RESUMO
Alzheimer's disease (AD) is a progressive neurological disorder featuring abnormal protein aggregation in the brain, including the pathological hallmarks of amyloid plaques and hyperphosphorylated tau. Despite extensive research efforts, understanding the molecular intricacies driving AD development remains a formidable challenge. This study focuses on identifying key protein conformational changes associated with the progression of AD. To achieve this, we employed quantitative cross-linking mass spectrometry (XL-MS) to elucidate conformational changes in the protein networks in cerebrospinal fluid (CSF). By using isotopically labeled cross-linkers BS3d0 and BS3d4, we reveal a dynamic shift in protein interaction networks during AD progression. Our comprehensive analysis highlights distinct alterations in protein-protein interactions within mild cognitive impairment (MCI) states. This study accentuates the potential of cross-linked peptides as indicators of AD-related conformational changes, including previously unreported site-specific binding between α-1-antitrypsin (A1AT) and complement component 3 (CO3). Furthermore, this work enables detailed structural characterization of apolipoprotein E (ApoE) and reveals modifications within its helical domains, suggesting their involvement in MCI pathogenesis. The quantitative approach provides insights into site-specific interactions and changes in the abundance of cross-linked peptides, offering an improved understanding of the intricate protein-protein interactions underlying AD progression. These findings lay a foundation for the development of potential diagnostic or therapeutic strategies aimed at mitigating the negative impact of AD.
Assuntos
Doença de Alzheimer , Apolipoproteínas E , Espectrometria de Massas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico , Humanos , Apolipoproteínas E/química , Apolipoproteínas E/metabolismo , Reagentes de Ligações Cruzadas/química , Conformação Proteica , alfa 1-Antitripsina/química , alfa 1-Antitripsina/metabolismo , Disfunção Cognitiva/metabolismoRESUMO
Histone citrullination is an essential epigenetic post-translational modification (PTM) that affects many important physiological and pathological processes, but effective tools to study histone citrullination are greatly limited due to several challenges, including the small mass shift caused by this PTM and its low abundance in biological systems. Although previous studies have reported frequent occurrences of histone citrullination, these methods failed to provide a high-throughput and site-specific strategy to detect histone citrullination. Recently, we developed a biotin thiol tag that enabled precise identification of protein citrullination coupled with mass spectrometry. However, very few histone citrullination sites were identified, likely due to the highly basic nature of these proteins. In this study, we develop a novel method utilizing limited digestion and biotin derivative tag enrichment to facilitate direct in vivo identification of citrullination sites on histones. We achieve improved coverage of histone identification via partial enzymatic digestion and lysine block by dimethylation. With biotin tag-assisted chemical derivatization and enrichment, we also achieve precise annotation of histone citrullination sites with high confidence. We further compare different fragmentation methods and find that the electron-transfer-dissociation-based approach enables the most in-depth analysis and characterization. In total, we unambiguously identify 18 unique citrullination sites on histones in human astrocytoma U87 cells, including 15 citrullinated sites being detected for the first time. Some of these citrullination sites are observed to exhibit noticeable alterations in response to DNA damage, which demonstrates the superiority of our strategy in understanding the roles of histone citrullination in critical biological processes.
Assuntos
Biotina , Histonas , Humanos , Histonas/metabolismo , Biotina/metabolismo , Citrulinação , Processamento de Proteína Pós-Traducional , Espectrometria de Massas , DigestãoRESUMO
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a serious threat to human health all over the world. The development of effective vaccines has been focusing on the spike (S) glycoprotein, which mediates viral invasion to human cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. In this work, we perform analytical characterization of N- and O-linked glycosylation of the SARS-CoV-2 S glycoprotein. We explore the novel use of dual-functionalized titanium (IV)-immobilized metal affinity chromatography (Ti-IMAC) material for simultaneous enrichment and separation of neutral and sialyl glycopeptides of a recombinant SARS-CoV-2 S glycoprotein from HEK293 cells. This strategy helps eliminate signal suppression from neutral glycopeptides for the detection of sialyl glycopeptides and improves the glycoform coverage of the S protein. We profiled 19 of its 22 potential N-glycosylated sites with 398 unique glycoforms using the dual-functional Ti-IMAC approach, which exhibited improvement of coverage by 1.6-fold compared to the conventional hydrophilic interaction chromatography (HILIC) glycopeptide enrichment method. We also identified O-linked glycosylation site that was not found using the conventional HILIC approach. In addition, we reported on the identification of mannose-6-phosphate (M6P) glycosylation, which substantially expands the current knowledge of the spike protein's glycosylation landscape and enables future investigation into the influence of M6P glycosylation of the spike protein on its cell entry.
Assuntos
Glicopeptídeos/isolamento & purificação , Ácido N-Acetilneuramínico/química , SARS-CoV-2/química , Glicoproteína da Espícula de Coronavírus/química , Sequência de Aminoácidos , Cromatografia Líquida/métodos , Glicopeptídeos/química , Células HEK293 , Humanos , Manosefosfatos/química , Eletricidade Estática , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignancy in liver. Transarterial chemoembolization (TACE) is recommended as an effective treatment in advanced HCC patients. Recent studies showed iodine-125 seed (a low-energy radionuclide) can provide long-term local control and increase survival for HCC patients. The aim of the study was to evaluate the outcome of TACE plus iodine-125 seed in comparison with TACE alone for HCC. METHODS: A comprehensive search of studies among PubMed, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews was conducted with published date from the earliest to January 10th, 2018. No language restrictions were applied, while only prospective randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) were eligible for a full-text review. The primary outcome was overall survival (OS), response rate (the rate of partial atrophy or complete clearance of the tumor lesion) and adverse events (AEs). The odds ratios (ORs) were combined using either fixed-effects model or random-effects model. All statistical analyses were performed using the Stata 12.0 software. RESULTS: 9 studies were included, involving 894 patients. Among them, 473 patients received combined therapy of TACE plus iodine-125 implantation, compared with 421 patients with TACE alone. Patients receiving combined therapy of TACE plus iodine-125 showed significantly improvement in 1-year OS (OR = 4.47, 95% confidence intervals (CI): 2.97-6.73; P < 0.001), 2-year OS (OR = 4.72, 95% CI: 2.63-8.47; P < 0.001). No significant publication bias was observed in any of the measured outcomes. CONCLUSIONS: Based on these findings, TACE plus iodine-125 implantation achieves better clinical efficacy compared with TACE alone in the treatment of HCC.
Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Quimiorradioterapia/métodos , Radioisótopos do Iodo/administração & dosagem , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Humanos , Radioisótopos do Iodo/efeitos adversos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Compostos Radiofarmacêuticos/efeitos adversos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: To compare 3-year clinical outcomes of radiofrequency ablation (RFA) targeting 5- or 10-mm margins for small hepatocellular carcinomas (HCCs) in cirrhotic patients. METHODS: In total, 96 cirrhotic patients with a small solitary HCC (diameter ≤3 cm) were included in this prospective trial (ChiCTRTRC-10000954). Patients were stratified by Child-Pugh class and randomly allocated into groups targeting either wide margins (≥10 mm, WM) or narrow margins (≥5 mm but <10 mm, NM). RFA was performed under real-time monitoring, and ablative margins were evaluated by pre- and post-operative three-dimensional registration on CT. RESULTS: The mean follow-up time was 38.3 ± 4.8 months, 83.3% (40/48) of patients succeeded in obtaining a 10-mm margin in WM group. Based on intention-to-treat analysis, the 3-year incidences of local tumor progression (LTP) (14.9% vs 30.2%), intrahepatic recurrence (IHR) (15.0% vs 32.7%), and recurrence-free survival (RFS) (31.7 ± 12.1 vs 24.0 ± 11.7 months) for WM group were significantly improved compared to NM group. Several prognostic factors were identified from univariate and multivariate analyses. Additionally, cirrhosis-stratified subgroup analyses demonstrated significant survival benefits of WM in patients with Child-Pugh class B cirrhosis. CONCLUSIONS: RFA treatment targeting 10-mm margin may reduce the risk of tumor recurrence in cirrhotic patients with a single small HCC.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter/métodos , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of adjuvant transarterial chemoembolization (TACE) after curative hepatectomy in improving the survival of patients with primary hepatocellular carcinoma (HCC). METHODS: MEDLINE, Embase and the Cochrane Library were searched for randomized or nonrandomized studies comparing postoperative adjuvant TACE with curative resection alone. Meta-analysis was performed after converting time-event data into a hazard ratio (HR), using an inverse diversity model. RESULTS: Eight randomized controlled trials (RCTs) and 12 retrospective studies matched the selection criteria, thereby including 3191 patients (779 in RCT, 2412 in observational studies) for the meta-analysis. The meta-analysis showed that receiving adjuvant TACE was associated with improved overall survival (OS, ln[HR] = 0.70, 95%CI: 0.63-0.78, p < .001) and recurrence-free survival (RFS, ln[HR] = 0.69, 95%CI: 0.63-0.76, p < .001) after curative hepatectomies. The results of observational studies were consistent with those of RCTs. Furthermore, meta-regression was utilized to detect study-level factors associated with treatment outcome. It revealed that overall survival was similar among patients treated with various combinations of chemotherapeutic drugs. Subgroup analyses demonstrated that repeated TACE interventions do not provide a higher survival benefit compared with a single course, and patients with a single tumor or tumor size ≥5cm might stand to benefit the most from adjuvant TACE therapy. CONCLUSIONS: This meta-analysis demonstrated that postoperative adjuvant TACE could achieve higher OS and RFS than surgical resection alone. However, these results need to be validated through further high-quality clinical studies.
Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica , Quimioterapia Adjuvante , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Terapia Combinada , Hepatectomia/métodos , Humanos , Período Pós-Operatório , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
Hepatocellular carcinoma is the most common malignancy in liver, is also a global problem and is the fourth most commonly diagnosed cancers among men and the fourth leading causes of cancer death among both men and women in China. Liver resection or hepatic resection and radiofrequency ablation is widely accepted as a first-line surgical approach for hepatocellular carcinoma in China. However, the indications of radiofrequency ablation or hepatic resection are different and not unified in China. In this article, we review the current status of hepatic resection and radiofrequency ablation therapies in hepatocellular carcinoma management in China.
Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , China , Hepatectomia , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Several studies have been performed to investigate the relationship between psoriasis and epicardial fat tissue (EFT). However, the number of patients of every single study is relatively small. OBJECTIVES: We carried out a meta-analysis to evaluate whether EFT is associated with psoriasis. METHODS: A search of PubMed, Ovid Embase, Ovid Medline, the Cochrane Library and Chinese BioMedical Literature Database (CBM) for controlled trials was done from inception to January 20th, 2016. Published trials that included a psoriasis group and a control group without psoriasis with data for at least epicardial fat tissue (EFT) were included. All statistical analyses were conducted using the Stata 12.0 (Stata Corporation, College Station, TX, USA). RESULTS: There were 5 trials involving 731 patients. Patients with psoriasis showed significantly higher EFT than control group (SMD: 0.86, 95 % CI: 0.27-1.46, P = 0.004). CONCLUSIONS: Patients with psoriasis have higher EFT compared to control subjects without psoriasis.
Assuntos
Tecido Adiposo/patologia , Doenças Cardiovasculares/patologia , Pericárdio/patologia , Psoríase/patologia , Tecido Adiposo/diagnóstico por imagem , Adulto , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/etiologia , Ensaios Clínicos como Assunto , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pericárdio/diagnóstico por imagem , Psoríase/complicações , Psoríase/diagnóstico por imagem , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Background: Hepatocellular carcinoma (HCC, or hepatic cancer, HC) and cholangiocarcinoma (CCA, or hepatic bile duct cancer, HBDC) are two major types of primary liver cancer (PLC). Previous studies have suggested that microbiota can either act as risk factors or preventive factors in PLC. However, no study has reported the relationship between skin microbiota and PLC. Therefore, we conducted a two-sample Mendelian randomization (MR) study to assess the causality between skin microbiota and PLC. Methods: Data from the genome-wide association study (GWAS) on skin microbiota were collected. The GWAS summary data of GCST90018803 (HBDC) and GCST90018858 (HC) were utilized in the discovery and verification phases, respectively. The inverse variance weighted (IVW) method was utilized as the principal method in our MR study. The MR-Egger intercept test, Cochran's Q-test, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis were conducted to identify the heterogeneity and pleiotropy. Results: The results showed that Veillonella (unc.) plays a protective role in HBDC, while the family Neisseriaceae has a positive association with HBDC risk. The class Betaproteobacteria, Veillonella (unc.), and the phylum Bacillota (Firmicutes) play a protective role in HC. Staphylococcus epidermidis, Corynebacterium (unc.), the family Neisseriaceae, and Pasteurellaceae sp. were associated with an increased risk of HC. Conclusion: This study provided new evidence regarding the association between skin microbiota and PLC, suggesting that skin microbiota plays a role in PLC progression. Skin microbiota could be a novel and effective way for PLC diagnosis and treatment.
RESUMO
Psoriasis vulgaris (PV) and Atopic dermatitis (AD) are the two major types of immune-mediated inflammatory skin disease (IMISD). Limited studies reported the association between Ubiquitin-conjugating enzyme E2 (UBE2) and IMISD. We employed a two-sample Mendelian randomization (MR) study to assess the causality between UBE2 and PV & AD. UBE2 association genome-wide association study (GWAS) data were collected. The inverse variance weighted (IVW) method was utilized as the principal method in our Mendelian randomization (MR) study, with additional using the MR-Egger, weighted median, simple mode, and weighted mode methods. The MR-Egger intercept test, Cochran's Q test, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy, colocalization analysis was also performed. The results showed that Ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) was causally associated with PV (OR = 0.909, 95% CI: 0.830-0.996, P = 0.040), Ubiquitin-conjugating enzyme E2 L3 (UBE2L3) was causally associated with AD (OR = 0.799, 95% CI: 0.709-0.990, P < 0.001). Both UBE2V1 and UBE2L3 may play protective roles in patients with PV or AD, respectively. No other significant result has been investigated. No heterogeneity or pleiotropy was observed. This study provided new evidence of the relationship between UBE2V1 and PV, UBE2L3 and AD. Our MR suggested that UBE2V1 plays an inhibitory role in PV progression, UBE2L3 plays an inhibitory role in AD. These could be novel and effective ways to treat PV and AD.
Assuntos
Dermatite Atópica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Psoríase , Enzimas de Conjugação de Ubiquitina , Humanos , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Psoríase/genética , Psoríase/imunologia , Enzimas de Conjugação de Ubiquitina/genéticaRESUMO
Alzheimer's disease (AD) is the most common representation of dementia, with brain pathological hallmarks of protein abnormal aggregation, such as with amyloid beta and tau protein. It is well established that posttranslational modifications on tau protein, particularly phosphorylation, increase the likelihood of its aggregation and subsequent formation of neurofibrillary tangles, another hallmark of AD. As additional misfolded proteins presumably exist distinctly in AD disease states, which would serve as potential source of AD biomarkers, we used limited proteolysis-coupled with mass spectrometry (LiP-MS) to probe protein structural changes. After optimizing the LiP-MS conditions, we further applied this method to human cerebrospinal fluid specimens collected from healthy control, mild cognitive impairment (MCI), and AD subject groups to characterize proteome-wide misfolding tendencies as a result of disease progression. The fully tryptic peptides embedding LiP sites were compared with the half-tryptic peptides generated from internal cleavage of the same region to determine any structural unfolding or misfolding. We discovered hundreds of significantly up- and down-regulated peptides associated with MCI and AD indicating their potential structural changes in AD progression. Moreover, we detected 53 structurally changed regions in 12 proteins with high confidence between the healthy control and disease groups, illustrating the functional relevance of these proteins with AD progression. These newly discovered conformational biomarker candidates establish valuable future directions for exploring the molecular mechanism of designing therapeutic targets for AD.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteômica , Biomarcadores , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
Rho guanine nucleotide exchange factor 11 (ARHGEF11) has been proved to promote tumor metastasis in glioblastoma and ovarian carcinoma. However, the role of ARHGEF11 in hepatocellular carcinoma (HCC) progression is largely unknown. Here, we found that ARHGEF11 was upregulated in HCC samples and highly metastatic hepatoma cell lines. Knockdown of ARHGEFF11 inhibited the cell proliferation and invasion in both HCCLM3 and SKHEP1 cell lines. Subsequent mechanistic investigation showed that downregulation of ARHGEF11 significantly attenuated ß-catenin nuclear translocation, thereafter repressed the expression of ZEB1 and cyclinD1, finally contributing to inhibition of epithelial-mesenchymal transition (EMT) and cell cycle arrest. Moreover, high levels of ARHGEF11 were found to be associated with shorter disease free and overall survival. A prognostic nomogram model that integrated ARHGEF11, tumor size and BCLC classification showed good performance in predicting clinical outcomes of HCC patients. Overall, this study demonstrated that ARHGEF11 could promote proliferation and metastasis of HCC via activating ß-catenin pathway, suggesting that ARHGEF11 might serve as a potential prognostic biomarker for HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Técnicas de Apoio para a Decisão , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo , Adolescente , Adulto , Idoso , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Movimento Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Nomogramas , Valor Preditivo dos Testes , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Carga Tumoral , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/genéticaRESUMO
BACKGROUND: Drosophila prune protein (h-prune) has been proved to play an essential role in regulating tumor metastasis. However, the clinical relevance of h-prune and its potential mechanism in regulating hepatocellular carcinoma (HCC) are still poorly understood. METHODS: In this study, we used tissue microarrays (TMA) containing 304 HCC tumor samples to evaluate the expression of h-prune and its correlation with prognosis. Data of RNAseq, mutation profiles, copy number variation (CNV), miRNAseq and methylation array from The Cancer Genome Atlas (TCGA) dataset were adopted to analyze the distinctive genomic patterns associated with h-prune expression. RESULTS: By using TMA, we found increased expression of h-prune in HCC tumor cells compared with adjacent normal tissues. Higher expression of h-prune was correlated with poorer OS and DFS outcomes. In addition, multivariate analysis showed that h-prune expression was an independent risk factor for both OS and DFS. Gene enrichment analysis showed that the gene signatures of cell proliferation, DNA methylation and canonical Wnt signaling pathway were enriched in h-prune-high patients. Notably, somatic mutation analysis demonstrated that higher mutation burden of RB1 and RPS6KA3 could be observed in h-prune-high patients. Moreover, integrative analysis revealed a strong correlation between h-prune expression and epigenetic changes. INTERPRETATION: This study has highlighted the clinical value of h-prune in predicting the prognosis of HCC patients and its essential role in promoting tumorigenesis of HCC.
Assuntos
Carcinoma Hepatocelular/patologia , Proteínas de Transporte/metabolismo , Neoplasias Hepáticas/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Proteínas de Transporte/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Intervalo Livre de Doença , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Monoéster Fosfórico Hidrolases , Prognóstico , Modelos de Riscos Proporcionais , Via de Sinalização WntRESUMO
BACKGROUND: MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration. METHODS: The Sprague-Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA. RESULTS: Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle. CONCLUSION: Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4.
Assuntos
Exoma , Regeneração Hepática , MicroRNAs/fisiologia , Receptor EphA4/genética , Animais , Ciclo Celular , Proliferação de Células , Regulação para Baixo , Masculino , Ratos , Ratos Sprague-Dawley , Receptor EphA4/antagonistas & inibidoresRESUMO
BACKGROUND: Studies focusing on the efficacy of SOF+DCV regimen on liver transplantation recipients with HCV infection are still limited. In the current study, we aimed to perform a systematic review and meta-analysis to evaluate the efficacy and tolerability of SOF+DCV regimen, with or without ribavirin, on post-LT setting. METHODS: A systematic literature search of various databases as well as abstracts of major liver diseases conferences was performed. Studies with SVR data in HCV infected liver transplantation recipients treated with daclatasvir/sofosbuvir regimen were included. All statistical analyses were conducted by R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Seven studies with a total of 379 LT recipients were included in this study. Most of these LT recipients had genotype 1 HCV infection. The overall rate of SVR12 reached 93.3% (95% CI: 83.3% to 99.4%). After excluding the study of Fontana et al., the SVR12 reached 96.8% and heterogeneity was lowered down (P=0.17). In three studies, patients treated with SOF+DCV (n=146) had a higher SVR12 rate than that of patients treated with SOF+DCV+RBV (n=83) (OR 0.33, 95% CI: 0.12 to 0.87; P=0.02). There was no difference in SVR12 between patients infected with HCV genotype 1 and genotype 3 (P=0.57) and no difference was found in SVR12 rate between 12-week therapy and 24-week therapy (P=0.82). The most common adverse effects (AEs) were: anemia 32% (n=64/202), infections 26% (n=38/149), neutropenia 23% (n=35/149), thrombocytopenia 21% (n=32/149) and renal failure 8% (n=12/149). CONCLUSION: SOF+DCV±RBV regimen is of high efficacy and tolerability in LT recipients with HCV infection.
Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Transplante de Fígado , Sofosbuvir/uso terapêutico , Carbamatos , Quimioterapia Combinada , Genótipo , Humanos , Pirrolidinas , Ribavirina/uso terapêutico , Resultado do Tratamento , Valina/análogos & derivadosRESUMO
OBJECTIVE: To examine whether pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ) is the better reconstructive method to reduce postoperative complications, especially pancreatic fistula (PF), after pancreaticoduodenectomy (PD). BACKGROUND: PF is a severe complication after PD. The best reconstructive method to reduce occurrence of PF is controversial. We carried out this meta-analysis to compare PG with PJ. METHODS: A systematic review was conducted on PubMed, EMBASE, and Cochrane Library published up to October 2015 to identify studies comparing PG with PJ. Postoperative complications and mortality were evaluated. A meta-analysis was carried out by Review Manager 5.0. RESULTS: 10 RCTs representing 1629 patients (826 PG, 803 PJ) were included. There was a significant difference in favor of PG over PJ (OR 0.72, 95% CI 0.56-0.92, P = 0.009, I2 = 10%). No significant differences were found in biliary fistula (OR 0.58, 95% CI 0.31-1.06, P = 0.08, I2 = 38%), DGE (OR 1.08, 95% CI 0.68-1.70, P = 0.75, I2 = 53%), overall morbidity (OR 0.97, 95% CI 0.77-1.23, P = 0.82, I2 = 28%), and mortality (OR 0.98, 95% CI 0.60-1.61, P = 0.94, I2 = 0%). CONCLUSIONS: The meta-analysis showed a significant difference between PG and PJ on PF: PG was associated with significantly less PF when compared to PJ, indicating that PG is superior to PJ for reconstruction after PD.
Assuntos
Gastrostomia/efeitos adversos , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticojejunostomia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica/efeitos adversos , Feminino , Gastrostomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/cirurgia , Fístula Pancreática/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto JovemRESUMO
OBJECTIVE: The aim of the study was to compare transcatheter arterial chemoembolization (TACE) plus 131I-labelled metuximab with TACE alone for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A comprehensive search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Chinese BioMedical Literature Database with published date from the earliest to February 29th, 2016. No language restrictions were applied, but only prospective randomized controlled trials (RCTs) or non-RCTs were eligible for a full-text review. The primary outcome was the overall survival (OS) and effective rate (the rate of partial atrophy or complete clearance of the tumor lesion). The odds ratios (ORs) were combined using either the fixed-effects model or random-effects model. RESULTS: Eight trials (3 RCTs and 5 non-RCTs) were included, involving a total of 1121 patients. Patients receiving combined therapy of TACE plus 131I-labelled metuximab showed significant improvement in effective rate {OR = 4.00, (95% confidence interval [CI]: 2.40-6.66), p < 0.001}, 1-year OS (OR = 2.03 [95% CI: 1.55-2.67], p < 0.001) and 2-year OS (OR = 2.57 [95% CI: 1.41-4.66], p = 0.002]. CONCLUSION: TACE plus 131I-labelled metuximab is more beneficial for treating advanced HCCs than TACE alone in terms of tumor response and OS. Large, multi-center, and blinded randomized trials are required to confirm these findings.