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2.
J Urol ; 162(4): 1291-4, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10492182

ABSTRACT

PURPOSE: Penile self-injection therapy, a second line treatment for erectile dysfunction, is the most efficacious means of reestablishing functional erections when first line therapies fail and the patient wants to avoid penile prosthesis implantation. Despite high efficacy rates, injection therapy has high dropout rates. To our knowledge studies to date analyzing patient attrition have reviewed small numbers of patients followed for only short periods. We elucidate the main reasons for patient dropout in a large penile self-injection program with long-term followup. MATERIALS AND METHODS: A questionnaire was mailed to 1,424 patients who completed the office training and home use phases of a penile self-injection program. RESULTS: The overall attrition rate was 31% of the 720 men who completed the questionnaire, with a mean followup of 38 months. The main reasons for dropout were cost of therapy, patient and partner problems with the concept of penile injection, lack of partner availability and spontaneous improvement in erections. Lack of efficacy of therapy was the primary reason for only 1 of 7 dropouts. Furthermore, adverse effects of penile injections (priapism, penile nodules, pain) appeared to be only minor contributors to dropout. CONCLUSIONS: To our knowledge this study is the largest published, single center cohort of patients treated with injection and followed for an analysis of dropout rates. Based on study data a reduction in dropout rates may be achieved by keeping the cost of therapy low, and ensuring patient and partner education as well as continued support throughout treatment.


Subject(s)
Erectile Dysfunction/drug therapy , Patient Dropouts/statistics & numerical data , Adult , Aged , Follow-Up Studies , Humans , Injections , Male , Middle Aged , Penis , Self Administration , Surveys and Questionnaires
3.
Oncogene ; 14(2): 185-93, 1997 Jan 16.
Article in English | MEDLINE | ID: mdl-9010220

ABSTRACT

Loss of p53 function is associated with the acquisition of cisplatin resistance in the human ovarian adenocarcinoma A2780 cell line. Selection for cisplatin resistance of A2780 cells was used to isolate genetic suppressor elements (GSEs) from a retroviral library expressing random fragments of human or murine TP53 cDNA. Six GSEs were identified, encoding either dominant negative mutant peptides or antisense RNA molecules which corresponded to various regions within the TP53 gene. Both types of GSE induced cisplatin resistance when introduced individually into A2780 cells. Expression of antisense GSEs led to decreased intracellular levels of p53 protein. One sense GSE induced loss of p53-mediated activities such as DNA damage induced cell cycle arrest and apoptosis. A synthetic peptide, representing the predicted amino acid sequence of this GSE, conferred resistance to cisplatin when introduced into A2780 cells and inhibited the sequence specific DNA binding activity of p53 protein in vitro. Overall, these results directly indicate that inactivation of p53 function confers cisplatin resistance in these human ovarian tumour cells. We have identified short structural domains of p53 which are capable of independent functional interactions and highlighted the efficacy of this approach to discriminate biologically active GSEs from a random fragment library.


Subject(s)
Antineoplastic Agents/pharmacology , Antisense Elements (Genetics)/genetics , Cisplatin/pharmacology , DNA, Complementary/genetics , Genes, p53/genetics , Ovarian Neoplasms/genetics , Animals , Antisense Elements (Genetics)/isolation & purification , DNA Damage/genetics , Drug Resistance, Neoplasm/genetics , Female , Humans , Mice , Ovarian Neoplasms/metabolism , Retroviridae/genetics , Serine Endopeptidases/metabolism , Transfection , Tumor Cells, Cultured/drug effects , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
4.
J Virol ; 70(12): 9041-5, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8971040

ABSTRACT

The E8 open reading frame of bovine papillomavirus type 4 encodes a small hydrophobic polypeptide which contributes to cell transformation by conferring anchorage-independent growth. Using an in vitro translation system, we show that the E8 polypeptide binds to ductin, the 16-kDa proteolipid that forms transmembrane channels in both gap junctions and vacuolar H+-ATPase. This association is not due to nonspecific hydrophobic interactions. PPA1, a Saccharomyces cerevisiae polypeptide homologous (with 25% identity) to ductin, does not complex with E8. Furthermore, E5B, structurally similar to E8 but with no transforming activity, does not form a complex with ductin. Primary bovine fibroblasts expressing E8 show a loss of gap junctional intercellular communication, and it is suggested that this results from the interaction between E8 and ductin.


Subject(s)
Bovine papillomavirus 1/metabolism , Fibroblasts/metabolism , Oncogene Proteins, Viral/metabolism , Proteolipids/metabolism , Proton-Translocating ATPases/metabolism , Vacuolar Proton-Translocating ATPases , Animals , Bovine papillomavirus 1/genetics , Cattle , Cell Communication , Down-Regulation , Fibroblasts/cytology , Gap Junctions , Gene Expression , Oncogene Proteins, Viral/genetics
5.
Carcinogenesis ; 16(8): 1997-2001, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7634432

ABSTRACT

Exposure to the flavonoid quercetin and transfection with bovine papillomavirus type 4 (BPV-4) DNA lead to oncogenic transformation of primary bovine cells. Here we show that the synergism between quercetin and BPV-4 (or its E7 oncogene) is stronger the shorter the interval between the two treatments. Quercetin immortalizes transformed cells, confers anchorage-independent growth and induces tumorigenicity in cells transfected only with the E7 oncogene.


Subject(s)
Bovine papillomavirus 1/genetics , Cell Transformation, Neoplastic , Quercetin/toxicity , Animals , Bovine papillomavirus 4 , Cattle , Mice , Transfection
6.
Virology ; 193(2): 614-20, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8384749

ABSTRACT

Bovine papillomavirus type 4 (BPV-4) morphologically transforms primary bovine cells in vitro only in the presence of an activated ras gene. The transformed cells are capable of anchorage-independent growth, but are not immortal and are incapable of inducing tumors in nude mice. BPV-4 does not possess an E6 ORF and failure to induce full transformation may be due to the lack of this gene. Here we report the contribution of individual BPV-4 genes to cell transformation and the effect of adding the E6 ORF of HPV-16 to the system. We show that BPV-4 E7 ORF is responsible for morphological transformation, the E8 ORF is responsible for anchorage-independent growth, and addition of HPV-16 E6 ORF rescues cells from senescence. By immunocytostaining, E7 and E8 have been visualized in transiently transfected cultured cells. E8 is localized in the membranes while E7 is found both in the cytoplasm and in the nucleus.


Subject(s)
Bovine papillomavirus 1/genetics , Cell Transformation, Viral , Animals , Bovine papillomavirus 1/pathogenicity , Bovine papillomavirus 4 , Cattle , Cell Adhesion , Cell Division , Cells, Cultured , DNA, Viral/genetics , DNA, Viral/isolation & purification , Genome, Viral , Mice , Mice, Nude , Open Reading Frames , Palate , Transfection , Tumor Virus Infections/microbiology
7.
Oncogene ; 8(1): 151-6, 1993 Jan.
Article in English | MEDLINE | ID: mdl-8380914

ABSTRACT

BPV-4-induced malignant transformation of C127 mouse fibroblasts in vitro is the result of a 'hit and run' mechanism. Viral DNA is lost on continued subculture of transformed cell lines without loss of any malignant characteristics. The DNA from these cells harbours specific amplified sequences. Two such amplified fragments of approximately 10 kb and 12 kb were molecularly cloned and designated HL-10 and HL-12 respectively. HL-10 transformed C127 cells efficiently and therefore encodes a transforming function, whereas the 12 kb clone did not. Heteroduplexes showed that HL-12 was homologous to HL-10 except for two additional tandem copies of an approximately 1.7 kb sequence. Sequence analysis of HL-10 revealed that the clone contained a 5.2 kb region from BPV-1 including the transforming ORFs. Transformation studies have shown differences between HL-10 and BPV-1, indicating that the host flanking sequences may contribute to the transforming potential of the BPV-1 ORFs. The BPV-1 DNA was associated with sequences homologous to murine autonomously replicating sequences (ARS) implicated in the establishment of multiple tandem DNA repeats. As the parental cells contain the set of sequences amplified in transformed cells in single copy and show none of the characteristics of transformed cells, we conclude that BPV-4 has activated these sequences by amplification and rearrangement. These phenomena may be mediated through an interaction between BPV-4 proteins and the BPV-1 origin of DNA replication or via the ARS region.


Subject(s)
Bovine papillomavirus 1/genetics , Gene Amplification , Gene Expression Regulation , Animals , Base Sequence , Bovine papillomavirus 4 , Cell Line, Transformed , Cloning, Molecular , DNA, Viral/analysis , Mice , Molecular Sequence Data , Repetitive Sequences, Nucleic Acid
8.
Differentiation ; 41(3): 208-15, 1989 Sep.
Article in English | MEDLINE | ID: mdl-2693169

ABSTRACT

Transfection of cells with cloned genes or total genomic DNA offers a means for studying aspects of neoplastic behaviour. We have used this method to examine whether incorporation of the cloned 6.6-kilobase (kb) fragment of DNA containing the mutant c-Ha-ras human oncogene can confer metastatic capability on murine NIH 3T3 cells. Cells co-transfected with the mutated ras gene and the neomycin resistance marker pSV2neo were selected by culture in neomycin. On subcutaneous inoculation into MF 1 nude mice, these cells proved to be tumourigenic with short latent periods (approximately 14 days)--nude mice were used to circumvent immunological rejection of the mouse cells expressing the product of the human oncogene. Transfectants were capable of lung colonisation after intravenous injection, but there was no evidence of spontaneous metastasis at autopsy, or on histological examination of the lungs and other organs, 90 days after inoculation. Incorporation of the transfected oncogene was confirmed by Southern blotting and its expression by dot-blot hybridisation and immunoprecipitation. The results in this experimental system indicate that transfection of a mutated human ras oncogene into non-neoplastic 3T3 cells can confer part of the metastatic phenotype, namely lung colonisation, but is not by itself sufficient to induce spontaneous metastatic behaviour.


Subject(s)
Cell Transformation, Neoplastic , Gene Expression Regulation, Neoplastic , Proto-Oncogene Proteins/genetics , Transfection , Animals , Cells, Cultured , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Proto-Oncogene Proteins p21(ras)
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