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1.
J Dig Dis ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33742780

RESUMO

OBJECTIVE: To discern the symptomatic features of coronavirus disease 2019 (COVID-19) and to evaluate the severity and prognosis of the disease. METHODS: In this retrospective cohort study, 932 hospitalized patients with COVID-19 in Wuhan were enrolled, including 52 severe and 880 non-severe cases. All patients were followed up for 3 months after discharge. The symptomatic features and follow-up data of the patients in both groups were analyzed and compared. RESULTS: Of the 932 patients, fever (60.0%), cough (50.8%) and fatigue (36.4%) were the most common symptoms. In total, 32.7% of the severe cases presented with gastrointestinal symptoms at disease onset, including anorexia, nausea, vomiting or diarrhea, which was significantly higher than that of the non-severe group (P = 0.0015). The incidence of olfactory disturbance and dysgeusia was only 3.1% and 6.2%, respectively. After adjusting for age and sex, multivariate regression analysis showed that fever lasting for over 5 days (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.00-3.62, P = 0.0498), anorexia at onset (OR 2.61, 95% CI 1.26-5.40, P = 0.0096), and modified Medical Research Council level above grade 2 when dyspnea occurred (OR 14.19, 95% CI 7.01-28.71, P < 0.0001) were symptomatic risk factors for severe COVID-19. During the follow-up, cough (6.2%), dyspnea (7.2%), fatigue (1.8%), olfactory disturbance and dysgeusia (1.5%) were the significant remaining symptoms. CONCLUSIONS: COVID-19 causes clusters of symptoms with multiple systems involved. Certain symptomatic characteristics have predictive value for severe COVID-19. Short-term follow-up data reveal that most patients have a good prognosis.

2.
Signal Transduct Target Ther ; 6(1): 58, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568628

RESUMO

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.


Assuntos
/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Cordão Umbilical , Idoso , Aloenxertos , /fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
J Pathol ; 254(1): 57-69, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33512716

RESUMO

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

5.
Hepatol Int ; 15(1): 155-165, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385299

RESUMO

BACKGROUND AND AIMS: Rifaximin has been recommended as a prophylactic drug for hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP). This study aims to explore whether low-dose rifaximin can prevent overall complications and prolong survival in cirrhotic patients. METHODS: In this multi-centre randomized open-labelled prospective study, 200 patients with decompensated cirrhosis were randomly assigned at a ratio of 1:1. Patients in rifaximin group were administered 400 mg rifaximin twice daily for 6 months, and all other therapeutic strategies were kept unchanged in both groups as long as possible. The primary efficacy endpoints were the incidence of overall complications and liver transplantation-free survival. The secondary endspoints were the incidence of each major cirrhosis-related complication, as well as the Child-Pugh score and class. RESULTS: The major baseline characteristics were similar in the two groups except for HE. The cumulative incidence and frequency of overall complications were significantly lower in rifaximin group than in the control group (p < 0.001). Though liver transplantation-free survival was not significantly different between the two groups, subgroup analysis showed rifaximin markedly prolonged liver transplantation-free survival in patients with Child-Pugh score ≥ 9 (p = 0.007). Moreover, rifaximin markedly reduced the episodes of ascites exacerbation (p < 0.001), HE (p < 0.001) and gastric variceal bleeding (EGVB, p = 0.031). The incidence of adverse events was similar in the two groups. CONCLUSION: Low-dose rifaximin significantly decreases the occurrence of overall complications, leading to prolonged survival in patients with advanced stages of cirrhosis in this trail. Further study should be carried out to compare the effect of this low-dose rifaximin with normal dose (1200 mg/day) rifaximin in preventing cirrhosis-related complications. CLINICAL TRIAL NUMBER: NCT02190357.

6.
Cancer Res ; 81(4): 860-872, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33361394

RESUMO

Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.

8.
Pharmacol Ther ; 215: 107626, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32659305

RESUMO

Portal hypertension (PH) is the most common non-neoplastic complication of chronic liver disease, determining clinical complications that lead to death or liver transplantation. PH results from increased resistance to portal blood flow through the cirrhotic liver, which is due to hepatic fibrosis and microcirculatory dysfunction. The present review focuses on the pathophysiology of fibrosis and PH, describes currently used treatments, and critically discusses potential therapeutic options.

9.
FEBS Lett ; 594(18): 2965-2974, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619269

RESUMO

Inflammation is the main contributor for the pathogenesis of nonalcoholic steatohepatitis (NASH). Src homology region 2 domain-containing phosphatase 1 (SHP-1, also known as PTPN6) is regarded as a negative regulator of inflammation, but its role in NASH remains unknown. Here, hepatocyte-specific Ptpn6 knockout mice (Ptpn6HKO ) and adenovirus vector-mediated ectopic expression of SHP-1 (AdSHP1) were used to evaluate the role of SHP-1 in a methionine- and choline-deficient diet-induced NASH model. Compared with the control littermates, Ptpn6HKO mice show exacerbated hepatic steatosis, inflammation, and fibrosis. Additionally, administration of AdSHP1 significantly ameliorates steatohepatitis and inhibits the expression of proinflammatory cytokines, including transforming growth factor-ß, interleukin-6, and tumor necrosis factor-α. Our data indicate that SHP-1 could be a potential therapeutic target for NASH.

10.
Emerg Microbes Infect ; 9(1): 1467-1469, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32552365

RESUMO

A maternal woman was positive for SARS-CoV-2 tested in throat swabs but negative tested in other body fluids, and she had IgG and IgA detected in breast milk. Her infant negative for SARS-CoV-2 at birth had elevated IgG in serum but quickly decayed. These findings suggest that breastfeeding might have the potential benefit to the neonates.


Assuntos
Anticorpos Antivirais/análise , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Leite Humano/imunologia , Pneumonia Viral/imunologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Anticorpos Antivirais/imunologia , China , Feminino , Humanos , Imunoglobulina A/análise , Imunoglobulina G/análise , Recém-Nascido , Leite Humano/virologia , Pandemias , Gravidez , Complicações Infecciosas na Gravidez/imunologia
11.
J Dig Dis ; 21(4): 237-245, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32166900

RESUMO

OBJECTIVE: To explore the prevalence of and risk factors for gallstone disease in Shanghai, China. METHODS: A population-based cross-sectional study was conducted in Shanghai between 2016 and 2017. Using a three-stage stratified sampling strategy, 4009 participants (1753 men and 2256 women) from 10 districts were enrolled. RESULTS: The overall prevalence of gallstones was 6.83% (6.22% for men vs 7.31% for women, P = 0.173). According to the multivariate analysis, individuals aged ≥40 years (odds ratio [OR] 3.058, 95% confidence interval [CI] 2.110-4.433, P < 0.001), hypertension (OR 1.479, 95% CI 1.076-2.034, P = 0.016), thyroid disease (OR 1.409, 95% CI 1.029-1.928, P = 0.032), a family history of gallstones (OR 2.234, 95% CI 1.362-3.662, P = 0.001) and a waist-to-height ratio ≥0.5 (OR 1.656, 95% CI 1.197-2.292, P = 0.002) had an increased risk of developing gallstones. The risk of gallstone disease was 2.232 (95% CI 1.167-4.268, P = 0.015) times higher in individuals with elevated C4 levels than in those with normal C4 levels. Diabetes (OR 4.144, 95% CI 1.171-14.671, P = 0.028) was a risk factor for the formation of gallstones with diameters ≥1 cm, and men were more susceptible to develop multiple stones (OR 2.356, 95% CI 1.321-4.200, P = 0.004). CONCLUSION: Individuals aged ≥40 years, with a history of hypertension and familial gallstones, a high waist-to-height ratio, thyroid disease and high C4 levels were related to an increased risk of gallstone disease.

12.
Gut ; 69(7): 1309-1321, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31727683

RESUMO

OBJECTIVE: Autophagy participates in the progression of hepatocellular carcinoma (HCC) and the resistance of HCC cells to sorafenib. We investigated the feasibility of sensitising HCC cells to sorafenib by modulating miR-541-initiated microRNA-autophagy axis. DESIGN: Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the malignant properties and autophagy of human HCC cells. Autophagy was quantified by western blotting of LC3, transmission electron microscopy analyses and confocal microscopy scanning of mRFP-GFP-LC3 reporter construct. Luciferase reporter assays were conducted to confirm the targets of miR-541. HCC xenograft tumours were established to analyse the role of miR-541 in sorafenib-induced lethality. RESULTS: The expression of miR-541 was downregulated in human HCC tissues and was associated with malignant clinicopathologic phenotypes, recurrence and survival of patients with HCC. miR-541 inhibited the growth, metastasis and autophagy of HCC cells both in vitro and in vivo. Prediction software and luciferase reporter assays identified autophagy-related gene 2A (ATG2A) and Ras-related protein Rab-1B (RAB1B) as the direct targets of miR-541. Consistent with the effects of the miR-541 mimic, inhibition of ATG2A or RAB1B suppressed the malignant phenotypes and autophagy of HCC cells. Furthermore, siATG2A and siRAB1B partially reversed the enhancement of the malignant properties and autophagy in HCC cells mediated by the miR-541 inhibitor. More interestingly, higher miR-541 expression predicted a better response to sorafenib treatment, and the combination of miR-541 and sorafenib further suppressed the growth of HCC cells in vivo compared with the single treatment. CONCLUSIONS: Dysregulation of miR-541-ATG2A/RAB1B axis plays a critical role in patients' responses to sorafenib treatment. Manipulation of this axis might benefit survival of patients with HCC, especially in the context of the highly pursued strategies to eliminate drug resistance.

13.
Clin Gastroenterol Hepatol ; 18(7): 1618-1625.e7, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31712074

RESUMO

BACKGROUND & AIMS: The EncephalApp Stroop test is a high-sensitivity but low-specificity test that has been used to identify patients with covert hepatic encephalopathy (CHE). We aimed to develop a new strategy to detect CHE, combining EncephalApp Stroop test score with scores from subtests of the psychometric hepatic encephalopathy scoring system (PHES). METHODS: We performed a survey of 569 adult volunteers (229 men) in 9 communities in Shanghai, China, administering the EncephalApp Stroop test to determine the range of scores in the general population. Data from the standard PHES, including the number connection test-A, number connection test-B (NCT-B), line tracing test, serial dotting test (SDT), and digit symbol test, were used as the reference standard for diagnosis of CHE. A combination of the EncephalApp Stroop with subtests of the PHES was used to establish a new strategy for CHE diagnosis. We validated our findings using data from 160 patients with cirrhosis from 5 centers China. RESULTS: We determined the range of EncephalApp Stroop test scores for the volunteers of different decades of age, education levels, and sexes. Age, education level, and sex were independently associated with EncephalApp Stroop test scores. A combination of scores from the EncephalApp Stroop test, the NCT-B, and the SDT identified patients with CHE with the highest level of accuracy, when the standard PHES was used as the reference standard. A combination of scores of 187 sec for the EncephalApp Stroop test and below -1 for the NCT-B or below -1 for the SDT identified patients with CHE with an area under the curve (AUC) of 0.86, 81.0% sensitivity, and 91.9% specificity, and 87.5% accuracy. In the validation cohort, these cutoff scores identified patients with CHE with an AUC of 0.88, 97.1% sensitivity, 79.3% specificity, and 86.9% accuracy. The average time to calculate this score was 374±140 sec, compared 424±115 sec for the entire PHES. CONCLUSION: Scores from the EncephalApp Stroop test, NCT-B, and SDT identify patients with CHE with approximately 87% accuracy, and in a much shorter time than the standard PHES. This score combination could be a valid and convenient method for identifying patients with CHE. chictr.org.cn number, ChiCTR-EDC-17012007, ChiCTR1800019954.

14.
Neuromodulation ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31859433

RESUMO

BACKGROUND/AIM: Gastric dysmotility is one of pathophysiologies of gastroesophageal reflux disease (GERD). The aim of this study was to investigate the effects of transcutaneous electrical acustimulation (TEA) on gastric accommodation and gastric slow waves, and evaluate possible mechanisms in patients with GERD. METHODS: Thirty patients were studied in two randomized sessions of sham-TEA and TEA with the measurements of esophageal high-resolution manometry (HRM), gastric accommodation assessed by a nutrient-drinking test, electrogastrogram (EGG), electrocardiogram (ECG), and postprandial dyspeptic symptoms. RESULTS: Compared with sham-TEA, TEA improved nutrient drinking-induced fullness (42.0 ± 3.3 vs. 31.0 ± 3.5, P = 0.003) at 10 min after the drink, and belching right after the drink (22.0 ± 4.6 vs. 11.7 ± 3.1, P = 0.012) and at 10 min (16.0 ± 3.8 vs. 3.0 ± 1.5, P = 0.002) after the drink. TEA also improved gastric accommodation (954 ± 37 mL vs. 857 ± 47 mL, P = 0.001) and normalized maximal drink-induced impairment in gastric slow waves. Concurrently, TEA enhanced vagal activity assessed from spectral analysis of heart rate variability in the postprandial state (0.42 ± 0.03 vs. 0.49 ± 0.04, P = 0.039). The vagal activity was positively correlated with the percentage of normal slow waves (r = 0.528; P = 0.003) and negatively correlated with the regurgitation score (r = -0.408, P = 0.025). CONCLUSIONS: Acute TEA increases gastric accommodation, improves gastric slow waves, and reduces postprandial fullness and belching, possibly mediated via the vagal mechanisms.

15.
Cell Stem Cell ; 25(1): 54-68.e5, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31271748

RESUMO

Following injury, differentiated epithelial cells can serve as a stem cell-independent source for tissue regeneration by undergoing reprogramming into other cell types. The intrinsic molecular basis underlying plasticity of differentiated cells remains largely unaddressed. Here we show that Arid1a, a key component of the SWI/SNF chromatin remodeling complex, controls liver regeneration and gene expression associated with emergence of injury-induced liver-progenitor-like cells (LPLCs). Hepatocyte-specific Arid1a ablation reduces LPLC gene expression in several models of periportal liver injury and impairs liver regeneration, leading to organ dysfunction. Arid1a establishes a permissive chromatin state at LPLC-enriched genes during homeostasis, suggesting it endows hepatocytes with competence to respond to injury-induced signals. Consistently, Arid1a facilitates binding of YAP, a critical regeneration signaling pathway, to LPLC-enriched genes, and Arid1a deletion prevents their YAP-associated induction following injury. Together, these findings provide a framework for studying the contributions of injury-induced LPLCs to periportal liver regeneration.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hepatócitos/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Autorrenovação Celular , Montagem e Desmontagem da Cromatina , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Homeostase , Regeneração Hepática , Camundongos , Camundongos Transgênicos , Transdução de Sinais
16.
Theranostics ; 9(9): 2606-2617, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131056

RESUMO

Background: Liver cancer stem cells (LCSCs) are responsible for the initiation, progression and chemoresistance of liver cancer. However, no agent targeting LCSC is available in the clinic to date. Here, we investigated the effects of targeting protein arginine methyltransferase 5 (PRMT5), an epigenetic regulator, on LCSCs and HCC using a novel PRMT5 inhibitor DW14800. Methods: Tumor spheroid formation culture was used to enrich LCSCs and assess their self-renewal capability. Human alpha-1-antitrypsin (A1AT) ELISA, acetylated low-density lipoprotein (ac-LDL) uptake, periodic acid-Schiff (PAS) reactions and senescence associated ß-galactosidase (SA-ß-gal) activity assays were performed to examine the differentiation status of HCC cells. The effects of DW14800 on HCC malignancy were assessed in HCC cell lines and on an HCC xenograft model in mice. Chromatin immunoprecipitation was applied to clarify the transcriptional regulation of HNF4α by PRMT5-mediated Histone H4 arginine-3 symmetrical dimethylation (H4R3me2s). Results: Quantitative real-time PCR revealed that the expression of PRMT5 was upregulated in LCSCs. DW14800 specifically decreased the symmetrical dimethylation of arginine residues in HCC cells. Treatment of DW14800 suppressed the self-renewal capacity of LCSCs while re-establishing hepatocyte-specific characteristics in HCC cells. DW14800 displayed antitumor effects in HCC cells in vitro and in xenograft HCC in vivo. Importantly, ChIP assay showed that PRMT5 and H4R3me2s bound to the promoter region of HNF4α gene, and DW14800 increased the expression of HNF4α via reducing the H4R3me2s levels and enhancing the transcription of HNF4α. Conclusions: Our data revealed the significance of targeting PRMT5 activity in LCSC elimination and HCC differentiation, and proposed that DW14800 may represent a promising therapeutic agent for HCC in the clinic.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Fator 4 Nuclear de Hepatócito/biossíntese , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores Enzimáticos/administração & dosagem , Xenoenxertos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Transcrição Genética , Resultado do Tratamento , Células Tumorais Cultivadas
17.
J Gastroenterol Hepatol ; 34(10): 1843-1850, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30861191

RESUMO

BACKGROUND AND AIM: Considering the large size of the potential population and limitations of common detection methods, covert hepatic encephalopathy (CHE) is difficult to screen for routinely. The present study aims to explore EncephalApp Stroop Test as a smartphone-based CHE screening tool in China. METHODS: A multicenter, single-visit study was carried out. The cutoff of the Chinese EncephalApp translation was determined by using Chinese standardized psychometric hepatic encephalopathy score (PHES) in cirrhotic patients as the gold standard. Indicators reflecting time required and number of tests on subtask on (naming the color of pound signs) and off (naming the color of the word in discordant coloring) were recorded, with the feedback from investigators and patients. RESULTS: One hundred forty-four patients were included; 58 (40.28%) patients were diagnosed with CHE by PHES. The cutoff of > 97.34 s for off time and > 186.63 s for on time + off time had the maximum area under the curve values (0.77) in all patients. Furthermore, with the cutoff of 186.63 s, on time + off time has the highest sensitivity (0.86). However, the specificity was unsatisfactory (0.59). Age and alcoholic hepatitis (odds ratio = 1.05 and 3.12, both P < 0.05) were positively correlated with the risk of CHE. The experience with electronic devices and education duration were negatively correlated (odds ratio = 0.21 and 0.92, both P < 0.05). Compared with PHES, EncephalApp represented 38% time saving. Furthermore, it was superior to PHES regarding accessibility, convenience, and acceptability by administrators (all P < 0.05). CONCLUSIONS: The EncephalApp Stroop Test is an efficient screening tool for CHE in Chinese cirrhotic patients.


Assuntos
Encefalopatia Hepática/diagnóstico , Cirrose Hepática/complicações , Aplicativos Móveis , Smartphone , Teste de Stroop , Adolescente , Adulto , Idoso , China , Feminino , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/psicologia , Humanos , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Psicometria , Reprodutibilidade dos Testes , Adulto Jovem
18.
J Dig Dis ; 20(3): 122-126, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30582289

RESUMO

Drug-induced liver injury (DILI) is a liver toxicity induced by a drug or its metabolite. The incidence of DILI continues to increase and it has been an enormous challenge worldwide, while the prognosis is not optimistic. Currently, the most effective treatment for DILI is to suspend the offending drug(s) and to avoid re-exposure, with no definitive therapy available for idiosyncratic DILI with or without acute liver failure. Given the anti-inflammatory effects of corticosteroids, they have been widely used in DILI in clinical practice, although their efficacy remains controversial. Several studies have shown their beneficial effects but a few reports have refuted the efficacy of corticosteroids in treating patients with DILI. In this review, we summarized the history and current status of corticosteroid use in liver diseases and the pros and cons of corticosteroid treatment in DILI, and we explored the DILI candidates who may benefit from corticosteroid therapy, the administration route and dosage, and the adverse effects related to corticosteroid use.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucocorticoides/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Incidência , Prognóstico
19.
Cell Stem Cell ; 23(1): 114-122.e3, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29937200

RESUMO

Chronic liver injury can cause cirrhosis and impaired liver regeneration, impairing organ function. Adult livers can regenerate in response to parenchymal insults, and multiple cellular sources have been reported to contribute to this response. In this study, we modeled human chronic liver injuries, in which such responses are blunted, without genetic manipulations, and assessed potential contributions of non-parenchymal cells (NPCs) to hepatocyte regeneration. We show that NPC-derived hepatocytes replenish a large fraction of the liver parenchyma following severe injuries induced by long-term thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment. Through lineage tracing of biliary epithelial cells (BECs), we show that BECs are a source of new hepatocytes and gain an Hnf4α+CK19+ bi-phenotypic state in periportal regions and fibrotic septa. Bi-phenotypic cells were also detected in cirrhotic human livers. Together, these data provide further support for hepatocyte regeneration from BECs without genetic interventions and show their cellular plasticity during severe liver injury.


Assuntos
Células Epiteliais/patologia , Hepatócitos/patologia , Cirrose Hepática/patologia , Animais , Doença Crônica , Humanos , Cirrose Hepática/induzido quimicamente , Camundongos , Camundongos Endogâmicos , Tioacetamida
20.
Cancer Res ; 78(16): 4680-4691, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29776962

RESUMO

Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1, also known as PTPN6) is a nonreceptor protein tyrosine phosphatase that acts as a negative regulator of inflammation. Emerging evidence indicates that SHP-1 plays a role in inhibiting the progression of hepatocellular carcinoma (HCC). However, the role of SHP-1 in hepatocarcinogenesis remains unknown. Here, we find that levels of SHP-1 are significantly downregulated in human HCC tissues compared with those in noncancerous tissues (P < 0.001) and inversely correlate with tumor diameters (r = -0.4130, P = 0.0002) and serum α-fetoprotein levels (P = 0.047). Reduced SHP-1 expression was associated with shorter overall survival of patients with HCC with HBV infection. Overexpression of SHP-1 suppressed proliferation, migration, invasion, and tumorigenicity of HCC cells, whereas knockdown of SHP-1 enhanced the malignant phenotype. Moreover, knockout of Ptpn6 in hepatocytes (Ptpn6HKO ) enhanced hepatocarcinogenesis induced by diethylnitrosamine (DEN) as well as metastasis of primary liver cancer in mice. Furthermore, systemic delivery of SHP-1 by an adenovirus expression vector exerted a therapeutic effect in an orthotopic model of HCC in NOD/SCID mice and DEN-induced primary liver cancers in Ptpn6HKO mice. In addition, SHP-1 inhibited the activation of JAK/STAT, NF-κB, and AKT signaling pathways, but not the MAPK pathway in primary hepatocytes from DEN-treated mice and human HCC cells. Together, our data implicate SHP-1 as a tumor suppressor of hepatocarcinogenesis and HCC progression and propose it as a novel prognostic biomarker and therapeutic target of HCC.Significance: The nonreceptor protein tyrosine phosphatase SHP-1 acts as a tumor suppressor in hepatocellular carcinoma. Cancer Res; 78(16); 4680-91. ©2018 AACR.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteínas Supressoras de Tumor/genética , Animais , Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Análise em Microsséries , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
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