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R D Burk

Publications and source records attributed to R D Burk.

At least 37 records · Page 2Linked to original sources
PubMed2000

A prospective study of human papillomavirus (HPV) type 16 DNA detection by polymerase chain reaction and its association with acquisition and persistence of other HPV types.

Human papillomavirus (HPV)-16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the risk of infection with other types, a theoretical concern with current vaccination efforts.

Cohort Studies↗
PubMed2000

Elongin BC complex prevents degradation of von Hippel-Lindau tumor suppressor gene products.

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene causes the familial cancer syndrome, VHL disease, characterized by a predisposition to renal cell carcinoma and other tumor types. Loss of VHL gene function also is found in a majority of sporadic renal carcinomas. A preponderance of the tumor-disposing inherited missense mutations detected in VHL disease are within the elongin-binding domain of VHL. This region mediates the formation of a multiprotein VHL complex containing elongin B, elongin C, cul-2, and Rbx1. This VHL complex is thought to function as an E3 ubiquitin ligase. Here, we report that VHL proteins harboring mutations which disrupt elongin binding are unstable and rapidly degraded by the proteasome. In contrast, wild-type VHL proteins are directly stabilized by associating with both elongins B and C. In addition, elongins B and C are stabilized through their interactions with each other and VHL. Thus, the entire VHL/elongin complex is resistant to proteasomal degradation. Because the elongin-binding domain of VHL is frequently mutated in cancers, these results suggest that loss of elongin binding causes tumorigenesis by compromising VHL protein stability and/or potential VHL ubiquitination functions.

Cell Line, Transformed↗
PubMed2000

Liver cell-specific transcriptional regulation of connexin32.

Gap junctional intercellular communication facilitates liver homeostasis and growth control in the liver. The major gap junction protein expressed by hepatocytes is connexin32 (Cx32) and non-parenchymal hepatic cells do not express this gene. We investigated the regulation of Cx32 transcription by trans-activating factors in liver cells. Transient transfection assays using deletions of the rat Cx32 promoter (nt -753 to -33) linked to the luciferase gene were performed in MH1C1 rat hepatoma cells that express endogenous Cx32 compared with WB-F344 rat liver epithelial cells that do not. The basal promoter element was located within nt -134 to -33 and was 1.4-fold more active in MH1C1 cells than WB-F344 cells whereas the entire promoter fragment (nt -754 to -33) was four-fold more active in MH1C1 cells. Specific nuclear protein-DNA complexes that bound to Sp1 consensus sites within the basal promoter were formed using nuclear extracts from both types of cells. Additional promoter sequences increased promoter activity more strongly in MH1C1 cells than WB-F344 cells and this was correlated with the binding of hepatocyte nuclear factor-1 (HNF-1) to two HNF-1 consensus sites centered at -187 and -736. Expression of HNF-1 and binding to these elements was only observed with MH1C1 cells. Other specific protein-DNA complexes were formed, however, that included YY-1- and NF-1-containing complexes, but these were not related to promoter activity. Dexamethasone increased Cx32 promoter activity and expression in MH1C1 cells, but had little effect in WB-F344 cells and did not alter protein-DNA complex formation. These data suggest that Sp1 is responsible for Cx32 promoter basal activity, that HNF-1 determines the cell-specific expression of Cx32, and that dexamethasone increases Cx32 expression through other mechanisms.

Animals↗
PubMed2000

Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica.

BACKGROUND: Human papillomavirus (HPV) is the main cause of cervical neoplasia. Because few population-based studies have investigated the prevalence of type-specific infection in relation to cervical disease, we studied a high-risk population, estimating the prevalence of HPV infection and the risk associated with various HPV types. METHODS: We screened 9175 women in Guanacaste, Costa Rica, to obtain a referent standard final diagnosis, and tested 3024 women for more than 40 types of HPV with a polymerase chain reaction-based system. RESULTS: Among women with normal cytology, HPV infections peaked first in women younger than 25 years, and they peaked again at age 55 years or older with predominantly non-cancer-associated types of HPV and uncharacterized HPV types. Low-grade squamous intraepithelial lesions (LSILs) (n = 189) decreased consistently with age. The prevalence of high-grade squamous intraepithelial lesions (HSILs) (n = 128) peaked first around age 30 years and again at age 65 years or older. Seventy-three percent of LSILs were HPV positive, with HPV16 being the predominant type (16% of positive subjects). HPV was found in 89% of HSILs and 88% of cancers, with HPV16 being strongly predominant (51% and 53% of positive subjects). Virtually all HSILs and cancers had cancer-associated HPV types, with high odds ratios (ORs) and attributable fractions around 80%. Risk for HPV16 was particularly high (OR for HSILs = 320, 95% confidence interval [CI] = 97-1000; OR for cancer = 710, 95% CI = 110-4500). CONCLUSIONS: We confirm the early decline of HPV infection with age but note increased prevalence after menopause, which could be related to a second peak of HSILs, an observation that warrants further investigation. At least 80% of HPVs involved in cervical carcinogenesis in this population have been characterized. Polyvalent vaccines including the main cancer-associated HPV types may be able to prevent most cases of cervical disease in this region.

Adult↗
PubMed1999

Human papillomavirus and the risk of cervical cancer.

Human papillomavirus (HPV) is now recognized as the driving force behind the dysregulation of the cell cycle that underlies cervical malignant transformation. Although nearly all cervical cancers contain HPV genomes, the vast majority of HPVs are not oncogenic but merely induce benign lesions. Because progressive abnormalities take at least a decade to develop into invasive cancers, young women with low-grade lesions can often be managed with watchful waiting rather than ablative therapy.

Female↗
PubMed1999

Detection of human papillomavirus DNA in cytologically normal women and subsequent cervical squamous intraepithelial lesions.

BACKGROUND: Human papillomavirus (HPV) infection has been strongly associated with cervical carcinoma and its cytologic precursors, squamous intraepithelial lesions (SIL). We investigated the risk of SIL prospectively following polymerase chain reaction (PCR)-based DNA testing for a wide range of genital HPV types in a cohort of initially cytologically normal women, to clarify the role of HPV in the etiology of SIL. METHODS: Starting in April 1989, 17,654 women who were receiving routine cytologic screening at Kaiser Permanente (Portland, OR) were followed for the development of incident SIL. During follow-up, 380 incident case patients and 1037 matched control subjects were eligible for this nested case-control study. Cervical lavages collected at enrollment and, later, at the time of case diagnosis (or the corresponding time for selection of control subjects) were tested for HPV DNA using a PCR-based method. The data were analyzed as contingency tables with two-sided P values or, for multivariable analyses, using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In comparison with initially HPV-negative women, women who tested positive for HPV DNA at enrollment were 3.8 times (95% CI = 2.6-5.5) more likely to have low-grade SIL subsequently diagnosed for the first time during follow-up and 12.7 times more likely (95% CI = 6.2-25.9) to develop high-grade SIL. At the time of diagnosis, the cross-sectional association of HPV DNA and SIL was extremely strong (OR = 44.4 and 95% CI = 24.2-81.5 for low-grade SIL and OR = 67.1 and 95% CI = 19.3-233.7 for high-grade SIL). HPV16 was the virus type most predictive of SIL, even low-grade SIL. CONCLUSIONS: These findings are consistent with the hypothesis that HPV infection is the primary cause of cervical neoplasia. Furthermore, they support HPV vaccine research to prevent cervical cancer and efforts to develop HPV DNA diagnostic tests.

Carcinoma, Squamous Cell↗
PubMed1999

Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. Women's Interagency HIV Study Group.

BACKGROUND: Cervical neoplasia occurs with increased frequency among women infected with HIV-1. OBJECTIVE: To characterize prevalence of and risk factors for abnormal cervical cytology among women with HIV and to compare them to uninfected women. METHODS: Baseline cervical cytology was obtained from 1713 women seropositive for HIV and 482 at-risk control women who were enrolled in the Women's Interagency HIV Study, a multicenter prospective cohort study conducted in six U.S. cities. Associations with sociodemographic, medical, and sexual variables were assessed by Fisher's exact test, Mantel extension test, and logistic regression analysis. RESULTS: Cervical cytology was abnormal in 38.3% of HIV-infected women (atypical squamous cells of uncertain significance [ASCUS] 20.9%, low-grade squamous cells of uncertain significance [LSIL] 14.9%, high-grade squamous cells of uncertain significance [HSIL] 2.3%, cancer 0.2%) and 16.2% of HIV-uninfected women (ASCUS 12.7%, LSIL 2.3%, HSIL 1.2%, cancer 0.0%). Risk factors for any abnormal cytology in multivariate analysis included HIV infection, CD4 cell count, HIV RNA level, detection of human papillomavirus (HPV), a prior history of abnormal cytology, employment, and number of male sex partners within 6 months of enrollment. Prior abortion was associated with a decreased risk of cytologic abnormality. CONCLUSIONS: Cervical cytologic abnormalities were frequent among women infected with HIV, although high-grade changes were found in only 2.5%. Factors linked to sexual and reproductive history, HPV infection, and HIV disease all influenced risk.

Adult↗
PubMed1999

Adeno-associated virus and development of cervical neoplasia.

Evidence from several sources has suggested that adeno-associated virus (AAV) infection might protect against cervical cancer, in part, by interfering with human papillomavirus (HPV)-induced tumorigenesis. Detection of AAV type 2 (AAV-2) DNA in cervical tissues has been reported. However, there have been few in vivo studies of women with cervical HPV infection or neoplasia, and these have reported inconsistent results. Therefore, we used polymerase chain reaction (PCR) assays targeted to the AAV-2 rep and cap genes to test tissue specimens from women in an epidemiological study of cervical neoplasia in Jamaica. We tested 105 women with low-grade cervical intraepithelial neoplasia (CIN-1), 92 women with CIN-3/carcinoma in situ or invasive cancer (CIN-3/CA), and 94 normal subjects. PCR amplification of human beta-globin DNA was found in almost all cervical specimens, indicating that these materials were adequate for PCR testing. The prevalence of HPV DNA, determined by HPV L1 consensus primer PCR was, as expected, strongly associated with presence and grade of neoplasia. Each of the AAV PCR assays detected as few as 10 copies of the virus genome. However, none of the 291 cervical specimens from Jamaican subjects tested positive for AAV DNA. Negative AAV PCR results were also obtained in tests of cervical samples from 79 university students in the United States. Exposure to AAV was assessed further by serology. Using a whole virus AAV-2 sandwich enzyme-linked immunosorbent assay, we found no relationship between AAV antibodies and presence or grade of neoplasia in either the Jamaican study subjects or women enrolled in a U.S. cervical cancer case (n = 74) -control (n = 77) study. Overall, the data provide no evidence that AAV infection plays a role in cervical tumorigenesis or that AAV commonly infects cervical epithelial cells.

Adolescent↗
PubMed1999

Seroreactivity to human papillomavirus types 16, 18, 31, and 45 virus-like particles in a case-control study of cervical squamous intraepithelial lesions.

Serum IgG antibodies to human papillomavirus (HPV) types 16, 18, 31, and 45 virus-like particles were measured in a nested case-control study of cervical squamous intraepithelial lesions. HPV-16 seroreactivity was strongly associated with HPV-16 DNA detection (odds ratio, 9.0; 95% confidence interval, 4.4-19.4), and similar type specificity was observed for HPV-31 and -45. In contrast, seroreactivity to any type was associated with elevated seroreactivity to all others. Among cases and controls, HPV-16 showed the highest seroprevalence, with 23.8% of 80 cases and 10.5% of 258 controls seroreactive to HPV-16 alone, and another 27.5% and 5.4%, respectively, seroreactive to HPV-16 plus other types. Overall, 24 (30.0%) cases and 17 (6.6%) controls were seroreactive to multiple types. These data suggest that seroreactivity to a given type reflects mainly type-specific HPV infection as measured by DNA detection and may also signal past exposure to other types that are now only serologically detected.

Antibodies, Viral↗
PubMed1999

Regulation of connexin32 and connexin43 gene expression by DNA methylation in rat liver cells.

Gap junction proteins (connexins) are expressed in a cell-specific manner and expression is often reduced in neoplastic cells. We investigated the mechanisms of connexin32 (Cx32) and connexin43 (Cx43) expression in hepatic cells using MH1C1 rat hepatoma cells and freshly isolated, adult rat hepatocytes that express Cx32 but not Cx43 and WB-F344 rat liver epithelial cells that express Cx43 but not Cx32. Southern blotting after DNA restriction with MspI and HpaII indicated that two MspI/HpaII restriction sites in the Cx32 promoter (positions -147 and -847) were methylated in WB-F344 cells, but not in MH1C1 cells or hepatocytes. In contrast, an MspI/HpaII restriction site in the Cx43 promoter (position -38) was methylated in MH1C1 cells, but not in WB-F344 cells or hepatocytes. Transient transfection of the cell lines with connexin promoter-luciferase constructs indicated that the Cx32 promoter was 7-fold more active in MH1C1 cells and the Cx43 promoter was 5-fold more active in WB-F344 cells. These results suggest that transcription of Cx32 and Cx43 in hepatic cells is controlled by promoter methylation and by cell-specific transcription factors. Similar mechanisms may be involved in the reduced expression of these genes frequently observed in neoplastic cells.

Animals↗
PubMed1999

Transplanted hepatocytes proliferate differently after CCl4 treatment and hepatocyte growth factor infusion.

To understand regulation of transplanted hepatocyte proliferation in the normal liver, we used genetically marked rat or mouse cells. Hosts were subjected to liver injury by carbon tetrachloride (CCl4), to liver regeneration by a two-thirds partial hepatectomy, and to hepatocellular DNA synthesis by infusion of hepatocyte growth factor for comparative analysis. Transplanted hepatocytes were documented to integrate in periportal areas of the liver. In response to CCl4 treatments after cell transplantation, the transplanted hepatocyte mass increased incrementally, with the kinetics and magnitude of DNA synthesis being similar to those of host hepatocytes. In contrast, when cells were transplanted 24 h after CCl4 administration, transplanted hepatocytes appeared to be injured and most cells were rapidly cleared. When hepatocyte growth factor was infused into the portal circulation either subsequent to or before cell transplantation and engraftment, transplanted cell mass did not increase, although DNA synthesis rates increased in cultured primary hepatocytes as well as in intact mouse and rat livers. These data suggested that procedures causing selective ablation of host hepatocytes will be most effective in inducing transplanted cell proliferation in the normal liver. The number of transplanted hepatocytes was not increased in the liver by hepatocyte growth factor administration. Repopulation of the liver with genetically marked hepatocytes can provide effective reporters for studying liver growth control in the intact animal.

Animals↗
PubMed1999

Soluble interleukin 2 receptor levels and cervical neoplasia: results from a population-based case-control study in Costa Rica.

Progression from infection with human papillomavirus (HPV) to cervical cancer in some women is thought to involve a permissive host environment, one in which immune response is mobilized in an inappropriate manner. In a previous study (A. Hildesheim et al., Cancer Epidemiol. Biomark. Prev., 6: 807-813, 1997), increasing levels of soluble interleukin 2 receptor (sIL-2R), a known proxy for general immune activation, was found to be positively associated with increasing levels of cervical neoplasia. We attempted to confirm this finding by conducting a nested case-control study of 478 women within a 10,000-woman population-based cohort in Costa Rica. We selected for the study all of the women diagnosed (at enrollment into the cohort) with: (a) low-grade squamous intraepithelial lesions (LSIL, n = 191); (b) high-grade squamous intraepithelial lesions (HSIL, n = 130); or (c) cancer (n = 37). Controls were 120 cytologically normal, HPV-negative women selected from a random sample of the entire cohort. A questionnaire was administered to participants to elicit information on cervical cancer risk factors. All of the women received a pelvic examination during which cervical cells were collected and used for HPV DNA testing by PCR. Blood samples were also collected. Plasma obtained from the blood samples was tested for sIL-2R levels by ELISA. Results indicated that sIL-2R levels increased with age. Among controls, we observed that 44.3% of women over the age of 50 had high levels of sIL-2R (defined as >735 units/ml) compared with 15.8% of women <30 years of age (P = 0.008). When women with cervical disease (LSIL+) were compared with controls, women in the upper quartile of the sIL-2R distribution had an age-adjusted odds ratio (OR) of 2.1 [95% confidence interval (CI), 1.1-4.1]. Comparing each advancing state of neoplasia with its precursor, we found that women with LSIL had higher sIL-2R levels than controls (OR for upper quartile of sIL-2R, 2.3; 95% CI, 1.1-5.2; comparing LSIL cases with controls); women diagnosed with HSIL were similar to the LSIL group (OR for upper quartile of sIL-2R, 1.1; 95% CI, 0.5-2.4; comparing HSIL cases with LSIL cases); and those with cancer had higher sIL-2R levels than subjects with an HSIL diagnosis (OR for upper quartile of sIL-2R = 1.8; 95% CI, 0.5-7.1; comparing cancer cases with HSIL cases). These data suggest that among our study subjects, sIL-2R levels most likely rise as a response to the events of infection and cancerous invasion, but that sIL-2R levels are unlikely to be predictive of disease progression among women with LSIL.

Adolescent↗
PubMed1999

"ASCUS, rule out HSIL": cytologic features, histologic correlates, and human papillomavirus detection.

Risk factors, cytologic and histopathologic features, and human papillomavirus (HPV) detection associated with 75 cervical smears classified as atypical squamous cells of undetermined significance, rule out high-grade squamous intraepithelial lesion (ASCUS, rule out HSIL) were reviewed. Cases were identified in a pathology panel review of material collected from 1953 women participating in a 5-year prospective study of HPV infection and squamous intraepithelial lesions at Kaiser Permanente, Portland, Oregon, sponsored by the National Cancer Institute. Initial abnormal smears diagnosed as ASCUS, rule out HSIL by one panelist or diagnosed as ASCUS by one pathologist and as HSIL by another were included. The 75 ASCUS, rule out HSIL smears identified were examined again by two pathologists after the study. These cases were compared with cases of ASCUS, not otherwise specified (ASCUS, NOS) and HSIL identified in the same group of 1953 women. Findings in ASCUS, rule out HSIL included tissue fragments (21%); atypical immature metaplasia (17%); atypical mature metaplasia (15%); small atypical cells (9%); and atypical repair (4%). A final patient classification of HSIL, reflecting all available data, was assigned to 11 (24%) of 46 women with ASCUS, rule out HSIL and to 1(1%) of 80 women with ASCUS, NOS in the original review (P < .001). Detection of oncogenic HPV types at diagnosis in ASCUS, rule out HSIL; ASCUS, NOS; and HSIL was similar, but data were unavailable for many subjects. Among women not tested at diagnosis, enrollment testing (1 to 4 years earlier) revealed that HPV detection in women with ASCUS, rule out HSIL was intermediate in frequency between ASCUS, NOS and HSIL. These data suggest that ASCUS, rule out HSIL is a distinct diagnosis from ASCUS, NOS because it is more often associated with an underlying HSIL. Consequently, women with ASCUS, rule out HSIL should be referred for colposcopic examination.

Adolescent↗
PubMed1998

Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia.

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case-control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo-pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma alpha-tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of > or = 0.803 mg/dl (OR = 0.46). CIN was not associated with plasma retinol and beta-carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies.

Adult↗
PubMed1998

HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia.

Although genital human papillomavirus (HPV) infection is well established as the etiologic agent for cervical intraepithelial neoplasia (CIN), little is known about the cofactors involved in the development of high-grade lesions or the progression of low-grade to high-grade lesions. In our study of HPV-infected women with CIN (163 CIN I, 51 CIN II and 44 CIN III), women with CIN II or III were compared with those with CIN I for risk factors associated with high-grade lesions. After controlling for age, education, ethnicity and frequency of Pap smear screening, infection with HPV 16, but not high viral load or infection with multiple types, was associated with high-grade lesions (OR for CIN II = 11.96, OR for CIN III = 23.74). Risk of CIN III, but not CIN II, increased with number of cigarettes smoked per day (ORs = 1.49 and 3.35 for < or = 10 and > 10 cigarettes per day, respectively) and decreased with frequency of condom use during sex (ORs = 0.60 and 0.32 for women who used condoms occasionally/sometimes and most/all of the time, respectively). There were no associations between high-grade lesions and plasma levels of micronutrients (retinol, beta-carotene, alpha-tocopherol and reduced ascorbic acid). Our results indicate that infection with HPV 16 is associated with high-grade lesions. Additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV-infected cells toward neoplastic progression.

Adult↗
PubMed1998

A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor.

The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in both sporadic and inherited clear cell renal carcinoma associated with VHL disease. We have identified two distinct native products of the human VHL gene, with apparent molecular masses of 24 and 18 kDa. The 18-kDa VHL protein was more abundant in nearly all cell lines examined. Reintroduction of the 18-kDa VHL gene product into renal carcinoma cells lacking wild-type VHL protein led to down-regulation of vascular endothelial growth factor (VEGF) mRNA and glucose transporter GLUT1 protein and suppressed tumor formation in nude mice. The 18-kDa VHL protein also demonstrated binding to elongins B and C. In an in vitro assay, the second in-frame AUG codon present in VHL mRNA was shown to be necessary and sufficient for production of the 18-kDa VHL protein, consistent with an internal translation mechanism. These data provide evidence for a second major VHL gene product, which contains the functional domains of the VHL gene. Moreover, these results indicate that internal translation initiation is an important mechanism for production of the major VHL protein.

Animals↗