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Biomedical subjects

R Burk

Publications and source records attributed to R Burk.

At least 19 recordsLinked to original sources
PubMed2002

Germline mutations in the ribonuclease L gene in families showing linkage with HPC1.

Although prostate cancer is the most common non-cutaneous malignancy diagnosed in men in the United States, little is known about inherited factors that influence its genetic predisposition. Here we report that germline mutations in the gene encoding 2'-5'-oligoadenylate(2-5A)-dependent RNase L (RNASEL) segregate in prostate cancer families that show linkage to the HPC1 (hereditary prostate cancer 1) region at 1q24-25 (ref. 9). We identified RNASEL by a positional cloning/candidate gene method, and show that a nonsense mutation and a mutation in an initiation codon of RNASEL segregate independently in two HPC1-linked families. Inactive RNASEL alleles are present at a low frequency in the general population. RNASEL regulates cell proliferation and apoptosis through the interferon-regulated 2-5A pathway and has been suggested to be a candidate tumor suppressor gene. We found that microdissected tumors with a germline mutation showed loss of heterozygosity and loss of RNase L protein, and that RNASEL activity was reduced in lymphoblasts from heterozyogous individuals compared with family members who were homozygous with respect to the wildtype allele. Thus, germline mutations in RNASEL may be of diagnostic value, and the 2-5A pathway might provide opportunities for developing therapies for those with prostate cancer.

Adenine Nucleotides↗
PubMed2001

The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women.

OBJECTIVE: Cervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DESIGN: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). METHODS: HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participant's consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. RESULTS: Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4-81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52-0.88) to demonstrate progression CONCLUSIONS: HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

Adolescent↗
PubMed2001

Five-chlorodeoxycytidine, a tumor-selective enzyme-driven radiosensitizer, effectively controls five advanced human tumors in nude mice.

PURPOSE: The study's goals were as follows: (1) to extend our past findings with rodent tumors to human tumors in nude mice, (2) to determine if the drug protocol could be simplified so that only CldC and one modulator, tetrahydrouridine (H4U), would be sufficient to obtain efficacy, (3) to determine the levels of deoxycytidine kinase and dCMP deaminase in human tumors, compared to adjacent normal tissue, and (4) to determine the effect of CldC on normal tissue radiation damage to the cervical spinal cord of nude mice. METHODS AND MATERIALS: The five human tumors used were as follows: prostate tumors, PC-3 and H-1579; glioblastoma, SF-295; breast tumor, GI-101; and lung tumor, H-165. The duration of treatment was 3-5 weeks, with drugs administered on Days 1-4 and radiation on Days 3-5 of each week. The biomodulators of CldC were N-(Phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartyl transcarbamoylase, 5-fluorodeoxycytidine (FdC), resulting in tumor-directed inhibition of thymidylate synthetase, and H4U, an inhibitor of cytidine deaminase. The total dose of focused irradiation of the tumors was usually 45 Gy in 12 fractions. RESULTS: Marked radiosensitization was obtained with CldC and the three modulators. The average days in tumor regrowth delay for X-ray compared to drugs plus X-ray, respectively, were: PC-3 prostate, 42-97; H-1579 prostate, 29-115; glioblastoma, 5-51; breast, 50-80; lung, 32-123. Comparative studies with PC-3 and H-1579 using CldC coadministered with H4U, showed that both PALA and FdC are dispensable, and the protocol can be simplified with equal and possibly heightened efficacy. For example, PC-3 with X-ray and (1) no drugs, (2) CldC plus the three modulators, (3) a high dose of CldC, and (4) escalating doses of CldC resulted in 0/10, 3/9, 5/10, and 6/9 cures, respectively. The tumor regrowth delay data followed a similar pattern. After treating mice only 11/2 weeks with CldC + H4U, 92% of the PC-3 tumor cells were found to possess CldU in their DNA. The great majority of head-and-neck tumors from patient material had markedly higher levels of dC kinase and dCMP deaminase than found in adjacent normal tissue. Physiologic and histologic studies showed that CldC + H4U combined with X-ray, focused on the cervical spinal cord, did not result in damage to that tissue. CONCLUSIONS: 5-CldC coadministered with only H4U is an effective radiosensitizer of human tumors. Ninety-two percent of PC-3 tumor cells have been shown to take up ClUra derived from CldC in their DNA after only 11/2 weeks and 2 weeks of bolus i.p. injections. Enzymatic alterations that make tumors successful have been exploited for a therapeutic advantage. The great electronegativity, coupled with the relatively small Van der Waal radius of the Cl atom, may result in CldC's possessing the dual advantageous properties of FdC on one hand and BrdU and IdU on the other hand. These advantages include autoenhancing the incorporation of CldUTP into DNA by not only overrunning but also inhibiting the formation of competing TTP pools in tumors. A clinical trial is about to begin, with head-and-neck tumors as a first target of CldC radiosensitization.

Animals↗
PubMed2001

Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women.

Human immunodeficiency virus (HIV) infection and related immunosuppression are associated with excess risk for cervical neoplasia and human papillomavirus (HPV) persistence. Type-specific HPV infection was assessed at 6-month intervals for HIV-positive and HIV-negative women (median follow-up, 2.5 and 2.9 years, respectively). The type-specific incidence of HPV infection was determined, and risk factors for HPV persistence were investigated by statistical methods that accounted for repeated measurements. HIV-positive women were 1.8, 2.1, and 2.7 times more likely to have high-, intermediate-, and low-risk HPV infections, respectively, compared with HIV-negative women. In multivariate analysis, high viral signal, but not viral risk category, was independently associated with persistence among HIV-positive subjects (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-2.9). Furthermore, persistence was 1.9 (95% CI, 1.5-2.3) times greater if the subject had a CD4 cell count <200 cells/microL (vs. >500 cells/microL). Thus, HIV infection and immunosuppression play an important role in modulating the natural history of HPV infection.

Adult↗
PubMed2001

Human papillomavirus-associated cervical cytologic abnormalities among women with or at risk of infection with human immunodeficiency virus.

OBJECTIVE: Correlates of abnormal human immunodeficiency virus cervical cytologic findings were examined among women infected with human immunodeficiency virus and uninfected women. STUDY DESIGN: We performed a cross-sectional analysis of baseline data on demographically similar women with infection or risk factors for it. RESULTS: Among 1050 women without hysterectomy, squamous intraepithelial lesions were more common among women infected with human immunodeficiency virus than among uninfected women (18.8% vs 5.3%; P <.001). In multivariate analysis the association of squamous intraepithelial lesions with human papillomavirus infection was strong; adjusted prevalence ratios were 27 for high-risk, 25 for intermediate-risk, and 10 for low-risk types (95% confidence intervals, 12-58, 12-54, and 4-25, respectively). Much lower adjusted prevalence ratios were seen for the only other factor significantly associated with squamous intraepithelial lesions, namely, infection with human immunodeficiency virus in conjunction with a reduced CD4(+) cell count. Adjusted prevalence ratios were 1.9 for CD4(+) cell counts <200 and 1.6 for CD4(+) cell counts between 200 and 500 (95% confidence intervals, 1.2-3.0 and 1.0-2.5, respectively). Adjusted attributable fractions calculated for this study population indicated that if both human immunodeficiency virus and human papillomavirus were removed, 47.6% of the observed lesions with atypical squamous cells of uncertain significance and 93.4% of the observed squamous intraepithelial lesions would be prevented. CONCLUSION: Squamous intraepithelial lesions are more common among human immunodeficiency virus-infected women and are associated most commonly with high- and intermediate-risk human papillomavirus types and secondarily with human immunodeficiency virus-associated immune compromise.

CD4 Lymphocyte Count↗
PubMed1999

Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women.

BACKGROUND: Human papillomavirus (HPV) infection is associated with precancerous cervical squamous intraepithelial lesions commonly seen among women infected with human immunodeficiency virus-1 (HIV). We characterized HPV infection in a large cohort of HIV-positive and HIV-negative women participating in the Women's Interagency HIV Study to determine the prevalence of and risk factors for cervicovaginal HPV infection in HIV-positive women. METHODS: HIV-positive (n = 1778) and HIV-negative (n = 500) women were tested at enrollment for the presence of HPV DNA in a cervicovaginal lavage specimen. Blood samples were tested for HIV antibody status, level of CD4-positive T cells, and HIV RNA load (copies/mL). An interview detailing risk factors was conducted. Univariate and multivariate analyses were performed. RESULTS: Compared with HIV-negative women, HIV-positive women with a CD4+ cell count of less than 200/mm3 were at the highest risk of HPV infection, regardless of HIV RNA load (odds ratio [OR] = 10.13; 95% confidence interval [CI] = 7.32-14.04), followed by women with a CD4+ count greater than 200/mm3 and an HIV RNA load greater than 20,000 copies/mL (OR = 5.78; 95% CI = 4.17-8.08) and women with a CD4+ count greater than 200/mm3 and an HIV RNA load less than 20,000 copies/mL (OR = 3.12; 95% CI = 2.36-4.12), after adjustment for other factors. Other risk factors among HIV-positive women included racial/ethnic background (African-American versus Caucasian, OR = 1.64; 95% CI = 1.19-2.28), current smoking (yes versus no; OR = 1.55; 95% CI = 1.20-1.99), and younger age (age < 30 years versus > or = 40 years; OR = 1.75; 95% CI = 1.23-2.49). CONCLUSIONS: Although the strongest risk factors of HPV infection among HIV-positive women were indicators of more advanced HIV-related disease, other factors commonly found in studies of HIV-negative women, including racial/ethnic background, current smoking, and age, were important in HIV-positive women as well.

AIDS-Related Opportunistic Infections↗
PubMed1999

Prevalence and incidence of gynecologic disorders among women infected with human immunodeficiency virus.

OBJECTIVE: Our purpose was to ascertain the prevalence, incidence, and predictors of gynecologic disorders among women infected with human immunodeficiency virus. STUDY DESIGN: We serially assessed 292 women infected with human immunodeficiency virus and 681 uninfected women. Outcomes were incidence and prevalence of sexually transmitted diseases, viral shedding, findings of Papanicolaou smears, fungal infections, and menstrual disorders. RESULTS: Women infected with the virus were more likely to have prevalent vulvovaginal candidiasis (odds ratio 1.80, 95% confidence interval 1. 0-3.25, P =.05), oncogenic human papillomavirus (odds ratio 3.79, 95% confidence interval 2.43-5.91, P =.001), abnormal Papanicolaou smears (odds ratio 5.40, 95% confidence interval 3.35-8.78, P =.001), amenorrhea (4.8% vs 0%, P =.05), positive results on Treponema pallidum hemagglutination assay (odds ratio 1.83, 95% confidence interval 1.16-2.88, P =.01), infection with cytomegalovirus (odds ratio 4.2, 95% confidence interval 1.82-10.62, P =.001), and genital warts (odds ratio 6.93, 95% confidence interval 3.16-16.30, P =.001) but were less likely to have Chlamydia trachomatis infection (odds ratio 0.28, 95% confidence interval 0.10-0.66, P =.01). Annual incidence rates among women infected with human immunodeficiency virus were 4.0% for candidiasis, 22.0% for oncogenic human papillomavirus, 11.4% for genital warts, 1.7% for infection with C trachomatis, 1.7% for infection with Neisseria gonorrhoeae, 10.3% for Trichomonas vaginalis, 1.1% for positive results on T pallidum hemagglutination assay, 7.4% for an abnormal Papanicolaou smear, and 10.9% for infection with herpes simplex virus. Overall, 46.9% had at least 1 incident condition. Women infected with human immunodeficiency virus were more likely to have incident oncogenic human papillomavirus infection (odds ratio 2.0, 95% confidence interval 1.01-3.8), abnormal Papanicolaou smears (odds ratio 7.76, 95% confidence interval 2.08-42.8), and genital warts (odds ratio 9. 32, 95% confidence interval 3.04-38.0). Incidence and prevalence of sexually transmitted diseases and oncogenic human papillomavirus infection increased with increased CD4(+) cell counts. CONCLUSIONS: Women infected with the human immunodeficiency virus are significantly more likely to have prevalent and incident gynecologic disorders but not disorders related to risk taking (eg, incident sexually transmitted diseases). The latter disorders increased in women with CD4(+) cell counts >500 cells/mm3. Clinicians should be aware of these patterns so that they can provide appropriate evaluation and treatment of gynecologic disorders.

Adult↗
PubMed1998

Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade.

Caveolin-1 is a principal component of caveolae membranes in vivo. Caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). However, it remains unknown whether downregulation of caveolin-1 is sufficient to mediate cell transformation or tumorigenicity. Here, we employ an antisense approach to derive stable NIH 3T3 cell lines that express dramatically reduced levels of caveolin-1 but contain normal amounts of caveolin-2. NIH 3T3 cells harboring antisense caveolin-1 exhibit anchorage-independent growth, form tumors in immunodeficient mice and show hyperactivation of the p42/44 MAP kinase cascade. Importantly, transformation induced by caveolin-1 downregulation is reversed when caveolin-1 protein levels are restored to normal by loss of the caveolin-1 antisense vector. In addition, we show that in normal NIH 3T3 cells, caveolin-1 expression levels are tightly regulated by specific growth factor stimuli and cell density. Our results suggest that upregulation of caveolin-1 may be important in mediating contact inhibition and negatively regulating the activation state of the p42/44 MAP kinase cascade.

3T3 Cells↗
PubMed1998

A multifaceted study of human papillomavirus and prostate carcinoma.

BACKGROUND: The presence of human papillomavirus (HPV) in the prostate and its role in prostate carcinoma are in dispute. To address these issues, two laboratories with extensive HPV experience were selected to test specimens from two populations at different risk for prostate carcinoma, using three different polymerase chain reaction (PCR) assays and two serologic assays for HPV. METHODS: The cases were comprised of 51 African-American (men at high risk for prostate carcinoma) and 15 Italian (men at intermediate risk for prostate carcinoma) men with prostate carcinoma. Controls were 108 African-American men and 40 Italian men with histologically proven benign prostate hypertrophy (BPH). Prostate tissue was obtained from each patient at surgery and immediately frozen in liquid nitrogen. The PCR primer sets included two (MY09/MY11 and GP5+/ GP6+) that amplify different regions of L1 and a third (WD66,67,154/WD72,76) targeted to E6. Sensitivity in the 2 L1 PCR assays was shown to be 1 HPV DNA genome per 100 cells. Serum antibodies to HPV-16 and HPV-11 virus-like particles (VLPs) were detected using enzyme-linked immunosorbent assays. RESULTS: All available prostate carcinoma tissue specimens (n = 63) and BPH specimens from selected controls (n = 61) were tested by PCR. Human beta-globin DNA could be amplified from all specimens except three carcinomas, but no HPV DNA was detected in any case or control specimens by MY09/MY11 or E6 PCR. Microdissection of 27 carcinoma specimens was conducted to minimize nontumor DNA, but results remained negative by MY09/MY11 and GP5+/GP6+ PCR. In addition, serum specimens in cases (n = 63) and controls (n = 144) showed no differences in their responses against HPV-16 (P = 0.54) or HPV-11 VLPs (P = 0.64). CONCLUSIONS: The findings suggest that HPV is not associated with prostate carcinoma, and that HPV DNA is not at all common in the prostate glands of older men.

Aged↗
PubMed1998

A longitudinal study of human papillomavirus carriage in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women.

OBJECTIVE: We sought to determine the relationship of human immunodeficiency virus serostatus to carriage of oncogenic human papillomavirus. MATERIAL AND METHODS: A total of 268 human immunodeficiency virus-infected and 265 human immunodeficiency virus-uninfected women were seen every 6 months, at which time they had laboratory tests performed including a CD4 count. Human papillomavirus deoxyribonucleic acid was analyzed by polymerase chain reaction. Statistical methods included Kaplan-Meier and Cox's proportional hazard models. RESULTS: The prevalence at baseline of any human papillomavirus type was 73% and 43% among human immunodeficiency virus-seropositive and seronegative women, respectively (p < 0.0001) and of oncogenic types was 32.5% and 17.0% (p < 0.001). The prevalence of oncogenic human papillomavirus was higher in women with CD4 counts <200 mm3 (p < 0.001). The rate of detection of new oncogenic human papillomavirus per 100 patient years of follow-up in human immunodeficiency virus-seropositive women was almost three times higher than among human immunodeficiency virus-seronegative women (p < 0.01). The rate of loss of an oncogenic human papillomavirus was higher in the human immunodeficiency virus-seronegative women but the difference was not significant. The relative risk of a human immunodeficiency virus-infected woman who did not initially have a specific type of oncogenic human papillomavirus having one detected during follow-up was 6.6 times greater than among human immunodeficiency virus-negative women (p < 0.001). CONCLUSIONS: Human immunodeficiency virus-seropositive women are more likely to have newly detectable oncogenic types of human papillomavirus at follow-up and to show persistent carriage of oncogenic types of human papillomavirus types. Among human immunodeficiency virus-infected women, those with higher CD4 counts were more likely to have a newly detected oncogenic human papillomavirus during follow-up.

CD4 Lymphocyte Count↗
PubMed1993

First isolation of Borrelia burgdorferi from an iris biopsy.

The persistence of Borrelia burgdorferi in six patients is described. Borrelia burgdorferi has been cultivated from iris biopsy, skin biopsy, and cerebrospinal fluid also after antibiotic therapy for Lyme borreliosis. Lyme Serology: IgG antibodies to B. burgdorferi were positive, IgM negative in four patients; in two patients both IgM and IgG were negative. Antibiotic therapy may abrogate the antibody response to the infection as shown by our results. Patients may have subclinical or clinical disease without diagnostic antibody titers. Persistence of B. burgdorferi cannot be excluded when the serum is negative for antibodies against it.

Adolescent↗
PubMed1988

[Penetrating keratoplasty--indications with special reference to artificial lens keratopathy].

During the period from 1980 until the beginning of 1986, 1,219 corneal buttons removed in the course of penetrating keratoplasty were histologically examined. In 16.5% (201 cases) a re-keratoplasty was necessary. Indications for a primary corneal transplant (n = 1,018) were keratitis-induced corneal changes (35.0%), dystrophies (30.5%), surgical traumas (17.2%), nonsurgical traumas (11.4%), congenital corneal clouding (3.1%) and degenerations (2.8%). Over the six-and-a-half-year period the incidence of pseudophakic bullous keratopathy was 6.9%, with an increase from 1.6% in 1980 to 12.4% in 1986. Besides an unspecific endothelial cell atrophy, fibroblast-like cell structures, possible macrophages, were found in some specimens by histologic examination on corneal buttons as well as on explanted intraocular lenses.

Cornea↗
PubMed1987

[Attempt at preoperative differentiation of malignant melanoma of the choroid. A comparison of nuclear magnetic resonance tomography, ultrasound echography and histopathology].

In a large choroidal melanoma (prominence 12 mm, volume approx. 1,900 mm3) diagnostic sonography revealed an unusual compartmentation, corresponding to the internal reflectivity of the tumor. When NMR imaging was performed, marked differences in signal behavior were seen between the tumor's center and its periphery. Histopathology revealed a highly pigmented spindle B melanoma containing an amelanotic island with signs of necrosis. The ultrasound pattern was explained on the basis of well known physical phenomena, whereas the NMR signals are still not fully understood.

Adult↗
PubMed1987

Tissue changes induced by intraocular lenses. A histopathologic study.

The histopathologic findings in autopsy and surgically enucleated eyes are described. Tissue atrophy and inflammatory reaction can be demonstrated in every eye examined in our laboratory. Scanning electron microscopy was used to detect tissue formation on intraoccular lenses.

Atrophy↗