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2.
BMC Genomics ; 21(Suppl 1): 872, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32138651

RESUMO

BACKGROUND: The Type II clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) is a powerful genome editing technology, which is more and more popular in gene function analysis. In CRISPR/Cas, RNA guides Cas nuclease to the target site to perform DNA modification. RESULTS: The performance of CRISPR/Cas depends on well-designed single guide RNA (sgRNA). However, the off-target effect of sgRNA leads to undesired mutations in genome and limits the use of CRISPR/Cas. Here, we present OffScan, a universal and fast CRISPR off-target detection tool. CONCLUSIONS: OffScan is not limited by the number of mismatches and allows custom protospacer-adjacent motif (PAM), which is the target site by Cas protein. Besides, OffScan adopts the FM-index, which efficiently improves query speed and reduce memory consumption.

3.
Int J Surg ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32173611

RESUMO

BACKGROUND: Microwave ablation (MWA) is an important method in the treatment of liver cancer. This systematic review compared MWA with liver resection (LR) for liver cancer treatment. In recent years, the MWA has been also reported to play an important role. Studies comparing MWA and LR are lacking. This study aims to compare the efficacy of MWA and LR in the treatment of hepatocellular carcinoma (HCC). METHODS: A systematic search of PubMed, Embase, Cochrane Library and Web of Science up to April 1, 2019 was conducted for relevant studies that compared the efficacy of MWA and LR in the treatment of HCC. The primary outcomes were local tumor recurrence (LTR) and overall survival (OS) of patients. The secondary outcomes included disease free survival (DFS), extrahepatic metastasis, intrahepatic de novo lesions, length of stay, complications, intraoperative blood loss and operative time. RESULTS: A total of 16 studies including 2622 patients were identified. Incidence of LTR was significantly higher in patients with MWA than LR, with a pooled OR of 2.69 (95% CI 1.33 ‒ 5.41; P = 0.006). No significant difference in 1-year OS was found. However, patients with MWA experienced higher 3- and 5-year OS, with pooled ORs of 1.40 (95% CI 1.07 ‒ 1.84; P = 0.01) and 1.41 (95% CI 1.10 ‒ 1.80; P = 0.007) respectively. In secondary measures, the 1- and 3-year DFS were significantly higher in patients with MWA. However, no significant difference of 5-year DFS was observed. In addition, lower incidence of complications, less intraoperative blood loss and shorter operative time and shorter length of stay were observed in MWA. CONCLUSIONS: Though MWA may lead to higher incidence of recurrence, it may be an effective and safe alternative in patients with HCC or liver metastases. MWA may have benefits in patients' survival and safety. Randomized studies should be performed to determine the target population that benefits most from MWA in the future.

4.
Fish Physiol Biochem ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32130563

RESUMO

NUCB1 and NUCB2, two novel nucleobindins, have attracted extensive attention for their role in the appetite regulation in mammals. However, little is known about the appetite regulation of NUCB1 and NUCB2 in fish species. Therefore, we investigated the role of these peptides in the regulation of feeding in Schizothorax davidi (S. davidi). In this study, full-length cDNA sequences of nucb1 and nucb2A of S. davidi were obtained for the first time. Additionally, the tissue distribution and the effects of different energy status on nucb1 and nucb2A mRNAs abundance were assessed, showing that nucb1 and nucb2A are widely distributed in 18 detected tissues, with the highest expression in the cerebellum. The abundances of nucb1 and nucb2A increased in the hypothalamus at 1 h and 3 h post-feeding. Furthermore, fasting and re-feeding experiments showed that the expressions of nucb1 and nucb2A in hypothalamus significantly decreased after fasting for 7 days, and returned to the control level after re-feeding for 3 or 5 days. In conclusion, the present study suggests that both NUCB1 and NUCB2A are involved in the short-term and long-term appetite regulation, as an anorexigenic factor, in S. davidi. These results can provide a basis for further investigation into the appetite regulatory role of NUCB family in teleost.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32167908

RESUMO

A multi-channel analog front-end (AFE) ASIC for wearable EEG recording application is presented in this paper. Two techniques, namely chopping stabilization (CS) and time-division-multiplexing (TDM) are combined in a unified manner to improve the input-referred noise and the system level common-mode rejection ratio (CMRR) for multi-channel AFE. With the proposed TDM/CS structure, multiple channels can share single second-stage amplifier for significant reduction in chip size and power consumption. Dual feedback loops for input impedance boosting as well as electrode offset cancellation are incorporated in the system. Implemented in a 0.18-µm CMOS process, the AFE consumes 24 µW under 1 V supply. The input referred noise is 0.63 µVrms in 0.5 Hz - 100 Hz and the input impedance is boosted to 560 MΩ at 50 Hz. The measured amplifier intrinsic CMRR and system-level AFE CMRR are 89 dB and 82 dB, respectively.

6.
J Chromatogr A ; : 460983, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32098683

RESUMO

In general counter-current chromatography systems, there are several off-column fittings between injector and column inlet, such as bends, valves, connecting tubes and joints. Due to these off-column fittings, the sample will diffuse in the mobile phase and form an irregular distribution when it flows from the injector to the column inlet. Thus, the concentration distribution of the solutes at the column inlet is a continuous curve (called the injection profile). As some previous research reveals, it is necessary to input actual injection profile into the simulation model to mimic elution profile. Therefore, we built a non-ideal CCC model whose initial value is from the actual injection profile, and validated the rationality of this model with iteration method. The simulation analysis of different injection profiles shows the conditions whereby a discrete injection profile can replace the actual injection profile in the non-ideal CCC model for accurate simulation elution. Simulation elution under such conditions reveal that non-ideal injection model can reflect the relationship between the injection profile and elution profile, and help to explain the reasons of irregular change in elution profile, like the tailed peak and flat peak.

7.
Stem Cell Res Ther ; 11(1): 86, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32102690

RESUMO

BACKGROUND: Parthenogenetic stem cells (PSCs) are a promising source of regenerated cardiomyocytes; however, their application may be limited without a paternal genome. Insulin-like growth factor-II (IGF-II), a paternally expressed growth hormone, is critical in embryonic differentiation. This study investigated whether forced expression of IGF-II in PSCs can accelerate their differentiation. METHODS: Overexpression and re-knockdown of IGF-II in PSCs were performed to investigate the role of IGF-II in PSC differentiation. The derivatives of PSCs with different IGF-II manipulations were transplanted into infarcted murine hearts to investigate the role of IGF-II in cardiomyocyte differentiation in vivo. RESULTS: Data showed that the expression of cardiac troponin T and troponin I in IGF-II-PSC outgrowths preceded that of parental PSC outgrowths, suggesting that IGF-II can accelerate PSC differentiation into cardiac lineage. Overexpression of IGF-II accelerated PSC differentiation towards cardiomyocytes while inhibiting PSC proliferation via the IGF-II/IGF1R signaling. Similar to that observed in cardiac marker expression, on differentiation day 24, IGF-II-PSCs showed PCNA and cyclin D2 expression comparable to juvenile mouse cardiomyocytes, showing that IGF-II-PSCs at this stage possess differential and proliferative properties similar to those of juvenile cardiomyocytes. Moreover, the expression pattern of cardiac markers in IGF-II-overexpressing PSC derivatives resembled that of juvenile mouse cardiomyocytes. After transplantation into the infarcted mouse hearts, IGF-II-PSC-derived cardiomyocytes displayed significant characteristics of mature cardiomyocytes, and IGF-II-depletion by shRNA significantly reversed these effects, suggesting the critical role of IGF-II in promoting cardiomyocyte maturation in vivo. Furthermore, IGF-II-overexpressing PSC derivatives reduced collagen deposition and mitochondrial damage in the infarcted areas and improved cardiac function. The re-knockdown of IGF-II could counteract these favorable effects of IGF-II. CONCLUSIONS: These findings suggest that the ectopic expression of IGF-II accelerates PSC differentiation into the cardiac lineage and promotes cardiomyocyte maturation. The underlying process includes the IGF-II/IGF1R signaling, which is involved in the suppressive effect of IGF-II on PSC proliferation. Moreover, transplanting IGF-II-overexpressing PSC derivatives into the infarcted heart could reduce collagen deposition and improve mitochondria biogenesis and measurements of cardiac function, highlighting the importance of IGF-II in the application of PSCs in cardiac regeneration.

8.
BMC Genomics ; 21(1): 120, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013879

RESUMO

BACKGROUND: Fluralaner is a novel isoxazoline insecticide with a unique action site on the γ-aminobutyric acid receptor (GABAR), shows excellent activity on agricultural pests including the common cutworm Spodoptera litura, and significantly influences the development and fecundity of S. litura at either lethal or sublethal doses. Herein, Illumina HiSeq Xten (IHX) platform was used to explore the transcriptome of S. litura and to identify genes responding to fluralaner exposure. RESULTS: A total of 16,572 genes, including 451 newly identified genes, were observed in the S. litura transcriptome and annotated according to the COG, GO, KEGG and NR databases. These genes included 156 detoxification enzyme genes [107 cytochrome P450 enzymes (P450s), 30 glutathione S-transferases (GSTs) and 19 carboxylesterases (CarEs)] and 24 insecticide-targeted genes [5 ionotropic GABARs, 1 glutamate-gated chloride channel (GluCl), 2 voltage-gated sodium channels (VGSCs), 13 nicotinic acetylcholine receptors (nAChRs), 2 acetylcholinesterases (AChEs) and 1 ryanodine receptor (RyR)]. There were 3275 and 2491 differentially expressed genes (DEGs) in S. litura treated with LC30 or LC50 concentrations of fluralaner, respectively. Among the DEGs, 20 related to detoxification [16 P450s, 1 GST and 3 CarEs] and 5 were growth-related genes (1 chitin and 4 juvenile hormone synthesis genes). For 26 randomly selected DEGs, real-time quantitative PCR (RT-qPCR) results showed that the relative expression levels of genes encoding several P450s, GSTs, heat shock protein (HSP) 68, vacuolar protein sorting-associated protein 13 (VPSAP13), sodium-coupled monocarboxylate transporter 1 (SCMT1), pupal cuticle protein (PCP), protein takeout (PT) and low density lipoprotein receptor adapter protein 1-B (LDLRAP1-B) were significantly up-regulated. Conversely, genes encoding esterase, sulfotransferase 1C4, proton-coupled folate transporter, chitinase 10, gelsolin-related protein of 125 kDa (GRP), fibroin heavy chain (FHC), fatty acid synthase and some P450s were significantly down-regulated in response to fluralaner. CONCLUSIONS: The transcriptome in this study provides more effective resources for the further study of S. litura whilst the DEGs identified sheds further light on the molecular response to fluralaner.

9.
Sci Rep ; 10(1): 2269, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042045

RESUMO

To explore the editing specificity of CRISPR/Cpf1 system, effects of target mutation were systematically examined using a reporter activation assay, with a set of single-nucleotide mutated target site. Consistent with our previous study performed with CRISPR/Cas9, a "core" sequence region that is highly sensitive to target mutation was characterized. The region is of 4-nucleotide long, located from +4 to +7 position of the target site, and positioned within a positively charged central channel when assembled into Cpf1 endonuclease. Single-nucleotide mutation at the core sequence could abolish gene editing mediated by a however active sgRNA. With a great majority of the target sites, a kind of 'super' off-target gene editing was observed with both CRISPR/Cpf1 and CRISPR/Cas9. For a given target site, mutation at certain positions led to greatly enhanced off-target gene editing efficacy, even up to 10-fold of that of the fully-matched target. Study further found that these effects were determined by the identity of target nucleotide, rather than the nucleotide of crRNA. This likely suggests that the interactions between target nucleotide and the endonuclease are involved in this process.

10.
Sci Transl Med ; 12(531)2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075946

RESUMO

MYCN-amplified neuroblastoma (NB) is characterized by poor prognosis, and directly targeting MYCN has proven challenging. Here, we showed that aldehyde dehydrogenase family 18 member A1 (ALDH18A1) exerts profound impacts on the proliferation, self-renewal, and tumorigenicity of NB cells and is a potential risk factor in patients with NB, especially those with MYCN amplification. Mechanistic studies revealed that ALDH18A1 could both transcriptionally and posttranscriptionally regulate MYCN expression, with MYCN reciprocally transactivating ALDH18A1 and thus forming a positive feedback loop. Using molecular docking and screening, we identified an ALDH18A1-specific inhibitor, YG1702, and demonstrated that pharmacological inhibition of ALDH18A1 was sufficient to induce a less proliferative phenotype and confer tumor regression and prolonged survival in NB xenograft models, providing therapeutic insights into the disruption of this reciprocal regulatory loop in MYCN-amplified NB.

11.
Brain Behav ; 10(2): e01520, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31908160

RESUMO

BACKGROUND: Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy. METHODS: This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters. RESULTS: Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively. Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI. Furthermore, according to metabolite-protein database searches, 25 metabolite-protein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5'-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways. CONCLUSION: The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.

12.
Med Sci Monit ; 26: e918599, 2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31955176

RESUMO

BACKGROUND The aim of this study was to explore the influence of mitofusin-2 (Mfn-2) on phosphatidylinositol transfer protein 3 (PITPNM3) and tumor growth and the potential mechanism behind the regulation of Mfn-2 on PITPNM3 in hepatic carcinoma cell line SMMC-7721. MATERIAL AND METHODS We obtained promoter sequence of PITPNM3 gene from University of Santa Cruz (UCSC) genomic database, and we predict transcriptional factor of PITPNM3 genes by JASPAR database. Target transcription factor was determined by comparison of binding sites number for promoter. SMMC-7721 cells were transfected with expression plasmid containing Mfn-2, transcription factor gene and PITPNM3. The cells transfected with empty vector were used as control. Real-time polymerase chain reaction was used to determine the mRNA level of target genes. Co-immunoprecipitation (Co-IP) assay was used to determine the interaction between Mfn-2 and target transcription factor. Chromatin immunoprecipitation assay (ChIP) assay was used to determine the binding of transcription factor with PITPNM3 promoter. Tumorigenicity assay was used to compare the effect of Mfn-2, SP1, and PITPNM3 on tumor development. RESULTS SP1 was selected as the target transcriptional factor. In the Co-IP assay, Mfn-2 was shown to interact with SP1. In the ChIP assay Mfn-2 transfection resulted in decreased binding number of SP1 with PITPNM3 promoter. Furthermore, PITPNM3 mRNA levels were significantly increased in SMMC-7721 cells transfected with SP1 but were decreased after transfection with Mfn-2. In nude mice, PITPNM3 and SP1 upregulation lead to larger tumor lump and conversely Mfn-2 upregulation lead to smaller tumor lump. CONCLUSIONS Mfn-2 could suppress expression of PITPNM3 through interaction with transcription factor SP1; Mfn-2 may have anti-tumor activity; SP1 and PITPNM3 may promote tumor development.

13.
Gene ; 733: 144265, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805318

RESUMO

To explore its roles in adipogenesis, the levels of genomic 5mC methylation were examined across the adipocyte differentiation of 3 T3-L1 cells. This led to the identification of an up-regulating 5mC profile during the process. To further explore the regulation, gene expression assay was performed with a set of 5mC metabolic enzymes. Among them, TET2 was found to be the most regulated 5mC demethylase, in addition to a well-investigated 5mC methylase DNMT1. In the process, the expression of Tet2 increased for over 16-fold, suggesting its implications in the differentiation. Therefore, loss-of-function and gain-of-function assays were performed with Tet2. It was found that in relative to the differentiation of wild-type cells, knockdown of Tet2 expression led to greatly enhanced differentiation process, while over-expression of the gene resulted in repressed differentiation. Pathway study found that during the differentiation, TET2 demethylates Adrb3 promoter to up-regulate its expression. This led to enhanced lipolysis and decreased lipid production. To the upstream pathway, vitamin C treatment was found to enhance the activity of TETs, decrease 5mC levels and repress lipid production. Taken together, TET2 was characterized as an anti-adipogenic demethylase in adipocyte differentiation of 3 T3-L1 cells.

14.
J Chromatogr A ; 1609: 460503, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31561970

RESUMO

In counter-current chromatography (CCC), the hydrodynamic motion of a two-phase solvent system in the column/coil is very important. There are some previous visualization studies on CCC using stroboscopic photography. As CCC separation is a continuous liquid-liquid extraction process, observing the distribution and movement of the solvent system on-line will be helpful to understand the hydrodynamic behavior during the whole CCC separation process. In the present study, a high-speed imaging camera was employed to take videos of a running CCC bobbin (visualized continuously on-line). The dynamic motion and phase distribution of conventional quaternary solvent system hexane/ethyl acetate/methanol/water (HEMWat) and ternary solvent system dichloromethane/methanol/water were both investigated. Wave-like mixing was observed in the area where the centrifugal force is minimum in different diameter columns. When the coil rotated, the mixing zone was "fixed" at the minimum centrifugal force position. Several photographs of the rotating coiled tube were taken which revealed that the phase dispersion hardly changes once equilibrium is established. Finally, the sample dispersion process was also recorded. These results will help us to understand the separation process in a CCC column/coil and also present some more interesting questions related to separation efficiency which are shown in discussion part of this paper.

15.
Neurosci Lett ; 716: 134634, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31751668

RESUMO

BACKGROUND & AIMS: Studies have shown that moderate to severe stenosis of the carotid was associated with abnormal neural activity and functional connectivity (FC). However, whether there is a change of neuronal activity in individuals with asymptomatic vulnerable carotid plaque but mild stenosis (VCP) remains unknown. METHODS: From December 2015 to December 2017, a total of 31 patients with VCP and 31 no carotid plaque (NCP) controls were performed multi-modal state functional magnetic resonance imaging and investigated the regional brain activity and FC. Two basic algorithms of rs-fMRI, arterial spin labeling, and inflammatory biomarkers were comprehensively evaluated. The time series of aberrant ReHo and FC were also extracted and correlated with other clinical imaging features. RESULTS: As compared with NCP group, decreased regional brain activity was found mainly in left middle occipital gyrus (MOG) in the VCP group, but there was no significant difference in cerebral blood flow between the two groups. With the left MOG as seed, decreased FC was found between left MOG and right MOG and frontoparietal network in VCP group. Carotid intima-media thickness but not inflammatory biomarkers including high sensitivity c-reactive protein and interleukin-6 was significantly correlated with aberrant ReHo and FC in left MOG and right MOG. CONCLUSIONS: regional brain activity and FC may serve as early imaging markers for vascular-related brain dysfunctions and clinical indicators for early intervention of both atherosclerotic cerebral infarction and vascular cognitive impairments.

16.
Sci Total Environ ; 711: 134750, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31810670

RESUMO

Metacommunity ecology emphasizes that community structure and diversity are not only determined by local environmental conditions through environmental filtering, but also by dispersal-related processes, such as mass effects, dispersal limitation and patch dynamics. However, the roles of dispersal processes are typically ignored in bioassessment approaches. Here, we simultaneously explored the potential influences of four groups of factors: local stressors, climatic factors, within-basin spatial factors and basin identity in explaining variation in diversity indices of macroinvertebrate assemblages from seven subtropical tributary rivers. A total of 12 biodiversity indices based on species identities, functional traits and taxonomic relatedness were calculated and used in the subsequent statistical analysis. Our results showed that, although differing in their relative importance, the four explanatory factor groups all played important roles in explaining variation in biodiversity indices. Of the pure fractions, index variation was best explained by local environmental stressors, whereas the other three explanatory factor groups appeared less influential. Furthermore, diversity indices from species, functional and taxonomic dimensions responded distinctly to the focal ecological factors, and differed in their abilities to portray the effects of human disturbances on macroinvertebrate communities. Taxonomic distinctness indices performed best, with the highest amount of variation associated to local stressors and hardly any variation explained by other factors, implying that these indices are robust in portraying human disturbances in streams. However, species diversity and functional diversity indices were also affected by spatial processes and climatic factors, suggesting that these indices should be used with caution in bioassessment. We hence conclude that environmental assessment of riverine ecosystems should not rely entirely on the perspective of species sorting. In contrast, both roles of spatial processes and environmental variables related to human disturbances and climatic variation should be incorporated in management and conservation of riverine ecosystems.

17.
Sci Total Environ ; 704: 135268, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31810677

RESUMO

Streams are influenced by watershed-scale factors, such as climate, geology, topography, hydrology, and soils, which mostly vary naturally among sites, as well as human factors, agriculture and urban development. Thus, natural factors could complicate assessment of human disturbance. In the present study, we use structural equation modeling and data from the 2008-2009 United States National Rivers and Streams Assessment to quantify the relative importance of watershed-scale natural and human factors for in-stream conditions. We hypothesized that biological condition, represented using a diatom multimetric index (MMI), is directly affected by in-stream physicochemical environment, which in turn is regulated by natural and human factors. We evaluated this hypothesis at both national and ecoregion scales to understand how influences vary among regions. We found that direct influences of in-stream environment on diatom MMIs were greater than natural and human factors at the national scale and in all but one ecoregion. Meanwhile, in-stream environments were jointly explained by natural variations in precipitation, base flow index, hydrological stability, % volcanic rock, soil water table depth, and soil depth and by human factors measured as % crops, % other agriculture, and % urban land use. The explained variance of in-stream environment by natural and human factors ranged from 0.30 to 0.75, for which natural factors independently accounted for the largest proportion of explained variance at the national scale and in seven ecoregions. Covariation between natural and human factors accounted for a higher proportion of explained variance of in-stream environment than unique effects of human factors in most ecoregions. Ecoregions with relatively weak effects by human factors had relatively high levels of covariance, high levels of human disturbance, or small ranges in human disturbance. We conclude that accounting for effects of natural factors and their covariation with human factors will be important for accurate ecological assessments.


Assuntos
Monitoramento Ambiental , Rios/química , Poluição da Água/análise , Biodiversidade , Ecologia , Ecossistema , Humanos , Hidrologia , Estados Unidos
18.
Cancer Med ; 9(2): 745-756, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31782259

RESUMO

BACKGROUND: Gene mutations may play an important role in the development, response to treatment and prognosis of colorectal cancer (CRC). This retrospective study aimed to investigate the mutation profiling of Chinese patients with CRC, and its correlation with clinicopathological features and prognosis. METHODS: This study included 1190 Chinese CRC patients who were diagnosed between May 1998 and December 2018 and received clinical genetic testing. The OncoCarta Panel was used to test a total of 238 possible mutations in 19 common oncogenes. RESULTS: Five hundred and eighty-two (48.9%) cases were detected with gene mutations. Of the 582 cases, there were 111 cases (19.7%) with two concurrent mutations, and six cases (1.0%) with three concurrent mutations. KRAS was the most common gene mutation that occurred in all cases (429, 36.1%), followed by PIK3CA (121, 10.2%), NRAS (47, 3.9%), BRAF (35, 2.9%), HRAS (11, 0.9%) and epidermal growth factor receptor (EGFR) (11, 0.9%). AKT1, KIT, FGFR1, FGFR3, FLT3, CDK, ERBB2, ABL1, MET, RET and PDGFRA mutations were also detected in several cases. When it came to prognosis, we found that KRAS/NRAS/PIK3CA/BRAF mutation was not associated with prognosis. But BRAF mutation was associated with poor prognosis in patients who accepted anti-EGFR therapy. CONCLUSIONS: The molecular testing offered the clinical data and mutation profile of Chinese CRC patients. The information of these mutated genes may help to find out the correlation between mutated genes and the development or prognosis of CRC.

19.
Cell Death Differ ; 27(1): 210-226, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31097789

RESUMO

Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.

20.
J Cell Mol Med ; 24(2): 1750-1759, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31876059

RESUMO

Stomach cancer is the fourth most common cancer worldwide. Identification of novel molecular therapeutic targets and development of novel treatments are critical. Against a panel of gastric carcinoma cell lines, the activity of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) was investigated. Adopting RT-PCR, Western blot and immunohistochemical techniques, we sought to determine molecular pharmacodynamic (PD) markers of sensitivity and investigate arylhydrocarbon (AhR) receptor-mediated signal transduction activation by 5F 203. Potent (IC50  ≤ 0.09 µmol/L), selective (>250-fold) in vitro antitumour activity was observed in MKN-45 and AGS carcinoma cells. Exposure of MKN-45 cells to 5F 203 triggered cytosolic AhR translocation to nuclei, inducing CYP1A1 (>50-fold) and CYP2W1 (~20-fold) transcription and protein (CYP1A1 and CYP2W1) expression. G2/M arrest and γH2AX expression preceded apoptosis, evidenced by PARP cleavage. In vivo, significant (P < .01) 5F 203 efficacy was observed against MKN-45 and AGS xenografts. In mice-bearing 5F 203-sensitive MKN-45 and 5F 203-insensitive BGC-823 tumours in opposite flanks, CYP1A1, CYP2W1 and γH2AX protein in MKN-45 tumours only following treatment of mice with 5F 203 (5 mg/kg) revealed PD biomarkers of sensitivity. 5F 203 evokes potent, selective antitumour activity in vitro and in vivo in human gastric cancer models. It triggers AhR signal transduction, CYP-catalysed bioactivation to electrophilic species causing lethal DNA double-strand breaks exclusively in sensitive cells. 5F 203 represents a novel therapeutic agent with a mechanism of action distinct from current clinical drugs, exploiting novel molecular targets pertinent to gastric tumourigenesis: AhR, CYP1A1 and CYP2W1. PD markers of 5F 203 sensitivity that could guide patient selection have been identified.

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