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1.
Talanta ; 207: 120293, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594564

RESUMO

Droplet digital PCR (ddPCR) has attracted much attention in the detection of genetic signatures of cancer present at low levels in circulating tumor DNA (ctDNA) in blood. A growing number of laboratory-developed liquid biopsy tests based on such technology have become commercially available for clinical settings. To obtain consistent and comparable results, an international standard is necessary for validation of the analytical performance. In this study, a novel and SI-traceable "ctDNA" reference material (RM) carrying BRAF V600E was prepared by gravimetrically mixing a 152 bp PCR amplicon and sonicated wild-type genomic DNA. The ddPCR performance was evaluated by analyzing serial "ctDNA" dilutions using a competitive MGB assay. The mutant frequency concordance (k) between ddPCR and the gravimetrical value was 1.03 in the range from 53.9% to 0.1%. The limit of blank (LoB), detection (LoD) and quantification (LoQ) of ddPCR assay were determined to be 0.01%, 0.02% and 0.1%, respectively. Results from the interlaboratory study, using challenging low levels of BRAF V600E ctDNA RMs, demonstrated that the participating laboratories had the appropriate technical competency to perform accurate ddPCR-based low level of ratio measurements. However, a systematic error caused by uncorrected droplet volume in Naica Crystal ddPCR platform was found by using the ctDNA RM. Between-laboratory consistency in copy number measurement was greatly improved when a correct droplet volume was applied for the ddPCR measurement by using the ctDNA RM. This confirms that the "ctDNA" RM is fit for the validation of ddPCR systems for ctDNA quantification. This would also support translation of tests for circulating tumor DNA by ddPCR into routine use.

2.
Medicine (Baltimore) ; 98(39): e17187, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574825

RESUMO

BACKGROUND: Surgical resection is the recommended procedure for colorectal cancer (CRC), but majority of the patients were diagnosed with advanced or metastatic CRC. Currently, there were inconsistent results about the diagnostic value of magnetic resonance colonography (MRC) and computed tomography colonography (CTC) in early CRC diagnosis. Our study conducted this meta-analysis to investigate the diagnostic value of MRC and CTC for CRC surveillance. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and the Cochrane library to select relevant studies. The summary sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curves (AUC) were calculated to evaluate the diagnostic value of MRC and CTC, respectively. RESULT: Twenty-five studies including 2985 individuals were selected in the final analysis. Eight studies evaluated the diagnostic value of MRC, and 17 studies assessed CTC. The summary sensitivity, specificity, PLR, NLR, DOR, and AUC in MRC for early detection of CRC were 0.98 (95% confidence interval, CI: 0.80-1.00), 0.94 (95% CI: 0.85-0.97), 15.48 (95% CI: 6.30-38.04), 0.02 (95% CI: 0.00-0.25), 115.09 (95% CI: 15.37-862.01), and 0.98 (95% CI: 0.97-0.99), respectively. In addition, the sensitivity, specificity, PLR, NLR, DOR, and AUC of CTC for diagnosing CRC were 0.97 (95% CI: 0.88-0.99), 0.99 (95% CI: 0.99-1.00), 154.11 (95% CI: 67.81-350.22), 0.03 (95% CI: 0.01-0.13), 642.51 (95% CI: 145.05-2846.02), and 1.00 (95% CI: 0.99-1.00). No significant differences were found between MRC and CTC for DOR in all the subsets. CONCLUSION: The findings of meta-analysis indicated that MRC and CTC have higher diagnostic values for early CRC diagnosis. However, the DOR for diagnosing CRC between MRC and CTC showed no significance.

3.
Medicine (Baltimore) ; 98(39): e17286, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574847

RESUMO

BACKGROUND: This study aims to systematically investigate the impact of ultrasound angiography (UA) combined with fine needle aspiration (FNA) for the diagnosis of thyroid nodules (TNs). METHODS: The following electronic databases will be searched: MEDLINE, EMBASE, Cochrane Library, PsycINFO, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. We will search them from their inceptions to the present without language limitations. We will consider all case-controlled studies on investigating the impact of diagnosis UA combined FNA for TNs. We will apply Quality Assessment of Diagnostic Accuracy Studies tool to assess methodological quality for all eligible studies. RESULTS: In this study, outcomes consist of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio. All these outcomes will be analyzed to evaluate the diagnostic accuracy of UA combined with FNA for TNs. CONCLUSION: This study will provide evidence of the diagnostic accuracy of UA combined with FNA for TNs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019138884.

4.
PLoS One ; 14(10): e0222221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31584951

RESUMO

BACKGROUND: This study investigated the incidence and predictors of retreatment after discontinuation of either entecavir (ETV) or tenofovir disoproxil fumarate (TDF) treatment in Taiwan. METHODS: A total of 535 non-cirrhotic chronic hepatitis B (CHB) patients undergoing either ETV (n = 358) or TDF (n = 177) treatment were enrolled. Patients were followed for at least 12 months after stopping ETV or TDF treatment. Most patients (86.3%) fulfilled the retreatment criteria of Taiwan's National Health Plan. RESULTS: The 5-year cumulative rates of clinical relapse and retreatment were 52.1% and 47%, respectively, in 160 hepatitis B e antigen (HBeAg)-positive patients, and were 62% and 54.8%, respectively, in 375 HBeAg-negative patients. The median duration from the end of treatment until clinical relapse and retreatment was 40 and 57 weeks, respectively, for all patients. Multivariate Cox regression analysis revealed that discontinuing TDF treatment, old age, male gender, and higher baseline HBsAg levels were independent factors of retreatment in HBeAg-positive patients; old age, HBV genotype B, and higher baseline and end-of-treatment HBsAg levels were independent factors in HBeAg-negative patients. A total of 18.8% of retreated patients satisfied the retreatment criteria of hepatic decompensation according to Taiwan's National Health Plan. Of the 64 patients who had clinical relapse without retreatment, 17 achieved sustained virological remission and 26 did not experience clinical relapse until their last visit after clinical relapse. Four patients developed HBsAg loss. CONCLUSIONS: The 5-year retreatment rate was about 50% in HBeAg-positive and HBeAg-negative patients. Discontinuing TDF treatment was an independent factor of retreatment in HBeAg-positive patients.

5.
J Food Biochem ; : e13067, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599006

RESUMO

Nf-E2-related transcription factor 2 (Nrf2) helps cells fight oxidative stress events in vivo and in vitro by promoting the expression of antioxidants and detoxification enzymes. The necessary factors regulating Nrf2 activity and stability during analgesic nephropathy are not fully understood. Our results suggest that acetaminophen produces nephrotoxicity in HK-2 cells by inhibiting keap1 degradation. APAP subsided Nrf2 nuclear accumulation by inhibition of keap1 degradation, thereby reducing the binding of Nrf2 to ARE, leading to the loss of expression of antioxidant proteins such as HO-1, inducing a series of oxidative stress and apoptosis events. Therefore, Nrf2/keap1/HO-1 signal transduction pathway has a poor prognosis during analgesic nephrotoxicity. Sika deer antler protein (SDAPR) significantly prevented APAP-induced HK-2 cell damage by constitutively stabilized Nrf2 nuclear retention. Excess APAP leads to a decrease in Nrf2 nuclear translocation, leading to severe oxidative stress, increasing the levels of GSH and MDA in HK-2 cells, and reducing the enzyme activities of SOD and CAT in HK-2 cells. Increased biomarker levels of acute kidney injury (AKI) in HK-2 cells, including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and cystatin C, decrease the mitochondrial membrane potential in HK-2 cells, and cause mitochondrial dysfunction, it also reduced the ratio of mitochondria-associated apoptotic protein Bax/Bcl-2, leading to cell apoptosis. SDAPR dose dependently accorded protection against acetaminophen-induced nephrotoxicity, oxidative damage, and cell apoptosis by its molecular intervention with Nrf2/keap1/HO-1 pathway via keap1 degradation. PRACTICAL APPLICATIONS: In this paper, we investigated the protective effect of SDAPR on APAP-induced AKI in HK-2 cells, and briefly explained its possible mechanism of action, providing a basis for future clinical trials and the development of anti-APAP AKI drugs.

6.
Chembiochem ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31592561

RESUMO

High resolution melting has been improved and for the first time applied to quantitative analysis of enzymatic reactions. By using the relative ratio of peak intensities of substrates and products, the quantitativity of conventional HRM analysis has been improved to allow detailed kinetic analysis. As an example, the ligation of sticky ends by T4 DNA ligase was kinetically analyzed, and comprehensive data on substrate specificity and other properties were obtained. For the first time, the kinetic parameters (kobs and apparent Km) of sticky end ligation were obtained for both full match and mismatched sticky ends. The effect of ATP concentration on sticky end ligation was also investigated. The improved HRM method can be also applicable to versatile DNA-transforming enzymes, since the only requirement is that the products have Tm values different enough from the substrates.

7.
Microbiology ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31592759

RESUMO

Defining phenotypic and associated genotypic variation among Bdellovibrio may further our understanding of how this genus attacks and kills different Gram-negative bacteria. We isolated Bdellovibrio sp. NC01 from soil. Analysis of 16S rRNA gene sequences and average amino acid identity showed that NC01 belongs to a different species than the type species bacteriovorus. By clustering amino acid sequences from completely sequenced Bdellovibrio and comparing the resulting orthologue groups to a previously published analysis, we defined a 'core genome' of 778 protein-coding genes and identified four protein-coding genes that appeared to be missing only in NC01. To determine how horizontal gene transfer (HGT) may have impacted NC01 genome evolution, we performed genome-wide comparisons of Bdellovibrio nucleotide sequences, which indicated that eight NC01 genomic regions were likely acquired by HGT. To investigate how genome variation may impact predation, we compared protein-coding gene content between NC01 and the B. bacteriovorus type strain HD100, focusing on genes implicated as important in successful killing of prey. Of these, NC01 is missing ten genes that may play roles in lytic activity during predation. Compared to HD100, NC01 kills fewer tested prey strains and kills Escherichia coli ML35 less efficiently. NC01 causes a smaller log reduction in ML35, after which the prey population recovers and the NC01 population decreases. In addition, NC01 forms turbid plaques on lawns of E. coli ML35, in contrast to clear plaques formed by HD100. Linking phenotypic variation in interactions between Bdellovibrio and Gram-negative bacteria with underlying Bdellovibrio genome variation is valuable for understanding the ecological significance of predatory bacteria and evaluating their effectiveness in clinical applications.

8.
Oxid Med Cell Longev ; 2019: 9719618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565157

RESUMO

Eucommia ulmoides flavones (EUF) have been demonstrated to alleviate oxidative stress and intestinal damage in piglets, but their effect target is still poorly understood. NF-E2-related factor 2 (Nrf2) pathway plays a very important role in the defense mechanism. This study was designed to investigate the regulation of EUF on the Nrf2 pathway and inhibition of Nrf2 on oxidative stress in the intestine of piglets. An in vivo study was conducted in weaned piglets treated with basal diet, basal diet+diquat, and 100 mg/kg EUF diet+diquat for 14 d to determine Nrf2 and Keap1 protein expressions, as well as downstream antioxidant gene mRNA expression. An in vitro study was performed in a porcine jejunal epithelial cell line to investigate the effect of inhibiting Nrf2 on cell growth and intracellular oxidative stress parameters. The results showed that the supplementation of EUF decreased the oxidized glutathione (GSSG) concentration and the ratio of GSSG to glutathione (GSH) but increased the protein expressions of nuclear Nrf2 and Kelch-like ECH-associated protein 1 (Keap1) as well as mRNA expression of heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1), and glutamate cysteine ligase catalytic subunit (GCLC) in the small intestinal mucosa of diquat-challenged piglets. When Nrf2 was inhibited by using ML385, cell viability, cellular antioxidant activities, expressions of nuclear Nrf2 and Keap1 protein, and downstream antioxidant enzyme (HO-1, NQO-1, and GCLC) mRNA were decreased in paraquat-treated enterocytes. These results showed that the Nrf2 signaling pathway played an important role in EUF-regulating oxidative stress in the intestine of piglets.

9.
Pharmacology ; : 1-7, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31587003

RESUMO

INTRODUCTION: Cynaroside is a biological component isolated from Lonicera japonica Thunb, and it possesses numerous pharmacological activities. However, whether cynaroside affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. The purpose of this study was to investigate the effects of cynaroside on 8 major CYP isoforms in human liver microsomes (HLMs). METHODS: In this study, the inhibitory effects of cynaroside on the 8 human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using HLMs. RESULTS: The results showed that cynaroside inhibited the activity of CYP1A2, 3A4, and 2C9, with IC50 values of 21.74, 15.88, and 16.58 µmol/L, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that cynaroside was not only a noncompetitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.33, 11.60, and 8.09 µmol/L, respectively. In addition, cynaroside is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.049/11.62 µmol/L-1min-1. CONCLUSION: The in vitro studies of cynaroside with CYP isoforms indicate that cynaroside has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2, 3A4, and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.

10.
J Exp Bot ; 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587070

RESUMO

An increased concentration of cytosolic Ca2+ is an early response of plant cells to heat shock (HS). Arabidopsis thaliana cyclic nucleotide-gated ion channel 6 (CNGC6) mediates heat-induced Ca2+ influx and is activated by cyclic adenosine monophosphate. However, it remains unclear how Ca2+ conductivity of the CNGC6 is negatively regulated under the elevated concentration of cytosolic Ca2+. In this study, A. thaliana CaM1/4, CaM2/3/5, CaM6 and CaM7 isoforms were found to bind to CNGC6 in varying degrees, and this binding was dependent on the presence of Ca2+ and IQ6, an atypical isoleucine glutamine motif in CNGC6. Knockout of CaM2, CaM3, CaM5 and CaM7 genes led to a marked increase in plasma membrane (PM) inward Ca2+ current under HS conditions; however, knockout of CaM1, CaM4 and CaM6 genes had no significant effect on PM Ca2+ current. Moreover, the deletion of the IQ6 from CNGC6 led to a marked increase in PM Ca2+ current under HS conditions. Taken together, the data presented here suggest that the CNGC6-mediated Ca2+ influx is likely to be negatively regulated by CaM2/3/5 and CaM7 isoforms under HS conditions, and the IQ6 plays important roles in CaM binding and the feedback regulation of the channel.

11.
Cancer Cell ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31588020

RESUMO

We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.

12.
Biomater Sci ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588463

RESUMO

The development of gene therapy puts forward the requirements for efficient delivery of genetic information into diverse cells. However, in some cases of transfection, especially those for transfecting some primary cells and for delivering large size plasmid DNA (pDNA), the existing conventional transfection methods show poor efficiency. How to further improve transfection efficiency in these hard-to-achieve issues remains a crucial challenge. Here, we report a photothermal-assisted surface-mediated gene delivery based on a polydopamine-polyethylenimine (PDA-PEI) surface. The PDA-PEI surface was prepared through PEI-accelerated dopamine polymerization, which showed efficiency in the immobilization of PEI/pDNA polyplexes and remarkable photothermal properties. Upon IR irradiation, we observed improved transfection efficiencies of two important hard-to-achieve transfection issues, namely the transfection of primary endothelial cells, which are kinds of typical hard-to-transfect cells, and the transfection of cells with large-size pDNA. We demonstrate that the increases of transfection efficiency were due to the hyperthermia-induced pDNA release, the local cell membrane disturbance, and the polyplex internalization. This work highlights the importance of local immobilization and release of pDNA to gene deliveries, showing great potential applications in medical devices in the field of gene therapy.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31588724

RESUMO

Rational design and construction of theranostic nanomedicines based on clinical characteristics of cervical cancer is an important strategy to achieve precise cancer therapy. Herein, we fabricate a cervical cancer-targeting gold nanorod-mesoporous silica heterostructure for co-delivery of synergistic cisplatin and antiangiogenic drug Avastin (cisplatin-AuNRs@SiO2-Avastin@PEI/AE105) to achieve synergistic chemo-photothermal therapy. Based on database analysis and clinical samples staining, conjugation of AE105 targeting peptide obviously improves the intracellular uptake of the nanosystem, and enhances the cancer-killing ability and selectivity between cervical cancer and normal cells. It could also be used to specifically monitor urokinase plasminogen activator receptor (uPAR) expression level in clinical cervical specimens, which would be an early indicator of prognosis in cancer treatment. Under 808 nm laser irradiation, the nanosystem demonstrates smart NIR-light-triggered drug release and prominent photodynamic activity via induction of ROS overproduction-mediated cell apoptosis. The nanosystem also simultaneously suppresses HeLa tumor growth and angiogenesis in vivo, with no evident histological damage observed in the major organs. In short, this study not only provides a clinical data-based rational design strategy of smart nanomedicine for precise treatment and rapid clinical diagnosis of cervical cancer, but also contributes to the development of the clinical translation of nanomedicines.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31589021

RESUMO

In-situ growth of carbon nanostructures such as carbon nanotubes and graphene for micro-supercapacitors commonly involves a multi-step fabrication process in which good control of catalyst layers and/or substrates is needed. In addition, the contact area of the current collector with carbon nanostructures is relatively low, limiting electron transfer efficiency. In this work, the performance of a novel carbon-based planar micro-supercapacitor electrode structure is investigated. An in-situ template-free fabrication of Cu nanowire network structure acting as the current collector is first prepared through a chemical oxidation phase of sputtered Cu films, followed by a thermal reduction phase. Carbon is subsequently grown over the Cu nanostructure. In a 2-electrode electrochemical test, the patterned interdigitated carbon/Cu nanowire network device exhibits an excellent maximum areal and volumetric capacitance of 1.45 mF cm-2 and 7.43 mF cm-3, respectively, while retaining 94.2% of its capacitance after 10000 charge-discharge cycles. This relatively simple foundry-compatible fabrication process provides an excellent method in which planar micro-supercapacitors can be patterned and fabricated for energy storage solutions in microelectronics.

15.
Mol Cancer Ther ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575655

RESUMO

Fluorouracil (5-FU) remains a first-line chemotherapeutic agent for colorectal cancer (CRC). However, a subset of CRC patients who have defective mismatch repair (dMMR) pathway show resistance to 5-FU. Here, we demonstrate that the efficacy of 5-FU in dMMR CRC cells is largely dependent on the DNA base excision repair (BER) pathway. Downregulation of APE1, a key enzyme in BER pathway, decreases IC50 of 5-FU in dMMR CRC cells by 10-fold. Furthermore, we discover that Facilitates Chromatin Transcription (FACT) complex facilitates 5-FU repair in DNA via promoting the recruitment and acetylation of APE1 (AcAPE1) to damage sites in chromatin. Downregulation of FACT affects 5-FU damage repair in DNA and sensitizes dMMR CRC cells to 5-FU. Targeting FACT complex with curaxins, a class of small molecules, significantly improves 5-FU efficacy in dMMR CRC in vitro (~50-fold decrease in IC50) and in vivo xenograft models. We show that primary tumor tissues of CRC patients have higher FACT and AcAPE1 levels compared to adjacent non-tumor tissues. Additionally, there is a strong clinical correlation of FACT and AcAPE1 levels with CRC patients' response to chemotherapy. Together, our study demonstrates that targeting FACT with curaxins is a promising strategy to overcome 5-FU resistance in dMMR CRC patients.

16.
Eur J Clin Nutr ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575972

RESUMO

BACKGROUND/OBJECTIVES: To evaluate the role of the potential inflammatory effects of diet using the Energy adjusted Dietary Inflammatory Index (E-DII) for oral cancer. SUBJECTS/METHODS: A case-control study including 295 oral cancer cases and 425 controls from September 2010 to June 2018 was performed in Fujian Province, China. The E-DII was calculated based on the food frequency questionnaire (FFQ) and adjusted by total energy intake. The association between E-DII and the risk of oral cancer was estimated with unconditional logistic regression model. RESULTS: Compared with E-DII score in the lowest quartile, those with E-DII score in the fourth quartile were at the higher risk of oral cancer (OR = 2.57; 95% CI: 1.54, 4.29, Ptrend = 0.013). When analyses were carried out using E-DII as a continuous variable, one-unit increase in E-DII increased the odds of having oral cancer by 3% (95% CI: 1.00, 1.06). Moreover, there was a significant interaction between the E-DII and oral hygiene for oral cancer (Pinteraction < 0.001, in those without and with poor hygiene, the OR (95% CI) were 1.96 (0.96, 4.00) and 4.23 (1.83, 9.81), respectively). CONCLUSIONS: The present study suggests that the higher E-DII score, indicated a pro-inflammatory diet, may be a risk factor for oral cancer in southeast of China. More large samples and prospective studies need to validate our results and explore the prevention strategies of oral cancer via changing dietary habits.

17.
PLoS One ; 14(10): e0222605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581209

RESUMO

BACKGROUND & AIMS: Previous studies from western countries have reported that active hepatocellular carcinoma (HCC) was associated with direct-acting antiviral (DAA) treatment failure. We sought to examine this issue in an Asian cohort. METHODS: A retrospective cohort study was conducted on hepatitis C virus (HCV)-infected patients with advanced fibrosis who were treated with DAAs at our hospital between January 2017 and June 2018. RESULTS: We treated 1021 HCV-infected patients during this period. A total of 976 of those patients were enrolled in a per-protocol analysis, including 556 (57.2%) who had genotype 1b infections, and 314 (32.3%) who had genotype 2 infections. The mean age of all 976 patients was 65.5 years, and 44.5% were male. 781 of the patients had no HCC, 172 had inactive HCC, and 23 had active HCC. Non-sustained virologic response (SVR) was noted in 10 (1.3%) patients without HCC, 5 (2.9%) patients with inactive HCC, and 4 (13.0%) patients with active HCC. After adjustment for confounders, active HCC (versus inactive HCC and non-HCC) was associated with non-SVR (adjusted odds ratio [AOR] = 24.5 (95% confidence interval [CI] = 4.4-136.9), P<0.001). Next, we excluded the 23 patients with active HCC from the multivariate analysis. After adjustment for confounders, inactive HCC (versus non-HCC) was not associated with non-SVR (AOR = 3.1 (95% CI = 0.94-9.95), P = 0.06). CONCLUSION: Active HCC was associated with non-SVR, while inactive HCC was not. We thus suggest the deferral of DAA treatment until after the complete radiological response of HCCs to treatment.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31582208

RESUMO

Currently, 5-fluorouracil (5-FU) resistance became a major obstacle to its clinical use for patients with hepatocellular carcinoma (HCC). It's urgent to develop a novel strategy for enhancing the therapeutic efficacy of 5-FU. Herein, we found that H1 (a derivative of Tetrandrine) exerted a potent anti-MDR effect on growth of 5-FU resistant HCC cells (Bel7402/5FU). The resistant fold (RF) of 5-FU is over 160-fold, while the RF of H1 is only 4.8-fold in Bel7402/5-FU cells. Further studies demonstrated that blockage of STAT3/MCL-1 signaling and induction of PUMA is responsible to anti-MDR activity of H1. Moreover, combination of H1 and 5-FU (Ratio = 1:2) could synergistically induce apoptosis of Bel7402/5-FU cells. Co-treatment of H1 enhances the suppression of p-STAT3 and MCL-1, and significantly increases PUMA expression. Finally, the combination of H1 and 5-FU results in an increase of cleaved PARP. Taken together, H1 effectively improve the cytotoxic effect of 5-FU against Bel7402/5-FU cells via blocking STAT3/MCL-1 pathway and inducing PUMA. Our findings suggested that combination 5-FU with anti-MDR agents might present a novel strategy to enhance the therapeutic efficacy of 5-FU in resistant HCC.

19.
J Nutr ; 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31586202

RESUMO

BACKGROUND: A Western-type diet (WD), rich in fat and cholesterol but deficient in fiber, induces development of diabetes and atherosclerosis. Colonic bacteria use the gut's mucous lining as an alternate energy source during periods of fiber deficiency, resulting in intestinal barrier erosion. OBJECTIVE: We hypothesized that supplementing a WD with galactooligosaccharide (GOS) fiber would attenuate WD-induced mucin layer disruption and attenuate development of metabolic diseases. METHODS: C57BL/6 mice (both sexes, 8-10 wk of age) were fed a standard rodent diet (TD7012, reference) or a high-fat, high-cholesterol-containing WD (TD88137, 21% fat, 0.15% cholesterol, 19.5% caesin) or a WD supplemented with 5% GOS fiber (TD170432, WD + GOS) for 16 wk. WD-fed mice that were gavaged daily with curcumin (100 mg/kg) served as positive controls. Glucose tolerance, colonic mucin layer, gene expression, and circulating macrophage/neutrophil levels were determined. Hyperlipidemic Ldlr-/- mice (both sexes, 8-10 wk of age) fed a WD with or without GOS supplementation (for 16 wk) were used to assess plasma LPS and atherosclerosis. Effects of dietary supplementation on different parameters were compared for each genotype. RESULTS: Compared with a WD, glucose tolerance was significantly improved in male C57BL/6 mice fed a WD + GOS (mean ± SEM: AUC = 53.6 ± 43.9 compared with 45.4 ± 33.3 g ⋅ min/dL; P = 0.015). Continuity of colonic mucin layer (MUC-2 expression) was improved in mice receiving GOS supplementation, indicating improved intestinal barrier. GOS supplementation also reduced circulating macrophages (30% decrease) and neutrophils (60% decrease), suggesting diminished systemic inflammation. In Ldlr-/- mice, GOS supplementation significantly reduced plasma LPS concentrations (mean ± SEM: 0.81 ±  0.43 EU/mL compared with 0.32 ± 0.26 EU/mL, P   < 0.0001, in females and 0.56 ± 0.24 EU/mL compared with 0.34 ± 0.12 EU/mL, P = 0.036, in males), improved glucose tolerance in male mice, and attenuated atherosclerotic lesion area (mean ± SEM: 54.2% ± 6.19% compared with 43.0% ± 35.12%, P   = 0.0006, in females and 54.6% ± 3.99% compared with 43.1% ± 8.11%, P = 0.003, in males). CONCLUSIONS: GOS fiber supplementation improves intestinal barrier in C57BL/6 and Ldlr-/- mice and significantly attenuates WD-induced metabolic diseases and, therefore, may represent a novel strategy for management of these diseases.

20.
Clin Drug Investig ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586305

RESUMO

BACKGROUND AND OBJECTIVE: Because of the narrow therapeutic window and huge inter-individual variation, the individual precision on anticoagulant therapy of warfarin is challenging. In our study, we aimed to construct a Back Propagation Neural Network (BPNN) model to predict the individual warfarin maintenance dose among Chinese patients who have undergone heart valve replacement, and validate its prediction accuracy. METHODS: In this study, we analyzed 13,639 eligible patients extracted from the Chinese Low Intensity Anticoagulant Therapy after Heart Valve Replacement database, which collected data on patients using warfarin after heart valve replacement from 15 centers all over China. Ten percent of patients who were finally enrolled in the database were used as the external validation, while the remaining were randomly divided into the training and internal validation groups at a ratio of 3:1. Input variables were selected by univariate analysis of the general linear model; 2.0, the mean value of the international normalized ratio (INR) range 1.5-2.5, was used as the mandatory variable. The BPNN model and the multiple linear regression (MLR) model were constructed by the training group and validated through comparisons of the mean absolute error (MAE), mean squared error (MSE), root mean squared error (RMSE), and ideal predicted percentage. RESULTS: Finally, 10 input variables were selected and a three-layer BPNN model was constructed. In the BPNN model, the value of MAE (0.688 mg/day and 0.740 mg/day in internal and external validation, respectively), MSE (0.580 mg/day and 0.599 mg/day in internal and external validation, respectively), and RMSE (0.761 mg/day and 0.774 mg/day in internal and external validation, respectively) were achieved. Ideal predicted percentages were high in both internal (63.0%) and external validation (59.7%), respectively. Compared with the MLR model, the BPNN model showed a higher ideal prediction percentage in the external validation group (59.7% vs. 56.6%), and showed the best prediction accuracy in the intermediate-dose subgroup (internal validation group: 85.2%; external validation group: 84.7%) and a high predicted percentage in the high-dose subgroup (internal validation group: 36.2%; external validation group: 39.8%), but poor performance in the low-dose subgroup (internal validation group: 0%; external validation group: 0.3%). Meanwhile, the BPNN model showed better ideal prediction percentage in the high-dose group than the MLR model (internal validation: 36.2% vs. 31.6%; external validation: 42.8% vs. 37.8%). CONCLUSION: The BPNN model shows promise for predicting the warfarin maintenance dose after heart valve replacement.

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