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2.
J Viral Hepat ; 18(6): 377-83, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21143343

RESUMEN

Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of end-stage liver disease, including cirrhosis, liver failure and primary liver cancer. There are now seven antiviral agents approved by the United States Food and Drug Administration (FDA) for the management of chronic HBV infection. Despite the fact that there are between 1.4 and 2 million chronic HBV infections in the United States, fewer than 50,000 people per year receive prescriptions for HBV antiviral medications. This report discusses possible explanations for the disparity between the number of people who are chronically infected and the number of people who receive treatment. Explanations for this incongruence include the potentially large number of infected persons who are unscreened and thus remain undiagnosed, and lack of access, including insurance, education and referral to appropriate medical care, particularly for disproportionately infected populations.


Asunto(s)
Antivirales/uso terapéutico , Disparidades en Atención de Salud , Hepatitis B Crónica/tratamiento farmacológico , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Virus de la Hepatitis B , Hepatitis B Crónica/diagnóstico , Humanos , Estados Unidos , Vacunación
5.
Genes Chromosomes Cancer ; 30(3): 245-53, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11170281

RESUMEN

Comparative genomic hybridization (CGH) analysis was used to identify chromosomal imbalances in 52 human primary hepatocellular carcinomas (HCCs). The most prominent changes were gains of part or all of chromosome arms 8q (83% of cases) and 1q (73%) and loss of 16q (63%). Other commonly overrepresented sites were 5p, 7q, and Xq. Recurrent sites of DNA sequence amplification included 8q23--24 (five cases) and 11q13--14 (four cases). Other frequently underrepresented sites were 4q, 8p, 16p, and 17p. Taken collectively, these findings and data from other CGH studies of HCCs define a subset of chromosome segments that are consistently over- or underrepresented and highlight sites of putative oncogenes and tumor suppressor genes, respectively, involved in hepatocellular oncogenesis. Loss of heterozygosity analysis with a panel of polymorphic microsatellite markers distributed along 16q defined a minimal region of chromosomal loss at 16q23.1--24.1, suggesting that this region harbors a tumor suppressor gene whose loss/inactivation may contribute to the pathogenesis of many HCCs.


Asunto(s)
Desequilibrio Alélico/genética , Carcinoma Hepatocelular/genética , Cromosomas Humanos Par 16/genética , Neoplasias Hepáticas/genética , Pérdida de Heterocigocidad/genética , Femenino , Dosificación de Gen , Humanos , Masculino , Hibridación de Ácido Nucleico
6.
Dis Markers ; 17(3): 179-89, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11790885

RESUMEN

Individuals chronically infected with hepatitis B or C virus (HBV, HCV) are at high risk for the development of hepatocellular carcinoma (HCC), with disease progression occurring relentlessly over many years. The diagnosis of HCC usually occurs at late stages in the disease when there are few effective treatment options and the prognosis for patients with HCC is very poor. The long latency period, together with clearly identified at risk populations, provide opportunities for earlier detection that will allow more timely and effective treatment of this devastating cancer. We are using a proteomic approach to test the hypothesis that changes in the amount of certain serum polypeptides, or changes in their post-translational modifications, can be used to predict the onset of HCC. Advances in the standardization of two dimensional gel electrophoresis (2DE) coupled with computerized image analysis now permit the reproducible resolution of thousands of polypeptides per run. Serum polypeptides from individuals at different stages in the disease continuum are being resolved by 2DE to identify those that change with disease progression. Polypeptides found by this method can be further characterized by mass spectrometry. In addition, the potential for changes in the glycan structure of certain polypeptides to serve as a marker for disease progression can be explored. The proteomic approach is expected to liberate us from the need to "cherry pick" or guess the best biomarkers and let the data tell us which are the best indicators of disease. Information may also be gleaned about the pathobiology of the disease process.


Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Proteoma , Biomarcadores , Humanos , Métodos
8.
Cancer Epidemiol Biomarkers Prev ; 7(7): 559-65, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9681522

RESUMEN

The risk of hepatocellular carcinoma (HCC) varies significantly among hepatitis B virus (HBV) carriers from different geographic regions. We compared serological markers of HBV infection in adult male carriers from Haimen City, China and Senegal, West Africa, where the prevalence of chronic infection is similar. HCC mortality among HBV carriers is much higher in Haimen City than it is in Senegal (age-standardized rate, 878 versus 68 per l0(5) person-years). A dramatic difference was observed when HBV DNA levels in serum were assessed among carriers by Southern blot. In the Senegalese group (n = 289), 14.5% were HBV DNA positive by Southern blot in their 20s, and this percentage declined in each subsequent decade of age to 3.3, 2.9, and 0% thereafter. In the Chinese group (n = 285), a higher prevalence of HBV DNA positivity and a less consistent reduction were seen; 29.4% were positive in their 20s, and 30.2, 23.6, and 20.6%, respectively, were positive in each subsequent decade of age. Among 102 male Asian-American HBV carriers, the prevalence of HBV DNA positivity was intermediate between the Chinese and Senegalese populations (36.8, 10.7, 3.0, and 4.6% in each subsequent decade of age). Viral titers were similar among those who were HBV DNA positive in all three populations [median value, 10(7) virions/ml (range, 10(6)-10(9) virions/ml)]. The presence of HBV DNA in serum was positively associated with serum glutathione S-transferase, a marker of liver damage. These findings suggest that the more prolonged maintenance of productive virus infection in the Chinese carriers compared with the Senegalese carriers may explain their higher risk of HCC. This profound difference in the natural history of chronic infection may be due to earlier age of infection in China or to as yet unknown environmental or genetic factors.


Asunto(s)
Carcinoma Hepatocelular/virología , Portador Sano/virología , Virus de la Hepatitis B , Hepatitis B/virología , Neoplasias Hepáticas/virología , Carga Viral/estadística & datos numéricos , Adulto , Factores de Edad , Asia/etnología , Biomarcadores/sangre , Carcinoma Hepatocelular/epidemiología , China/epidemiología , Estudios de Cohortes , ADN Viral/sangre , Hepatitis B/epidemiología , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/sangre , Humanos , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Senegal/epidemiología , Estados Unidos/epidemiología
10.
J Infect Dis ; 176(4): 845-50, 1997 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-9333140

RESUMEN

This study compared rates of spontaneous hepatitis B e antigen (HBeAg)-positive to -negative seroconversion in chronic carriers of hepatitis B virus (HBV) with rates reported during interferon-alpha therapy. Four hundred fifty-four Asian-American HBeAg-positive HBV carriers, followed for 1-10 years, were tested approximately every 6 months for HBeAg. Patients with alanine aminotransferase levels > or = 50 IU/mL at entry had 1067.3 seroconversions/10(5) person-months in the 5- to 19-year age group, 1753.3 in the 20- to 34-year group, and 1257.2 in the 35- to 50-year group. Published data indicate that 30% of children and 33% of adults seroconvert during interferon-alpha treatment and follow-up. In our study population, spontaneous seroconversion occurred in 15% of children (95% confidence interval [CI], 8%-27%), 23% of adults 20-34 years (95% CI, 15%-34%), and 17% of adults 35-50 years (95% CI, 10%-28%) during the same interval. The high rate of spontaneous seroconversion should be weighed in decisions to treat HBV carriers with interferon-alpha.


Asunto(s)
Anticuerpos contra la Hepatitis B/análisis , Anticuerpos contra la Hepatitis B/inmunología , Antígenos e de la Hepatitis B/inmunología , Hepatitis B/inmunología , Adolescente , Adulto , Factores de Edad , Alanina Transaminasa/análisis , Asiático , Portador Sano , Niño , Preescolar , Enfermedad Crónica , Hepatitis B/epidemiología , Hepatitis B/etnología , Humanos , Incidencia , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Seroepidemiológicos
12.
Cancer Res ; 57(13): 2749-53, 1997 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-9205086

RESUMEN

Hepatitis B virus (HBV) and aflatoxin B1 represent the main risk factors for the development of hepatocellular carcinoma (HCC) in areas endemic for liver cancer. The glutathione S-transferases (GSTs) are a family of Phase II detoxification enzymes that catalyze the conjugation of a wide variety of endogenous and exogenous toxins, including aflatoxin B1, with glutathione. This study characterizes the GST isoenzyme composition (alpha, mu, and pi) of both HBV-infected normal hepatic tissues and HCCs. Analysis of matched pairs of hepatic tissue (normal and tumor) from 32 HCC patients indicated that total GST activity was significantly higher in normal tissues than in tumor tissues, although the percentage of samples expressing GST alpha and pi was equivalent. GST mu was detected by Western blot in the normal tissue from 87.5% of the subjects possessing the GST M1 gene but only 28.6% of the corresponding tumor tissues. The GST activity of normal tissue from GST M1 null patients was significantly decreased as compared to that of subjects possessing the GST M1 gene (264.6 and 422.2 nmol/min/mg, respectively; P = 0.005). GST pi appeared to be overexpressed in the normal tissue of GST M1 null patients, a potential compensatory effect. Patients positive for HBV DNA had significantly lower GST activity than those who were HBV negative (302.1 versus 450.0 nmol/min/mg, respectively; P = 0.02). These results suggest that cellular protection within the human liver is compromised by HBV infection and further decreased during hepatocellular tumorigenesis.


Asunto(s)
Carcinoma Hepatocelular/enzimología , Glutatión Transferasa/metabolismo , Hepatitis B/metabolismo , Neoplasias Hepáticas/enzimología , Adulto , Factores de Edad , Anciano , Carcinoma Hepatocelular/genética , Femenino , Glutatión Transferasa/genética , Humanos , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad
13.
Clin Lab Med ; 16(2): 251-71, 1996 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8792071

RESUMEN

Chronic viral hepatitis is caused mainly by chronic infection with hepatitis viruses B (HBV), C (HCV), or delta (HDV). Persons chronically infected with one or more of these viruses may develop chronic progressive hepatitis, cirrhosis, and liver failure. In addition, chronic HBV and HCV infections are major causal risk factors for hepatocellular carcinoma. Alcohol consumption accelerates the development of chronic liver disease among HCV-infected individuals and may have similar effects on persons chronically infected with HBV alone or HBV and HDV, but the reported studies are inconsistent.


Asunto(s)
Hepatitis B/epidemiología , Hepatitis C/epidemiología , Hepatitis D/epidemiología , Animales , Hepatitis B/inmunología , Hepatitis B/transmisión , Hepatitis B/virología , Hepatitis C/inmunología , Hepatitis C/transmisión , Hepatitis C/virología , Hepatitis D/inmunología , Hepatitis D/transmisión , Hepatitis D/virología , Humanos
15.
J Virol ; 69(2): 955-67, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7815563

RESUMEN

Previous studies suggested that simian immunodeficiency viruses isolated from African green monkeys (SIVagm) are relatively nonpathogenic. The report describes the isolation and biologic and molecular characterization of a pathogenic SIVagm strain derived from a naturally infected African green monkey. This virus induced an AIDS-like syndrome characterized by early viremia, frequent thrombocytopenia, severe lymphoid depletion, opportunistic infections, meningoencephalitis, and death of five of eight macaques within 1 year after infection. An infectious clone derived from this isolate reproduced the immunodeficiency disease in pig-tailed (PT) macaques, providing definitive proof of the etiology of this syndrome. Although the virus was highly pathogenic in PT macaques, no disease was observed in experimentally infected rhesus macaques and African green monkeys despite reproducible infection of the last two species. Whereas infection of PT macaques was associated with a high viral load in plasma, peripheral blood mononuclear cells, and tissues, low-level viremia and infrequent expression in lymph nodes of rhesus macaques and African green monkeys suggest that differences in pathogenicity are associated with the extent of in vivo replication. The availability of a pathogenic molecular clone will provide a useful model for the study of viral and host factors that influence pathogenicity.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida del Simio/etiología , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Replicación Viral , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos , Chlorocebus aethiops , Clonación Molecular , Humanos , Macaca mulatta , Datos de Secuencia Molecular , Virus de la Inmunodeficiencia de los Simios/genética , Especificidad de la Especie
16.
Intervirology ; 38(3-4): 155-61, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-8682610

RESUMEN

To identify specific environmental, viral, and genetic risk factors for hepatocellular carcinoma (HCC) and the interaction of such factors, we are conducting a prospective study in a high-incidence area of China. Questionnaires were completed and biosamples collected by 60,984 men ages 30-64 years, at study entry. Within 2.5 years, 183 deaths from HCC had occurred. Each HCC case was matched with 5 controls and compared for items on the questionnaire. In addition to chronic hepatitis B virus (HBV) infection, the significant risk factors were: occupation (peasant), corn consumption (in the 1970s), family history of HCC, and history of an episode of acute hepatitis as an adult. HBV, consumption of aflatoxins, a genetic factor, and possibly a second hepatitis virus infection contribute to the risk of HCC.


Asunto(s)
Carcinoma Hepatocelular/etiología , Hepatitis B/complicaciones , Neoplasias Hepáticas/etiología , Adulto , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/mortalidad , China/epidemiología , Susceptibilidad a Enfermedades , Exposición a Riesgos Ambientales , Humanos , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de Riesgo , Fumar , Infecciones Tumorales por Virus
17.
Princess Takamatsu Symp ; 25: 51-60, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-8875609

RESUMEN

To identify environmental, viral, and genetic factors that may influence the risk of developing hepatocellular carcinoma (HCC), large prospective studies are being conducted in Haimen City, China and Senegal, and a case-control study of genetic variation in the detoxification of aflatoxin-B1 was carried out in Shanghai, China. Analysis of 78 HCCs that have occurred among 51,020 men enrolled in a large prospective study in Haimen City, China showed a strong association of HCC with chronic hepatitis B virus (HBV) infection. There were also significant associations of HCC risk with occupation (farming), history of a clinical episode of hepatitis in adulthood, and a family history of HCC. Study of 52 HCC cases and 116 controls for genetic polymorphisms and HCC risk showed a significant association with epoxide hydrolase (EPHX) mutant alleles (1/2, 2/2) and a borderline association with homozygous deletion of the glutathione-S-transferase mu (GSTM1) gene. There was a multiplicative interaction of these polymorphisms with chronic HBV infection such that HBsAg-positive persons who were GSTM1 null and were EPHX 1/2 or 2/2 had 135 times the risk of HCC as HBsAg-negative persons with the wild type genotypes for GSTM1 and EPHX. The risk of HCC is not uniform among persons with chronic HBV or HCV infections. Studies of genetic, viral, and environmental interactions may permit identification of those individuals at highest risk within groups at increased risk of HCC. Prevention strategies could then be targeted at those individuals.


Asunto(s)
Carcinoma Hepatocelular/etiología , Neoplasias Hepáticas/etiología , Aflatoxina B1/toxicidad , Carcinoma Hepatocelular/genética , China , Hepatitis Viral Humana/complicaciones , Humanos , Neoplasias Hepáticas/genética , Masculino , Senegal
18.
J Infect Dis ; 170(1): 51-9, 1994 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8014520

RESUMEN

Simian immunodeficiency virus (SIV) infection of macaques is a useful and relevant model for evaluating candidate human immunodeficiency virus (HIV) vaccines. One important feature of this model is that SIV vaccines can be evaluated for their ability to prevent infection as well as to prevent or delay the onset of AIDS. In the present study, a group of macaques was vaccinated with whole inactivated SIV and challenged with peripheral blood mononuclear cells from an SIV-infected macaque. This challenge represented a rigorous and realistic test of the immunization protocol. All macaques became infected after challenge; however, immunized animals survived significantly longer (P < .03) than naive controls. These data suggest that similar vaccines administered to humans at risk for HIV-1 infection might delay or prevent AIDS even if the vaccine failed to prevent infection.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas Virales/inmunología , Vacunas contra el SIDA , Secuencia de Aminoácidos , Animales , Anticuerpos Antivirales/sangre , Antígenos Virales/sangre , Secuencia de Bases , Células Cultivadas , ADN Viral , Humanos , Macaca nemestrina , Datos de Secuencia Molecular , Monocitos/microbiología , Homología de Secuencia de Aminoácido , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/mortalidad , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Virus de la Inmunodeficiencia de los Simios/inmunología , Virus de la Inmunodeficiencia de los Simios/fisiología , Subgrupos de Linfocitos T/inmunología , Vacunas de Productos Inactivados/inmunología , Latencia del Virus
19.
Vaccine ; 12(8): 691-9, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8091846

RESUMEN

A cold-passaged RSV mutant, designated cp-RSV, which acquired host range mutations during 52 passages at low temperature in bovine tissue culture, was completely attenuated for seropositive adults and children but retained the capacity to cause upper respiratory disease in seronegative infants. We sought to introduce additional attenuating mutations, such as temperature-sensitive (ts) and small-plaque (sp) mutations, into the cp-RSV mutant, which is a ts+ virus, in order to generate a mutant which would be satisfactorily attenuated in seronegative infants and young children. Nine mutants of cp-RSV, which had acquired either the ts or small-plaque sp phenotype, were generated by chemical mutagenesis with 5-fluorouracil. The two ts mutants with the lowest in vitro shut-off temperature, namely the cpts-248 (38 degrees C) and cpts-530 (39 degrees C) mutants, were the most restricted of the nine cp-RSV mutant progeny tested for efficiency of replication in Balb/c mice. In seronegative chimpanzees, the cpts-248 mutant replicated fourfold less efficiently in the nasopharynx and caused significantly less rhinorrhoea than its cp-RSV parent. The cpts-248 mutant virus, like its cp-RSV parent, was 1000-fold restricted in replication in the trachea compared with wild-type RSV. Previously, another candidate RSV live attenuated vaccine strain, a mutant designated ts-1, exhibited some instability of its ts phenotype following replication in susceptible humans or chimpanzees. Hence, we sought cp-RSV ts progeny that exhibited a greater degree of stability of the ts phenotype than the prototype ts-1 mutant.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Virus Sincitiales Respiratorios/inmunología , Vacunas Virales/inmunología , Animales , Línea Celular , Chlorocebus aethiops , Frío , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutagénesis , Pan troglodytes , Infecciones por Virus Sincitial Respiratorio/prevención & control , Pase Seriado , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Células Vero , Vacunas Virales/genética , Replicación Viral
20.
J Virol ; 68(4): 2649-61, 1994 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8139042

RESUMEN

Simian immunodeficiency virus (SIV) exists within tissues of infected macaques as a mixture of diverse genotypes. The goal of this study was to investigate the biologic significance of this variation in terms of cellular tropism and pathogenicity. PCR was used to amplify and clone 3'-half genomes from the spleen of an immunodeficiency SIV-infected pig-tailed macaque (Macaca nemestrina). Eight infectious clones were generated by ligation of respective 3' clones into a related SIVsm 5' clone, and virus stocks were generated by transient transfection. Four of these viruses were infectious for macaque peripheral blood mononuclear cells (PBMC) or monocyte-derived macrophages (MDM). Three viruses with distinct tropism for macaque PBMC or MDM were tested for in vivo infectivity and pathogenicity. The ability of these three viruses to infect PBMC and macrophages correlated with differences in infectivity and pathogenicity. Thus, a virus that was infectious for both PBMC and MDM was highly infectious for macaques and induced AIDS in half of the inoculated animals. In contrast, virus that was less infectious for PBMC and not infectious for MDM induced only transient viremia. Finally, a virus that was not infectious for either primary cell type did not infect macaques. Chimeric clones exchanging portions of the envelope gene of the 62A and smH4 molecular clones and a series of point mutants were used to map the determinant of tropism to a 60-amino-acid region of gp120 encompassing the V3 analog of SIV. Naturally occurring mutations within this region were critical for determining tropism and, as a result, pathogenicity of these SIVsm clones.


Asunto(s)
Proteína gp120 de Envoltorio del VIH/genética , Glicoproteínas de Membrana , Síndrome de Inmunodeficiencia Adquirida del Simio/microbiología , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Proteínas del Envoltorio Viral , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Efecto Citopatogénico Viral , Análisis Mutacional de ADN , Leucocitos Mononucleares/microbiología , Macaca , Macrófagos/microbiología , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la Polimerasa , Pruebas de Precipitina , Proteínas Recombinantes de Fusión , Homología de Secuencia de Aminoácido , Bazo/microbiología , Transfección
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