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1.
J Cell Biochem ; 121(1): 70-80, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31074095

RESUMO

Numbers of emerging evidence suggest that variable microRNA (miRNA) expression facilitates the aging process. In this study, we distinguished aberrant miRNA expression in aged skin and explored the biological functions and potential mechanism of upregulated miR-302b-3p. At first, miRNA microarray analysis was examined to explore miRNA expression profiling in the skin of aging mice model by D-galactose (d-gal) injection. We identified 29 aberrant miRNAs in aged mice skin. Next, KEGG enrichment analysis was conducted with DIANA-miPath v3.0, which was revealed that enrichment pathways involved in such processes as extracellular matrix-receptor interaction, MAPK signaling pathway, and mammalian target of rapamycin (mTOR) signaling pathway. The target genes of deregulated miRNAs were predicted from four bioinformatic algorithms (miRDB, Targetscan, miRwalk, and Tarbase). The interaction network of miRNAs and their targets were visualized using Cytoscape software. As a result, we found that some hub genes (including JNK2, AKT1/2/3, PAK7, TRPS1, BCL2L11, and IKZF2) were targeted by 12 potential miRNAs (including miR-302b-3p, miR-291a-5p, miR-139-3p, miR-467c-3p, miR-186-3p, etc.). Subsequently, we identified five upregulated miRNA via quantitative polymerase chain reaction and all of them were confirmed increased significantly in aged skin tissues compared with young control tissues. Among them, high expression of miR-302b-3p was verified in both aged skin tissues and senescence fibroblasts. Furthermore, miR-302b-3p mimic accelerated skin fibroblast senescence and suppressed the longevity-associated gene Sirtuin 1(Sirt1) expression, whereas miR-302b-3p inhibitor could delay skin fibroblast senescence and contribute Sirt1 expression. In addition, we demonstrated that c-Jun N-terminal kinase 2(JNK2) is a direct target of miR-302b-3p by a luciferase reporter assay. An inverse correlation was verified in fibroblasts between miR-302b-3p and JNK2. Most importantly, siRNA JNK2 confirmed that low expression of JNK2 could accelerate fibroblasts senescence. In conclusion, our results indicated that overexpressed miR-302b-3p plays an important biological role in accelerating skin aging process via directly targeting JNK2 gene.

2.
Med Image Anal ; 59: 101565, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630010

RESUMO

The availability of a large amount of annotated data is critical for many medical image analysis applications, in particular for those relying on deep learning methods which are known to be data-hungry. However, annotated medical data, especially multimodal data, is often scarce and costly to obtain. In this paper, we address the problem of synthesizing multi-parameter magnetic resonance imaging data (i.e. mp-MRI), which typically consists of Apparent Diffusion Coefficient (ADC) and T2-weighted (T2w) images, containing clinically significant (CS) prostate cancer (PCa) via semi-supervised learning and adversarial learning. Specifically, our synthesizer generates mp-MRI data in a sequential manner: first utilizing a decoder to generate an ADC map from a 128-d latent vector, followed by translating the ADC to the T2w image via U-Net. The synthesizer is trained in a semi-supervised manner. In the supervised training process, a limited amount of paired ADC-T2w images and the corresponding ADC encodings are provided and the synthesizer learns the paired relationship by explicitly minimizing the reconstruction losses between synthetic and real images. To avoid overfitting limited ADC encodings, an unlimited amount of random latent vectors and unpaired ADC-T2w Images are utilized in the unsupervised training process for learning the marginal image distributions of real images. To improve the robustness for training the synthesizer, we decompose the difficult task of generating full-size images into several simpler tasks which generate sub-images only. A StitchLayer is then employed to seamlessly fuse sub-images together in an interlaced manner into a full-size image. In addition, to enforce the synthetic images to indeed contain distinguishable CS PCa lesions, we propose to also maximize an auxiliary distance of Jensen-Shannon divergence (JSD) between CS and nonCS images. Experimental results show that our method can effectively synthesize a large variety of mp-MRI images which contain meaningful CS PCa lesions, display a good visual quality and have the correct paired relationship between the two modalities of a pair. Compared to the state-of-the-art methods based on adversarial learning (Liu and Tuzel, 2016; Costa et al., 2017), our method achieves a significant improvement in terms of both visual quality and several popular quantitative evaluation metrics.

3.
Chemosphere ; 238: 124658, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31548174

RESUMO

Adsorption is a common process used to remove pharmaceuticals, personal care products and endocrine disrupting chemicals (PPCPs/EDCs) from water. However, as PPCPs/EDCs cover a wide range of molecules and chemical structures, prediction of the adsorption capacity is very challenging. In this study, a novel model was developed to predict adsorption isotherms of PPCPs/EDCs onto various types of adsorbents using a combination of Polanyi potential theory, molecular connectivity indices (MCIs) and molecular characteristics. Polanyi theory provided the basic mathematical form for the correlation. MCIs, hydrophobicity and H-bond count were used to normalize the Polanyi equation based on the molecular structure and interactions among the chemicals, the adsorbents, and the solution. In total, adsorption data were collected from 158 reports for 55 PPCPs/EDCs onto 306 different adsorbent materials. The correlation was first trained with 46 PPCPs/EDCs adsorbed onto 162 carbonaceous adsorbents (CAs), with 44.8% SDEV. Then the model was employed to predict 46 PPCPs/EDCs onto 118 other CAs and 9 new PPCPs/EDCs onto 23 CAs in ultrapure water, with error from 42 to 48% SDEV. When applying to non-carbonaceous adsorbents, the models can still predict the adsorption of PPCPs/EDCs with 90.09% SDEV. For the first time, a model, the PD - MCI - hydrophobic - H bond model, was developed to predict adsorption of a wide group of complicated PPCPs/EDCs onto a big variety of carbonaceous and non-carbonaceous adsorbents. The proposed model approach may provide a simple means for predicting adsorption capacities of PPCPs/EDCs onto various adsorbents.

4.
Chemosphere ; 239: 124758, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31514009

RESUMO

Trace elements such as copper (Cu) and arsenic (As) are two of the major contaminants and well-known inducers of cognitive deficits and neurobehavioral changes. This study evaluated the immunotoxicity of their individual or combined exposure on different brain regions in chickens. Consequently, nuclear damage and organelle lesions, especially mitochondria were observed under Cu or/and As stress, in which positive regulation of key proteins, dynamin-related protein 1 (Drp1), Cytochrome C (Cyt c), BCL2-associated X (Bax), Caspases 3 and P53 was detected by qRCR and Western blot analyses, indicating disturbed mitochondrial dynamic equilibrium and apoptosis execution. In addition, qRCR analysis confirmed the involvement of cytokines secreted by different populations of helper T cells, indicative of cellular immunity. Gene expression studies showed marked up regulation of Th1/Th17 cytokines along with heat shock protein (HSP) 70, a synergism was noted in co-administration group. Interesting, lower apoptosis index was noted in brainstem compared to cerebrum and cerebellum. An intense immunosuppression and heat shock response against Cu or/and As was also seen in cerebrum and cerebellum but not in brainstem. In conclusion, our study suggests a synergistic neurotoxicity in chickens under Cu and As exposure. These findings provide a basic understanding of mitochondrial abnormality-initiated neuropathology in response to environmental pollutant mixtures, suggesting an adaptive response to the frangibility of the central nerve system.

5.
J Nanosci Nanotechnol ; 20(3): 1440-1446, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492305

RESUMO

The effects of six metal oxide nanoparticles (MO-NPs) on the activity and biosynthesis of an enzyme (ß-galactosidase) were examined using a mutant strain of E. coli. Different sensitivities were observed according to the type of NP and metabolic process. The toxic effects on enzyme activity were significantly greater than on biosynthesis (p < 0.011), except in the presence of NiO. In both cases, ZnO NP caused the greatest inhibition among the tested NPs, followed by CuO. The EC50s for ZnO were 0.19 and 3.68 mg/L for enzyme activity and biosynthesis, respectively. Similar orders of toxicity were observed as follows: ZnO > CuO > NiO > Co3O4 > TiO2, Al2O3 for enzyme activity; and ZnO > CuO > NiO ≫ Al2O3, TiO2, Co3O4 for the biosynthetic process. More systematic research, including in-depth studies like investigation of the molecular mechanisms, is necessary to elucidate the detailed mechanisms of inhibition involved in both metabolic processes.

6.
World Neurosurg ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31790840

RESUMO

BACKGROUND: The supraorbital keyhole approach (SKA) and pterional approach (PA) have been recommended for clipping intracranial aneurysms (IAs). We aimed to conduct a meta-analysis to systematically and comprehensively compare the clinical outcomes between two approaches. METHOD: This study retrieved potential academic articles comparing the clinical outcomes between SKA and PA for clipping IAs from the database of Cochrane Library, Medline, PubMed, and EMBASE. The reference articles of the identified studies were carefully reviewed to certain that all available documents were represented in the study. The meta-analysis was conducted in accordance with the acknowledged the prioritized reported items for systematic review and meta-analysis (PRISMA) guidelines. RESULTS: A total of 8 studies were involved in our study including 1016 participants. Of these 1016 patients with IAs, 518 were assigned to the SKA group and 498 were assigned to the PA group. Our results showed that SKA is preferable for clipping IAs compared with PA as its shorter operation time (WMD = -3.163, 95% CI: -5.577 to -0.749, P =0.01) and length of stay especially for the patients with unruptured IAs (WMD = -52.107, 95% CI: -81.597 to -22.618). Meanwhile, a lower risk of postoperative infection was found in SKA group (4.6% versus 8.5%; OR, 0.398; 95% CI, 0.186-0.850; P=0.017), which seems derive from ruptured IAs (OR, 0.330; 95% CI, 0.136-0.800; P=0.014). However, there was no significant difference in frontal sinus opening, completed occlusion, procedural complications, intraoperative rupture, postoperative hematoma, and cerebral vessels spasm. CONCLUSIONS: SKA is associated with a shorter length of stay and operation time, and a lower risk of postoperative infection. Hence, the SKA seems to be equally effective and safe for clipping IAs compared with PA, and it should be recommended for surgeons who have acquired sufficient experience with this technique owing to its advantages over the PA.

7.
Sci Total Environ ; : 134553, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31791795

RESUMO

Livestock grazing activities substantially contribute to worldwide grassland degradation and potentially alter the growth of arbuscular mycorrhizal fungi. The global patterns of arbuscular mycorrhizal fungi in response to grazing, especially grazing intensity, are still unclear. In this study, we performed a meta-analysis of grazing intensity experiments to examine the grazing intensity effects on arbuscular mycorrhizal fungi across global grasslands. The results showed that heavy or moderate grazing consistently reduced arbuscular mycorrhizal fungal abundance by 34.38% and 9.14%, but light grazing had no significant effect. Arbuscular mycorrhizal fungal abundance was reduced with longer duration of grazing (-22.91%) and lower annual precipitation (-17.43%). Grazing decrease the abundance of arbuscular mycorrhizal fungal was possibly attributedto the reduction of above-ground biomass, in agreement with the carbon limitation hypothesis. It suggests the inhibition of arbuscular mycorrhizal fungal abundance by grazing at the cost of plant above-ground biomass. These findings highlight the negative effect of heavy grazing on arbuscular mycorrhizaes across worldwide grassland, and which may contribute to understand the effects of livestock grazing activities on symbiotic relationships between host plants and arbuscular mycorrhizal fungi.

8.
Plant Dis ; : PDIS05191047RE, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801036

RESUMO

Rice orange leaf disease (ROLD), caused by rice orange leaf phytoplasma (ROLP), is transmitted by leafhopper vectors Recilia dorsalis and Nephotettix cinticeps. ROLD severely devastates rice production in Asia. Accurate detection of the pathogen is important for disease management. Current nested polymerase chain reaction (nested PCR) method using phytoplasma universal primers is widely used to detect phytoplasmas; however, it has shortcoming of inconvenience and inaccuracy, for it needs two round of PCR reactions and could produce false positive results due to nontarget amplification. In this study, we developed a PCR assay using a set of primers designed based on the ROLP genome sequence to amplify house-keeping gene FtsH-1 in rice and leafhopper vector samples. This method is simple and rapid, and its sensitivity up to 10 pg/µl of total ROLP DNA. It also minimizes the false positive problem produced by nested PCR. This method was used to survey the geographic distribution of ROLD in southern China from 2016 to 2018. The results showed that the distribution areas and vector carrying rate of ROLD had gradually increased.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31753724

RESUMO

The objective of this study is to analyze the expression of ILC2 cells (type 2 innate lymphoid cells) in nasal mucosa based on animal model of allergic bacterial infection rhinitis. 45 female BALB/c mice were selected as research subject. They were randomly divided into control group (group A), sensitization group (group B) and inhibitor group (group C) to establish a mouse model of allergic rhinitis. The pathological changes of mouse nasal mucosa were observed by HE (hematoxylin-eosin) staining. The number of ILC2 cells in mouse nasal mucosa was detected by immunofluorescence double staining assay. Real-time quantitative Polymerase Chain Reaction (PCR) was used to detect the expression of ILC2 cell-associated factor in mouse nasal mucosa. The expression of cytokine protein in serum was detected by enzyme linked immunosorbent assay. The results showed that there was no inflammatory cell infiltration in the nasal mucosa of group A, and the number of ILC2 cells was small. Inflammatory cell infiltration and obvious ILC2 cells were observed in the nasal mucosa of group B and C, and the number of ILC2 cells in group B and C was significantly increased compared with that in group A. Compared with group A, ROR α, Thy-1, ST2, and CD90 genes were significantly increased in nasal mucosa tissues of group B and C, and protein levels of IL-4, IL-5, IL-13, and IgE in serum were significantly increased. Compared with group B, the protein expression levels of IL-13 and IgE in serum of group C mice were significantly increased, while the expression levels of IL-4 and IL-5 were not significantly different. In conclusion, in the pathogenesis of allergic rhinitis, ILC2 cells play a role in promoting the development of inflammation, and its expression is related to RORα, Thy-1, ST2 and CD90. Meanwhile, ILC2 cells are also important cells for the synthesis and secretion of IL-13. The study on the pathogenesis of allergic rhinitis provides a new target for its treatment.

10.
Water Res ; 169: 115202, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31669899

RESUMO

The degradation of tetrabromobisphenol A (TBBPA), one of the most widely used brominated flame retardant, was evaluated during peroxymonosulfate (PMS) oxidation. TBBPA degradation was pH-dependent, with peak degradation rate constants occurring at pH 8.0-9.0, which was distinct from some other phenolic compounds. Singlet oxygen and radicals were found to play negligible roles in TBBPA degradation. TBBPA oxidation by PMS mainly proceeded via a direct oxidation pathway and the in-situ formed HOBr was found to greatly accelerate its degradation rates. The values of species-specific second-order rate constants for the reactions of PMS with the TBBPA kHSO5-+TBBPA, kHSO5-+TBBPA- and kHSO5-+TBBPA2- were determined to be (1.11 ±â€¯0.84) × 10-2, (8.05 ±â€¯2.31) × 10-2, and (1.34 ±â€¯0.25) × 10-1 M-1 s-1, respectively, while the reaction rate constants for HOBr/OBr- with TBBPA kHOBr+TBBPA, kHOBr+TBBPA-, kHOBr+TBBPA2-and kOBr-+TBBPA2- were determined to be (9.38 ±â€¯2.10) × 103, (1.59 ±â€¯0.56) × 105, (8.22 ±â€¯0.41) × 106, and (1.81 ±â€¯0.12) × 106 M-1 s-1, respectively. The bromine mass balance analysis showed that bromide ion and HOBr/OBr- occupied 19.5% of total Br and brominated organic compounds accounted for the remaining percentages at pH 7.0. No formation of bromate was observed. Based on the identified products, a reaction pathway was proposed, which included oxidation, ß-scission, hydroxylation, and dimerization reaction pathways. The results indicate that unactivated PMS is useful for the remediation of TBBPA contaminated water.

11.
Mol Genet Genomic Med ; : e1023, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31774634

RESUMO

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

12.
Environ Sci Technol ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31729864

RESUMO

Nitrite (NO2-) and its conjugate acid, nitrous acid (HNO2), have long been recognized as a ubiquitous atmospheric pollutant as well as an important photochemical source of hydroxyl radicals (·OH) and reactive nitrogen species (·NO, ·NO2, ·N2O3, etc.) in both the gas phase and aqueous phase. Although NO2-/HNO2 plays an important role in atmospheric chemistry, our understanding on its role in the chemical evolution of organic components in atmospheric waters is rather incomplete and is still in dispute. In this study, the nitrite-mediated photooxidation of vanillin (VL), a phenolic compound abundant in biomass burning emissions, was investigated under pH conditions relevant for atmospheric waters. The influence of solution pH, dissolved oxygen, and ·OH scavengers on the nitrite-mediated photooxidation of VL was discussed in detail. Our study reveals that the molecular composition of the products is dependent on the molar ratio of NO2-/VL in the solution and that nitrophenols are the major reaction products. We also found that the light absorbance of the oxidative products increases with increasing pH in the visible region, which can be attributed to the deprotonation of the nitrophenols formed. These results contribute to a better understanding of methoxyphenol photooxidation mediated by nitrite as a source of toxic nitrophenols and climatically important brown carbon in atmospheric waters.

13.
Int J Biol Macromol ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31712145

RESUMO

For further applications of Alpiniae oxyphyllae fructus in modern clinical medicine, Alpiniae oxyphyllae fructus polysaccharide (AOFP) was studied in the present work. The extraction conditions of AOFP were optimized by the response surface method with a Box-Behnken design. The maximum extraction rate of AOFP was 3.18%. An anion-exchange DEAE-52 cellulose column and a Sephadex G-100 gel column were used to isolate the AOFP, and three polysaccharides (AOFP1, AOFP2, AOFP3) were obtained. All three polysaccharides possessed immunoregulatory activity, but the effects of AOFP1 were greater than the other two polysaccharides. AOFP1 significantly stimulated Th1- and Th2-type immune responses and specific immune responses. Meanwhile, the characterization of AOFP1 was studied. AOFP1 was composed of arabinose, galactose, glucose, xylose, mannose, galacturonic acid, and glucuronic acid at a molar ratio of 16.46:12.7:4.9:17.11:4.35:6.52:6 with an average molecular weight of 43.4 kDa. These results suggest that AOFP1 can be developed as a natural immunomodulatory drug.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31745598

RESUMO

Hexachloro-1,3-butadiene (HCBD) is a persistent organic pollutant listed in Annex A and C of the Stockholm Convention. This review summarized the sources, occurrence, toxicity, and transformation of HCBD in the environment. HCBD had no natural sources, and anthropogenic sources made it frequently detected in environmental medium, generally at µg L- 1 and µg kg- 1 in water and soil (or organism) samples, respectively. HCBD posed reproductive, genetic, and potentially carcinogenic toxicity to organisms, threatening human health and the ecosystem. Upon biodegradation, photodegradation and physicochemical degradation processes, HCBD can be degraded to a different extent. Nevertheless, further studies should be focused on the potential emission sources and the impact of HCBD on human health and the environment. Additionally, exploring removal technologies based on advanced oxidation and reduction are recommended.

15.
17.
Artigo em Inglês | MEDLINE | ID: mdl-31748160

RESUMO

In this paper, a unique water-soluble heptamethine cyanine dye as NIR photosensitizer was synthesized to explore its properties associated with potential applications in photodynamic therapy (PDT). In the strategy of designing this photosensitizer, a sulfonic acid was used as a water soluble functional group and linked to the fluorophore through alkyl chains. 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl(Tempo) moiety was used as the a nitroxide spin label in obtaining biochemical reaction information in vivo due to it could greatly increase the inter-system crossing (ISC) process for triplet-state photosensitizers and low toxicity. As expected, the photosensitizers performed well in vitro photodynamic therapy. There were a remarkable absorbance band located at 692 nm and emission peaks falls at 762 nm, the quantum yield (Φf) was calculated to be 12.12% in pure aqueous solution using ICG as standards. The photosensitizer also has high singlet oxygen quantum yield (Φ△) for 16.96% with NIR LED irradiation. This photosensitizer can rapidly produce singlet oxygen and exhibit high phototoxicity under NIR light irradiation. It has excellent cellular uptake ability and better cell compatibility. It was also successfully applied in Near-infrared fluorescence imaging and AO/EB staining. In a whole, the organic dye based on Heptamethine cyanine used as photosensitizer has great potential in vivo cancer treatment.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31705175

RESUMO

PURPOSE: Accurate evaluation of hypoxia is particularly important in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The aim of this study was to propose a novel imaging strategy for quantitative three-dimensional (3D) evaluation of hypoxia in a small animal model of NPC. METHODS: A carbonic anhydrase IX (CAIX)-specific molecular probe (CAIX-800) was developed for imaging of hypoxia. Mouse models of subcutaneous, orthotopic, and spontaneous lymph node metastasis from NPC (5 mice per group) were established to assess the imaging strategy. A multi-modality imaging method that consisted of a hybrid combination of fluorescence molecular tomography-computed tomography (FMT-CT) and multispectral optoacoustic tomography (MSOT) was used for 3D quantitative evaluation of tumour hypoxia. Magnetic resonance imaging, histological examination, and immunohistochemical analysis were used as references for comparison and validation. RESULTS: In the early stage of NPC (2 weeks after implantation), FMT-CT enabled precise 3D localisation of the hypoxia biomarker with high sensitivity. At the advanced stage (6 weeks after implantation), MSOT allowed multispectral analysis of the biomarker and haemoglobin molecules with high resolution. The combination of high sensitivity and high resolution from FMT-CT and MSOT could not only detect hypoxia in small-sized NPCs but also visualise the heterogeneity of hypoxia in 3D. CONCLUSIONS: Integration of FMT-CT and MSOT could allow comprehensive and quantifiable evaluation of hypoxia in NPC. These findings may potentially benefit patients with NPC undergoing radiotherapy in the future. Graphical abstract A novel multimodality imaging strategy for three-dimensional evaluation of tumour hypoxia in an orthotopic model of nasopharyngeal carcinoma.

19.
Biopharm Drug Dispos ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31674039

RESUMO

Reaction phenotyping using human liver microsomes or hepatocytes with chemical inhibitors is one of the most commonly applied methods to assess fraction metabolized (fm ) of drug candidates by enzymes. The fm information is critical to the understanding the risk of victim drug-drug interactions in the clinic. Inhibitor selectivity is essential in order to generate reliable data and irreversible inhibitors are often preferred over reversible inhibitors to minimize the impact of inhibitor depletion. Although many selective cytochrome P450 (CYP) inhibitors are available, identification of selective CYP2B6 inhibitors have been challenging due to cross inhibition to the other enzymes. In this study, dasotraline is evaluated as a selective inactivator of CYP2B6 under reaction phenotyping conditions with human hepatocytes. The results show that dasotraline is a very selective inactivator for CYP2B6 with minimal inhibition to other enzymes. A concentration of 0.1 µM dasotraline is recommended for reaction phenotyping with a hepatocyte cell density of 0.5 million cells/mL or 0.5 µM for 2 million cells/mL, when using a 15 minute preincubation, as well as the protocol of inactivator removal before addition of substrates.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31751214

RESUMO

OBJECTIVE: Bioluminescence tomography (BLT) is a non-invasive technique designed to enable three-dimensional (3D) visualization and quantification of viable tumor cells in living organisms. However, despite the excellent sensitivity and specificity of bioluminescence imaging (BLI), BLT is limited by the photon scattering effect and ill-posed inverse problem. If the complete structural information of a light source is considered when solving the inverse problem, reconstruction accuracy will be improved. METHODS: This paper proposed a block sparse Bayesian learning method based on K-nearest neighbor strategy (KNNBSBL), which incorporated several types of a priori information including sparsity, spatial correlations among neighboring points, and anatomical information to balance over-sparsity and morphology preservation in BLT. Furthermore, we considered the Gaussian weighted distance prior in a light source and proposed a KNN-GBSBL method to further improve the performance of KNN-BSBL. RESULTS: The results of numerical simulations and in vivo glioma-bearing mouse experiments demonstrated that KNNBSBL and KNN-GBSBL achieved superior accuracy for tumor spatial positioning and morphology reconstruction. CONCLUSION: The proposed method KNN-BSBL incorporated several types of a priori information is an efficient and robust reconstruction method for BLT.

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