RESUMO
About 80% of persons with chronic hepatitis B virus (HBV) infection in the United States are non-US-born. Despite improvements in infant hepatitis B vaccination globally since 2000, work remains to attain the World Health Organization's (WHO) global 2030 goal of 90% vaccination. We explore the impacts on the United States of global progress in hepatitis B vaccination since 2000 and of achieving WHO hepatitis B vaccination goals. We simulated immigrants with HBV infection arriving to the United States from 2000 to 2070 using models of the 10 countries from which the largest numbers of individuals with HBV infection were born. We estimated costs in the United States among these cohorts using a disease simulation model. We simulated three scenarios: a scenario with no progress in infant vaccination for hepatitis B since 2000 (baseline), current (2020) progress and achieving WHO 2030 goals for hepatitis B vaccination. We estimate current hepatitis B vaccination progress since the 2000 baseline in these 10 countries will lead to 468,686 fewer HBV infections, avoid 35,582 hepatitis B-related deaths and save $4.2 billion in the United States through 2070. Achieving the WHO 2030 90% hepatitis B infant vaccination targets could lead to an additional 16,762 fewer HBV infections, 989 fewer hepatitis B-related deaths and save $143 million through 2070. Global hepatitis B vaccination since 2000 reduced prevalence of HBV infection in the United States. Achieving the WHO 2030 infant vaccination goals globally could lead to over one hundred million dollars in additional savings.
RESUMO
BACKGROUND: Endovascular deep vein arteriaization (DVA) is a novel technique aimed at salvaging peripheral arterial disease unamenable to conventional surgical intervention. This study aims to review contemporary literature on the efficacy, safety, and durability of DVA on patients with no-option critical limb ischemia (NO-CLI). METHODS: The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using predefined search terms of "percutaneous deep vein arterialization" or "percutaneous deep venous arterialization" in PubMed, Web of Sciences, OvidSP, and Embase. Only studies with 5 or more patients were included, and studies involving open or hybrid DVA were excluded. The primary outcomes included technical success and primary amputation rates. Secondary outcomes included rates of wound healing, complication, reintervention, and all-cause mortality. RESULTS: Ten studies encompassing a total of 233 patients were included. Patients were primarily those deemed to have NO-CLI. The median follow-up period was 12 months (range 1-63 months). The technical success rate was 97% (95% confidence interval [CI] 96.2%-97.9%) and the major amputation rate was 21.8% (95% 21.1%-22.4%). The wound healing rate was 69.5% (95% CI 67.9-71.0%), complication rate was 13.8% (95% CI 11.7%-15.9%), reintervention rate was 37.4% (95% CI 34.9%-39.9%), and all-cause mortality rate was 15.7% (95% CI 14.1%-17.2%). CONCLUSIONS: Our study showed that endovascular DVA is safe for patients with NO-CLI. Nonetheless, studies were small with follow-up period of less than 1 year. There is currently lack of level 1 evidence to recommend routine use in patients with NO-CLI.
Assuntos
Amputação Cirúrgica , Procedimentos Endovasculares , Salvamento de Membro , Doença Arterial Periférica , Humanos , Resultado do Tratamento , Fatores de Risco , Fatores de Tempo , Doença Arterial Periférica/cirurgia , Doença Arterial Periférica/fisiopatologia , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Idoso , Feminino , Masculino , Veias/cirurgia , Veias/fisiopatologia , Pessoa de Meia-Idade , Cicatrização , Estado Terminal , Idoso de 80 Anos ou mais , Isquemia/cirurgia , Isquemia/fisiopatologia , Isquemia/mortalidade , Isquemia/diagnóstico por imagemRESUMO
BACKGROUND: Chronic hepatitis B (CHB) carries an increased risk of death from cirrhosis and hepatocellular carcinoma (HCC). The American Association for the Study of Liver Diseases recommends patients with CHB receive monitoring of disease activity, including ALT, hepatitis B virus (HBV) DNA, hepatitis B e-antigen (HBeAg), and liver imaging for patients who experience an increased risk for HCC. HBV antiviral therapy is recommended for patients with active hepatitis and cirrhosis. METHODS: Monitoring and treatment of adults with new CHB diagnoses were analyzed using Optum Clinformatics Data Mart Database claims data from January 1, 2016, to December 31, 2019. RESULTS: Among 5978 patients with new CHB diagnosis, only 56% with cirrhosis and 50% without cirrhosis had claims for≥1 ALT and either HBV DNA or HBeAg test, and among patients recommended for HCC surveillance, 82% with cirrhosis and 57% without cirrhosis had claims for≥1 liver imaging within 12 months of diagnosis. Although antiviral treatment is recommended for patients with cirrhosis, only 29% of patients with cirrhosis had≥1 claim for HBV antiviral therapy within 12 months of CHB diagnosis. Multivariable analysis showed patients who were male, Asian, privately insured, or had cirrhosis were more likely (P<0.05) to receive ALT and either HBV DNA or HBeAg tests and HBV antiviral therapy within 12 months of diagnosis. CONCLUSION: Many patients diagnosed with CHB are not receiving the clinical assessment and treatment recommended. A comprehensive initiative is needed to address the patient, provider, and system-related barriers to improve the clinical management of CHB.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Adulto , Humanos , Masculino , Estados Unidos , Feminino , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Antígenos E da Hepatite B/uso terapêutico , DNA Viral/uso terapêutico , Antivirais/uso terapêutico , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologiaRESUMO
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a typically fatal malignancy with limited treatment options and poor survival rates, despite recent FDA approvals of newer treatment options. We aim to address this unmet need by using a proprietary computational drug discovery platform that identifies drug candidates with the potential to advance rapidly and successfully through preclinical studies. METHODS: We generated an in silico model of HCC biology to identify the top 10 small molecules with predicted efficacy. The most promising candidate, CYT997, was tested for its in vitro effects on cell viability and cell death, colony formation, cell cycle changes, and cell migration/invasion in HCC cells. We used an HCC patient-derived xenograft (PDX) mouse model to assess its in vivo efficacy. RESULTS: CYT997 was significantly more cytotoxic against HCC cells than against primary human hepatocytes, and sensitized HCC cells to sorafenib. It arrested cell cycle at the G2/M phase with associated up-regulations of p21, p-MEK1/2, p-ERK, and down-regulation of cyclin B1. Cell apoptosis and senescence-like morphology were also observed. CYT997 inhibited HCC cell migration and invasion, and down-regulated the expressions of acetylated tubulins, ß-tubulin, glypican-3 (GPC3), ß-catenin, and c-Myc. In vivo, CYT997 (20 mg/kg, three times weekly by oral gavage) significantly inhibited PDX growth, while being non-toxic to mice. Immunohistochemistry confirmed the down-regulation of GPC3, c-Myc, and Ki-67, supporting its anti-proliferative effect. CONCLUSION: CYT997 is a potentially efficacious and non-toxic drug candidate for HCC therapy. Its ability to down-regulate GPC3, ß-catenin, and c-Myc highlights a novel mechanism of action.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/patologia , beta Catenina/metabolismo , Neoplasias Hepáticas/patologia , Apoptose , Microtúbulos/metabolismo , Microtúbulos/patologia , Linhagem Celular Tumoral , Proliferação de Células , GlipicanasRESUMO
Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.
Assuntos
Pequeno RNA não Traduzido/genética , RNA de Transferência de Leucina/genética , Proteínas Ribossômicas/biossíntese , Ribossomos/genética , Ribossomos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Pareamento de Bases , Sequência de Bases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Ribossômico 18S/genética , RNA Ribossômico 18S/metabolismo , Pequeno RNA não Traduzido/antagonistas & inibidores , RNA de Transferência de Leucina/antagonistas & inibidores , Proteínas Ribossômicas/genética , Subunidades Ribossômicas Menores de Eucariotos/metabolismo , Ribossomos/efeitos dos fármacos , Especificidade por Substrato/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: An estimated 862 000 to 2.4 million people have chronic hepatitis B infection (CHB). Hepatitis B screening is recommended for pregnant women and populations with increased CHB risk. However, diagnosis rates remain low, with only 33% of people with CHB aware of their infection. This study aimed to assess the cost-effectiveness of universal adult screening for CHB. METHODS: We used a Markov model to calculate the costs, population health impact, and cost-effectiveness of 1-time universal screening and CHB monitoring and treatment compared with current practice. Sensitivity analysis was performed on model parameters to identify thresholds for cost-saving or cost-effectiveness based on a willingness to pay of $50 000/quality-adjusted life-year. The analysis assumed testing would be performed during routine healthcare visits and that generic tenofovir or entecavir would be dispensed for treatment. Testing costs were based on Medicare reimbursement rates. RESULTS: At an estimated 0.24% prevalence of undiagnosed CHB, universal hepatitis B surface antigen (HBsAg) screening in adults aged 18-69 years is cost-saving compared with current practice if antiviral treatment drug costs remain below $894/year. Compared with current practice, universal screening would avert an additional 7.4 cases of compensated cirrhosis, 3.3 cases of decompensated cirrhosis, 5.5 cases of hepatocellular carcinoma, 1.9 liver transplants, and 10.3 hepatitis B virus-related deaths at a saving of $263 000/100 000 adults screened. CONCLUSIONS: Universal HBsAg screening of adults in the US general population for CHB is cost-effective and likely cost-saving compared with current CHB screening recommendations.
Assuntos
Hepatite B Crônica , Neoplasias Hepáticas , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Análise Custo-Benefício , Feminino , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Medicare , Pessoa de Meia-Idade , Gravidez , Anos de Vida Ajustados por Qualidade de Vida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The estimated number of people living with hepatitis B virus (HBV) infection acquired through sexual transmission was 103,000 in 2018, with an estimated incidence of 8300 new cases per year. Although hepatitis B (HepB) vaccination is recommended by the Advisory Committee for Immunization Practices for persons seeking evaluation and treatment for sexually transmitted infections (STIs), prevaccination testing is not yet recommended. Screening may link persons with chronic hepatitis B to care and reduce unnecessary vaccination. METHODS: We used a Markov model to calculate the health impact and cost-effectiveness of 1-time HBV testing combined with the first dose of the HepB vaccine for adults seeking care for STI. We ran a lifetime, societal perspective analysis for a hypothetical population of 100,000 aged 18 to 69 years. The disease progression estimates were taken from recent cohort studies and meta-analyses. In the United States, an intervention that costs less than $100,000 per quality-adjusted life-year (QALY) is generally considered cost-effective. The strategies that were compared were as follows: (1) vaccination without HBV screening, (2) vaccination and hepatitis B surface antigen (HBsAg) screening, (3) vaccination and screening with HBsAg and anti-HBs, and (4) vaccination and screening with HBsAg, anti-HBs, and anti-HBc. Data were obtained from Centers for Medicare & Medicaid services reimbursement, the Centers for Disease Control and Prevention vaccine price list, and additional cost-effectiveness literature. RESULTS: Compared with current recommendations, the addition of 1-time HBV testing is cost-saving and would prevent an additional 138 cases of cirrhosis, 47 cases of decompensated cirrhosis, 90 cases of hepatocellular carcinoma, 33 liver transplants, and 163 HBV-related deaths, and gain 2185 QALYs, per 100,000 adults screened. Screening with the 3-test panel would save $41.6 to $42.7 million per 100,000 adults tested compared with $41.5 to $42.5 million for the 2-test panel and $40.2 to $40.3 million for HBsAg alone. CONCLUSIONS: One-time HBV prevaccination testing in addition to HepB vaccination for unvaccinated adults seeking care for STI would save lives and prevent new infections and unnecessary vaccination, and is cost-saving.
Assuntos
Hepatite B , Infecções Sexualmente Transmissíveis , Adulto , Idoso , Análise Custo-Benefício , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B , Vírus da Hepatite B , Humanos , Cirrose Hepática , Medicare , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Estados Unidos/epidemiologia , VacinaçãoRESUMO
BACKGROUND & AIMS: We aim to capture the economic impact of a potential cure for chronic hepatitis B infection (CHB) in three countries (USA, China and Australia) with different health systems and epidemics to estimate the threshold drug prices below which a CHB cure would be cost-saving and/or highly cost-effective. METHODS: We simulated patients' hepatitis B progression, under three scenarios: current long-term suppressive antiviral therapy, functional cure defined as sustained undetectable HBsAg and HBV DNA, and partial cure defined as sustained undetectable HBV DNA only after a finite, 48-week treatment. RESULTS: Compared with current long-term antiviral therapy, a 30% effective functional cure among patients with and without cirrhosis in the USA, China and Australia would yield 17.50, 17.32 and 20.42 QALYs per patient, and 20.61, 20.42 and 20.62 QALYs per patient respectively. In financial terms, for CHB patients with and without cirrhosis, this would be cost-saving at a one-time treatment cost under US$11 944 and US$6694, respectively, in the USA, US$1744 and US$1001 in China, and US$12 063 and US$10 983 in Australia. CONCLUSION: We show that in purely economic terms, a CHB cure will be highly cost-effective even if effective in only 30% of treated patients. The threshold price for cure is largely determined by the current antiviral drug costs, since it will replace a daily antiviral pill that is inexpensive and effective, although not curative. The likely need for combination therapies to achieve cure will also present cost challenges. While cost-effectiveness is important, it cannot be the only consideration, as cure will provide many benefits in addition to reduced liver disease and HCC, including eliminating the need for a long-term daily pill and reducing stigma often associated with chronic viral infection.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Hepatite B , Neoplasias Hepáticas , Antivirais , Austrália , Carcinoma Hepatocelular/tratamento farmacológico , China/epidemiologia , Análise Custo-Benefício , Hepatite B/tratamento farmacológico , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
BACKGROUND: Our study aims to describe how obstetricians manage pregnant women infected with chronic hepatitis B in a region with a large high-risk population. METHODS: We performed a cross-sectional study among practicing obstetricians in Santa Clara County, California. All obstetricians practicing in Santa Clara County were invited to participate in the study. Obstetricians were recruited in person or by mail to complete a voluntary, multiple choice survey on hepatitis B (HBV). Survey questions assessed basic HBV knowledge and obstetricians' self-reported clinical practices of the management of HBV-infected pregnant women. Pooled descriptive analyses were calculated for the cohort, as well as, correlation coefficients to evaluate the association between reported clinical practices and hepatitis B knowledge. RESULTS: Among 138 obstetricians who completed the survey, 94% reported routinely testing pregnant women for hepatitis B surface antigen (HBsAg) with each pregnancy. Only 60.9% routinely advised HBsAg-positive patients to seek specialist evaluation for antiviral treatment and monitoring and fewer than half (48.6%) routinely provided them with HBV information. While most respondents recognized the potential complications of chronic HBV (94.2%), only 21% were aware that chronic HBV carries a 25% risk of liver related death when left unmonitored and untreated, and only 25% were aware of the high prevalence of chronic HBV in the foreign-born Asian, Native Hawaiian and Pacific Islander population. Obstetricians aware of the high risk of perinatal HBV transmission were more likely to test pregnant women for HBV DNA or hepatitis B e-antigen in HBV-infected women (r = 0.18, p = 0.033). Obstetricians who demonstrated knowledge of the long-term consequences of untreated HBV infection were no more likely to refer HBV-infected women to specialists for care (r = 0.02, p = 0.831). CONCLUSION: Our study identified clear gaps in the practice patterns of obstetricians that can be readily addressed to enhance the care they provide to HBV-infected pregnant women.
Assuntos
Competência Clínica , Hepatite B Crônica/terapia , Obstetrícia , Padrões de Prática Médica , Complicações Infecciosas na Gravidez/terapia , Encaminhamento e Consulta , Adulto , Antivirais/uso terapêutico , Estudos Transversais , DNA Viral/sangue , Gerenciamento Clínico , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/etnologia , Humanos , Transmissão Vertical de Doenças Infecciosas , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/etnologiaRESUMO
Chronic hepatitis B infection (CHB) is a condition that needs ongoing care such as monitoring for liver enzymes (ALT) and HBV DNA tests in treated and untreated patients, and annual imaging evaluation for liver cancer. Although follow-up care and treatment might seem straight forward, an estimated two-thirds of those who are aware of their infection are not seeing a health care provider, and more than half of those who are eligible for treatment do not receive it. This study aimed to compile and examine studies related to the barriers of disease monitoring, treatment, and liver cancer surveillance for CHB patients in the United States (US). A total of 4439 studies on monitoring and surveillance of CHB published between 2007 and 2018 were identified through a search of electronic databases. After critical assessment, the authors included 42 studies, divided into categories: 'patient-related barriers'; 'provider-related barriers'; and 'system-related barriers'. Among the patient-related barriers, one of the most frequent factors invoked in failing to have adequate surveillance was lack of patient's knowledge. In the provider-related barrier category, a lack of disease knowledge and adherence to guidelines was frequently reported. For the system-related barrier category, the only recurrent mention was a lack of clarity in guidelines or lack of guidelines from certain national institutions. This review summarizes and highlights the need for long-term disease management improvement of chronic hepatitis B infection for patients and healthcare providers that care for them.
Assuntos
Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Neoplasias Hepáticas/etiologia , Vigilância em Saúde Pública/métodos , Adulto , Antivirais/uso terapêutico , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The incidence of hepatocellular carcinoma (HCC) has been rising rapidly in the United States. California is an ethnically diverse state with the largest number of incident HCC cases in the country. Characterizing HCC disparities in California may inform priorities for HCC prevention. METHODS: By using data from the Surveillance, Epidemiology, and End Results 18-Registry Database and the California Cancer Registry, age-adjusted HCC incidence in California from 2009 through 2013 was calculated by race/ethnicity and neighborhood ethnic enclave status. A geographic analysis was conducted using Medical Service Study Areas (MSSAs) as the geographic unit, and race/ethnicity-specific standardized incidence ratios (SIRs) were calculated to identify MSSAs with higher-than-expected HCC incidence compared with the statewide average. RESULTS: During 2009 through 2013, the age-adjusted incidence of HCC in California was the highest in Asians/Pacific Islanders (APIs) and Hispanics (>100% higher than whites), especially those living in more ethnic neighborhoods (20%-30% higher than less ethnic neighborhoods). Of the 542 MSSAs statewide, 42 had elevated HCC incidence (SIR ≥ 1.5; lower bound of 95% confidence interval > 1) for whites, 14 for blacks, 24 for APIs, and 36 for Hispanics. These MSSAs have 24% to 52% higher proportions of individuals below the 100% federal poverty line than other MSSAs. CONCLUSIONS: APIs and Hispanics residing in more ethnic neighborhoods and individuals residing in lower income neighborhoods require more extensive preventive efforts tailored toward their unique risk factor profiles. The current race/ethnicity-specific geographic analysis can be extended to other states to inform priorities for HCC targeted prevention at the subcounty level, eventually reducing HCC burden in the country.
Assuntos
Carcinoma Hepatocelular/etnologia , Disparidades nos Níveis de Saúde , Neoplasias Hepáticas/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/prevenção & controle , Etnicidade/estatística & dados numéricos , Feminino , Geografia , Implementação de Plano de Saúde/organização & administração , Implementação de Plano de Saúde/estatística & dados numéricos , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Oncologia/organização & administração , Oncologia/estatística & dados numéricos , Pessoa de Meia-Idade , Medicina Preventiva/organização & administração , Medicina Preventiva/estatística & dados numéricos , Grupos Raciais/estatística & dados numéricos , Sistema de Registros , Características de Residência/estatística & dados numéricos , Programa de SEERRESUMO
BACKGROUND & AIMS: Drug repositioning offers a shorter approval process than new drug development. We therefore searched large public datasets of drug-induced gene expression signatures to identify agents that might be effective against hepatocellular carcinoma (HCC). METHODS: We searched public databases of messenger RNA expression patterns reported from HCC specimens from patients, HCC cell lines, and cells exposed to various drugs. We identified drugs that might specifically increase expression of genes that are down-regulated in HCCs and reduce expression of genes up-regulated in HCCs using a nonparametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov statistic. We evaluated the anti-tumor activity of niclosamide and its ethanolamine salt (NEN) in HCC cell lines (HepG2, Huh7, Hep3B, Hep40, and PLC/PRF/5), primary human hepatocytes, and 2 mouse models of HCC. In one model of HCC, liver tumor development was induced by hydrodynamic delivery of a sleeping beauty transposon expressing an activated form of Ras (v12) and truncated ß-catenin (N90). In another mouse model, patient-derived xenografts were established by implanting HCC cells from patients into livers of immunocompromised mice. Tumor growth was monitored by bioluminescence imaging. Tumor-bearing mice were fed a regular chow diet or a chow diet containing niclosamide or NEN. In a separate experiment using patient-derived xenografts, tumor-bearing mice were given sorafenib (the standard of care for patients with advanced HCC), NEN, or niclosamide alone; a combination of sorafenib and NEN; or a combination sorafenib and niclosamide in their drinking water, or regular water (control), and tumor growth was monitored. RESULTS: Based on gene expression signatures, we identified 3 anthelmintics that significantly altered the expression of genes that are up- or down-regulated in HCCs. Niclosamide and NEN specifically reduced the viability of HCC cells: the agents were at least 7-fold more cytotoxic to HCCs than primary hepatocytes. Oral administration of NEN to mice significantly slowed growth of genetically induced liver tumors and patient-derived xenografts, whereas niclosamide did not, coinciding with the observed greater bioavailability of NEN compared with niclosamide. The combination of NEN and sorafenib was more effective at slowing growth of patient-derived xenografts than either agent alone. In HepG2 cells and in patient-derived xenografts, administration of niclosamide or NEN increased expression of 20 genes down-regulated in HCC and reduced expression of 29 genes up-regulated in the 274-gene HCC signature. Administration of NEN to mice with patient-derived xenografts reduced expression of proteins in the Wnt-ß-catenin, signal transducer and activator of transcription 3, AKT-mechanistic target of rapamycin, epidermal growth factor receptor-Ras-Raf signaling pathways. Using immunoprecipitation assays, we found NEN to bind cell division cycle 37 protein and disrupt its interaction with heat shock protein 90. CONCLUSIONS: In a bioinformatics search for agents that alter the HCC-specific gene expression pattern, we identified the anthelmintic niclosamide as a potential anti-tumor agent. Its ethanolamine salt, with greater bioavailability, was more effective than niclosamide at slowing the growth of genetically induced liver tumors and patient-derived xenografts in mice. Both agents disrupted interaction between cell division cycle 37 and heat shock protein 90 in HCC cells, with concomitant inhibition of their downstream signaling pathways. NEN might be effective for treatment of patients with HCC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Chaperoninas/antagonistas & inibidores , Simulação por Computador , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Etanolamina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Chaperonas Moleculares/antagonistas & inibidores , Niclosamida/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/genética , Chaperoninas/metabolismo , Biologia Computacional , Bases de Dados Genéticas , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP90/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Niclosamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fatores de Tempo , Transcriptoma , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This Viewpoint describes new recommendations from the CDC regarding universal screening of adults for hepatitis B virus infection.
Assuntos
Erradicação de Doenças , Vacinas contra Hepatite B , Hepatite B , Programas de Rastreamento , Vacinação , Adulto , Humanos , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B , Programas de Rastreamento/métodos , Vacinação/métodos , Erradicação de Doenças/métodosRESUMO
BACKGROUND: With recent improvements in vaccines and treatments against viral hepatitis, an improved understanding of the burden of viral hepatitis is needed to inform global intervention strategies. We used data from the Global Burden of Disease (GBD) Study to estimate morbidity and mortality for acute viral hepatitis, and for cirrhosis and liver cancer caused by viral hepatitis, by age, sex, and country from 1990 to 2013. METHODS: We estimated mortality using natural history models for acute hepatitis infections and GBD's cause-of-death ensemble model for cirrhosis and liver cancer. We used meta-regression to estimate total cirrhosis and total liver cancer prevalence, as well as the proportion of cirrhosis and liver cancer attributable to each cause. We then estimated cause-specific prevalence as the product of the total prevalence and the proportion attributable to a specific cause. Disability-adjusted life-years (DALYs) were calculated as the sum of years of life lost (YLLs) and years lived with disability (YLDs). FINDINGS: Between 1990 and 2013, global viral hepatitis deaths increased from 0·89 million (95% uncertainty interval [UI] 0·86-0·94) to 1·45 million (1·38-1·54); YLLs from 31·0 million (29·6-32·6) to 41·6 million (39·1-44·7); YLDs from 0·65 million (0·45-0·89) to 0·87 million (0·61-1·18); and DALYs from 31·7 million (30·2-33·3) to 42·5 million (39·9-45·6). In 2013, viral hepatitis was the seventh (95% UI seventh to eighth) leading cause of death worldwide, compared with tenth (tenth to 12th) in 1990. INTERPRETATION: Viral hepatitis is a leading cause of death and disability worldwide. Unlike most communicable diseases, the absolute burden and relative rank of viral hepatitis increased between 1990 and 2013. The enormous health loss attributable to viral hepatitis, and the availability of effective vaccines and treatments, suggests an important opportunity to improve public health. FUNDING: Bill & Melinda Gates Foundation.
Assuntos
Expectativa de Vida , Anos de Vida Ajustados por Qualidade de Vida , Efeitos Psicossociais da Doença , Pessoas com Deficiência , Saúde Global , Hepatite , Humanos , MorbidadeRESUMO
BACKGROUND: Despite the high prevalence of chronic hepatitis B virus (HBV) infection in China, HBV infection prevention and long-term care knowledge of health professionals is inadequate. To address this knowledge gap, we developed an open-access evidence-based online training course, "KnowHBV", to train health professionals on prevention of HBV transmission and safe injections. We conducted an evaluation of the course with health professionals in China to examine its effectiveness in improving knowledge and learner's satisfaction of the course. METHODS: Between July and December 2011, 1015 health professionals from selected hospitals and disease control institutions of Shandong province registered for the course and 932 (92 %) completed the three-module course. Participants' demographic information, pre- and post-course knowledge test results and learner's feedback were collected through the course website. RESULTS: Pre-course knowledge assessment confirmed gaps in HBV transmission routes, prevention and long-term care knowledge. Only 50.4 % of participants correctly identified all of the transmission routes of HBV, and only 40.7 % recognized all of the recommended tests to monitor chronically infected persons. The number of participants that answered all six multi-part multiple-choice knowledge questions correctly increased from 183 (19.7 %) before taking the course to 395 (42.4 %) on their first attempt upon completion of the course. Over 90 % of the 898 participants who completed the learner-feedback questionnaire rated the course as 'good' or 'very good'; over 94 % found the course instructional design helpful; 57.5 %, 65.7 % and 68.5 % reported that half or more than half of the course content in modules 1, 2 and 3 respectively provided new information; and 93.2 % of the participants indicated they preferred the online learning over traditional face-to-face classroom learning. CONCLUSIONS: The "KnowHBV" online training course appears to be an effective online training tool to improve HBV prevention and care knowledge of the health professionals in China.
Assuntos
Pessoal de Saúde/educação , Hepatite B/prevenção & controle , Injeções/efeitos adversos , Acesso à Informação , China , Instrução por Computador , Currículo , Humanos , Injeções/normas , Avaliação de Programas e Projetos de SaúdeRESUMO
BACKGROUND: Granulin-epithelin precursor (GEP), a secretory growth factor, demonstrated overexpression in various human cancers, however, mechanism remain elusive. Primary liver cancer, hepatocellular carcinoma (HCC), ranks the second in cancer-related death globally. GEP controlled growth, invasion, metastasis and chemo-resistance in liver cancer. Noted that GEP gene locates at 17q21 and the region has been frequently reported to be amplified in subset of HCC. The study aims to investigate if copy number gain would associate with GEP overexpression. METHODS: Quantitative Microsatellite Analysis (QuMA) was used to quantify the GEP DNA copy number, and fluorescent in situ hybridization (FISH) was performed to consolidate the amplification status. GEP gene copy number, mRNA expression level and clinico-pathological features were analyzed. RESULTS: GEP DNA copy number determined by QuMA corroborated well with the FISH data, and the gene copy number correlated with the expression levels (n = 60, r = 0.331, P = 0.010). Gain of GEP copy number was observed in 20% (12/60) HCC and associated with hepatitis B virus infection status (P = 0.015). In HCC with increased GEP copy number, tight association between GEP DNA and mRNA levels were observed (n = 12, r = 0.664, P = 0.019). CONCLUSIONS: Gain of the GEP gene copy number was observed in 20% HCC and the frequency comparable to literatures reported on the chromosome region 17q. Increased gene copy number contributed to GEP overexpression in subset of HCC.
Assuntos
Carcinoma Hepatocelular/genética , Dosagem de Genes/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Hepáticas/genética , Idoso , Carcinoma Hepatocelular/patologia , Cromossomos Humanos Par 17/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Neoplasias Hepáticas/patologia , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , ProgranulinasRESUMO
BACKGROUND & AIMS: The molecular cochaperone CDC37 regulates the activities of multiple protein kinases, and is an attractive broad-spectrum target in many types of cancers in which it is over-expressed. This study investigates the antitumour effects of inhibiting CDC37 in human hepatocellular carcinoma (HCC). METHODS: A total of 91 patients were enrolled for CDC37 mRNA detection by using quantitative real-time PCR. Cell proliferation, gene expression changes and tumourigenicity were determined by targeting CDC37 using RNA interference in human hepatoma cell lines. RESULTS: We confirmed the significant over-expression of CDC37 transcript and protein in HBV-associated HCC patients. Using a CDC37-specific small oligo-siRNA, we silenced CDC37 expression in HepG2 and Huh7 hepatoma cell lines, and observed inhibition of in vitro cell proliferation, cell cycle arrest at the G1 phase, and enhanced apoptosis. Specifically, we found concomitant down-regulation of Cyclin D1, CDK4, and pRB (S807/811 and S795) upon CDC37 suppression, which could mediate the arrest of cell cycle progression at the G1 phase. Gene expression profiling further identified several genes involved in cell proliferation, cell cycle progression, and apoptosis that are regulated by CDC37 suppression. Huh7 cells with stable knockdown of CDC37 showed decreased in vitro colony formation ability, and significantly slowed xenograft growth in vivo. CONCLUSIONS: On the basis of the observed antitumour effects of inhibiting CDC37 expression, we propose that CDC37 is a promising therapeutic target in HCC. Its ability to regulate multiple pathways makes it potentially valuable in treating the heterogeneous subtypes of this malignancy.
Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Chaperoninas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Neoplasias Hepáticas/metabolismo , Adolescente , Adulto , Idoso , Animais , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/genética , Chaperoninas/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Interferência de RNA , RNA Mensageiro/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Carga Tumoral , Adulto JovemRESUMO
CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.
Assuntos
Antígenos de Diferenciação/metabolismo , Antígeno CD47/imunologia , Neoplasias/imunologia , RNA Mensageiro/genética , Receptores Imunológicos/metabolismo , Anticorpos/imunologia , Antígeno CD47/genética , Divisão Celular/imunologia , Citometria de Fluxo , Humanos , Neoplasias/patologia , Neoplasias/terapia , Fagocitose/imunologia , Prognóstico , Análise de SobrevidaRESUMO
Hepatocellular carcinoma (HCC) is the fifth most lethal malignancy worldwide with no curative therapies. To discover potentially novel therapeutic targets for HCC, we previously studied the gene expression profiles of HCC patients and identified that significant upregulation of N-Myc downstream regulated gene 1 (NDRG1) is associated with more aggressive phenotypes and poorer overall survival of HCC patients. In this study, we further used a loss-of-function approach (RNA interference) to understand the role of NDRG1 in hepatocarcinogenesis. We found that suppression of NDRG1 significantly impaired HCC cell growth through inducing extensive cellular senescence of HCC cells both in vitro and in vivo, accompanied by cell cycle arrest at the G1 phase. The observed antitumor effects of NDRG1 suppression were correlated with activation of major senescence-associated signaling pathways, such as upregulation of tumor suppressors p53, p21 and p16, and decreased phosphorylated Rb. To obtain further insights into the clinical significance of NDRG1-modulated senescence in HCC patients, immunohistochemistry staining of 92 cases of HCC patients was done. We found that high NDRG1 expression (n = 66) is associated with low p21 (n = 82; P < 0.001) and low p16 (n = 86; P < 0.001) levels. In conclusion, this study demonstrated that NDRG1 is a potential therapeutic target for HCC because its suppression triggers senescence of HCC cells through activating glycogen synthase kinase-3ß-p53 pathway, thereby inhibiting tumor progression.