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1.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911547

RESUMO

PURPOSE: This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. EXPERIMENTAL DESIGN: Periphery blood samples from 79 AML patients (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors. RESULTS: Immune defects in AML were reflected in T and NK cells whereas B cell function remained unaffected. Both CD8+ T and CD4+ T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly-activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8+ T cells was independently predictive of poor overall survival (OS) and event-free survival (EFS). CONCLUSIONS: T cell senescence and exhaustion, together with impaired NK and γδ T cell function, are dominant aspects involved in immune dysfunction in AML. Non-invasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse and unfavorable prognosis.

2.
Gigascience ; 9(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904811

RESUMO

BACKGROUND: The swimming crab, Portunus trituberculatus, is an important commercial species in China and is widely distributed in the coastal waters of Asia-Pacific countries. Despite increasing interest in swimming crab research, a high-quality chromosome-level genome is still lacking. FINDINGS: Here, we assembled the first chromosome-level reference genome of P. trituberculatus by combining the short reads, Nanopore long reads, and Hi-C data. The genome assembly size was 1.00 Gb with a contig N50 length of 4.12 Mb. In addition, BUSCO assessment indicated that 94.7% of core eukaryotic genes were present in the genome assembly. Approximately 54.52% of the genome was identified as repetitive sequences, with a total of 16,796 annotated protein-coding genes. In addition, we anchored contigs into chromosomes and identified 50 chromosomes with an N50 length of 21.80 Mb by Hi-C technology. CONCLUSIONS: We anticipate that this chromosome-level assembly of the P. trituberculatus genome will not only promote study of basic development and evolution but also provide important resources for swimming crab reproduction.

3.
Analyst ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909779

RESUMO

Compared with normal cells, cancer or tumor cells have a specific microenvironment and apparently possess a relatively large amount of ROS/RNS, and their overexpression is one of the important reasons for tumor development and deterioration. Therefore, monitoring the changes of intracellular ROS/RNS can improve the awareness of the clinical manifestations of the disease, which will be beneficial for the early diagnosis of cancer and improving treatment efficiency. Herein, in this study we have exploited and constructed a novel strategy based on the SiC@C nanowire electrode for intracellular electrochemical analysis to monitor ROS levels in cancer or tumor cells. Firstly, the SiC@C nanowire electrode was utilized to detect the intracellular ROS radical changes involved in the relevant biological processes of cancer cells where fluorescent zinc nanoclusters were biosynthesized in situ in target cancer cells by using the intracellular microenvironment and specificity of these cancer cells. By combining a confocal fluorescence microscopy study simultaneously, our observations illustrate that accompanied by the apparent change of the intracellular ROS, these in situ biosynthesized fluorescent nanoclusters gradually accumulate inside the cytosolic area with the increase of the reaction time. Moreover, it is evident that the size of the SiC@C nanoelectrodes can match the single cell dimensions, and its unique high spatial resolution provides the possibility of relevant intracellular molecular detection. These nanoelectrochemical biosensors can be adopted to quantitatively determine the change of the ROS content in target single cells in the relevant biological microenvironment or during the in situ biosynthesis process, and are also beneficial for understanding the related mechanism of some specific biological processes including the in situ synthesis at the single cell level.

4.
Anal Chem ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31948230

RESUMO

RNA modification, such as N1-methyladenosine (m1A), affect the secondary structure of RNA and its ability to recognize specific reader proteins. Methods for detecting site-specific m1A are in demand. We report here a ligation-assisted differentiation approach for quantitative detection of m1A in mRNA with single-base resolution. The methyl group in m1A disrupts the Watson-Crick base pairing with uridine, resulting in lower ligation efficiency of certain ligases and lower amounts of ligation products. Detection of the ligation products using quantitative real-time PCR provided site-specific evaluation of m1A. We first screened appropriate ligase and found that T3 DNA ligase offered the best discrimination between m1A and adenosine. We successfully detected and quantified m1A at position 1674 of bromodomain containing 2 (BRD2) mRNA from HEK293T cells. In lung carcinoma tissues, the level of m1A at position 1674 of BRD2 mRNA was significantly decreased compared to the tumor-adjacent normal tissues, suggesting that site-specific m1A may be involved in carcinogenesis.

5.
Anal Chim Acta ; 1098: 56-65, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31948587

RESUMO

RNA molecules carry diverse modifications that exert important influences in many cellular processes. In addition to the single modification occurring in either nucleobase or 2' hydroxyl of ribose in RNA, some dual modifications occur in both the nucleobase and 2' hydroxyl of ribose in RNA. 2'-O-methyl-5-methylcytidine (m5Cm), the dual modifications of cytidine, was first discovered from the tRNA of archaea. Recent studies identified that 2'-O-methyl-5-hydroxymethylcytidine (hm5Cm) and 2'-O-methyl-5-formylcytidine (f5Cm) were present in the anticodon of cytoplasmic tRNA of mammals. Similar to the series of single modification of cytidines of 5-methylcytosine (m5C), 5-hydroxymethylcytidine (hm5C), 5-formylcytidine (f5C), and 5-carboxylcytidine (ca5C) in nucleic acids, the dual modifications of m5Cm, hm5Cm, f5Cm and 2'-O-methyl-5-carboxylcytidine (ca5Cm) may also constitute the series of cytidine modifications in mammals. However, it is normally challenging to detect these modifications because of their low endogenous levels. Here, we established a method by chemical labeling-assisted liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS) analysis for the sensitive and simultaneous determination of all these four cytidine dual modifications, i.e., m5Cm, hm5Cm, f5Cm and ca5Cm. Three different labeling reagents (2-bromo-1-(3,4-dimeth oxyphenyl)-ethanone, BDMOPE; 2-bromo-1-(4-methoxyphenyl)-ethanone, BMOPE; 2-bromo-1-(4-diethylaminophenyl)-ethanone, BDEPE) were used for the chemical labeling. The results showed that the detection sensitivities of m5Cm, hm5Cm, f5Cm and ca5Cm increased up to 462 folds after chemical labeling. With the developed method, we achieved the simultaneous detection of m5Cm, hm5Cm and f5Cm in RNA of mammals. In addition, we found these cytidine dual modifications mainly exist in small RNA (<200 nt) and barely detected in other types of RNA. Moreover, we found that the levels of m5Cm in RNA of human lung carcinoma tissues significantly increased, while hm5Cm and f5Cm significantly decreased compared to tumor adjacent normal tissues. The significant changes of m5Cm, hm5Cm and f5Cm levels may serve as indicator for the detection and prognosis of lung cancer.

6.
JAMA Oncol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944221

RESUMO

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

7.
Abdom Radiol (NY) ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31932878

RESUMO

OBJECTIVES: To accurately identify the relationship between a portal radiomics score (rad-score) and pathologic superior mesenteric vein (SMV) resection margin and to evaluate the diagnostic performance in patients with pancreatic head cancer. MATERIALS AND METHODS: A total of 181 patients with postoperatively and pathologically confirmed pancreatic head cancer who underwent multislice computed tomography within one month of resection between January 2016 and December 2018 were retrospectively investigated. For each patient, 1029 radiomics features of the portal phase were extracted, which were reduced using the least absolute shrinkage and selection operator (LASSO) logistic regression algorithm. Multivariate logistic regression models were used to analyze the association between the portal rad-score and SMV resection margin. RESULTS: Patients with negative (R0) and positive (R1) margins accounted for 70.17% (127) and 29.83% (54) of the cohort, respectively. The rad-score was significantly associated with the SMV resection margin status (p < 0.05). Multivariate analyses confirmed a significant and independent association between the portal rad-score and SMV resection margin (OR 4.62; 95% CI 2.19-9.76; p < 0.0001). The portal rad-score had high accuracy (area under the curve = 0.750). The best cut point based on maximizing the sum of sensitivity and specificity was - 0.741 (sensitivity = 64.8%; specificity = 74.0%; accuracy = 71.3%). Decision curve analysis indicated the clinical usefulness of radiomics score. CONCLUSIONS: The portal rad-score is significantly associated with the pathologic SMV resection margin, and it can accurately and noninvasively predict the SMV resection margin in patients with pancreatic cancer.

8.
Ultrason Sonochem ; 63: 104957, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31945572

RESUMO

Impacts of localized enzymolysis and sonication on physical, techno-functional, and structure attributes of sunflower meal protein (SMP) and its hydrolysate (SMPH) were studied. SMP was subjected to enzymolysis (using alcalase) to prepare SMPH with various degrees of hydrolysis (6-24% DH). Enzymolysis decreased colour lightness, turbidity, and particle size of unsonicated and sonicated SMP, while it increased the absolute values of zeta potential (P < 0.05). Sonication improved oil absorption capacity and dispersibility over unsonicated samples. Contrarily, sonicated preparations showed a decrease in water holding capacity. Intrinsic fluorescence and FTIR spectral analyses suggested that SMPH had more movable/flexible secondary structures than SMP. Moreover, the changes in sulfhydryl clusters and disulfide linkages following sonication demonstrated limited unfolding of SMP and SMPH structure and decrease in intermolecular interactions. SDS-PAGE profile exhibited significant reduction in molecular weight (MW) of sonicated SMP, whereas did not display differences between unsonicated and sonicated SMPH. From further MW analysis, SMPH was categorized with high proportion of small-sized peptides ≤ 3 kDa fractions, which increased from 78.64 to 93.01% (control) and from 82.3 to 93.88% (sonication) with enzymolysis (6-24DH). Localized enzymolysis and sonication can be utilised to modify the physical and conformational attributes of SMP and SMPH, which could enhance their functionalities and broaden the utilisation area in food industry.

9.
J Infect ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31954742

RESUMO

OBJECTIVES: The long-term dynamics of antibody responses in patients with influenza A(H7N9) virus infection are not well understood. METHODS: We conducted a longitudinal serological follow-up study in patients who were hospitalized with A(H7N9) virus infection, during 2013-2018. A(H7N9) virus-specific antibody responses were assessed by hemagglutination inhibition (HAI) and neutralization (NT) assays. A random intercept model was used to fit a curve to HAI antibody responses over time. HAI antibody responses were compared by clinical severity. RESULTS: Of 67 patients with A(H7N9) virus infection, HAI antibody titers reached 40 on average 11 days after illness onset and peaked at a titer of 290 after three months, and average titers of ≥80 and ≥40 were present until 11 months and 22 months respectively. HAI antibody responses were significantly higher in patients who experienced severe disease, including respiratory failure and acute respiratory distress syndrome, compared with patients who experienced less severe illness. CONCLUSIONS: Patients with A(H7N9) virus infection who survived severe disease mounted higher antibody responses that persisted for longer periods compared with those that experienced moderate disease. Studies of convalescent plasma treatment for A(H7N9) patients should consider collection of donor plasma from survivors of severe disease between 1-11 months after illness onset.

10.
PLoS One ; 15(1): e0227455, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914155

RESUMO

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is considered incurable, with relapse occurring in almost all patients. There has been limited data reported on the lipid metabolism changes in plasma cells during MM progression. Here, we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient plasma cells, and report these data on a limited number of patient samples, demonstrating the feasibility of the method, and establishing hypotheses to be evaluated in the future. METHODS: Plasma cells were purified from fresh bone marrow aspirates using CD138 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted lipidomics were performed on 7 patient samples using liquid chromatography-mass spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public transcriptomic dataset from Multiple Myeloma Research Consortium reference collection (n = 222) at gene and pathways level. RESULTS: From one million purified plasma cells, we were able to extract material and complete untargeted (~6000 and ~3600 features in positive and negative mode respectively) and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (~4100 reviewed proteins). Comparative analyses revealed limited differences between high and low risk groups (according to the standard clinical criteria), hence we focused on drawing comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed MM. Although there was limited overlap of the differential proteins/transcripts, 76 significantly enriched pathways in relapsed MM were common between proteomics and transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol metabolism pathways to be exclusively correlated among relapsed but not in newly-diagnosed patients. CONCLUSIONS: This study establishes the feasibility and workflow to conduct integrated lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid metabolism changes associated with MM relapse warrant further investigation.

11.
J Synchrotron Radiat ; 27(Pt 1): 146-157, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31868747

RESUMO

The speckle-based X-ray imaging technique (SBT), which includes the three imaging modalities of absorption, phase contrast and dark field, is widely used in many fields. However, the influence of the grain size of the diffuser, the coherence of the X-ray source and the pixel size of the detector on the multi-mode imaging quality of SBT is still woefully unclear. In this paper, the whole SBT process is simulated and the influence of these three factors on image quality is discussed. Based on this discussion, the grain size of the diffuser for SBT applications should be limited by the pixel size of the detector and the coherence length of the X-ray source. According to analysis of the noise signal and correlation map, a suitable grain size is an indispensable condition for high-quality SBT images, because an excessively small or large grain size degrades the resolution of the imaging results and generates false signals. In addition, the power spectral density of the measured raw speckle patterns demonstrates that a smaller grain can better retain high-frequency information from an imaged sample. The simulated and experimental results verify these conclusions. The conclusions of this work will be helpful in designing suitable experimental setups for SBT applications and have the potential to promote the performance of SBT in other applications, such as X-ray optics metrology and coherence measurement.

12.
Indoor Air ; 30(1): 126-136, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31797459

RESUMO

Cooking is one of the main sources of indoor air pollution in China. Given emerging evidence of a link between air pollutants and neurodevelopmental delays, we examined whether maternal experiences with cooking during gestation might increase their child's hyperactivity at 3 years of age. The participants involved 45 518 mothers of children who were newly enrolled at kindergarten in the Longhua District of Shenzhen from 2015 to 2017. The results show that maternal exposure to cooking fumes during pregnancy was related to an increased risk of their offspring having hyperactivity behaviors at the age of 3 years. Compared with pregnant mothers who never cooked, pregnant mothers who cooked sometimes, often, or always had children who showed a significantly higher hyperactivity risk. Households using cooking fuels such as coal, gas during the mothers' pregnancy, exhibited more hyperactivity behaviors in the young child when compared to those using electricity for cooking. In addition, poor ventilation during cooking, while mothers were pregnant, was found to be a significant risk factor for clinical levels of the offspring's hyperactive behaviors. Furthermore, the positive association with maternal cooking during pregnancy and their offsprings' hyperactivity was relatively consistent across strata defined by social class, education, and other covariates.

13.
Proc Natl Acad Sci U S A ; 117(1): 308-316, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31843938

RESUMO

Cancer remains one of the most challenging diseases to treat. For accurate cancer diagnosis and targeted therapy, it is important to assess the localization of the affected area of cancers. The general approaches for cancer diagnostics include pathological assessments and imaging. However, these methods only generally assess the tumor area. In this study, by taking advantage of the unique microenvironment of cancers, we effectively utilize in situ self-assembled biosynthetic fluorescent gold nanocluster-DNA (GNC-DNA) complexes to facilitate safe and targeted cancer theranostics. In in vitro and in vivo tumor models, our self-assembling biosynthetic approach allowed for precise bioimaging and inhibited cancer growth after one injection of DNA and gold precursors. These results demonstrate that in situ bioresponsive self-assembling GNC-PTEN (phosphatase and tensin homolog) complexes could be an effective noninvasive technique for accurate cancer bioimaging and treatment, thus providing a safe and promising cancer theranostics platform for cancer therapy.

14.
Gene ; : 144279, 2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31821871

RESUMO

AIM OF THE STUDY: Chronic glomerulonephritis (CGN) is the most common form of primary glomerular disease. Qi Teng Xiao Zhuo granules have been proposed as a prescription of traditional Chinese medicine (TCM) for treatment of CGN, however,the comprehensive molecular mechanism underlying this therapeutic effectremains unclear to date. Our study aimed to evaluate and analyze the possible roles and molecular mechanisms of Qi Teng Xiao Zhuo granule-mediated treatment of CGN induced by adriamycin in rats. MATERIALS AND METHODS: RNA-sequencing and real-time polymerase chain reaction (RT-PCR) were applied to identify specifically expressed long noncoding RNAs (lncRNAs) in glomerular tissues of rats from the control group, adriamycin-induced group, and Qi Teng Xiao Zhuo granules group (n=3). Differentially expressed lncRNAs and mRNAs (messengerRNAs) were screened out among the 3 groups. Gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for mRNAs. LncRNA-mRNA co-expression network was constructed to analyse for the genes. The protein-protein interaction (PPI) network was visualized. RESULTS: A total of 473 significantly up and down-regulated lncRNAs, 753 up and down-regulated mRNAs were identified. Additionally, it is worth noting that TOP2a (topoisomerase (DNA) II alpha), with the highest connectivity degree in PPI network, was enriched in variouskinds of pathways. Coding-non-coding gene co-expression networks (CNC network) were drawn based on the correlation analysis between lncRNAs and mRNAs. Ten lncRNAs, NONRATT009275.2, NONRATT025409.2, NONRATT025419.2, MSTRG.7681.1, ENSRNOT00000084373, NONRATT000512.2, NONRATT006734.2, ENSRNOT00000084386, NONRATT021738.2, ENSRNOT00000084080, were selected to analyse the relationship between LncRNAs and Qi Teng Xiao Zhuo granules via the CNC network (Coding-non-coding gene co-expression networks) and GO analysis. Real-time PCR results confirmed that the six lncRNAs were specifically expressed in the Qi Teng Xiao Zhuo granules rats. CONCLUSIONS: The ten lncRNAs might play important roles in the Qi Teng Xiao Zhuo granules treatment of CGN. Key genes, such as Ptprc (protein tyrosine phosphatase, receptor type, C), TOP2a, Fos (FBJ osteosarcoma oncogene), Myc (myelocytomatosis oncogene), etc, may be crucial biomarkers for Qi Teng Xiao Zhuo granules.

15.
Pancreatology ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31831391

RESUMO

BACKGROUND/OBJECTIVES: Fibromodulin (FMOD) expression in chronic pancreatitis (CP) tissues and its effect on PSC was unknown. Our aim was to investigate the role of FMOD in regulating PSC profibrogenic phenotype and the molecular mechanism of CP. METHODS: Rat CP models were induced by dibutyltin dichloride. Pancreatic fibrosis was evaluated by Sirius Red staining. The expression of FMOD and α-SMA was measured, the correlation between FMOD expression and fibrosis was investigated in CP models and CP patients. The effects of FMOD on PSCs were examined by CCK-8 and migration assays. We investigated the mechanisms underlying FMOD expression using MND and a MAPK pathway inhibitor. Luciferase reporter and chromatin immunoprecipitation assays were used to investigate the effects of AP-1 on FMOD expression. RESULTS: Sirius Red staining revealed high collagen deposition in model rats. Higher expression of FMOD and α-SMA was observed in fibrotic tissues, and the expression of FMOD was correlated with that of α-SMA and the areas of Sirius Red staining. Upregulation of FMOD increased the expression of collagen I and α-SMA and the proliferation and migration of PSCs. MND induced FMOD and α-SMA expression, and knockdown of FMOD abated α-SMA expression. ERK and JNK inhibitors attenuated FMOD expression as induced by MND. AP-1 upregulated the expression of FMOD. AP-1 binds to the FMOD promoter and transcriptionally regulates FMOD expression. CONCLUSION: FMOD levels are upregulated in fibrosis tissues in CP and it is a critical downstream mediator of oxidative stress. FMOD induces PSC activation and maintains the fibrosis phenotype of PSCs.

16.
Am J Cancer Res ; 9(11): 2314-2330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815037

RESUMO

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

17.
BMC Bioinformatics ; 20(Suppl 16): 593, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31787074

RESUMO

BACKGROUND: A fundamental problem in RNA-seq data analysis is to identify genes or exons that are differentially expressed with varying experimental conditions based on the read counts. The relativeness of RNA-seq measurements makes the between-sample normalization of read counts an essential step in differential expression (DE) analysis. In most existing methods, the normalization step is performed prior to the DE analysis. Recently, Jiang and Zhan proposed a statistical method which introduces sample-specific normalization parameters into a joint model, which allows for simultaneous normalization and differential expression analysis from log-transformed RNA-seq data. Furthermore, an ℓ0 penalty is used to yield a sparse solution which selects a subset of DE genes. The experimental conditions are restricted to be categorical in their work. RESULTS: In this paper, we generalize Jiang and Zhan's method to handle experimental conditions that are measured in continuous variables. As a result, genes with expression levels associated with a single or multiple covariates can be detected. As the problem being high-dimensional, non-differentiable and non-convex, we develop an efficient algorithm for model fitting. CONCLUSIONS: Experiments on synthetic data demonstrate that the proposed method outperforms existing methods in terms of detection accuracy when a large fraction of genes are differentially expressed in an asymmetric manner, and the performance gain becomes more substantial for larger sample sizes. We also apply our method to a real prostate cancer RNA-seq dataset to identify genes associated with pre-operative prostate-specific antigen (PSA) levels in patients.

18.
Oncol Lett ; 18(6): 6066-6078, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788081

RESUMO

Melanoma is one of the most malignant types of skin cancer. However, the efficacy and utility of available drug therapies for melanoma are limited. The objective of the present study was to identify potential genes associated with melanoma progression and to explore approved therapeutic drugs that target these genes. Weighted gene co-expression network analysis was used to construct a gene co-expression network, explore the associations between genes and clinical characteristics and identify potential biomarkers. Gene expression profiles of the GSE65904 dataset were obtained from the Gene Expression Omnibus database. RNA-sequencing data and clinical information associated with melanoma obtained from The Cancer Genome Atlas were used for biomarker validation. A total of 15 modules were identified through average linkage hierarchical clustering. In the two significant modules, three network hub genes associated with melanoma prognosis were identified: C-X-C motif chemokine receptor 4 (CXCR4), interleukin 7 receptor (IL7R) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG). The receiver operating characteristic curve indicated that the mRNA levels of these genes exhibited excellent prognostic efficiency for primary and metastatic tumor tissues. In addition, the proximity between candidate genes associated with melanoma progression and drug targets obtained from DrugBank was calculated in the protein interaction network, and the top 15 drugs that may be suitable for treating melanoma were identified. In summary, co-expression network analysis led to the selection of CXCR4, IL7R and PIK3CG for further basic and clinical research on melanoma. Utilizing a network-based method, 15 drugs that exhibited potential for the treatment of melanoma were identified.

19.
Oncol Lett ; 18(6): 6829-6835, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788126

RESUMO

Metastasis, which involves the spread of cancer cells to distant tissues and organs, is a major cause of cancer-associated mortality. Although the use of anesthetics and analgesics may affect cancer cell metastasis, the underlying molecular mechanism remains unclear. Autophagy is a lysosome-based dynamic intracellular catabolic process that serves a crucial role in cancer cell metastasis. In order to investigate the role of autophagy in the migration of cancer cells treated with analgesics, immunofluorescence, western blotting, wound healing assay and cell invasion assay were performed in the present study. The results from immunofluorescence and western blotting demonstrated that the opioid analgesic sufentanil stimulated LC3 induction in NCI-H460 cells. Furthermore, sufentanil increased LC3 and Beclin1 protein levels, but inhibited the fusion of autophagosomes and lysosomes. In addition, sufentanil decreased cathepsin D protein level and increased p62 protein level. The addition of chloroquine (CQ) to sufentanil did not induce a further increase in LC3-II protein levels in NCI-H460 cells, suggesting the impairment of autophagic degradation. Furthermore, treatment with trehalose stimulated the migration of sufentanil-treated cells, whereas additional treatment with CQ did not further decrease the migration of sufentanil-treated cells. In addition, sufentanil co-treatment with trehalose significantly increased the invasion of lung cancer cells, whereas, additional treatment with CQ did not further reduce the invasion of sufentanil-treated cells. These results indicated that autophagy may be involved in the inhibition of NCI-H460 cell migration by sufentanil, and that sufentanil may be considered as a favorable analgesic for patients with lung cancer.

20.
Shanghai Kou Qiang Yi Xue ; 28(4): 417-421, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31792485

RESUMO

PURPOSE: To explore the aesthetic effect of orthodontics treatment combined with periodontal splint in the treatment of fan-shaped displacement of anterior teeth caused by periodontitis. METHODS: Fifty patients with fan-shaped displacement of anterior teeth caused by periodontitis in PLA air force hospital from January 2013 to October 2018 were selected and randomly divided into the control group (n=25) and the experimental group (n=25). Patients in the control group were treated with conventional periodontal splint, while patients in the experimental group were treated with combined orthodontic treatment on the basis of the control group. Florida periodontal probe exploration depth (PD), gingival index (GI), attachment loss (AL), sulcus bleeding index (SBI), plaque index (PLI) and mobility were observed and compared before and 1 month after treatment between both groups. The levels of serum inflammatory factors interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and osteocalcin (OC) were measured and compared by ELISA before treatment and 1 month after treatment in both 2 groups. The data were analyzed with SPSS 21.0 software package. RESULTS: Compared with before treatment, PD and GI in both groups decreased significantly after treatment, and significantly lower in the experimental group than that in the control group (P<0.05); the levels of AL, SBI, PLI and tooth looseness in both 2 groups were significantly lower after treatment, and significantly lower in the experimental than in the control group (P<0.05); compared with before treatment, the levels of IL-4, IL-6, TNF-a and serum CRP in both 2 groups were significantly lower after treatment, and the experimental group was much lower than that in the control group (P<0.05). The level of osteocalcin in the experimental group was significantly higher than that in the control group at different time points after treatment (P<0.05). The level of osteocalcin in the experimental group reached its peak one day after treatment, and then gradually declined, the preoperative level was basically restored 7 days after treatment. CONCLUSIONS: Using orthodontics combined with periodontal splint in the treatment of fan-shaped displacement of anterior teeth caused by periodontitis has a remarkable effect. The symptoms of periodontitis can be effectively improved, the teeth can be effectively corrected and facial profiles of the patients can be improved.

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