RESUMO
Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Neoplasias Hepáticas/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.
Assuntos
Antivirais/uso terapêutico , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Povo Asiático , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Sofosbuvir/efeitos adversos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. METHODS: Patients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when ~1500 treated patients were followed up for ≥ 4 months. RESULTS: Of the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800 mg initial sorafenib dose, regardless of Child-Pugh status; however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. CONCLUSIONS: Consistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in > 3000 patients are ongoing.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Estudos Prospectivos , Sorafenibe , Adulto JovemRESUMO
AIMS: Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON), a global, non-interventional, surveillance study, aims to evaluate the safety of sorafenib in all patients with unresectable hepatocellular carcinoma (uHCC) under real-life practice conditions, particularly Child-Pugh B patients, who were not well represented in clinical trials. METHODS: Treatment decisions are determined by each physician according to local prescribing guidelines and clinical practice. Patients with uHCC who are candidates for systemic therapy, and for whom a decision has been made to treat with sorafenib, are eligible for inclusion. Demographic data and medical and disease history are recorded at entry. Sorafenib dosing and adverse events (AEs) are collected throughout the study. RESULTS: From January 2009 to April 2011, >3000 patients from 39 countries were enrolled. The prespecified first interim analysis was conducted when the initial approximately 500 treated patients had been followed up for ≥4 months; 479 were valid for safety evaluation. Preplanned subgroup analyses indicate differences in patient characteristics, disease aetiology and previous treatments by region. Variation in sorafenib dosing by specialty are also observed; Child-Pugh status did not appear to influence the starting dose of sorafenib. The type and incidence of AEs was consistent with findings from previous clinical studies. AE profiles were comparable between Child-Pugh subgroups. DISCUSSION: The GIDEON study is generating a large, robust database from a broad population of patients with uHCC. First interim analyses have shown global and regional differences in patient characteristics, disease aetiology and practice patterns. Subsequent planned analyses will allow further evaluation of early trends.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Tomada de Decisões , Neoplasias Hepáticas/tratamento farmacológico , Prática Profissional , Piridinas/uso terapêutico , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Niacinamida/análogos & derivados , Compostos de Fenilureia , Ensaios Clínicos Controlados Aleatórios como Assunto , Características de Residência , Sorafenibe , Especialização/estatística & dados numéricosRESUMO
BACKGROUND: Infectious complications following living-donor liver transplantation (LDLT) remain a major cause of morbidity and mortality. We analyzed the frequency and type of infectious complications according to the post-transplantation period, and their risk factors with regard to morbidity and mortality. METHODS: We retrospectively analyzed 208 subjects who had undergone LDLT during a 9-year period. RESULTS: The rate of infection was 1.69 per patient during the study period. The predominant infections were intra-abdominal infections (37.6%), primary bacteremia (17.4%), and pneumonia (14.5%). Within the first post-transplant month, 140 (39.9%) infections were detected, and catheter-related coagulase-negative staphylococci (44) were the most common infectious agents. During the 2-6-month post-transplant period, 109 infectious episodes occurred (31.1%), and Enterococcus sp. (n=16) related to biliary infection was the most frequent isolate. After the sixth month, 96 infectious episodes (29%) occurred, and biliary tract-related Escherichia coli (n=19) was the major causative organism. The overall mortality was 24.5% (51/208); 1-year survival rate was 88% (196/208). Post-transplant infection-related mortality was 52.9% (27/51). Biliary tract complications, such as biliary stenosis or leakage, significantly increased the mortality (P=0.01); however, reoperation (retransplantation or resurgery for biliary tract obstruction/leakage or to control bleeding) significantly reduced the mortality (P=0.01). CONCLUSIONS: Our data showed that early catheter removal would mainly aid in reducing infectious complications in the 1-month post-transplantation period. Aggressive management, including reoperation, would lower the mortality in the LDLT recipients.
Assuntos
Infecções/epidemiologia , Transplante de Fígado/efeitos adversos , Doadores Vivos , Complicações Pós-Operatórias/epidemiologia , Condicionamento Pré-Transplante/efeitos adversos , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Bacteriemia/mortalidade , Doenças Biliares/epidemiologia , Doenças Biliares/etiologia , Doenças Biliares/mortalidade , Feminino , Humanos , Infecções/etiologia , Infecções/mortalidade , Coreia (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Peritonite/epidemiologia , Peritonite/etiologia , Peritonite/mortalidade , Pneumonia/epidemiologia , Pneumonia/etiologia , Pneumonia/mortalidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Reoperação , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de TempoRESUMO
BACKGROUND: Acinetobacter baumannii has become an increasingly important nosocomial pathogen. Carbapenem is the preferred drug of choice for treatment of multidrug-resistant gram-negative bacilli, but carbapenem-resistant A baumannii (CRAB) has now emerged. The aim of this study was to determine the incidence, outcomes, and risk factors for CRAB bacteremia in liver transplant recipients. METHODS: The medical records of 393 subjects who underwent living donor liver transplant at Seoul St. Mary's Hospital from January 2008 to April 2015 were reviewed. RESULTS: A total of 92 (23.4%) bacteremic patients, comprising 156 episodes, were identified. Fourteen patients, totaling 18 episodes, had CRAB bacteremia. The median time of emergence of CRAB bacteremia was 55.5 (range, 2-829) days after transplantation, and 72.2% of episodes (n = 13) occurred within 6 months of transplant. The presumed sources of infection were intra-abdominal (n = 11, 61.1%), biliary tract (n = 3, 16.7%), lung (n = 2, 11.1%), catheter (n = 1, 5.6%), and wound (n = 1, 5.6%). By multivariate analysis, length of post-transplant intensive care unit (ICU) stay (odds ratio [OR], 1.1, 95% confidence interval [CI], 1.11-1.15; P = .04) was associated with CRAB bacteremia. Overall mortality in 14 recipients with CRAB bacteremia was 50% (n = 7), but only 10% (30 of 301) in non-bacteremic patients and 20.5% (16 of 78) in other bacteremic patients excluding CRAB (P < .001). CONCLUSION: In our study, patients with CRAB bacteremia after liver transplant showed an unfavorable outcome and, recently, CRAB has become an increasingly major pathogen at our center. Reducing the length of ICU stay could be a solution for preventing CRAB bacteremia.
Assuntos
Infecções por Acinetobacter/complicações , Carbapenêmicos , Transplante de Fígado/efeitos adversos , Complicações Pós-Operatórias/microbiologia , Infecções por Acinetobacter/tratamento farmacológico , Infecções por Acinetobacter/epidemiologia , Acinetobacter baumannii , Adulto , Idoso , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Carbapenêmicos/uso terapêutico , Feminino , Humanos , Incidência , Transplante de Fígado/mortalidade , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Resistência beta-LactâmicaRESUMO
BACKGROUND: Uncontrolled infections are known to be an absolute contraindication for liver transplantation; however, the posttransplant prognosis of recipients treated for pretransplant infection is unclear. The aim of this study was to analyze pretransplant infections among liver transplant recipients and to determine their impact on posttransplant clinical outcomes. METHODS: This study retrospectively analyzed 357 subjects who had undergone living-donor liver transplantation between January 2008 and May 2014. RESULTS: Among 357 recipients, 71 patients (19.8%) had 74 episodes of infectious complications before liver transplantation. These complications consisted of pneumonia (n = 13), spontaneous bacterial peritonitis (n = 12), catheter-related infection (n = 10), urinary tract infection (n = 12), biliary tract infection (n = 6), and skin and soft-tissue infection (n = 3). Twenty-six patients experienced 29 episodes of bacteremia, and the most common pathogens were coagulase-negative staphylococci (n = 8), followed by Klebsiella pneumoniae (n = 7), Staphylococcus aureus (n = 4), and Streptococcus species (n = 3). Twenty-one bacteremic episodes (70%) occurred within 1 month before transplantation (n = 4). Recipients with pretransplant infections had significantly more frequent posttransplant infections (71.8% [51 of 71] vs 47.2% [35 of 286]; P = .0001), posttransplant bacteremia (33.8% [24 of 71] vs 20.3% [58 of 286]; P = .015), and longer posttransplant intensive care unit stays (11.2 ± 10.7 days vs 7.3 ± 4.2 days; P = .0004) than those without pretransplant infections. However, episodes of rejection (P = .36), length of hospitalization (P = .10), 28-day mortality (P = .31), and 1-year mortality (P = .61) after transplantation were not significantly different between the 2 groups. CONCLUSIONS: Pretransplant infection had an impact on posttransplant morbidity, although not on rejection and mortality. Alertness for posttransplant infection and proper management (including effective antimicrobial coverage) would improve patient morbidity.
Assuntos
Infecções Bacterianas/complicações , Doença Hepática Terminal/complicações , Doença Hepática Terminal/cirurgia , Transplante de Fígado , Período Pré-Operatório , Adulto , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. AIM: To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. RESULTS: We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 109 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. CONCLUSIONS: More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH.
Assuntos
Gastroenteropatias/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/epidemiologia , Adulto , Ásia/epidemiologia , Povo Asiático/estatística & dados numéricos , Biópsia , Índice de Massa Corporal , Estudos de Coortes , Feminino , Gastroenteropatias/complicações , Gastroenteropatias/patologia , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/patologia , Oceano Pacífico/epidemiologia , Estudos RetrospectivosRESUMO
Mice with recessive cataract, CXSD, show the first clinical symptoms of cataract at five weeks, with complete penetrance. We previously localized the cataract-causing lens rupture 2 gene (lr2) to mouse chromosome 14. In the process of positional cloning of the lr2 gene, we determined the genomic organization of the critical region, defined by D14Mit262 and D14Mit86, and compared it to recently published map information. In addition, mutational analysis using reverse transcription polymerase chain reaction (RT-PCR) followed by direct sequencing as well as quantitative realtime PCR (RQ-PCR) was performed to investigate Adam28 and Adamdec1 as lr2 candidate genes in this study. There was no mutation cosegregating with the phenotype of CXSD mice, which excluded these genes as the lr2 gene. Identification of more transcripts from this region and their mutation analyses are required to isolate the lr2 gene.
Assuntos
Proteínas ADAM/genética , Catarata/genética , Mapeamento Cromossômico/métodos , Genes/genética , Genoma , Sitios de Sequências Rotuladas , Animais , Análise Mutacional de DNA , Primers do DNA/química , Regulação da Expressão Gênica , Genes/fisiologia , Camundongos , Modelos Genéticos , Fenótipo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Although transarterial chemotherapy is used to retard tumour progression for hepatocellular carcinoma (HCC) patients awaiting orthotopic liver transplantation (OLT), information regarding the acceptable waiting time and appropriate patient selection for the therapy is lacking. AIM: To examine dropout times and determine the best candidates for pre-transplant transarterial therapy in a cohort study. METHODS: In total, 180 consecutive HCC candidates receiving pre-transplant chemo-lipiodolization were included in the study. RESULTS: Overall, 70 (38.9%) patients dropped off the waiting list during the median follow-up of 19 months. According to the Child-Pugh (C-P) classification, the estimated dropout rates at 1 and 2 years were 17.2% and 44.8% for the C-P A group and 33.4% and 81.3% for the C-P B/C group, respectively. C-P B/C patients experienced more frequent dropouts than C-P A patients (P < 0.001). Risk factor analysis identified C-P classification to be the strongest predictor of dropout (P < 0.001). On multivariate analysis, alpha-fetoprotein (AFP) >100 ng/mL, tumour size >3 cm and multiple nodules remained independently predictive of dropout for C-P A group (all P < 0.05). Candidates with none of these factors were found to be at the lowest risk of dropout, with only a 22.5% dropout rate up to 41 months. CONCLUSIONS: This study suggests that Child-Pugh A patients with one nodule <3 cm and AFP < 100 ng/mL may be the best candidates for pre-transplant chemo-lipiodolization, with the lowest dropout rate. However, comparative studies with other therapeutic options are needed to assess the definitive role of transarterial therapy in this setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Estudos de Coortes , Progressão da Doença , Epirubicina/administração & dosagem , Feminino , Humanos , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Seleção de Pacientes , Fatores de Risco , Listas de EsperaRESUMO
Essential hypertension (EH) is considered a typical polygenic disease, so the evaluation of gene-gene interactions rather than the determination of single gene effects is crucial to understanding any genetic influences. The G-protein beta3-subunit (GNB3) 825T allele, associated with enhanced G-protein signalling, is a strong candidate for interactions with polymorphisms, such as insertion/deletion (I/D) polymorphism of angiotensin I-converting enzyme (ACE) gene. We investigated whether there is an association between GNB3 C825T and ACE I/D polymorphisms for the development of EH. We carried out a case-control study of 688 hypertensive and 924 normotensive subjects recruited from South Korea. The GNB3 C825T and ACE I/D genotypes were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods, respectively. The distributions of alleles and genotypes for the GNB3 C825T and ACE I/D polymorphisms were not found to be significantly associated with hypertensive status in either males or females. Logistic regression analysis indicated that the GNB3 825T allele carriers were positively associated with EH in males (odds ratio (OR) for TT/CT, 1.459; 95% confidence interval (CI), 1.048-2.033, P=0.0255). In analysis of gene-gene interaction, we found that there was a significant interaction between the GNB3 825T and ACE D alleles (P<0.05). OR for EH was significantly higher in 825T allele carriers with ACE D allele (OR, 1.490; 95% CI, 1.117-1.987, P=0.0067). A significant interaction between the GNB3 825T and the ACE D alleles may contribute to the predisposing effect for the development of EH in Koreans.
Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/genética , Hipertensão/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
The SM1311 family is an Ashkenazi family with dominantly inherited predisposition to colorectal adenomas and carcinomas and has a high-penetrance locus in chromosome 15q, with a multipoint logarithm of the odds score of 3.06 at marker D15S118. In the present study, we performed a high-density loss of heterozygosity study with 13 polymorphic microsatellite markers, including D15S118, spanning 15q15.3-q22.1, on 70 cases of the sporadic form of colorectal tumors. Our deletion mapping data showed a locus at D15S968 in chromosomal sub-band 15q21.1 may harbor a tumor suppressor gene in an area <0.521 Mb in physical map distance defined by markers D15S514 and D15S222. THBS1, 0.185 Mb proximal to D15S968, is the nearest known gene to this specific narrow loss of heterozygosity region. Thus, we speculate that THBS1 might be the most probable candidate gene involved in colorectal cancer carcinogenesis.
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Cromossomos Humanos Par 15/genética , Neoplasias Colorretais/genética , Genes Supressores de Tumor/genética , Perda de Heterozigosidade , Mapeamento Cromossômico , Progressão da Doença , Marcadores Genéticos , Humanos , Repetições de Microssatélites/genéticaRESUMO
Estrogen receptor alpha (ERα) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ERα-positive breast cancer cells prompted us to investigate its role in chromatin modification required for ERα activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2-bound ERα and mediates ERα activation. Chromatin immunoprecipitation-sequencing analysis supports a positive role of ASXL2 at ERα target gene promoters. ASXL2 forms a complex with histone methylation modifiers including LSD1, UTX and MLL2, which all are recruited to the E2-responsive genes via ASXL2 and regulate methylations at histone H3 lysine 4, 9 and 27. The preferential binding of the PHD finger of ASXL2 to the dimethylated H3 lysine 4 may account for its requirement for ERα activation. On ASXL2 depletion, the proliferative potential of MCF7 cells and tumor size of xenograft mice decreased. Together with our finding on the higher ASXL2 expression in ERα-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Proliferação de Células , Receptor alfa de Estrogênio/metabolismo , Histonas/metabolismo , Proteínas Repressoras/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Histona Desmetilases/metabolismo , Humanos , Lisina/metabolismo , Células MCF-7 , Metilação , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Prognóstico , Ligação Proteica , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante HeterólogoRESUMO
Interleukin 6 (IL-6) is a pleiotropic cytokine that induces many biological activities, including some aspects of the immune reaction and inflammatory responses. In the liver, IL-6 regulates the synthesis of a broad spectrum of acute-phase proteins. IL-6 is also known to be a factor involved in the immunoregulatory perturbations in patients with chronic liver diseases (CLDs). Here, we report that IL-6 can be induced by hepatitis B virus (HBV)-X protein, as evidenced by high levels of serum IL-6 in patients with CLD with HBV infection, IL-6 productions observed in HBV-X-transfected cells, and transcriptional transactivations of the IL-6 gene by HBV-X. We determined serum levels of IL-6 in patients with chronic hepatitis B (CH-B), chronic hepatitis C (CH-C), liver cirrhosis (LC) caused by hepatitis B, and LC with hepatocellular carcinoma (HCC) caused by hepatitis B (LC+HCC). Mean serum levels of IL-6 in all CLD patients were higher than those in normal controls, and the difference was statistically significant (P < 0.05). Mean IL-6 levels of LC and LC+HCC patients were significantly higher than those of CH-B patients (P < 0.05). Because the etiological factor in all cases except CH-C (CH-B, LC, and LC+HCC) was HBV, we checked the possibility of HBV-transactivator-X activation of IL-6 promoter. Using deletion constructs of 5'-flanking regulatory regions of the IL-6 gene linked to the chloramphenicol acetyltransferase gene as a reporter, we found that the binding of nuclear factor-kappaB to a cis element is essential and sufficient for the induction of the IL-6 gene by HBV-X. We also found that HBV-X enhances the binding of two subunits of nuclear factor-kappaB (p65 and p52) to their target DNA binding sequences. These observations are relevant, in that HBV-X might play an important role in hepatic inflammation and diseases by up-regulating IL-6 production, which can eventually lead to LC and HCC.
Assuntos
Carcinoma Hepatocelular/sangue , Hepatite Crônica/sangue , Hepatite Viral Humana/sangue , Interleucina-6/genética , Cirrose Hepática/sangue , Neoplasias Hepáticas/sangue , NF-kappa B/metabolismo , Transativadores/fisiologia , Ativação Transcricional , Sítios de Ligação , Vetores Genéticos , Humanos , Interleucina-6/sangue , Regiões Promotoras Genéticas , Transfecção , Células Tumorais CultivadasRESUMO
The potential of cationic liposomes as nonviral vectors for in vivo gene delivery to the liver and to intrahepatic hepatocellular carcinoma (HCC) was investigated. Mice were injected via the tail vein or portal vein with a cationic lipid complexed to plasmid DNA (pDNA) encoding the chloramphenicol acetyltransferase (CAT) reporter gene at various cationic lipid:pDNA molar ratios to analyze the efficiency of gene delivery after intravenous administration. Tail vein injection resulted in high CAT expression levels in lung and spleen and low levels in the liver. Portal vein injection, by comparison, significantly enhanced hepatic reporter gene expression but also resulted in pronounced hepatic toxicity. Gene delivery to intrahepatic tumors produced by intrahepatic injection of human HCC cells was analyzed in nude mice. Tail vein injection as well as portal vein injection resulted in low levels of gene expression in intrahepatic tumors. By comparison, high levels of gene expression were achieved by direct, intratumoral injection of liposome-pDNA complexes, with only minimal expression in the surrounding normal liver. Therefore, direct liposome-pDNA complex injection appears far superior to systemic or portal intravenous administration for gene therapy of localized intrahepatic tumors, and may be a useful adjunct in the treatment of human HCCs.
Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Lipossomos/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Cátions/administração & dosagem , Cátions/efeitos adversos , Cátions/metabolismo , Cloranfenicol O-Acetiltransferase/genética , Cloranfenicol O-Acetiltransferase/metabolismo , Sistemas de Liberação de Medicamentos/efeitos adversos , Sistemas de Liberação de Medicamentos/métodos , Expressão Gênica , Genes Reporter/genética , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Injeções , Injeções Intravenosas , Lipossomos/administração & dosagem , Lipossomos/efeitos adversos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Veia Porta/fisiologia , Transgenes/genéticaRESUMO
Gene therapy may become an option for the treatment of malignant tumors such as hepatocellular carcinoma (HCC), once safe and efficient vector systems have been established. Due to their stability in vivo, recombinant adenoviral vectors are promising vectors for gene delivery to HCC. To study the characteristics of gene delivery into HCCs by recombinant adenoviral vectors in vivo, we established an in situ HCC model in the livers of athymic nude mice by intrahepatic injection of human HCC cells. Recombinant adenovirus vectors expressing beta-galactosidase (Ad2CMV beta gal) were injected via the tail vein of mice bearing HCC or directly into intrahepatic tumors. Levels of beta-galactosidase expression in tumor tissue and surrounding normal liver were analyzed by histochemistry or for quantification by a chemiluminescence assay in tissue homogenates. Following tail vein injection, high levels of beta-galactosidase expression were found in the liver, but virtually no gene expression could be detected in the tumor tissue. In contrast, after direct injection of Ad2CMV beta gal into intrahepatic HCCs, high levels of beta-galactosidase expression were detected in the tumor tissue. However, single transduced hepatocytes scattered throughout the normal liver could also be identified. These results indicate that barriers such as the endothelial lining of the tumor vasculature impair the efficiency of adenoviral vectors for gene delivery into HCCs by intravenous administration, which can be overcome by direct injection into the tumor tissue. However, due to the observed transduction of disseminated hepatocytes following intratumoral administration, additional HCC-specific targeting to further enhance the safety of adenoviral vectors may be required.
Assuntos
Adenoviridae/genética , Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Neoplasias Hepáticas/terapia , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos/métodos , Feminino , Expressão Gênica , Terapia Genética/efeitos adversos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Humanos , Técnicas Imunoenzimáticas , Injeções Intravenosas , Óperon Lac/fisiologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fatores de Risco , Transgenes/genética , beta-Galactosidase/metabolismoRESUMO
GB virus C and hepatitis G virus (GBV-C/HGV) have been identified from the patients with acute or chronic liver diseases as possible agents of non-B, non-C hepatitis by two different groups, independently. To investigate whether GBV-C/HGV plays a role among Korean patients with liver diseases, GBV-C/HGV RNA were evaluated in 337 sera by the reverse transcription polymerase chain reaction (RT-PCR) using specific primers derived from 5'-noncoding region of GBV-C/HGV genome. GBV-C/HGV RNA was identified in 11/337 (3.3%). They consisted of 1/160 (0.6%) and 10/177 (3.3%) among the general population and patients with liver diseases, respectively (P < 0.01). Nucleotide sequences of all PCR amplicons were determined by the dideoxy chain termination method and analyzed by molecular evolutionary methods. The phylogenetic tree showed all sequences could be divided into three genotypes. These results indicate that: (1) GBV-C/HGV already exist in Korea; (2) GBV-C/HGV may play some role as an etiologic factor among the Korean patients with liver diseases; (3) GBV-C/HGV infection is rare among Korean general population; and (4) there are at least three different types of GBV-C/HGV in Korea.
Assuntos
Flaviviridae/isolamento & purificação , Hepatite Viral Humana/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Feminino , Flaviviridae/química , Flaviviridae/genética , Hepatite Viral Humana/genética , Humanos , Coreia (Geográfico)/epidemiologia , Hepatopatias/complicações , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , Prevalência , RNA Viral/sangue , RNA Viral/genética , Análise de Sequência de DNARESUMO
[reaction: see text]. The copper iodide-catalyzed cross-coupling of terminal alkynes with hypervalent iodonium salts was accomplished with CuI (10 mol %) and NaHCO3 (2 equiv) in DME/H2O (4:1) at room temperature for 30 min to afford arylalkynes or enynes under mild conditions.
RESUMO
Human Fas associated factor 1 protein (hFAF1) is involved in the positive regulation of Fas signaling even though it can not initiate the signal for itself. By chromosomal assignment using somatic cell hybrids (CASH), the hFAF1 gene was located on human chromosome 1 between markers D1S443 and D1S197. The hFAF1 gene was mapped to human chromosome band 1p32 by FISH utilizing a genomic PAC clone containing the gene. In genomic Southern analysis using hFAF1 cDNA as a probe, several bands appeared in three different restriction enzyme digestions. The single band appearance in FISH analysis compared to several bands in Southern blots implies that the hFAF1 gene would be rather big or that an additional hFAF1 gene isotype(s) might be present in close vicinity.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 1 , Regiões 3' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal , Apoptose , Proteínas Reguladoras de Apoptose , Southern Blotting , Mapeamento Cromossômico , Humanos , Células Híbridas , Hibridização in Situ Fluorescente , Cariotipagem , Mapeamento por RestriçãoRESUMO
NF-kappaB is a transcription factor, which is activated by various stimuli. One of the well-known activators of NF-kappaB is oxidative stress, which is a cause of cell death in some tissue, or cell types. Optic nerve transection, axotomy, results in retinal cell death, because of oxidative stress, deprivation of neurotrophic factors, etc. Since it has been hypothesized that the retinal ganglion cell death after axotomy is due to the generation of reactive oxygen species, we investigated whether NF-kappaB is involved in the retinal cell death after axotomy. This study was performed to investigate the role of NF-kappaB in retinal ganglion cell death after optic nerve transection. We used double staining experiment by using anti-NF-kappaB antibody and ethidium bromide to observe the correlation of NF-kappaB activation and the cell death. NF-kappaB was observed only in the surviving cells. NF-kappaB translocation was observed 3 days after the optic nerve transection. The NF-kappaB inhibitor, sulfasalazine, was used to block the activation of NF-kappaB in the axotomized retina, and the number of ganglion cells was quantified using retrograde in the presence or absence of sulfasalazine after axotomy. Inhibition of NF-kappaB by sulfasalazine accelerated the degeneration of ganglion cells in the retina. The results suggest that the activated NF-kappaB plays a protective role from the cell death in the injured ganglion cells.