Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 473
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-32139295

RESUMO

BACKGROUND: Transarterial chemoembolization (TACE) and percutaneous microwave coagulation therapy (PMCT) are commonly used to treat intrahepatic recurrent liver cancers. However, there is no information regarding their effectiveness in patients with recurrent intrahepatic cholangiocarcinoma (ICC) after resection. METHODS: A total of 275 patients with localized recurrent ICC who received either TACE (n = 183) or PMCT (n = 92) were studied. A propensity score matching analysis was performed to compare prognostic impact of TACE and PMCT. Prognostic factors for TACE and PMCT were identified respectively. Predictive nomograms for each TACE and PMCT were developed using the Cox independent prognostic factors and were validated in independent patient groups by receiver operating characteristic curves and area under curve values. RESULTS: Both TACE and PMCT provided curativeness in partial patients (5-year overall survival: 21.4% and 6.1%, respectively), but TACE provided better survival benefit in both overall patients (hazard ratio [HR] = 0.71; 95% confidence interval [CI]: 0.50-0.97; P = 0.034) and propensity score matching analysis (HR = 0.69; 95% CI: 0.47-0.98; P = 0.041). Independent prognostic factors for TACE were tumor size >5 cm, poor differentiation, and major resection, whereas poor differentiation, hepatitis B virus infection, cholelithiasis, and lymph node metastasis were identified for PMCT. Both predictive nomograms for TACE and PMCT were validated to be effective with area under curve values of 0.77 and 0.70, respectively. CONCLUSIONS: TACE provided better survival benefits compared to PMCT. However, there was a disparity in prognostic factors, suggesting evaluation of the two nomograms may be supportive in modality selection. Further prospective validation studies are required for the results to be applied in clinical medicine.

2.
Liver Transpl ; 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32198964

RESUMO

We read with great interest the current issue by De Martin E et al.(1) regarding the analysis of liver transplantation (LT) versus liver resection (LR) on cirrhotic patients with small intrahepatic cholangiocarcinoma (iCCA) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The authors retrospectively evaluated a total of 75 cirrhotic patients who were confirmed iCCA/cHCC-CCA ≤5cm and compared them by different operation types of LT or LR0.

3.
Cancer Lett ; 477: 41-48, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32112905

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, despite improvements in the clinical trial and diagnosis, HCC still remains high mortality due to the 70% recurrence and lung metastasis after surgical resection. Exosomes are small membrane vesicles, which are shuttled from donor cells to recipient cells, contributing to the recruitment and reprogramming of constituents via an autocrine or paracrine fashion. HCC derived exosomes could redirect metastasis of tumor cells which lack the capacity to metastasize to a specific organ via generating pre-metastatic niche. These findings emphasize a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. We herein summarize recent findings that implicate oncogenes and non-canonical signaling of HCC exosomes, as well as the impact of exosomal bioactive molecules in high recurrence induced by organ-specific metastasis. The aim of review is to illustrate the underlying mechanism of exosomes in tumor metastasis, immune evasion, and the potential application of prognostic biomarker in HCC process.

4.
Int J Biol Sci ; 16(5): 869-881, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32071556

RESUMO

Cholangiocarcinoma (CCA) is an epithelial cancer and has high death and recurrence rates, current methods cannot satisfy the need for predicting cancer relapse effectively. So, we aimed at conducting a multi-mRNA signature to improve the relapse prediction of CCA. We analyzed mRNA expression profiling in large CCA cohorts from the Gene Expression Omnibus (GEO) database (GSE76297, GSE32879, GSE26566, GSE31370, and GSE45001) and The Cancer Genome Atlas (TCGA) database. The Least absolute shrinkage and selection operator (LASSO) regression model was used to establish a 7-mRNA-based signature that was significantly related to the recurrence-free survival (RFS) in two test series. Based on the 7-mRNA signature, the cohort TCGA patients could be divided into high-risk or low-risk subgroups with significantly different RFS [p < 0.001, hazard ratio (HR): 48.886, 95% confidence interval (CI): 6.226-3.837E+02]. Simultaneously, the prognostic value of the 7-mRNA signature was confirmed in clinical samples of Ren Ji hospital (p < 0.001, HR: 4.558, 95% CI: 1.829-11.357). Further analysis including multivariable and sub-group analyses revealed that the 7-mRNA signature was an independent prognostic value for recurrence of patients with CCA. In conclusion, our results might provide an efficient tool for relapse prediction and were beneficial to individualized management for CCA patients.

5.
AIDS ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32097125

RESUMO

BACKGROUND: Early diagnosis of HIV is important for the prevention of ongoing transmission and development of HIV-related illness. The purpose of this study is to develop an outcome indicator to monitor the progress in early HIV diagnosis. METHODS: Persons diagnosed with HIV in New York City and their first CD4 test results were used to estimate the distribution of HIV diagnosis delay, based on a CD4 count depletion model. The distribution was then used to estimate the probability of diagnosis within 1 year of HIV acquisition, which is the number of cases diagnosed in a given calendar year for which diagnosis occurred within 1 year of acquisition divided by the number of incident cases in that calendar year. RESULTS: In 2012-2016, the estimated annual probability of diagnosis within 1 year of HIV acquisition in New York City was 43.0% [95% confidence interval (CI): 37.9-48.2%), 42.5% (95% CI: 36.8--48.3%), 42.8% (95% CI: 36.3--49.2%), 42.9% (95% CI: 35.4--50.3%), and 42.2% (95% CI: 33.1--51.2%), respectively. CONCLUSION: National and local health jurisdictions should consider using this new outcome indicator, the probability of diagnosis within 1 year of HIV acquisition, to monitor their progress in early HIV diagnosis.

6.
Cell Death Dis ; 11(1): 17, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907348

RESUMO

Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an antiapoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

7.
J Dig Dis ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953907

RESUMO

OBJECTIVE: To evaluate the efficacy of living-donor liver transplantation (LDLT) in children with tyrosinemia type I. METHODS: Altogether 10 patients diagnosed with tyrosinemia type I underwent LDLT between June 2013 and April 2019. Cirrhosis was the indication for LDLT in all 10 patients, and hepatocellular carcinoma (HCC) was suspected in nine. Patients' outcomes, including liver function, restoration of metabolism, quality of life and physical development, were analyzed after LDLT. RESULTS: All recipients were alive with a normal liver function after a median follow-up period of 49 months. Pathological examinations detected HCC in one patient, dysplasia in five and cirrhosis in all. Nine patients were found to have elevated alpha-fetoprotein level, and their median alpha-fetoprotein level dropped from 2520 ng/mL to a normal level after LDLT, with no recurrence of HCC detected during the follow-up. Tyrosine metabolism was restored to its normal level with normalized plasma tyrosine and succinylacetone concentrations. Moreover, urinary succinylacetone excretion decreased significantly during the follow up. LDLT improved patients' renal tubular function, as evidenced by the normalized plasma phosphate concentration and improved glomerular filtration rate. Severe rickets symptoms, including spontaneous fractures and bone pain, were also ameliorated. Improved motor function was reported by all patients' parents during the follow-up. Dietary restriction was no longer required, which was associated with a favorable catch-up in growth and improved quality of life. Complete resolution of hypertrophic cardiomyopathy was observed one year after LDLT in one patient. CONCLUSION: LDLT is an effective treatment for patients with end-stage liver disease resulting from tyrosinemia type I.

8.
Hepatobiliary Pancreat Dis Int ; 19(1): 3-11, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31932195

RESUMO

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a lethal complication after pediatric liver transplantation, but information regarding risk factors for the development of PTLD remains unclear. This study was to identify characteristics and risk factors of PTLD. METHODS: A total of 705 pediatric patients who underwent liver transplantation between January 2017 and October 2018 were studied. Impact of clinical characteristics and Epstein-Barr virus (EBV) infection on the development of PTLD was evaluated. In addition, ImmuKnow assay was adopted in partial patients to analyze the immune status. RESULTS: Twenty-five (3.5%) patients suffered from PLTD with a median time of 6 months (3-14 months) after transplantation. Extremely high tacrolimus (TAC) level was found in 2 fatal cases at PTLD onset. EBV infection was found in 468 (66.4%) patients. A higher peak EBV DNA loads (>9590 copies/mL) within 3 months was a significant indicator for the onset of PTLD. In addition, the ImmuKnow assay demonstrated that overall immune response was significantly lower in patients with EBV infection and PTLD (P<0.0001). The cumulative incidence of PTLD was also higher in patients with lower ATP value (≤187 ng/mL, P<0.05). CONCLUSIONS: A careful monitoring of EBV DNA loads and tacrolimus concentration might be supportive in prevention of PTLD in pediatric patients after liver transplantation. In addition, application of the ImmuKnow assay may provide guidance in reducing immunosuppressive agents in treatment of PTLD.

9.
AIDS ; 34(3): 459-467, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794522

RESUMO

BACKGROUND: To develop a predictive model to prioritize persons with a transmissible HIV viral load for transmission-reduction interventions. METHODS: New York City (NYC) HIV molecular surveillance data from 2010 to 2013 were used to build a model to predict the probability that the partial pol gene of the virus of a person with a transmissible HIV viral load (>1500 copies/ml) would be genetically similar to that of a person with a new HIV infection (diagnosis at stage 0 or 1 according to the revised Centers for Disease Control and Prevention classification system). Data from 2013 to 2016 were then used to validate the model and compare it with five other selection strategies that can be used to prioritize persons for transmission-reduction interventions. RESULTS: A total of 10 609 persons living with HIV (PLWH) were included in the development dataset, and 8257 were included in the validation dataset. Among the six selection strategies, the predictive model had the highest area under the receiver operating characteristic curve (AUC) [0.86, 95% confidence interval (CI) 0.84--0.88], followed by the 'Young MSM' (0.79, 95% CI 0.77--0.82), 'MSM with high viral loads' (0.74, 95% CI 0.72--0.76), 'Random sample of MSM' (0.73, 95% CI 0.71--0.76), 'Persons with high viral loads' (0.56, 95% CI 0.54--0.59), and 'Random sample' (0.50, 95% CI 0.48--0.53) strategies. CONCLUSIONS: Jurisdictions should consider applying predictive modeling to prioritize persons with a transmissible viral load for transmission-reduction interventions and to evaluate its feasibility and effectiveness.

10.
Transpl Infect Dis ; 22(1): e13199, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31627248

RESUMO

INTRODUCTION: Tigecycline (TGC) is effective for the infections caused by carbapenem-resistant gram-negative bacteria (CRGNB) in adults, but it is not investigated systematically in children because of concern about adverse effects. This study aimed to analyze the effectiveness of TGC in treating CRGNB infections in children after receiving liver transplant. METHODS: The subjects in this retrospective study were pediatric liver transplant recipients treated with TGC for at least 3 days to fight microbiologically verified CRGNB infection after initial antibiotic failure during the period from January 2014 to May 2018. Clinical and microbiological outcomes were reviewed to evaluate the efficacy and safety of TGC. RESULTS: Of the 1177 pediatric liver transplant recipients, 13 patients were eligible for inclusion in this analysis. All the patients received TGC at dose of 2 mg/kg every 12 hours for a duration of 10.1 ± 5.1 days on average to treat CRGNB infections, including complicated intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. The isolates included Klebsiella pneumoniae (69.2%, 9/13) and Acinetobacter baumannii (30.8%, 4/13). Clinical efficacy was achieved in 84.6% (11/13) and pathogen eradicated in 69.2% (9/13) of the patients. The overall mortality rate was 15.4% (2/13). No TGC-related serious adverse event was reported. CONCLUSION: Tigecycline can be considered in combination antimicrobial regimen for treating CRGNB-related infections in pediatric liver transplant recipients.

11.
Nat Cell Biol ; 22(1): 135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31730051

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

12.
Chem Asian J ; 15(1): 136-147, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31749293

RESUMO

Host-guest encapsulation of functional organic dye into a porous metal-organic framework can give rise to the development of new functional materials. In this work, by intercalating the stilbazolium-type dye (DEAST)I (4'-diethylamino-N-methyl stilbazolium) into four lanthanide layered metal-organic complexes (Ln-LMOCs), i. e. {[Ln(BTB)(H2 O)2 ]⋅3(DMF)⋅2(H2 O)}n (Ln=La (1), Nd (2), Sm (3), Er (4)), four responsive (DEAST)I@Ln-LMOC composites have been prepared, serving as multifunctional performance platform. The core-shell structures of (DEAST)I@Ln-LMOC composites have been fully characterized by IR, UV/Vis, PXRD, SEM, TEM, TGA and ESR. Significantly, after intercalation of dyes, the (DEAST)I@Ln-LMOC composites exhibit enhanced luminescent sensing properties in detecting Fe3+ with much higher water stabilities. The luminescent sensing behavior stems from the fluorescence resonance energy transfer (FRET) from the π-electron-rich BTB ligands to the Fe3+ , and their higher water stabilities are induced by electrostatic interactions and lower porosity. Specially, the characteristic emissions of Sm3+ will not be affected after the encapsulation guest dyes, which provide a theoretical guide for the modulation of luminescence devices. Finally, better ion conductivities and diminished photocurrents can be achieved after the embedding of the functional organic dye. In all, the formation of (DEAST)I@Ln-LMOC composites with core-shell structures can be utilized as a multifunctional platform with good stability.

13.
AIDS Care ; 32(2): 202-208, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31146539

RESUMO

Screening for HIV in Emergency Departments (EDs) is recommended to address the problem of undiagnosed HIV. Serosurveys are an important method for estimating the prevalence of undiagnosed HIV and can provide insight into the effectiveness of an HIV screening strategy. We performed a blinded serosurvey in an ED offering non-targeted HIV screening to determine the proportion of patients with undiagnosed HIV who were diagnosed during their visit. The study was conducted in a high-volume, urban ED and included patients who had blood drawn for clinical purposes and had sufficient remnant specimen to undergo deidentified HIV testing. Among 4752 patients not previously diagnosed with HIV, 1403 (29.5%) were offered HIV screening and 543 (38.7% of those offered) consented. Overall, undiagnosed HIV was present in 12 patients (0.25%): six among those offered screening (0.4%), and six among those not offered screening (0.2%). Among those with undiagnosed HIV, two (16.7%) consented to screening and were diagnosed during their visit. Despite efforts to increase HIV screening, more than 80% of patients with undiagnosed HIV were not tested during their ED visit. Although half of those with undiagnosed HIV were missed because they were not offered screening, the yield was further diminished because a substantial proportion of patients declined screening. To avoid missed opportunities for diagnosis in the ED, strategies to further improve implementation of HIV screening and optimize rates of consent are needed.

14.
Nat Cell Biol ; 21(11): 1436-1448, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31685992

RESUMO

PTENα and PTENß are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTENα and PTENß promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also show that USP9X and FBXW11 bind to the amino-terminal extensions of PTENα/ß, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTENα to regulate PTENα/ß stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTENα/ß. Taken together, our results indicate that the Pten gene is a double-edged sword for carcinogenesis, and reinterpretation of the importance of the Pten gene in carcinogenesis is warranted.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , PTEN Fosfo-Hidrolase/genética , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Histonas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Proteólise , Transdução de Sinais , Análise de Sobrevida , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Contendo Repetições de beta-Transducina/genética , Proteínas Contendo Repetições de beta-Transducina/metabolismo
15.
Cell Mol Immunol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673056

RESUMO

Notch signaling plays important roles in the regulation of immune cell functioning during the inflammatory response. Activation of the innate immune signaling receptor NLRP3 promotes inflammation in injured tissue. However, it remains unknown whether Jagged1 (JAG1)-mediated myeloid Notch1 signaling regulates NLRP3 function in acute liver injury. Here, we report that myeloid Notch1 signaling regulates the NLRP3-driven inflammatory response in ischemia/reperfusion (IR)-induced liver injury. In a mouse model of liver IR injury, Notch1-proficient (Notch1FL/FL) mice receiving recombinant JAG1 showed a reduction in IR-induced liver injury and increased Notch intracellular domain (NICD) and heat shock transcription factor 1 (HSF1) expression, whereas myeloid-specific Notch1 knockout (Notch1M-KO) aggravated hepatocellular damage even with concomitant JAG1 treatment. Compared to JAG1-treated Notch1FL/FL controls, Notch1M-KO mice showed diminished HSF1 and Snail activity but augmented NLRP3/caspase-1 activity in ischemic liver. The disruption of HSF1 reduced Snail activation and enhanced NLRP3 activation, while the adoptive transfer of HSF1-expressing macrophages to Notch1M-KO mice augmented Snail activation and mitigated IR-triggered liver inflammation. Moreover, the knockdown of Snail in JAG1-treated Notch1FL/FL livers worsened hepatocellular functioning, reduced TRX1 expression and increased TXNIP/NLRP3 expression. Ablation of myeloid Notch1 or Snail increased ASK1 activation and hepatocellular apoptosis, whereas the activation of Snail increased TRX1 expression and reduced TXNIP, NLRP3/caspase-1, and ROS production. Our findings demonstrated that JAG1-mediated myeloid Notch1 signaling promotes HSF1 and Snail activation, which in turn inhibits NLRP3 function and hepatocellular apoptosis leading to the alleviation of IR-induced liver injury. Hence, the Notch1/HSF1/Snail signaling axis represents a novel regulator of and a potential therapeutic target for liver inflammatory injury.

16.
Mol Cancer ; 18(1): 163, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31735169

RESUMO

BACKGROUND: Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6A-methylation in hepatocellular carcinoma (HCC). RESULTS: Using liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m6A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. CONCLUSION: Our results have characterized the m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular 'rheostat' in epitranscriptome and cancer progression.

17.
Cancer Med ; 8(18): 7869-7880, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663692

RESUMO

Previous studies have shown that single-nucleotide polymorphisms (SNPs) of a disintegrin and metalloproteinase with thrombospondin type 1 motif 4 (ADAMTS4) may involve in the pathogenesis of some diseases. However, it is not clear whether they are associated with hepatocellular carcinoma (HCC). A hospital-based case-control study, including 862 cases with HCC and 1120 controls, was conducted to assess the effects of 258 SNPs in the coding regions of ADAMTS4 on HCC risk and prognosis. We found that six SNPs in ADAMTS4 were differential distribution between cases and controls via the primary screening analyses; however, only rs538321148 and rs1014509103 polymorphisms were further identified to modify the risk of HCC (odds ratio: 2.73 and 2.95; 95% confidence interval, 2.28-3.29 and 2.43-3.58; P-value, 5.73 × 10-27 and 1.36 × 10-27 , respectively). Significant interaction between these two SNPs and two known causes of hepatitis B virus and aflatoxin B1 were also observed. Furthermore, rs538321148 and rs1014509103 polymorphisms were associated not only with clinicopathological features of tumor such as tumor stage and grade, microvessel density, and vessel metastasis, but with poor overall survival. Additionally, these SNPs significantly downregulated ADATMS4 expression in tumor tissues. These data suggest that SNPs in the coding region of ADAMTS4, such as rs538321148 and rs1014509103, may be potential biomarkers for predicting HCC risk and prognosis.

18.
Cell Death Differ ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591471

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

19.
Cell Mol Immunol ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481754

RESUMO

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

20.
Ther Adv Med Oncol ; 11: 1758835919866960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489034

RESUMO

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and is generally caused by viral infections or consumption of mutagens, such as alcohol. While liver transplantation and hepatectomy is curative for some patients, many relapse into disease with few treatment options such as tyrosine kinase inhibitors, for example, sorafenib or lenvatinib. The need for novel systemic treatment approaches is urgent. Methods: MTH1 expression profile was first analyzed in a HCC database and MTH1 mRNA/protein level was determined in resected HCC and paired paracancerous tissues with polymerase chain reaction (PCR) and immunohistochemistry. HCC cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA. 8-oxoG was measured by the modified comet assay. The effect of MTH1 inhibition on tumor growth was explored in HCC xenograft in vivo models. Results: MTH1 protein level is elevated in HCC tissue compared with paracancerous liver tissue and indicates poor prognosis. The MTH1 inhibitor Karonudib (TH1579) and siRNA effectively introduce toxic oxidized nucleotides into DNA, 8-oxoG, and kill HCC cell lines in vitro. Furthermore, we demonstrate that HCC growth in a xenograft mouse model in vivo is efficiently suppressed by Karonudib. Conclusion: Altogether, these data suggest HCC relies on MTH1 for survival, which can be targeted and may open up a novel treatment option for HCC in the future.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA