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1.
Mol Ther ; 29(10): 2898-2909, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34461297

RESUMO

Recombinant adeno-associated viral (rAAV) vectors are considered promising tools for gene therapy directed at the liver. Whereas rAAV is thought to be an episomal vector, its single-stranded DNA genome is prone to intra- and inter-molecular recombination leading to rearrangements and integration into the host cell genome. Here, we ascertained the integration frequency of rAAV in human hepatocytes transduced either ex vivo or in vivo and subsequently expanded in a mouse model of xenogeneic liver regeneration. Chromosomal rAAV integration events and vector integrity were determined using the capture-PacBio sequencing approach, a long-read next-generation sequencing method that has not previously been used for this purpose. Chromosomal integrations were found at a surprisingly high frequency of 1%-3% both in vitro and in vivo. Importantly, most of the inserted rAAV sequences were heavily rearranged and were accompanied by deletions of the host genomic sequence at the integration site.


Assuntos
Dependovirus/fisiologia , Hepatócitos/transplante , Regeneração Hepática , Animais , Células Cultivadas , Cromossomos/genética , Dependovirus/genética , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos/administração & dosagem , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Camundongos , Transdução Genética , Integração Viral
2.
Mol Ther ; 29(2): 680-690, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33554867

RESUMO

Adeno-associated virus (AAV) integrates into host genomes at low frequency, but when integration occurs in oncogenic hotspots it can cause hepatocellular carcinoma (HCC). Given the possibility of recombinant AAV (rAAV) integration leading to HCC, common causes of liver inflammation like non-alcoholic fatty liver disease (NAFLD) may increase the risk of rAAV-induced HCC. A rAAV targeting the oncogenic mouse Rian locus was used, and as expected led to HCC in all mice infected as neonates, likely due to growth-related hepatocyte proliferation in young mice. Mice infected with rAAV as adults did not develop HCC unless they were fed a diet leading to NAFLD, with increased inflammation and hepatocyte proliferation. Female mice were less susceptible to rAAV-induced HCC, and male mice with NAFLD treated with estrogen exhibited less inflammation and immune exhaustion associated with oncogenesis compared to those without estrogen. Adult NAFLD mice infected with a non-targeted control rAAV also developed HCC, though only half as frequently as those exposed to the Rian targeted rAAV. This study shows that adult mice exposed to rAAV gene therapy in the context of chronic liver disease developed HCC at high frequency, and thus warrants further study in humans given the high prevalence of NAFLD in the population.


Assuntos
Carcinoma Hepatocelular/etiologia , Dependovirus/genética , Terapia Genética/efeitos adversos , Vetores Genéticos/genética , Hepatopatias/complicações , Hepatopatias/etiologia , Neoplasias Hepáticas/etiologia , Animais , Carcinoma Hepatocelular/diagnóstico , Modelos Animais de Doenças , Terapia Genética/métodos , Incidência , Hepatopatias/patologia , Neoplasias Hepáticas/diagnóstico , Camundongos
3.
J Clin Gastroenterol ; 54(8): 741-746, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31764489

RESUMO

GOAL: The goal of this study was to describe potential key differences in thromboelastography (TEG) variables in hospitalized cirrhotics compared with a healthy population, identify patterns of hematologic disturbance with disease progression, and assess the value of traditional tests such as international normalized ratio (INR) and platelet count to determine coagulopathy in cirrhotics. BACKGROUND: TEG, a functional assay of coagulation, has emerged as a useful tool for predicting bleeding risk in cirrhosis. STUDY: Hospitalized cirrhotics who received a TEG before any blood products between January 2017 and February 2018 at a liver transplant center were included. Reaction time (r-time), coagulation time (k-time), angle-rate of clot polymerization (α) and maximum clot strength (maximum amplitude) were measured with kaolin-activated citrated blood TEG assays. RESULTS: A total of 106 cirrhotic patients (Child-Turcotte-Pugh A, B, C; n=25, 25, 56) were identified for comparison against data from 53 healthy controls. TEG parameters in cirrhotics were statistically different from controls. Mean INR and platelet count for all cirrhotics were largely outside the normal reference range, contrary to TEG parameters which demonstrated parameters mostly within the normal reference ranges. The r-time, k-time, and α values in the cirrhotics progressively increased and maximum amplitude values progressively decreased as the liver disease progressed. Regression analysis showed no significant correlations between INR and r-time across any Child-Turcotte-Pugh class (r=0.01, 0.18, 0.23; P=0.95, 0.39, 0.08, respectively). CONCLUSIONS: Although cirrhotics had TEG parameters within normal ranges, there was a propensity for decreased clot formation as liver function worsened. Importantly, the INR did not correlate with TEG parameters in cirrhotic patients, and given the precarious hemostatic balance in these patients, a TEG may be a better predictor of bleeding risk.


Assuntos
Hemostáticos , Tromboelastografia , Coagulação Sanguínea , Criança , Humanos , Coeficiente Internacional Normatizado , Cirrose Hepática/complicações
4.
Mol Ther ; 26(5): 1327-1342, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29550076

RESUMO

Direct lineage reprogramming can convert readily available cells in the body into desired cell types for cell replacement therapy. This is usually achieved through forced activation or repression of lineage-defining factors or pathways. In particular, reprogramming toward the pancreatic ß cell fate has been of great interest in the search for new diabetes therapies. It has been suggested that cells from various endodermal lineages can be converted to ß-like cells. However, it is unclear how closely induced cells resemble endogenous pancreatic ß cells and whether different cell types have the same reprogramming potential. Here, we report in vivo reprogramming of pancreatic ductal cells through intra-ductal delivery of an adenoviral vector expressing the transcription factors Pdx1, Neurog3, and Mafa. Induced ß-like cells are mono-hormonal, express genes essential for ß cell function, and correct hyperglycemia in both chemically and genetically induced diabetes models. Compared with intrahepatic ducts and hepatocytes treated with the same vector, pancreatic ducts demonstrated more rapid activation of ß cell transcripts and repression of donor cell markers. This approach could be readily adapted to humans through a commonly performed procedure, endoscopic retrograde cholangiopancreatography (ERCP), and provides potential for cell replacement therapy in type 1 diabetes patients.


Assuntos
Reprogramação Celular , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Ductos Pancreáticos/citologia , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Adenoviridae/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores , Reprogramação Celular/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vetores Genéticos/genética , Hepatócitos/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Fatores de Transcrição Maf Maior/genética , Fatores de Transcrição Maf Maior/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
AJR Am J Roentgenol ; 210(6): 1366-1367, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29667887

RESUMO

OBJECTIVE: This commentary discusses research examining comparisons of locoregional therapy with systemic therapy for unresectable hepatocellular carcinoma (HCC). CONCLUSION: Comparison of patient outcomes after locoregional or systemic therapy for HCC is confounded by selection bias, wherein patients chosen for locoregional therapy usually have better underlying liver function that may contribute to the observed longer survival.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos
6.
Gastroenterology ; 149(3): 728-40.e15, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26028580

RESUMO

BACKGROUND & AIMS: The ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool. We investigated whether abnormal bile acid signaling affects the hepatostat in mice. METHODS: We crossed Fah(-/-), Rag2(-/-), Il2r(-/-) mice with nonobese diabetic mice to create FRGN mice, whose livers can be fully repopulated with human hepatocytes. We inserted the gene for human FGF19 (ortholog to mouse Fgf15), including regulatory sequences, into the FRGN mice to create FRGN19(+) mice. Livers of FRGN19(+) mice and their FRGN littermates were fully repopulated with human hepatocytes. Liver tissues were collected and bile acid pool sizes and RNA sequences were analyzed and compared with those of mice without humanized livers (controls). RESULTS: Livers were larger in FRGN mice with humanized livers (13% of body weight), compared with control FRGN mice; they also had much larger bile acid pools and aberrant bile acid signaling. Livers from FRGN19(+) normalized to 7.8% of body weight, and their bile acid pool and signaling more closely resembled that of control FRGN19(+) mice. RNA sequence analysis showed activation of the Hippo pathway, and immunohistochemical and transcription analyses revealed increased hepatocyte proliferation, but not apoptosis, in the enlarged humanized livers of FRGN mice. Cell sorting experiments showed that although healthy human liver does not produce FGF19, nonparenchymal cells from cholestatic livers produce FGF19. CONCLUSIONS: In mice with humanized livers, expression of an FGF19 transgene corrects bile acid signaling defects, resulting in normalization of bile acid synthesis, the bile acid pool, and liver size. These findings indicate that liver size is, in part, regulated by the size of the bile acid pool that the liver must circulate.


Assuntos
Proliferação de Células , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatócitos/transplante , Fígado/cirurgia , Transdução de Sinais , Animais , Ácidos e Sais Biliares/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Xenoenxertos , Humanos , Hidrolases/deficiência , Hidrolases/genética , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Tamanho do Órgão , Receptores de Interleucina-2/deficiência , Receptores de Interleucina-2/genética , Fatores de Tempo , Transcrição Gênica
7.
Clin Gastroenterol Hepatol ; 13(5): 827-35, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-24909910

RESUMO

Optimal care of the patient with hepatocellular carcinoma (HCC) necessitates the involvement of multiple providers. Because the patient with HCC often carries 2 conditions with competing mortality risks (cancer and underlying cirrhosis), no single provider is equipped to deal with all of these patients' needs adequately. Multidisciplinary teams (MDTs) have evolved to facilitate care coordination, reassessments of clinical course, and nimble changes in treatment plans required for this complex group of patients. Providers or sites that elect to manage patients with HCC thus are increasingly aware of the need to build their own MDT or communicate with an established one. The availability of new communication technologies, such as teleconferencing or teleconsultation, offers the possibility of MDT expansion into underserved or rural areas, as well as areas such as correctional facilities. Although the availability of resources for HCC patient care varies from site to site, construction of an MDT is possible in a wide spectrum of clinical practices, and this article suggests a blueprint for assembly of such collaboration. Research strategies are needed to explain how MDTs improve clinical outcomes so that MDTs themselves can be improved.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Gerenciamento Clínico , Comunicação Interdisciplinar , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Equipe de Assistência ao Paciente/organização & administração , Humanos
8.
Clin Gastroenterol Hepatol ; 13(5): 1025-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25277846

RESUMO

There have been few reports of acute liver failure (ALF), with encephalopathy and coagulopathy, caused by infiltration of the liver by malignant cells. We describe a case series of 27 patients with ALF caused by malignancy. We examined a large, multicenter ALF registry (1910 patients; mean age, 47.1 ± 13.9 y) and found only 27 cases (1.4%) of ALF attributed to malignancy. Twenty cases (74%) presented with abdominal pain and 11 presented with ascites. The most common malignancies included lymphoma or leukemia (33%), breast cancer, (30%), and colon cancer (7%); 90% of the patients with lymphoma or leukemia had no history of cancer, compared with 25% of patients with breast cancer. Overall, 44% of the patients had evidence of liver masses on imaging. Diagnosis was confirmed by biopsy in 15 cases (55%) and by autopsy for 6 cases. Twenty-four patients (89%) died within 3 weeks of ALF.


Assuntos
Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/secundário , Adulto , Biópsia , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/patologia , Feminino , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/patologia , Histocitoquímica , Humanos , Falência Hepática Aguda/complicações , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Análise de Sobrevida
9.
Liver Transpl ; 20(9): 1045-56, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24838471

RESUMO

Recipients of liver transplantation (LT) for hepatocellular carcinoma (HCC) have an 8% to 20% risk of HCC recurrence. Single-center studies suggest that a period of waiting after HCC therapy may facilitate the selection of patients at low risk for post-LT HCC recurrence and mortality. We evaluated whether a longer waiting time after Model for End-Stage Liver Disease (MELD) prioritization for HCC predicts longer post-LT survival. From the United Network for Organ Sharing registry, we selected 2 groups registered for LT between March 2005 and March 2009: (1) HCC patients receiving MELD prioritization and (2) non-HCC patients. Patients were stratified by their MELD status at LT (a marker of time on the wait list after HCC MELD prioritization) and were followed from LT until death or censoring through October 2012. By comparing post-LT survival to intention-to-treat (ITT) survival from registration, we assessed predictors of post-LT survival and estimated the benefit of LT. The median MELD scores at LT were 22 (HCC) and 24 (non-HCC). A higher MELD score at LT was independently associated with lower post-LT mortality in the HCC group [hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.73-0.98] and higher post-LT mortality in the non-HCC group (HR = 1.20, 95% CI = 1.15-1.25). Compared with the HCC group, the non-HCC group had lower post-LT mortality [relative risk (RR) = 0.85, log-rank P < 0.01] but higher ITT mortality (RR = 1.25, log-rank P < 0.01) because of a 33 percentage point lower probability of undergoing LT. In conclusion, a longer waiting time before LT for HCC predicted longer post-LT survival in a national transplant registry. Delaying LT for HCC may reduce disparities in ITT survival and access to LT among different indications and thereby improve system utility and organ allocation equity for the overall pool of LT candidates.


Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Tempo para o Tratamento , Doadores de Tecidos/provisão & distribuição , Listas de Espera , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Acessibilidade aos Serviços de Saúde , Disparidades em Assistência à Saúde , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Obtenção de Tecidos e Órgãos , Resultado do Tratamento , Estados Unidos/epidemiologia
11.
Dig Dis Sci ; 59(7): 1630-7, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24464209

RESUMO

PURPOSE: Acute liver failure (ALF) is a rare clinical syndrome associated with a high case fatality rate. Asymptomatic primary infection with Epstein-Barr virus (EBV) is common in the general population while acute hepatitis and jaundice are much less common and ALF has been rarely reported. We reviewed the presenting features as well as clinical outcomes amongst consecutive adults with EBV-related ALF. METHODS: Amongst the 1,887 adult ALF patients enrolled into the US ALF Study Group from January 1998 to February 2012, there were four patients (0.21 %) with EBV-related ALF. Diagnostic criteria for acute EBV infection included compatible serologies and/or the detection of EBV-encoded RNA (EBER) in liver tissue. RESULTS: Median patient age was 30 years (range 18-44); 75 % were male, and only 25 % were immunosuppressed. The median presenting ALT was 504 IU/mL (range 156-4,920), median Alk P was 431 (range 136-1,009), and median bilirubin was 17 mg/dL (range 13-22.1). Liver biopsy findings ranged from cholestasis to submassive necrosis with EBER + staining in two of the three samples tested. Although all of the patients were treated with an antiviral agent, two died of ALF, one underwent liver transplantation (LT) and one survived with supportive care and is well at 5 years. A review of the literature identified four additional LT recipients with favorable long-term outcomes. CONCLUSION: Primary EBV infection accounts for <1 % of consecutive adult ALF cases but is associated with a high case fatality rate. LT is associated with favorable short- and long-term outcomes.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Falência Hepática Aguda/virologia , Adolescente , Adulto , Antivirais/uso terapêutico , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Feminino , Humanos , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Masculino , Estudos Prospectivos , Resultado do Tratamento , Estados Unidos , Adulto Jovem
12.
Front Nephrol ; 4: 1403096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933742

RESUMO

Introduction: Liver transplant recipients may have pre-formed anti-HLA antibodies directed to mismatched HLA of the liver donor (donor specific antibodies, DSA) or not directed to the liver donor (non-donor specific, non-DSA). We observed the fate of these antibodies (DSA and non-DSA) at 12 months after transplant. Methods: Patients transplanted between 4/2015 and 12/2018 (N = 216) who had anti-HLA antibody measurements at both transplant and 12 months posttransplant (N = 124) and with DSAs at transplant (N = 31) were considered informative for a paired analysis of the natural history of DSA and non-DSA following liver transplantation. Results: Class I DSAs and non-DSAs decreased between transplant and 12 months; however, Class I DSAs essentially disappeared by 12 months while Class I non-DSAs did not. Anti-HLA Class II DSAs performed differently. While there was a significant drop in values between transplant and 12 months, these antibodies mostly persisted at a low level. Discussion: Our study demonstrated a significant difference in the kinetics of DSA compared to non-DSA following liver transplantation, most profoundly for anti-HLA Class I antibodies. Class I DSAs were mostly absent at 12 months while Class II DSAs persisted, although at lower levels. The mechanisms of reduction in anti-HLA antibodies following liver transplantation are not completely understood and were not pursued as a part of this study. This detailed analysis of Class I and Class II DSAs and non-DSAs represents and important study to explore the change in antibodies at one year from liver transplantation.

13.
Clin Transplant ; 27(1): E72-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23278701

RESUMO

Liver transplantation (LT) provides optimal long-term disease-free survival for hepatocellular carcinoma (HCC). High pre-LT alpha-fetoprotein (AFP) has been associated with HCC recurrence, but it is unclear whether a drop in AFP or locoregional therapy impacts survival/recurrence after LT. LT-recipients transplanted for HCC in three centers (UNOS Region 6) were reviewed (2006-2009) for demographics, tumor characteristics, locoregional therapy, AFP, recurrence, and survival. Among 211 LT recipients (mean age 56.4 yr, 83% male, mean MELD 12.2), 94% met Milan criteria and 61% received locoregional therapy. Mean disease-free survival (DFS) was 1549.7 d, and 84% are currently alive. Factors affecting DFS included recurrence (RR, 0.074; 95% CI, 0.038-0.14), normal peak AFP (29.6, 95% CI, 2.96-296.3), peak AFP >400 (RR, 0.15; 95% CI, 0.03-0.73) and AFP at LT >400 (RR, 15.5; 95% CI, 2.4-100.5). Twenty-one patients had recurrence and were more likely beyond Milan criteria (5/23(21%) vs. 8/220 (4%), p = 0.0038), with peak AFP >400 and AFP at LT >400 (p = 0.001). Locoregional therapy did not affect mean DFS (1458.0 vs. 1603.8 d, p = 0.05) or recurrence (12.5% vs. 6%). Predictors of recurrence were similar to previous studies, including high AFP and tumor outside Milan criteria. While locoregional therapy itself did not affect DFS/recurrence, a decrease in AFP pre-transplant appears to positively influence outcomes in those who received locoregional therapy.


Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Transplante de Fígado , Recidiva Local de Neoplasia/diagnóstico , alfa-Fetoproteínas/metabolismo , Adolescente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
14.
Curr Opin Genet Dev ; 18(1): 19-26, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18440219

RESUMO

A connection between inflammation and carcinogenesis has long been known, but the precise mechanisms are just beginning to be understood. NF-kappaB proteins, transcription factors which integrate stress signals and orchestrate immune responses, have also recently been linked to carcinogenesis. Hallmarks of cancer development include self-sufficiency in growth signals, insensitivity to growth-inhibitors, evasion of apoptosis, limitless replicative potential, tissue invasion and metastasis, and sustained angiogenesis. NF-kappaB signaling has been implicated in each of these hallmarks, and recent experimental studies have illuminated the mechanistic pathways by which NF-kappaB signaling contributes to these aspects of carcinogenesis. This review will focus on recent experimental data supporting the hypothesis that inflammation promotes carcinogenesis, and that NF-kappaB signaling is at the heart of such inflammation.


Assuntos
Inflamação/complicações , NF-kappa B/metabolismo , Neoplasias/imunologia , Apoptose , Proliferação de Células , Humanos , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica , Transdução de Sinais
15.
NPJ Precis Oncol ; 6(1): 28, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35468987

RESUMO

Cell-free RNA (cfRNA) in plasma reflects phenotypic alterations of both localized sites of cancer and the systemic host response. Here we report that cfRNA sequencing enables the discovery of messenger RNA (mRNA) biomarkers in plasma with the tissue of origin-specific to cancer types and precancerous conditions in both solid and hematologic malignancies. To explore the diagnostic potential of total cfRNA from blood, we sequenced plasma samples of eight hepatocellular carcinoma (HCC) and ten multiple myeloma (MM) patients, 12 patients of their respective precancerous conditions, and 20 non-cancer (NC) donors. We identified distinct gene sets and built classification models using Random Forest and linear discriminant analysis algorithms that could distinguish cancer patients from premalignant conditions and NC individuals with high accuracy. Plasma cfRNA biomarkers of HCC are liver-specific genes and biomarkers of MM are highly expressed in the bone marrow compared to other tissues and are related to cell cycle processes. The cfRNA level of these biomarkers displayed a gradual transition from noncancerous states through precancerous conditions and cancer. Sequencing data were cross-validated by quantitative reverse transcription PCR and cfRNA biomarkers were validated in an independent sample set (20 HCC, 9 MM, and 10 NC) with AUC greater than 0.86. cfRNA results observed in precancerous conditions require further validation. This work demonstrates a proof of principle for using mRNA transcripts in plasma with a small panel of genes to distinguish between cancers, noncancerous states, and precancerous conditions.

16.
Stem Cell Res ; 56: 102523, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34601385

RESUMO

BACKGROUND & AIMS: Mature hepatocytes have limited expansion capability in culture and rapidly loose key functions. Recently however, tissue culture conditions have been developed that permit rodent hepatocytes to proliferate and transform into progenitor-like cells with ductal characteristics in vitro. Analogous cells expressing both hepatic and duct markers can be found in human cirrhotic liver in vivo and may represent an expandable population. METHODS: An in vitro culture system to expand epithelial cells from human end stage liver disease organs was developed by inhibiting the canonical TGF-ß, Hedgehog and BMP pathways. RESULTS: Human cirrhotic liver epithelial cells became highly proliferative in vitro. Both gene expression and DNA methylation site analyses revealed that cirrhosis derived epithelial liver cells were intermediate between normal hepatocytes and cholangiocytes. Mouse hepatocytes could be expanded under the same conditions and retained the ability to re-differentiate into hepatocytes upon transplantation. In contrast, human cirrhotic liver derived cells had only low re-differentiation capacity. CONCLUSIONS: Epithelial cells of intermediate ductal-hepatocytic phenotype can be isolated from human cirrhotic livers and expanded in vitro. Unlike their murine counterparts they have limited liver repopulation potential.


Assuntos
Hepatócitos , Fígado , Animais , Diferenciação Celular , Células Cultivadas , Células Epiteliais , Cirrose Hepática , Camundongos
17.
Liver Transpl ; 16(10): 1186-94, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20879017

RESUMO

The aim of the present study is to compare the survival rates and cost-effectiveness of different treatment strategies for small (<2 cm) hepatocellular carcinoma (HCC). Markov chains are developed to model different management strategies for patients with compensated cirrhosis and small HCC. Probabilities of progression and survival and the likelihood of orthotopic liver transplantation are taken from the literature and incorporated into the models. As a starting population, 1000 patients are followed over a period of 10 years. Patients treated immediately with transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) live as long as or longer than patients who are monitored expectantly with the intention of liver transplantation once the HCC has grown larger than 2 cm and a higher transplant priority score becomes available. With TACE, immediate treatment results in an average survival time of 4.269 years versus 4.324 years with the monitoring strategy. With RFA, immediate treatment results in an average survival time of 5.273 years versus 5.236 years with the monitoring strategy. In addition, the cost analysis shows that immediate treatment with either TACE or RFA is less expensive than monitoring. The better cost-effectiveness of immediate therapy versus the monitoring strategy remains robust and unaffected by variations of the assumptions built into the model. In conclusion, in patients with compensated cirrhosis and small HCC, a strategy of immediate treatment with either TACE or RFA prevails over a strategy of expectant monitoring with the intention of transplantation.


Assuntos
Carcinoma Hepatocelular/terapia , Ablação por Cateter , Quimioembolização Terapêutica , Custos de Cuidados de Saúde , Cirrose Hepática/terapia , Neoplasias Hepáticas/terapia , Transplante de Fígado , Carcinoma Hepatocelular/economia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/economia , Ablação por Cateter/mortalidade , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/economia , Quimioembolização Terapêutica/mortalidade , Análise Custo-Benefício , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/economia , Cirrose Hepática/mortalidade , Cirrose Hepática/patologia , Neoplasias Hepáticas/economia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/economia , Transplante de Fígado/mortalidade , Cadeias de Markov , Modelos Econômicos , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
18.
Liver Int ; 30(5): 718-24, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20040051

RESUMO

BACKGROUND & AIMS: Liver disease is often characterized by an intricate network of multiple, simultaneously interacting factors with organ-specific, as well as systemic effects. The aim of the present study is to introduce a new mathematical model on how to weigh a variety of factors contributing to chronic liver disease by the relevance of their influence on the overall disease processes. METHODS: Liver disease is modelled as the interaction of multiple internal and external factors. Each factor can potentially interact with any of the other factors in the model. The strength of interactions is expressed as per cent. The sum of all interactions contributing to each individual factor adds up to 100%. This model corresponds mathematically to a transposed Markov matrix. The analysis uses the two examples of hepatitis C virus (HCV) and autoimmune hepatitis (AIH). RESULTS: Impaired liver function is the most influential factor and increases in relevance as the degree of hepatic fibrosis increases. The relative importance of treating the primary disease process (HCV or AIH) diminishes as fibrosis develops. Similarly, psychosocial factors become less important with disease progression. Liver transplant is most important for Child's C cirrhosis. It is relatively influential for the early phase of AIH but not HCV, reflecting the fact that some cases of non-cirrhotic AIH can progress rapidly to acute liver failure. CONCLUSION: In a disease process characterized by a large array of multiple interacting factors, the decision tool of a transposed Markov chain helps to sort the contributing factors by the magnitude of their influence.


Assuntos
Hepatopatias/etiologia , Cadeias de Markov , Doença Crônica , Hepatite C Crônica/etiologia , Hepatite Autoimune/etiologia , Humanos , Modelos Biológicos , Modelos Teóricos
19.
Clin Liver Dis ; 24(4): 771-787, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33012458

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, but unlike other leading causes of cancer death, HCC is increasing in mortality and burden of management. Management of HCC is unique because it usually arises in a diseased liver, which itself may be a driver of mortality. Multidisciplinary teams (MDTs) for the management of complex diseases are becoming more common, but are especially needed in the management of patients with HCC. Liver cancer MDTs are used in most centers providing comprehensive care for patients with HCC, and should be considered the standard of care for these patients.


Assuntos
Adenoma de Células Hepáticas/terapia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Equipe de Assistência ao Paciente/organização & administração , Padrão de Cuidado , Inteligência Artificial , Gerenciamento Clínico , Humanos
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