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1.
Liver Int ; 41(10): 2467-2473, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34219362

RESUMO

BACKGROUND & AIMS: Cirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis aetiology. We aimed to characterize the relationship between frailty and cirrhosis aetiology. METHODS: Included were adults with cirrhosis listed for liver transplantation (LT) at 10 US centrer who underwent ambulatory testing with the Liver Frailty Index (LFI; 'frail' = LFI ≥ 4.4). We used logistic regression to associate aetiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness). RESULTS: Of 1,623 patients, rates of frailty differed by aetiology: 22% in chronic hepatitis C, 31% in alcohol-associated liver disease (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic and 31% in 'other' (P < .001). In univariable logistic regression, ALD (OR 1.53, 95% CI 1.12-2.09), NAFLD (OR 1.64, 95% CI 1.18-2.29) and 'other' (OR 1.58, 95% CI 1.06-2.36) were associated with frailty. In multivariable logistic regression, only ALD (OR 1.40; 95% 1.01-1.94) and 'other' (OR 1.59; 95% 1.05-2.40) remained associated with frailty. A total of 281 (17%) patients died/were delisted for sickness. In multivariable competing risk regression, LFI was associated with waitlist mortality (sHR 1.05, 95% CI 1.03-1.06), but aetiology was not (P > .05 for each). No interaction between frailty and aetiology on the association with waitlist mortality was found (P > .05 for each interaction term). CONCLUSIONS: Frailty is more common in patients with ALD, NAFLD and 'other' aetiologies. However, frailty was associated with waitlist mortality independent of cirrhosis aetiology, supporting the applicability of frailty across all cirrhosis aetiologies.


Assuntos
Doença Hepática Terminal , Fragilidade , Transplante de Fígado , Adulto , Fragilidade/diagnóstico , Humanos , Cirrose Hepática , Listas de Espera
2.
Alcohol Clin Exp Res ; 39(6): 969-79, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25903395

RESUMO

BACKGROUND: The Wnt/ß-catenin pathway regulates liver growth, repair, and regeneration. Chronic ethanol (EtOH) exposure blunts normal liver regenerative responses, in part by inhibiting insulin/IGF signaling, and correspondingly, previous studies showed that EtOH-impaired liver regeneration could be restored by insulin sensitizer (proliferator-activated receptor [PPAR]-δ agonist) treatment. As Wnt/ß-catenin functions overlap and cross talk with insulin/IGF pathways, we investigated the effects of EtOH exposure and PPAR-δ agonist treatment on Wnt pathway gene expression in relation to liver regeneration. METHODS: Adult male Long Evans rats were fed with isocaloric liquid diets containing 0 or 37% EtOH for 8 weeks and also treated with vehicle or a PPAR-δ agonist during the last 3 weeks of the feeding regimen. The rats were then subjected to 70% partial hepatectomy (PH) and livers harvested at various post-PH time points were used to quantitate expression of 19 Wnt pathway genes using Quantigene 2.0 Multiplex Assay. RESULTS: EtOH broadly inhibited expression of Wnt/ß-catenin signaling-related genes, including down-regulation of Wnt1, Fzd3, Lef1, and Bcl9 throughout the post-PH time course (0 to 72 hours), and suppression of Wnt7a, Ccnd1, Fgf4, Wif1, Sfrp2, and Sfrp5 at 18- and 24-hour post-PH time points. PPAR-δ agonist treatments rescued the EtOH-induced suppression of Wnt1, Wnt7a, Fzd3, Lef1, Bcl9, Ccnd1, and Sfrp2 gene expression in liver, corresponding with the improvements in DNA synthesis and restoration of hepatic architecture. CONCLUSIONS: Chronic high-dose EtOH exposures inhibit Wnt signaling, which likely contributes to the impairments in liver regeneration. Therapeutic effects of PPAR-δ agonists extend beyond restoration of insulin/IGF signaling mechanisms and are mediated in part by enhancement of Wnt pathway signaling. Future studies will determine the degree to which targeted restoration of Wnt signaling is sufficient to improve liver regeneration and remodeling in the context of chronic EtOH exposure.


Assuntos
Etanol/farmacologia , PPAR delta/agonistas , Fenoxiacetatos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Hepatectomia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/genética , Masculino , Dados de Sequência Molecular , Ratos , Ratos Long-Evans , Via de Sinalização Wnt/genética
3.
Liver Int ; 33(10): 1536-48, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23648141

RESUMO

BACKGROUND: T-cell factor (TCF) proteins represent key transcription factors that activate Wnt/ß-catenin signalling. We have reported that a pair of TCF-4 isoforms (TCF-4C and TCF-4D) exhibit differential TCF transcriptional activity in hepatocellular carcinoma (HCC) cells, although their structure differs by only the presence (TCF-4D) or absence (TCF-4C) of exon 4. AIM: To demonstrate a regulatory role of exon 4 in HCC development. METHODS: TCF-4C and TCF-4D expression profiles were examined in 27 pairs of human HCC and adjacent liver tissues. The functional role of the TCF-4 isoforms was evaluated in OUMS-29 (an immortalized hepatocyte-derived) and HAK-1A (a well-differentiated HCC) cell lines using stable clones overexpressing the TCF-4 isoforms. RESULTS: TCF-4C was significantly upregulated in HCC tissues compared with corresponding peritumour and normal liver tissues; in contrast, there was no difference in TCF-4D expression. TCF-4C clones derived from both cell lines exhibited increased TCF activity, Wnt-responsive target genes, cell proliferation, cell cycle progression and resistance to chemotherapeutic drugs compared with TCF-4D clones. Capability of cell migration and colony formation was significantly higher in TCF-4C than TCF-4D clones. In a nude mice xenograft model, the HAK-1A-derived TCF-4C clone rapidly developed tumours compared with the TCF-4D clone. TCF-4C clone-derived tumours exhibited upregulation of Wnt-responsive target genes compared with the slow developing and small TCF-4D-derived tumours. CONCLUSION: These results demonstrate that the TCF-4C isoform lacking exon 4 is associated with a malignant phenotype compared with the exon 4-harbouring TCF-4D isoform, indicating that exon 4 of TCF-4 plays a prominent role in HCC development.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Animais , Western Blotting , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Éxons/genética , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Imunoprecipitação , Camundongos , Camundongos Nus , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas
4.
Transplant Direct ; 7(2): e651, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33437866

RESUMO

Frailty has emerged as a critical determinant of mortality in patients with cirrhosis. Currently, the United Network for Organ Sharing registry only includes the Karnofsky Performance Status (KPS) scale, which captures a single component of frailty. We determined the associations between frailty, as measured by the Liver Frailty Index (LFI), and KPS with waitlist mortality. METHODS: Included were 247 adult patients with cirrhosis listed for liver transplantation without hepatocellular carcinoma from February 2014 to June 2019, who underwent outpatient assessments using the LFI and KPS within 30 days of listing. "Frail" was defined using the established LFI cutoff of ≥4.4. Competing risk models assessed associations between the LFI and KPS with waitlist mortality (death/delisting for sickness). RESULTS: At a median 8 months follow-up, 25 (10%) patients died/were delisted. In this cohort, median Model for End-Stage Liver Disease-Sodium was 17, LFI was 3.9 (interquartile range 3.4-4.5), and KPS was 80 (interquartile range 70-90). In multivariable analysis, LFI (sub-hazard ratio 1.07, per 0.1 unit; 95% confidence interval, 1.01-1.12) was associated with waitlist mortality while KPS was not (sub-hazard ratio 1.00, per 10 units; 95% confidence interval, 0.78-1.29). CONCLUSIONS: Our data suggest that frailty, as measured by the LFI, may be more appropriate at capturing mortality risk than KPS and provide evidence in support of using the LFI more broadly in clinical transplant practice in the outpatient setting.

6.
Cancer Lett ; 336(2): 359-69, 2013 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-23562475

RESUMO

T-cell factor (TCF) proteins represent key transcription factors in Wnt signaling. We show that the SxxSS motif in TCF-4 regulates transcriptional activity in HCC cells. TCF-4K mutants increased transcriptional activity compared to TCF-4K (bearing the SxxSS); the binding pattern of co-factors in TCF-4K mutants was similar to that in TCF-4J (lacking the SxxSS). TCF activity in TCF-4K cells was suppressed by homeodomain-interacting protein kinase 2 (HIPK2), but not in TCF-4J cells. Together, our data indicates that the SxxSS motif in TCF-4K regulates transcriptional activity by modifying co-factors in the ß-catenin/TCF-4 transcriptional complex and these events may be mediated through HIPK2.


Assuntos
Motivos de Aminoácidos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Sequência de Aminoácidos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma Hepatocelular/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/genética , Dados de Sequência Molecular , Fosforilação , Isoformas de Proteínas , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Fator de Transcrição 4 , Fatores de Transcrição/genética , Ativação Transcricional , Transfecção , Proteínas Wnt/genética , beta Catenina/genética
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