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Biomedical subjects

Stephen K Tyring

Publications and source records attributed to Stephen K Tyring.

121 records · Page 7Linked to original sources
PubMed2002

Kaposi's sarcoma and other manifestations of human herpesvirus 8.

UNLABELLED: Kaposi's sarcoma (KS) was described by Moritz Kaposi in 1872 and was known for an entire century as a rare disorder of older men usually of Eastern European, Mediterranean, and/or Jewish origin. In the early 1980s, the prevalence of KS began to increase dramatically and soon became the most common malignancy in patients with AIDS, especially those who were male homosexuals. In 1994, a new human herpesvirus (HHV) was found to be present in almost 100% of KS lesions. This virus was found to be a gammaherpesvirus, closely related to Epstein-Barr virus, and was designated HHV-8. Subsequently, HHV-8 DNA was found in almost all specimens of classic KS, endemic KS, and iatrogenic KS, as well as epidemic KS (ie, AIDS KS). It is now believed that HHV-8 is necessary, but not sufficient, to cause KS and that other factors such as immunosuppression play a major role. The use of highly active antiretroviral therapy (HAART) since 1996 has markedly reduced the prevalence of AIDS KS in western countries, but because 99% of the 40 million patients with AIDS in the world cannot afford HAART, KS is still a very common problem. Primary effusion lymphoma and multicentric Castleman's disease are also thought to be due to HHV-8. Although HHV-8 DNA has been described in a number of other cutaneous disorders, there is little evidence that HHV-8 is of etiologic significance in these diseases. The mechanism by which HHV-8 causes KS, primary effusion lymphoma, and multicentric Castleman's disease is not well understood but is thought to involve a number of molecular events, the study of which should further our understanding of viral oncology. (J Am Acad Dermatol 2002;47:641-55.) LEARNING OBJECTIVE: At the completion of this learning activity, participants should be familiar with Kaposi's sarcoma and other manifestations of human herpesvirus 8.

Antiretroviral Therapy, Highly Active↗
PubMed2002

The management of herpes simplex virus infections.

Herpes simplex virus persists in a latent form for the life of its host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently no cure is available. Antiviral therapy is the main treatment modality, used either orally, intravenously, or topically to prohibit further replication of the virus and thereby minimize cellular destruction. However, immunologic advances in the treatment and prevention of herpes simplex infections are promising and continue to be studied.

Antiviral Agents↗
PubMed2002

Suppression of growth by all-trans retinoic acid requires prolonged induction of interferon regulatory factor 1 in cervical squamous carcinoma (SiHa) cells.

All-trans retinoic acid (ATRA) suppresses growth of cervical dysplasias in vivo, although the sensitivity to retinoids is frequently lost during cervical carcinogenesis. It has been suggested that prolonged treatment or use of higher doses of retinoids might offer favorable response rates. We found SiHa cervical squamous carcinoma cells that were virtually resistant to ATRA-induced growth-inhibitory effects at physiological doses (10(-7 to) 10(-6) M) to be more responsive at pharmacological doses (10(-5 to) 10(-4) M). The growth inhibition by high-dose (10(-4) M) ATRA was associated with a sustained activation of interferon regulatory factor 1 (IRF-1), while a low dose (10(-6) M) of ATRA activated IRF-1 only transiently. Antisense IRF-1 inhibited the high-dose (10(-4) M), ATRA-mediated growth arrest; forced expression of IRF-1 caused a significant reduction in cell growth. High-dose (10(-4) M) ATRA increased binding of NF-kappaB and STAT1 proteins to sequences that originated from the IRF-1 promoter region, while low-dose (10(-6) M) ATRA induced only NF-kappaB binding. A delayed tyrosine phosphorylation of the signal transducer and activator of transcription-1 (STAT1) was observed after high-dose (10(-4) M) but not low-dose (10(-6) M) ATRA treatment. In agreement with this, induction of IRF-1 mRNA by ATRA was only modest and transient in a STAT1 knockout cell line, suggesting the importance of STAT1 in sustained IRF-1 expression. Our data showed that ATRA is capable of inducing dose-dependent cellular changes, which might be appropriate to overcome resistance to retinoids that frequently develops during cervical carcinogenesis.

Antineoplastic Agents↗
PubMedDate not supplied

Oral famciclovir for the suppression of recurrent genital herpes: the combined data from two randomized controlled trials.

BACKGROUND: Genital herpes is a very common sexually transmitted disease. Safe and effective therapies are needed for patients with frequent recurrences. OBJECTIVE: The aim of our study was to determine the efficacy and safety of famciclovir for suppression of herpes simplex virus (HSV) infection in patients with history of clinically diagnosed recurrent genital HSV infection. METHOD: An analysis was conducted of the combined data from two randomized, double-blind, placebo-controlled studies of 52 weeks' duration involving a total of 469 patients (201 men, 268 women) from 47 university, hospital, or private referral centers in Europe and North America. The patients were 18 years or older with a history of six or more episodes of genital herpes during 12 of the 14-months prior to study entry and were not receiving suppressive therapy. They were randomized to receive oral famciclovir 250 mg twice daily or placebo for 52 weeks. The primary outcome measures were (1) the proportion of patients who remained free from clinical HSV recurrences, confirmed by viral culture, for at least 6 months after the start of study medication; (2) the time to first clinically confirmed lesional episode; and (3) the frequency of adverse events. RESULTS: A significantly greater proportion of famciclovir-treated patients (151/191, 79%) were free from HSV recurrences at 6 months compared with placebo recipients (48/184, 26%) (p<0.001); efficacy was maintained at 12 months. The median time for the first clinically confirmed lesional episode was significantly prolonged for famciclovir recipients (more than one year) compared with placebo recipients (59 days; p<0.0001). Famciclovir was well tolerated, with an adverse-experience profile comparable with placebo. CONCLUSIONS: Oral famciclovir 250 mg twice daily is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.

2-Aminopurine↗
PubMedDate not supplied

Viral and nonviral uses of imiquimod: a review.

BACKGROUND: Imiquimod is a topical immunomodulator that is indicated for the treatment of external genital and perianal warts. This drug has been recently approved for the treatment of actinic keratoses and superficial basal cell carcinoma. There is a growing body of evidence for its effectiveness in treating a variety of other skin conditions. OBJECTIVE: This review examines the role of imiquimod 5% cream in the treatment of skin diseases such as actinic keratoses, basal cell carcinoma, Bowen's disease, lentigo maligna, and extramammary Paget's disease. METHODS: Published literature containing the words "Imiquimod" or "Aldara" was reviewed and summarized. RESULTS: This agent has demonstrated indirect antiviral and antitumor effects in animal models. Although the exact mechanism of action is unknown, imiquimod is an agonist for toll-like receptor (TLR) 7 and is thought to act by inducing cytokines, such as interferon alpha (IFN-alpha), interleukin-12 (IL-12), and tumor necrosis factor alpha (TNF-alpha). These cytokines trigger the immune system to recognize the presence of a viral infection or tumor and the associated lesion is ultimately eradicated. Side effects are generally well tolerated with local skin reactions reported most frequently. CONCLUSION: Imiquimod has been shown to be a safe and effective treatment for a variety of skin conditions.

Adjuvants, Immunologic↗
PubMedDate not supplied

Changing paradigms in dermatology: antivirals in dermatology.

Almost all of the approved antiviral drugs have become available during the past two decades. Approximately one half of these agents are for the treatment of human immunodeficiency virus (HIV) infections and comprise five classes. The first three classes all act to inhibit reverse transcriptase: nucleoside analogs; nonnucleoside analogs; and nucleotide analogs. The fourth class, protease inhibitors, prevent viral packaging; the fifth class, fusion inhibitors, prevent fusion between HIV and the target cell. Four nucleoside analogs, acyclovir, valacyclovir, famciclovir and penciclovir, are approved for the therapy of herpes simplex and varicella zoster infections. Interferon alpha is approved in the injectable form for condyloma acuminatum and Kaposi's sarcoma, but the more efficient method of delivering this agent is via interferon induction following topical use of imiquimod cream. Antiviral agents are also approved for infections with cytomegalovirus, hepatitis B and C, respiratory syncytial virus, and influenza viruses. Most of these antiviral drugs are virastatic and not viracidal. Vaccines and public health measures are much more effective and cost effective than antiviral drugs and must be promoted accordingly in the defense against viral infections.

Adjuvants, Immunologic↗
PubMedDate not supplied

Selected sexually transmitted diseases and their relationship to HIV.

Although sexually transmitted diseases (STDs) are underreported and underrecognized, they are a major source of morbidity, mortality, and represent a major socioeconomic cost in developing and industrialized nations. Individuals who develop STDs are often coinfected with human immunodeficiency virus (HIV). Coinfection with HIV both facilitates the natural history of STDs and worsens the clinical picture. The objective of this article is to provide a review to the practicing clinician on the epidemiology, clinical manifestations, methods of diagnosis, and treatment for four cutaneous STDs--chancroid, genital herpes, granuloma inguinale, and lymphogranuloma venereum--in coinfected HIV patients.

Chancroid↗
PubMedDate not supplied

Aspartoacylase gene knockout in the mouse: impact on reproduction.

Canavan disease (CD) is an autosomal recessive disorder caused by aspartoacylase (ASPA) gene mutations resulting enzyme deficiency. The homozygous knockout mouse for CD showed symptoms similar observed in patients with CD. Canavan disease leads to early death. Therefore, a role of ASPA in reproduction was investigated using the mouse model for CD. Homozygous (KO/KO) pups, produced by mating female heterozygous (KO/+) mouse with KO/+ males had approximately 12% death incidence rates in the first 2 months of life. KO/KO mothers mated with KO/+ males showed fetal death. KO/KO mothers produced fewer offspring compared to KO/+ mothers. These data suggest that ASPA is necessary for normal reproduction and postnatal survival.

Amidohydrolases↗
PubMedDate not supplied

Canavan disease: a monogenic trait with complex genomic interaction.

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Amidohydrolases↗
PubMedDate not supplied

All-trans-retinoic acid activates caspase-1 in a dose-dependent manner in cervical squamous carcinoma cells.

Earlier we observed that all-trans-retinoic acid (ATRA) dose-dependently suppressed the growth of cervical carcinoma cells. Suppression of growth required sustained activation of interferon regulatory factor 1 (IRF-1), which was achieved by high-dose (10(-4) M), but not low-dose (10(-6) M), ATRA treatment. In this paper we examine the role of IRF-1 in cell death that accompanied the growth suppression in high-dose ATRA-treated cells. We found that high-dose, but not low-dose, ATRA treatment activated caspase-1 in those cervical carcinoma cells. Transient transfection of an antisense-IRF-1 construct diminished high-dose ATRA-mediated caspase-1 activation. On the other hand, ATRA was not able to induce caspase-1 expression in a STAT1 (signal transducer and activator of transcription 1) knockout cell line, but transient transfection of STAT1 restored it. These results suggested the importance of both IRF-1 and STAT1 in high-dose ATRA-induced activation of caspase-1. Our results might be useful in the treatment of retinoid-resistant cervical neoplasias.

Antineoplastic Agents↗
PubMedDate not supplied

Dose-dependent activation of p21WAF1 transcription by all-trans-acid in cervical squamous carcinoma cells.

SiHa cervical squamous carcinoma cells were resistant to ATRA-induced growth inhibitory effect at a physiological dose (10(-6) M), but responsive at a pharmacological dose (10(-4) M). The observed growth arrest was associated with increased levels of the interferon regulatory factor-1 (IRF-1). IRF-1 is a known inhibitor of cell growth, and thus our aim was to identify the downstream target of this growth inhibitory function. We found that, as with the induction of IRF-1, levels of p21WAF1 were similarly dose-dependently induced by ATRA. Semiquantitative RT-PCR, Western blotting, gel-shift analysis (EMSA), antisense gene expression and application of a STAT1-knockout cell line demonstrated that activation of the p21WAF1 gene was IRF-1 and STAT1-dependent. We concluded that activation of STAT1 and IRF-1 is crucial for the growth inhibitory action of ATRA, which is associated with the activation of p21WAF1. These results might be useful in chemoprevention of cervical cancers.

Antineoplastic Agents↗
PubMedDate not supplied

All-trans retinoic acid (ATRA) suppresses transcription of human papillomavirus type 16 (HPV16) in a dose-dependent manner.

Earlier we found that SiHa cervical squamous carcinoma cells that harbor HPV type 16 respond to ATRA treatment in a dose-dependent manner: high-dose (10(-5)-10(-4) M) but not low-dose (10(-7)-10(-6) M) ATRA induced growth arrest. Growth of HPV-infected cells is highly dependent on the expression of the viral E6/E7 proteins. Thus, targeting expression of the viral E6/E7 genes might influence growth properties of HPV-infected cells. Here, we demonstrated that high-dose ATRA inhibited expression of HPV16 E7 through suppression of the HPV16 promoter (p97) activity. Gelshift assay (EMSA) revealed that binding of the AP-1 transcription factor to an oligonucleotide originated from the HPV type 16 promoter was diminished after high-dose, but not low-dose ATRA treatment. This suggests that high-dose ATRA suppresses HPV 16 promoter activity, at least in part, via a decreased AP-1 binding. Our data might be useful in treatment of cervical dysplasias and/or carcinomas.

Antineoplastic Agents↗