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1.
Hepatol Int ; 14(1): 105-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31898210

RESUMO

BACKGROUND: Controversy exists on whether tenofovir disoproxil fumarate (TDF) is superior to entecavir (ETV) in lowering the risk of hepatocellular carcinoma (HCC) development. This meta-analysis was performed to clarify this issue with critical clinical and methodological considerations. METHODS: PubMed, EMBASE, and Cochrane Library were searched from inception to Oct 28, 2019. Randomized control trials and observational studies reporting the impact of TDF and ETV on the risk of HCC in patients with chronic hepatitis B (CHB) were eligible. Risk ratios (RRs) calculated with cumulative incidence rate and/or annual incidence rate, or hazard ratio (HR) were pooled using random-effect models. Subgroup analyses were performed to assess the potential impact of between-study level and within-study level factors. RESULTS: A total of 32 studies with 78,136 CHB patients were included. Overall cumulative incidence rate of HCC was lower in TDF group than ETV group (3.07% vs. 5.25%; RR 0.55; 95% CI 0.42-0.72). However, this difference was not statistically significant in pooled results of hazard ratio (HR 0.87; 95% CI 0.73-1.04) and RR calculated with annual incidence rate (RR 0.88; 95% CI 0.67-1.16). Potential confounding factors at between-study level included prior nucleos(t)ide usage, disease stage at baseline and region of study. More importantly, at within-study level, disparity in follow-up duration between TDF and ETV groups may impact the result, usually favoring a treatment with shorter follow-up duration. CONCLUSIONS: Compared with ETV, TDF treatment tended to have a lower overall cumulative incidence rate of HCC. However, disparity in follow-up duration may be a key factor to influence the result.

2.
Stem Cell Res Ther ; 10(1): 378, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823825

RESUMO

BACKGROUND: Magnesium (Mg2+)-enriched microenvironment promotes odontogenic differentiation in human dental pulp stem cells (DPSCs), but the regulatory mechanisms remain undefined. The aim of this work was to assess magnesium's function in the above process and to explore the associated signaling pathway. METHODS: DPSCs underwent culture in odontogenic medium with the addition of 0, 1, 5, or 10 mM MgCl2. Intracellular Mg2+ levels in DPSCs were evaluated flow cytometrically using Mag-Fluo-4-AM. Mg2+-entry was inhibited by TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB). RNA-Sequencing was carried out for assessing transcriptome alterations in DPSCs during odontogenic differentiation associated with high extracellular Mg2+. KEGG pathway analysis was performed to determine pathways related to the retrieved differentially expressed genes (DEGs). Immunoblot was performed for assessing magnesium's role and exploring ERK/BMP2/Smads signaling. RESULTS: Mg2+-enriched microenvironment promoted odontogenic differentiation in DPSCs via intracellular Mg2+ increase. Consistently, the positive effect of high extracellular Mg2+ on odontogenic differentiation in DPSCs was blocked by 2-APB, which reduced Mg2+ entry. RNA-sequencing identified 734 DEGs related to odontogenic differentiation in DPSCs in the presence of high extracellular Mg2+. These DEGs participated in many cascades such as MAPK and TGF-ß pathways. Consistently, ERK and BMP2/Smads pathways were activated in DPSCs treated with high extracellular Mg2+. In agreement, ERK signaling inhibition by U0126 blunted the effect of high extracellular Mg2+ on mineralization and odontogenic differentiation in DPSCs. Interestingly, BMP2, BMPR1, and phosphorylated Smad1/5/9 were significantly decreased by U0126, indicating that BMP2/Smads acted as downstream of ERK. CONCLUSIONS: Mg2+-enriched microenvironment promotes odontogenic differentiation in DPSCs by activating ERK/BMP2/Smads signaling via intracellular Mg2+ increase. This study revealed that Mg2+-enriched microenvironment could be used as a new strategy for dental pulp regeneration.

3.
Orphanet J Rare Dis ; 14(1): 292, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842933

RESUMO

BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. METHODS: The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18 years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. RESULTS: Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. CONCLUSIONS: The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.

4.
BMJ Open ; 9(11): e030293, 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31767583

RESUMO

INTRODUCTION: The best approach for choledocholithiasis remains a matter of debate. Choledocholithiasis is usually treated with endoscopic sphincterotomy (EST), laparoscopic common bile duct exploration (LCBDE) or laparoscopic transcystic common bile duct exploration (LTCBDE). Data pertaining to the clinical outcomes of these approaches in the management of patients with cholecysto-choledocholithiasis in China are limited. An analysis of the economic burden associated with these treatments is lacking. The Chinese REgistry Study on the Treatment of Cholecysto-Choledocholithiasis (CREST Choles) was designed to address these issues in a real-world setting. METHODS AND ANALYSIS: CREST Choles was an ambispective, multicenter, observational, open-cohort study. A total of 2700 patients undergoing one of the three treatments (EST+laparoscopic cholecystectomy (LC), LCBDE+LC and LTCBDE+LC) during the period from 1 January 2013 to 1 December 2018 at participating centres were enrolled in the study. Patients with gallstones and confirmed common bile duct stones were included. Data pertaining to demographics, disease history, procedural details, imaging features and follow-up were collected. Follow-up was conducted at least 6 months after enrolment in the study and annual follow-up will be conducted until December 2020. The primary outcome is the rate of adverse outcomes within 3 years postoperatively. Economic analysis (eg, incremental cost-effectiveness ratio) would be performed to compare expense across treatments. ETHICS AND DISSEMINATION: Ethical approval was obtained at all participating centres. The registry presented is the first attempt to comprehensively evaluate the cost of treatment for cholecysto-choledocholithiasis in China. Findings are expected to be available in 2020 and will facilitate clinical decision making in such cases. TRIAL REGISTRATION NUMBER: NCT02554097.

5.
Adv Clin Exp Med ; 28(11): 1459-1468, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31756062

RESUMO

BACKGROUND: Identification of biomarkers predicting a response to chemotherapeutic drugs would greatly ease the selection of personalized therapy. The protein xeroderma pigmentosum group D (XPD) functions in nucleotide excision repair (NER) to remove DNA cross-links and in the regulation of transcription. The potential role of the Asp312Asn polymorphism in predicting the response to chemotherapy has not been established. OBJECTIVES: This prospective study was designed to determine the role of the XPD Asp312Asn polymorphism in predicting the response to oxaliplatin-based first-line chemotherapy and survival in patients with metastatic colorectal cancer. MATERIAL AND METHODS: A total of 106 patients treated with 2 cycles of either FOLFOX4 (n = 72) or XELOX (n = 34) regimen as the chemotherapy were enrolled. The genotype of XPD Asp312Asn polymorphism was analyzed using TaqMan probe-based real-time polymerase chain reaction (PCR). Logistic regression was applied to predict the response to treatment protocols. Cox regression models were applied to predict overall survival. RESULTS: The overall response to chemotherapy was 57.6% (61/106). FOLFOX4 and XELOX regimens demonstrated comparable efficacy. The XPD Asp312Asn polymorphism was not associated with the response to either FOLFOX4 or XELOX regimen in univariate and in multivariate logistic regression analyses. Levels of carcinoembryonic antigen (CEA) ≥5 ng/mL and female gender were associated with a lack of response to FOLFOX4, but not to XELOX regimen. In a multivariate survival analysis, XPD Asp312Asn AA genotype, lack of response to chemotherapy, CEA ≥ 5 ng/mL, and age ≥65 were significantly associated with worse overall survival. CONCLUSIONS: The XPD Asp312Asn polymorphism is associated with overall survival, but it is not a biomarker in predicting the response to oxaliplatin-based first-line chemotherapy in patients with metastatic colorectal cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Oxaliplatina/uso terapêutico , Proteína Grupo D do Xeroderma Pigmentoso/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Análise de Sobrevida , Resultado do Tratamento , Xeroderma Pigmentoso
6.
Cancer Res ; 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732653

RESUMO

The AAA-ATPase TRIP13 drives multiple myeloma (MM) progression. Here we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small molecule inhibitor targeting TRIP13 was identified based on the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance binding assays. DCZ0415 induced anti-myeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant myeloma patients. The inhibitor impaired nonhomologous end joining repair and inhibited NF-κB activity. Moreover, combining DCZ0415 with the MM chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic anti-myeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for MM, particularly refractory or relapsed MM.

7.
J Clin Gastroenterol ; 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31651571

RESUMO

BACKGROUND AND AIM: The prevalence of lean/nonobese nonalcoholic fatty liver disease (NAFLD) ranges widely in studies. Thus, here, we aimed to perform a meta-analysis on NAFLD prevalence in the lean or nonobese population to give clarity. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library databases were systematically searched to identify studies reporting NAFLD prevalence in the lean/nonobese population. Lean or nonobese was defined by body mass index cutoffs reported by authors in original studies. NAFLD prevalence based on community, population, or health checkups was combined with random-effect model after logit transformation. Subgroup analysis and meta-regression were further performed to investigate the heterogenicity. RESULTS: A total of 45 studies were enrolled in the final analysis, with 55,936 lean/nonobese subjects included, among whom 7351 NAFLD patients were diagnosed. Overall, the pooled NAFLD prevalence of the lean or nonobese population was 10.2% (95% confidence interval: 7.6%-13.6%) and 15.7% (95% confidence interval: 12.5%-19.6%), respectively. Compared with western studies, the NAFLD prevalence in the lean or nonobese population was lower in eastern studies. In addition, the NAFLD prevalence in both the lean and nonobese population showed a general upward trend during recent years. The prevalence was similar in community-based and health checkup-based studies. Lean/nonobese NAFLD patients had significantly lower rates of hypertension, lower uric acid and fasting plasma glucose, and a higher level of high-density lipoprotein than nonlean/obese patients. CONCLUSIONS: The prevalence of NAFLD in the lean/nonobese population is not rare in either the western or eastern regions of the world. This meta-analysis of prevalence assessment and clinical characteristics should enable higher confidence in more specific interventions and health care standards for these patients.

8.
Med Educ Online ; 24(1): 1679944, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31630670

RESUMO

Background: There is a strong need to include training of research methods in training programs for physicians. International clinical research training programs (CRTP) that comprehensively introduce the methodology of clinical research and combined with practice should be a priority. However, few studies have reported a multimodal international CRTP that provides clinicians with an introduction to the quantitative and methodological principles of clinical research. Objective: This manuscript is intended to comprehensively describe the development process and the structure of this multimodal training program. Methods: The CRTP was comprised of three distinct, sequential learning components: part 1 - a six-week online eLearning self-study; part 2 - a series of three weekly interactive synchronous webinars conducted between Durham, North Carolina, USA and Beijing, China; and part 3 - a five-day in-person workshop held at Beijing Friendship Hospital, Capital Medical University (BFH-CMU). Self-assessment quiz scores and participation rates were used to evaluate effectiveness of the training program. Participants' demographic characteristics, research experience, satisfaction and feedback on the program were collected using questionnaires. Results: A total of 50 participants joined the CRTP. Forty-four participants (88%) completed the program satisfaction questionnaires. The average quiz score of the six eLearning units varied from 31% to 73%. Among the three components of the program, the online eLearning self-study was felt to be the most challenging. Thirty-nine (89%) of the surveyed respondents were satisfied with all components of the training program. Among the respondents, 43 (98%) felt the training was helpful in preparing them for future clinical research projects and expressed willingness to recommend the program to other colleagues. Conclusions: We established a multimodal international collaborative training program. The program demonstrated acceptable participation rates and high satisfaction among Chinese clinicians. It provides a model that may be used by others developing similar international clinical research training programs for physicians.

9.
Hepatol Int ; 13(6): 766-776, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31559605

RESUMO

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) commonly affects subjects with obesity, yet non-obese NAFLD is increasingly being recognized. We aimed to investigate the clinicopathological and genetic characteristics of non-obese NAFLD patients. METHODS: The clinical, histological and genetic data of 84 NAFLD patients with biopsy for abnormal liver function test were reviewed. Both NAS-CRN and SAF scoring systems were applied for histopathological evaluation. PNPLA3 and TMS6F2 genotyping were also performed. RESULTS: All of the 84 patients were histologically diagnosed with non-alcoholic steatohepatitis (NASH), with 36 of them (42.9%) being non-obese (BMI < 25 kg/m2). Compared with the obese group, non-obese group were predominantly females (88.9% vs 52.1%, p < 0.001), tended to have higher prevalence of diabetes (p = 0.068). More importantly non-obese patients had a significant higher prevalence of advanced fibrosis (F ≥ 3) (58.3% vs 29.2%, p = 0.013), and a trend of higher degree of ballooning (p = 0.061). In addition, values of liver stiffness measurement were also significantly higher in non-obese group (12.1 kPa vs 8.1 kPa, p = 0.032). There was also a trend of higher prevalence of TM6SF2 T allele in non-obese group (p = 0.085), while the prevalence of PNPLA3 risk allele did not differ between two groups. Multivariate analysis showed that higher fasting glucose (p = 0.038) and lower serum platelets (p = 0.040) were two independent predictors for advanced fibrosis in non-obese patients. CONCLUSIONS: Non-obese NASH patients have a female predominance and more advanced fibrosis. Liver biopsy is crucial to evaluate the severity of disease in non-obese patients especially those with abnormal liver biochemistry. CLINICAL TRIAL NUMBER: NCT03386890.

10.
Hepatol Int ; 13(6): 788-799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552558

RESUMO

AIMS: Epidemiological studies on primary biliary cholangitis (PBC) show heterogeneity. The aim of the present study was to synthesize the prevalence, incidence and clinical course of PBC in the Asia-Pacific region. METHODS: PubMed, Medline, Cochrane library and EMBASE were searched for epidemiology and clinical course of PBC published up to July, 2019. Meta-analysis was conducted on the epidemiology and clinical course (decompensation, hepatocellular carcinoma and death/liver transplantation) of PBC patients. Random-effect model and fixed-effect model were used to evaluate the pooled prevalence, incidence, mortality/liver transplantation and their 95% confidence intervals as appropriate. Subgroup analysis was performed by stratification with gender, pre- and post-UDCA era, sub-region and publication year. Meta-regression was used to examine the heterogeneity. RESULTS: Out of 3460 studies, 18 studies from 7 countries/regions were finally included. The overall prevalence of PBC was 118.75 cases per million (95% CI 49.96-187.55) in the Asia-Pacific region, with the high, medium and low prevalence being in Japan and China (191.18 cases per million), New Zealand (99.16 cases per million) and South Korea and Australia (39.09 cases per million), respectively. The incidence of PBC was 8.55 cases per million per year (95% CI 8.05-9.06). The 5-year accumulative incidence of decompensation, HCC and death/liver transplantation in PBC patients was 6.95% (95% CI 2.07-11.83%), 1.54% (95% CI 0.9-2.19%) and 4.02% (95% CI 2.49-5.54%), respectively. CONCLUSION: In the Asia-Pacific region, the prevalence and incidence of PBC are higher than once expected. PBC tends to be diagnosed at older age and has a relatively low incidence of HCC in this region.

11.
Comput Math Methods Med ; 2019: 7239780, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31428186

RESUMO

The diagnostic performance of an artificial neural network model for chronic HBV-induced liver fibrosis reverse is not well established. Our research aims to construct an ANN model for estimating noninvasive predictors of fibrosis reverse in chronic HBV patients after regular antiviral therapy. In our study, 141 consecutive patients requiring liver biopsy at baseline and 1.5 years were enrolled. Several serum biomarkers and liver stiffness were measured during antiviral therapy in both reverse and nonreverse groups. Statistically significant variables between two groups were selected to form an input layer of the ANN model. The ROC (receiver-operating characteristic) curve and AUC (area under the curve) were calculated for comparison of effectiveness of the ANN model and logistic regression model in predicting HBV-induced liver fibrosis reverse. The prevalence of fibrosis reverse of HBV patients was about 39% (55/141) after 78-week antiviral therapy. The Ishak scoring system was used to assess fibrosis reverse. Our study manifested that AST (aspartate aminotransferase; importance coefficient = 0.296), PLT (platelet count; IC = 0.159), WBC (white blood cell; IC = 0.142), CHE (cholinesterase; IC = 0.128), LSM (liver stiffness measurement; IC = 0.125), ALT (alanine aminotransferase; IC = 0.110), and gender (IC = 0.041) were the most crucial predictors of reverse. The AUC of the ANN model and logistic model was 0.809 ± 0.062 and 0.756 ± 0.059, respectively. In our study, we concluded that the ANN model with variables consisting of AST, PLT, WBC, CHE, LSM, ALT, and gender may be useful in diagnosing liver fibrosis reverse for chronic HBV-induced liver fibrosis patients.

12.
Cell Death Dis ; 10(9): 624, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31423010

RESUMO

Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using a microRNA target-scan algorithm, we identified miR-17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis-both in vitro and in vivo. miR-17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR-17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5'-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR-17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.

13.
Mod Pathol ; 32(12): 1795-1805, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31300804

RESUMO

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

14.
Gastroenterol Res Pract ; 2019: 8959103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281353

RESUMO

Objective: The diagnostic value of antinuclear antibodies (ANAs) including anti-gp210 and anti-sp100 for primary biliary cholangitis/cirrhosis (PBC) has been widely reported. However, their diagnostic performances for antimitochondrial antibody- (AMA-) negative PBC were less well elucidated. Therefore, the aim of the current meta-analysis was to evaluate the diagnostic accuracy of ANAs in patients with AMA-negative PBC. Materials and Methods: Literature on the diagnostic value of biomarkers for AMA-negative PBC was systematically searched in PubMed, MEDLINE, EMBASE, and the Cochrane Library. The qualities of the retrieved studies were assessed by the Quality Assessment of Diagnostic Accuracy Studies-version 2 (QUADAS-2) scale. Pooled sensitivity and specificity of the biomarkers were calculated with random-effects models. The areas under the summary receiver operating characteristic (AUSROC) curves were used to evaluate the overall diagnostic performance of ANAs. Results: A total of 11 studies (400 AMA-negative PBC patients and 6217 controls) were finally included in the meta-analysis. ANAs had an overall sensitivity of 27% (95% CI: 20%, 35%) and specificity of 98% (95% CI: 97%, 99%). The pooled sensitivities for anti-gp210 and anti-sp100 were 23% (95% CI: 13%, 37%) and 25% (95% CI: 13%, 43%), respectively, and their specificities were 99% (95% CI: 97%, 100%) and 97% (95% CI: 93%, 98%), respectively. Conclusions: ANAs exhibited high specificity but low sensitivity and therefore could be used as reliable biomarkers to reduce the necessity of liver histology.

15.
Front Microbiol ; 10: 1070, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31164876

RESUMO

The Ascomycetes fungus Colletotrichum fructicola causes severe diseases on a wide range of crops, fruits, and vegetables. Its pathogenic mechanisms, however, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are conserved regulators of fungal development and pathogenesis. In this study, a Fus3/Kss1-related MAPK from C. fructicola was functionally characterized via gene deletion. On potato dextrose agar (PDA) and oatmeal agar media, the CfPMK1 gene deletion mutants (ΔCfPMK1) were slightly reduced in radial growth rate, severely limited in aerial hyphal differentiation and hyphal melanization, and formed deformed perithecia that were smaller in size and more compactly organized relative to wild type. When artificially inoculated on plants, conidia of these mutants failed to differentiate appressoria or penetrate cuticle, and their pathogenicity defect could not be rescued by wounding plant tissue prior to inoculation. On PDA, ΔCfPMK1 mutants were hypersensitive to osmotic stresses, but were more tolerant to membrane and cell wall stresses. Genetic complementation rescued all phenotypic changes associated with CfPMK1 gene deletion. Based on GFP fusion expression, CfPMK1 protein accumulation was detected at all life stages, and the accumulation level was higher in nascent appressoria relative to conidia. Overall, this study identified CfPMK1 as a key regulator of appressorium and sexual development, pathogenesis, and stress tolerance in C. fructicola.

16.
Stem Cell Res Ther ; 10(1): 170, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196201

RESUMO

BACKGROUND: Exosomes derived from dental pulp stem cells (DPSCs) can be used as biomimetic tools to induce odontogenic differentiation of stem cells, but the regulatory mechanisms and functions of exosome-encapsulated microRNAs are still unknown. The present study aimed to clarify the role of microRNAs contained in the exosomes derived from human DPSCs and their potential signaling cascade in odontogenic differentiation. METHODS: Exosomes were isolated from human DPSCs cultured undergrowth and odontogenic differentiation conditions, named UN-Exo and OD-Exo, respectively. The microRNA sequencing was performed to explore the microRNA profile contained in UN-Exo and OD-Exo. Pathway analysis was taken to detect enriched pathways associated with the predicted target genes of microRNAs. The regulatory roles of a highly expressed microRNA in OD-Exo were investigated through its inhibition or overexpression (miRNA inhibitors and miRNA mimics). Automated western blot was used to identify the function of exosomal microRNA and the roles of TGFß1/smads pathway in odontogenic differentiation of DPSCs. A luciferase reporter gene assay was used to verify the direct target gene of exosomal miR-27a-5p. RESULTS: Endocytosis of OD-Exo triggered odontogenic differentiation of DPSCs by upregulating DSP, DMP-1, ALP, and RUNX2 proteins. MicroRNA sequencing showed that 28 microRNAs significantly changed in OD-Exo, of which 7 increased and 21 decreased. Pathway analysis showed genes targeted by differentially expressed microRNAs were involved in multiple signal transductions, including TGFß pathway. 16 genes targeted by 15 differentially expressed microRNAs were involved in TGFß signaling. Consistently, automated western blot found that OD-Exo activated TGFß1 pathway by upregulating TGFß1, TGFR1, p-Smad2/3, and Smad4 in DPSCs. Accordingly, once the TGFß1 signaling pathway was inhibited by SB525334, protein levels of p-Smad2/3, DSP, and DMP-1 were significantly decreased in DPSCs treated with OD-Exo. MiR-27a-5p was expressed 11 times higher in OD-Exo, while miR-27a-5p promoted odontogenic differentiation of DPSCs and significantly upregulated TGFß1, TGFR1, p-Smad2/3, and Smad4 by downregulating the inhibitory molecule LTBP1. CONCLUSIONS: The microRNA expression profiles of exosomes derived from DPSCs were identified. OD-Exo isolated under odontogenic conditions were better inducers of DPSC differentiation. Exosomal microRNAs promoted odontogenic differentiation via TGFß1/smads signaling pathway by downregulating LTBP1.

17.
Cancer Manag Res ; 11: 4797-4808, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213901

RESUMO

Purpose: The present study investigates the effect of DCZ0814 in multiple myeloma (MM) cells, and determines the molecular mechanism of its antitumor activity against MM. Methods: The effects of DCZ0814 were evaluated in vitro using human MM cell lines (ARP1 and OCI-MY5) and in vivo in a murine xenograft MM model. Cell viability was measured with the CCK-8 assay and mitochondrial membrane potential (MMP) was assessed with the JC-1 dye. Apoptosis and cell cycle distribution were examined by flow cytometry. Inhibition of mTORC1 and mTORC2 was assessed by western blot analysis, and the synergistic effect of DCZ0814 and known MM drugs was assessed by calculating the combination index value, using the CalcuSyn software. Results: DCZ0814 effectively inhibited proliferation in MM cells, an effect that was associated with the induction of apoptosis, G0/G1 cell cycle arrest, MMP reduction and reactive oxygen species (ROS) generation. Meanwhile, DCZ0814 repressed the mTOR signaling via dual mTORC1/C2 inhibition and overcame the protective effect of the bone marrow (BM) microenvironment in myeloma cells. In addition, co-treatment with DCZ0814 and other anti-MM agents induced synergistic effects. Finally, the efficacy of the DCZ0814 treatment was confirmed in an MM xenograft mouse model. Conclusion: DCZ0814 exhibits potent anti-MM activity and abrogates the activation of the mTOR/Akt signaling pathway mediated by the BM stroma-derived cytokines. Our results provide a theoretical basis for the development of novel therapeutic strategies in MM using DCZ0814 as a natural product combination compound.

18.
J Gastroenterol Hepatol ; 34(10): 1676-1684, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31146297

RESUMO

BACKGROUND AND AIM: Reported incidence and prevalence rates of autoimmune hepatitis (AIH) have been sparse and heterogeneous. The aim of this meta-analysis was to estimate the worldwide incidence and prevalence rates of AIH and reveal population difference. METHODS: Published articles on the epidemiology of AIH in PubMed, Embase, and Cochrane Library were systematically searched from inception to April 28, 2019. Two investigators independently reviewed these literatures and evaluated their quality. A random-effects model was used to pool the overall incidence and prevalence rates. The impact of population difference, gender, age, study period, study quality, diagnostic criteria, and study design was further analyzed with subgroup analysis and meta-regression. RESULTS: A total of 22 studies were included in the meta-analysis. The pooled worldwide annual incidence and prevalence of AIH were 1.37 (95% confidence interval [CI]: 0.95-1.80) and 17.44 (95% CI: 12.01-22.87) per 100 000 persons, respectively. Subgroup analysis showed that the pooled annual incidence for Asian, European, and American population was 1.31 (95% CI: 0.42-2.20), 1.37 (95% CI: 1.10-1.64), and 1.00 (95% CI: 0.44-1.56) per 100 000 persons, respectively; the pooled prevalence for Asian, European, and American population was 12.99 (95% CI: 2.05-23.92), 19.44 (95% CI: 15.63-23.24), and 22.80 (95% CI: -13.48 to 59.07) per 100 000 persons, respectively. In addition, higher incidence and prevalence rates were observed in women than men, and a higher prevalence rate was observed in elderly than young people. CONCLUSIONS: Autoimmune hepatitis is a rare disease, with a similar incidence worldwide and a higher prevalence in European and American than in Asian population.

20.
Infect Drug Resist ; 12: 745-757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015765

RESUMO

Background: De novo combination of lamivudine (Lam) and adefovir (Adv) was not rarely used in clinical practice. However, head-to-head comparisons of entecavir (Etv) monotherapy with this combination in hepatitis B virus (HBV)-related compensated cirrhosis patients are unavailable. This study aimed to compare the efficacy and safety of Etv monotherapy with combination therapy in patients with HBV-related compensated liver cirrhosis. Methods: Treatment-naïve patients with HBV-related compensated liver cirrhosis were recruited to receive either Etv monotherapy or a de novo combination of Lam and Adv. Data were collected at baseline and every 6 months thereafter. Results: A total of 578 patients (485 in Etv group, 93 in combination group) were included. Baseline characteristics were comparable between the two groups. At the end of 1, 2, and 3 years, HBV DNA was undetectable in 82.7%, 96.2%, and 94.3% of patients in the Etv group and 88.9%, 81.7%, and 84.6% in the combination group, respectively (all P>0.05). The cumulative virological breakthrough rate at 1, 2, and 3 years was 2.7%, 6.7%, and 9.8% in the Etv group and 2.9%, 13.3%, and 32.2% in the combination group, respectively (P=0.003). After propensity-score adjustment for age, sex, and baseline HBeAg, ALT, and total bilirubin, virological breakthrough was higher in the de novo combination of Lam and Adv (HR 2.83, 95% CI 1.37-5.86; P<0.01). The cumulative rate of liver-related events, including decompensation and hepatocellular carcinoma, at 1, 2, and 3 years was 2.9%, 4.2%, and 6.1% in the Etv group and 2.2%, 2.2%, and 6.7% in combination group, respectively (P=0.83). Biochemical response and serological response were similar between the groups. Conclusion: Etv treatment had less virological breakthrough and potentially higher HBV-DNA suppression than de novo combination of Lam and Adv during 3 years in treatment-naïve HBV-related compensated liver cirrhosis.

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