verrucous carcinoma (Buschke-Löwenstein tumour) together with full-length HPV6 genomes and HPV6 DNA molecules with a deletion of about 0.3 kb located in the non-coding region. HPV55 was isolated from a condyloma acuminatum. No cross-hybridization was observed between HPV54 DNA and the DNAs of the known cutaneous and genital HPVs by blot hybridization experiments performed under stringent conditions. In contrast, significant cross-hybridization was detected between HPV55 DNA and the DNA of HPV13, associated with benign oral lesions, and, to a lesser extent, with the DNAs of HPV6, 11, and 44, associated with benign genital proliferative lesions. The DNA sequence homology between HPV55 and HPV6, 11, and 13 was estimated at 12%, 12%, and 20%, respectively, by hybridization in liquid phase at saturation, followed by nuclease S1 analysis. The physical maps of HPV54 and 55 were aligned with the genetic maps of HPV16 and 11, respectively, by heteroduplex mapping and partial DNA sequencing. HPV54 is thus only weakly related to the known HPVs, while HPV55 represents an additional HPV6-related HPV type. HPV54 and HPV55 are uncommon genital HPV types since, in a survey of a large series of specimens of benign, pre-malignant or malignant anogenital and orolaryngeal tumours, HPV54 was not detected, and HPV55 was found in another case of condyloma acuminatum.

Adult↗
PubMed1990

Human papillomavirus type 16 DNA is integrated into chromosome region 12q14-q15 in a cell line derived from a vulvar intraepithelial neoplasia.

The SK-v cell line, established from a precancerous lesion (a vulvar intraepithelial neoplasia), contains 10 to 20 copies of the human papillomavirus type 16 (HPV16) genome, and was previously shown to derive from a clone of cells present in the patient's lesions. By in situ hybridization the integrated HPV16 DNA sequences were localized to a single site in chromosome region 12q14-q15. The localization of viral sequences to a single nonrearranged chromosome 12 suggests that integration occurred at this site in the patient's premalignant lesions. The INT1 and GLI protooncogenes are located in this chromosomal region. No detectable modification of the structure and expression of these genes was observed by blot hybridization experiments.

Carcinoma in Situ↗
PubMed1990

Natural cell-mediated cytotoxicity against various target cells in patients with epidermodysplasia verruciformis.

Natural cell-mediated cytotoxicity of peripheral blood mononuclear cells was studied in eight patients with epidermodysplasia verruciformis induced by human papillomaviruses specific for epidermodysplasia verruciformis and in five patients with epidermodysplasia verruciformis-induced exclusively by human papillomavirus type 3. Nine patients with various cutaneous warts and 25 age- and sex-matched healthy persons were control subjects. Natural cell-mediated cytotoxicity against both K-562 erythroleukemic and Sk-v cells was in the normal range in patients with epidermodysplasia verruciformis induced by epidermodysplasia verruciformis-specific human papillomaviruses and in patients with cutaneous warts. The lysis of both targets, however, was significantly decreased in patients with the form of epidermodysplasia verruciformis associated with human papillomavirus type 3. Experiments with normal keratinocytes and with keratinocytes isolated from a malignant lesion bearing human papillomavirus type 5 genomes showed that the latter were susceptible to lysis by the peripheral blood mononuclear cells of healthy persons and of patients with cutaneous warts. Lysis of keratinocytes in epidermodysplasia verruciformis, however, was strongly reduced in patients with epidermodysplasia verruciformis induced by specific human papillomaviruses. This reduction was not associated with a decrease in anti-K-562 natural cell-mediated cytotoxicity. Our results suggest that in patients with epidermodysplasia verruciformis induced by disease-specific human papillomaviruses, there is reduced natural cell-mediated cytotoxicity against epidermodysplasia verruciformis keratinocytes.

Adult↗
PubMed1990

Condylomata acuminata in children: frequent association with human papillomaviruses responsible for cutaneous warts.

To identify the papillomavirus types associated with condylomata acuminata in children and to evaluate their mode of transmission, we studied 32 children with anogenital warts. External condylomata were found in 12 of their mothers and in 10 of their fathers. Ten mothers, including two without external lesions, had cervical condylomata. Blot hybridization studies disclosed a genital human papillomavirus (HPV) in 14 of 27 children (HPV-6 in 12 and HPV-11 in two) and in 8 of 14 patients (HPV-6 in all). HPV-6 was found in another child by the polymerase chain reaction technique. Infection occurred most likely at birth or from nonsexual contact, but sexual abuse could not be excluded in one 11-year-old girl. Cutaneous HPV-2 was found in seven children and as yet uncharacterized papillomaviruses were found in two children. Three mothers of HPV-2-infected children had common hand warts, and two children had subungual warts. This study shows the frequent nonsexual transmission of genital papillomaviruses in children and the unexpectedly high association of children's condylomata with papillomaviruses responsible for skin warts, possibly transmitted by heteroinoculation or autoinoculation.

Adult↗
PubMed1990

Expression of the human papillomavirus type 16 genome in SK-v cells, a line derived from a vulvar intraepithelial neoplasia.

The SK-v cells, established from a premalignant vulvar lesion, contain human papillomavirus type 16 (HPV-16) sequences integrated at a single cellular site and derive from a cell clone present in vivo. Transcription of the HPV-16 genome in SK-v cells was analysed by cDNA heteroduplex mapping and sequencing, and by RNase mapping. Viral sequences were shown to be transcribed into virus-cell fusion messengers. The two major transcripts have a coding capacity for a truncated E6 protein, an E7 protein and an E1-E4 fusion protein, but differ in their 3' virus-cell junction. Minor transcripts have a coding capacity for a full-length E6 protein and another truncated version of E6. The transcription pattern in the E6-E7 region was found to be the same both in SK-v cells and in CaSki cells, a line derived from an invasive cervical carcinoma. Immunoprecipitation experiments showed that the E6 protein (18K) and, predominantly, the E7 protein (20K) are expressed in SK-v cells as in CaSki cells. The E7 protein was found in a two- to threefold lower amount in SK-v cells, but showing the same half-life (about 1 h).

Base Sequence↗
PubMed1990

Premalignant lesions and cancers of the skin in the general population: evaluation of the role of human papillomaviruses.

To evaluate the role of human papillomaviruses (HPV) in the development of premalignant lesions and cancers of the skin in the general population, 314 biopsies obtained from 227 patients with benign neoplasms, premalignant lesions, and cancers of the skin and from 25 patients with squamous cell carcinoma of the lip were analyzed by Southern blot hybridization. DNA probes specific for various cutaneous and genital HPV types were used in hybridizations conducted under nonstringent or stringent conditions. HPV DNA sequences were only detected in eight specimens obtained from six patients: HPV 34 in one case of periungual Bowen's disease, HPV 36 and an as yet uncharacterized HPV in two cases of actinic keratosis, HPV 20 in one case of basal cell carcinoma, an as yet unrecognized HPV in one case of squamous cell carcinoma, and HPV 16 in one case of squamous cell carcinoma of the lip. None of the specimens of cutaneous horn and keratoacanthoma contained detectable HPV DNA. In contrast, HPV DNA sequences, mostly HPV 16, were detected in 13 of 23 cases of anogenital Bowen's disease and invasive Bowen's carcinoma. HPV DNA sequences were not detected in 90 cutaneous samples further analyzed by the polymerase chain-reaction technique, using amplification primers that contain conserved sequences among the genomes of HPV. These results strongly suggest that the known HPV types play only a minor role, if any, in skin carcinogenesis in the general population.

Aged↗
PubMed1990

Vestibular papillae of the vulva. Lack of evidence for human papillomavirus etiology.

Vestibular papillae of the vulva are usually considered as anatomical variants of the vestibular mucosa. Clinically, however, they are quite often interpreted as condylomata acuminata and recent studies have suggested that they could be related to human papillomavirus infection. This prompted us to search for human papillomavirus DNA using the Southern blot hybridization technique, by analyzing biopsy specimens taken from 29 patients who presented with papillae of the vestibular mucosa. Human papillomavirus sequences were detected only in two (6.9%) cases. By the same technique, human papillomavirus sequences were detected in 24 (96%) of 25 vulvar warts used as the control specimens. Thus, it appears unlikely that vestibular papillae are related to human papillomavirus infection. They are usually distinguishable from condylomata acuminata by clinical examination alone.

Adult↗
PubMed1989

Abrogated NK-cell lysis of human papillomavirus (HPV)-16-bearing keratinocytes in patients with pre-cancerous and cancerous HPV-induced anogenital lesions.

Natural-cell-mediated cytotoxicity against K-562 erythroleukemic cells and human papillomavirus (HPV)-16 harboring Sk-v keratinocytes was tested in 38 age- and sex-matched healthy volunteers and in patients with HPV-induced benign and malignant anogenital lesions: 9 persons with HPV-16-induced bowenoid papulosis (BP), 8 with anogenital carcinomas (5 with HPV-16- or 33-associated squamous-cell carcinomas of Bowen's type and 3 with HPV-6-associated Buschke-Loewenstein verrucous carcinomas) and 12 with HPV-6-induced condylomata acuminata. Both K-562 and Sk-v cells were killed by a non-adherent CD16+ subset of PBMC as revealed by cell fractionation on the basis of their adherence to plastic and by treatment with Leu-IIb monoclonal antibody (MAb) and complement. "Cold" target competitive assays demonstrated that both cell types inhibited lysis of labelled Sk-v cells. In patients with BP and anogenital carcinomas induced by HPV-16 or 33, there was a significant (at least at p less than 0.01) decrease of Sk-v cell lysis as compared with the healthy control group. Anti-K-562 activity was not affected. In patients with anogenital carcinomas the degree of Sk-v lysis was decreased in proportion to the duration of lesions (correlation coefficient-r = -0.79). Neither anti-K-562 nor anti-Sk-v cytotoxicities were significantly affected in patients with condylomata and with HPV-6 associated verrucous carcinomas. Short-term (3 hr) pre-incubation of normal PBMC with sera from patients with BP and HPV-16-associated anogenital carcinomas resulted in significant inhibition of their ability to lyse Sk-v cells. Lysis of K-562 cells remained unaffected. In patients with carcinomas, the suppressive effect of sera was associated with a lowering of the ability of their PBMC to lyse Sk-v cells (r = -0.79). In patients with longer tumor persistence, the suppressive effect of serum was proportionally higher (r = 0.86).

Adult↗