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1.
Chempluschem ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017446

RESUMO

Invited for this month's cover is the group of Dr. Hua Dong from Chengdu University of Technology, China. The cover picture shows a nonmetal catalyst (SiO2 @H+PEI) that promotes hydrogen production by hydrolysis of NaBH4 . This newly developed catalyst, which is fabricated by covalently modifying SiO2 nanoparticles with protonated poly(ethylene imime), provides a promising choice for the cheap and efficient catalysis of NaBH4 hydrolysis. Read the full text of the article at 10.1002/cplu.201900609.

2.
Methods Mol Biol ; 2108: 43-55, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939169

RESUMO

Immunohistochemistry (IHC), also known as immunohistochemical staining, is an immune morphological analysis. It is a process of selectively identifying antigens (proteins) by antibodies in cells or tissue sections. This chapter introduces the procedure and application of immunohistochemistry. Although immunohistochemistry has a vast application in basic and clinical studies, this chapter focuses on its application in biomarker study, particularly in biomarkers that related to cancer diagnosis, prognosis, and drug development. Detail protocol of immunohistochemistry in formalin-fixed and paraffin-embedded tissue sections is included.

3.
Molecules ; 25(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991808

RESUMO

Four new diterpenoids, named aspidoptoids A-D (1-4), together with two known analogues (5-6) were isolated from Aspidopterys obcordata vine. Aspidoptoids A-B (1-2) are the first examples of phenylethylene-bearing 20-nor-diterpenoids of which aspidoptoid B (2) possesses a rare 3,10-oxybridge. Their structures and absolute configuration were determined by extensive spectroscopic analyses (IR, HRESIMS, 1D and 2D NMR) and electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their cytotoxic activities and inhibitory effects on the nitric oxide (NO) production.

4.
ACS Appl Mater Interfaces ; 12(6): 7565-7574, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31971764

RESUMO

Flexible wearable sensors are emerging as next-generation tools to collect information from the human body and surroundings in a smart, friendly, and real-time manner. A new class of such sensors with various functionality and amenability for the human body is essential for this goal. Unfortunately, the majority of the wearable sensors reported so far in the literature were of a single function (mostly strain sensors) and just a prototype without thinking of continuous mass production. In this paper, we report a series of multifunctional conductive hydrogel/ thermochromic elastomer hybrid fibers with core-shell segmental configuration and their application as flexible wearable strain and temperature sensors to monitor human motion and body/surrounding temperatures. Specifically, a conductive reduced-graphene-oxide-doped poly(2-acrylamido-2-methyl-1-propanesulfonic acid-co-acrylamide (rGO-poly(AMPS-co-AAm)) hydrogel and a thermochromic elastomer containing silicon rubber and thermochromic microcapsules are chosen as strain-sensitive and thermosensitive materials, respectively. A core-shell segmental structure is realized by programming the extrusion of either conductive hydrogel precursor solution or a thermochromic elastomer prepolymer as a core layer via dual-core coaxial wet spinning. Depending on the assembly order and length of the conductive hydrogel and the thermochromic elastomer, the as-prepared hybrid fibers can be used for different purposes, i.e., human-motion monitoring, body or room temperature detection, and color decoration. The strategy described above, i.e., fabrication of core-shell segmental fibers via the wet-spinning method, is especially suitable for mass production in industry and can be further extended to fabricate flexible wearable devices with more components and more functions such as transistors, sensors, displays, and batteries.

5.
Exp Cell Res ; : 111858, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31972220

RESUMO

Pevonedistat is a potent, selective, first-in-class NEDD8 activating enzyme inhibitor. It is now under multiple clinical trials that investigate its anticancer effect against solid tumors and leukemia. ATP-binding cassette (ABC) transporters are membrane proteins that are involved in mediating multidrug resistance (MDR). In this article, we reveal that pevonedistat is a substrate of ABCG2 which decreases the therapeutic effect of pevonedistat. The cytotoxicity of pevonedistat was significantly weakened in ABCG2-overexpressing cells, and the drug resistance can be reversed by ABCG2 inhibitors. The ATPase assay suggested that pevonedistat can stimulate ABCG2 ATPase activity in a concentration-dependent manner. Pevonedistat showed little effect on the expression level or subcellular localization of ABCG2 after 72 h treatment. Furthermore, a pevonedistat resistance cell line S1-PR was established and overexpressed ABCG2. Generally, our study provides evidence that ABCG2 can be a prominent factor leading to pevonedistat-resistance. Furthermore, ABCG2 may also be utilized as a biomarker to monitor the development of pevonedistat resistance during cancer treatment.

6.
Mol Med Rep ; 21(2): 607-614, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31789412

RESUMO

Ventilator­induced lung injury (VILI) is a life­threatening condition caused by the inappropriate use of mechanical ventilation (MV). However, the precise molecular mechanism inducing the development of VILI remains to be elucidated. In the present study, it was revealed that the calcineurin/NFATc4 signaling pathway mediates the expression of adhesion molecules and proinflammatory cytokines essential for the development of VILI. The present results revealed that a high tidal volume ventilation (HV) caused lung inflammation and edema in the alveolar walls and the infiltration of inflammatory cells. The calcineurin activity and protein expression in the lungs were increased in animals with VILI, and NFATc4 translocated into the nucleus following calcineurin activation. Furthermore, the translocation of NFATc4 and lung injury were prevented by a calcineurin inhibitor (CsA). Thus, the present results highlighted the critical role of the calcineurin/NFATc4 signaling pathway in VILI and suggest that this pathway coincides with the release of ICAM­1, VCAM­1, TNF­α and IL­1ß.

7.
Transl Oncol ; 13(1): 25-31, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743830

RESUMO

PURPOSE: In contrast to other studies, our previous study showed that adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) significantly worsened the prognosis of patients with stage II nasopharyngeal carcinoma (NPC). However, the population used was small; therefore, there is an urgent need to confirm the result in a larger population because IC is still widely used in certain sections of china for stage II NPC. METHODS AND MATERIALS: We retrospectively analyzed an additional 272 patients. Therefore, in total, we report the results for 445 patients with stage II NPC treated with IC + CCRT or CCRT between June 2003 to June 2016 at the Zhejiang Cancer Hospital and Sun Yat-Sen University Cancer Center. RESULTS: This study included 445 patients treated with IC + CCRT (n = 195) or CCRT (n = 250). By last analysis, 22 (11.3%) patients in the IC + CCRT group developed local-regional recurrence and 23 (11.8%) patients developed distant metastases. Twenty-four (9.6%) patients in the CCRT group developed local-regional recurrence and 12 (4.8%) patients developed distant metastases. Univariate analyses showed that adding IC to CCRT significantly decreased the 5-year disease-free survival (DFS) (80.6% vs. 88.5%, P = .043); however, there was no statistically significant difference in 5-year overall survival (OS) (90.5% vs. 95.0%, P = .375). CONCLUSION: Using a larger population, the present study showed that adding IC to CCRT had a negative effect on patients with stage II NPC, which warrants further investigation.

8.
Phytother Res ; 34(1): 153-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31497910

RESUMO

Neuroinflammation and oxidative stress are key contributors to intracranial hemorrhage (ICH)-induced brain injury. Parthenolide (PN) is a sesquiterpene lactone that has been observed to have antioxidative, anti-inflammatory, and neuroprotective potentials. However, the role of PN in ICH remains unclear. Therefore, we investigated the neuroprotective effects and underlying mechanisms of PN on an experimental model of ICH in rats. Our results showed that PN treatment improved neurological deficit and brain edema in ICH rats. The ipsilateral hemispheres of the brain were separated and homogenized. The concentrations of TNF-α, interleukin (IL)-6, and IL-17 in the homogenates were detected by enzyme-linked immunosorbent assay. We found that PN inhibited the production of proinflammatory cytokines in an ICH rat model. The ROS and glutathione (GSH) levels, as well as the activity of superoxide dismutase (SOD) in the homogenates were measured. ICH caused an increase in ROS level, and the decreases in GSH level and SOD activity were mitigated by PN treatment. Furthermore, PN significantly suppressed the expressions of active caspase-3 and Bax in ipsilateral hemispheres of the brain at Day 3 after ICH, as well as increased the surviving neurons. Finally, the ICH-induced activation of TLR4/NF-κB pathway was suppressed by PN treatment. These findings suggested that PN could be beneficial in the therapeutic strategy for ICH treatment.

9.
Cancer Lett ; 472: 132-141, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837444

RESUMO

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm primarily due to the presence of the BCR-ABL fusion gene that produces the constitutively active protein, BCR-ABL. Imatinib, a BCR-ABL-targeted drug, is a first-line drug for the treatment of CML. Resistance to imatinib occurs as a result of mutations in the BCR-ABL kinase domains. In this study, we evaluated S116836, a novel BCR-ABL inhibitor, for its anti-cancer efficacy in the wild-type (WT) and T315I mutant BCR-ABL. S116836 was efficacious in BaF3 cells with WT or T315I mutated BCR-ABL genotypes. S116836 inhibits the phosphorylation of BCR-ABL and its downstream signaling in BaF3/WT and BaF3/T315I cells. Mechanistically, S116836 arrests the cells in the G0/G1 phase of cell cycle, induces apoptosis, increases ROS production, and decreases GSH production in BaF3/WT and BaF3/T315I cells. Moreover, in mouse tumor xenografts, S116836 significantly inhibits the growth and volume of tumors expressing the WT or T315I mutant BCR-ABL without causing significant cardiotoxicity. Overall, our results indicate that S116836 significantly inhibits the imatinib-resistant T315I BCR-ABL mutation and could be a novel drug candidate for treating imatinib-resistant CML patients.

10.
ACS Appl Mater Interfaces ; 12(2): 2826-2834, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31852186

RESUMO

Transparent and flexible electromagnetic interference (EMI) shielding film is highly desirable due to the fast-growing flexible electronics. A silver nanowire (Ag NW) film is considered to be an ideal candidate for a transparent and flexible EMI shielding film but suffers low EMI shielding effectiveness (SE) at high transparency and poor bending durability. Herein, we introduce ferroferric oxide (Fe3O4) into a Ag NW film and demonstrate a robust EMI shielding film, which exhibits SE of 24.9 dB at 8.2 GHz and optical transparency of 90%. Fe3O4 exhibits roles of the improved absorption loss for electromagnetic radiation due to its high permeability, the enhanced reflection loss for electromagnetic radiation by increasing the conductivity of Ag NWs film, and the improved stability for the enhanced adhesion of the Ag NW EMI shielding film. Our work provides a facile method for high-performance transparent EMI shielding film, which exhibits great potential for protection for electronic devices.

11.
ACS Appl Mater Interfaces ; 12(2): 2835-2841, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31865697

RESUMO

To best catch human eyes in next-generation displays, the updated recommendation 2020 (Rec. 2020) standard has called for ultrapure green emitters to be qualified with a narrow emission of 525-535 nm with a full width at half-maximum (fwhm) below 25 nm. However, it is still challenging to find an emitter which can simultaneously cover these two criteria. Instead of traditional II-VI group semiconductor quantum dots, perovskite nanocrystals (NCs) can render versatile emitting tunability to allow them access to the Rec. 2020 standard. Herein, to realize the critical window of Rec. 2020, we have proposed a scalable, room temperature synthesis route of formamidinium lead bromide (FAPbBr3) NCs using a sole ligand of sulfobetaine-18 (SBE-18). The as-synthesized FAPbBr3 NCs exhibit an ideal emission at 534 nm with an ultranarrow fwhm of 20.5 nm and a high photoluminescence quantum yield of 90.6%, overwhelming the FAPbBr3 nanoplates capped with oleic acid/oleylamine (OA/OAM). Introducing these high quality NCs into backlight displays, an ultrapure green backlight which covers ≈85.7% of the Rec. 2020 standard in the CIE 1931 color space is achieved, signifying the "greenest" backlight till now. Thus, we can foresee perovskite NCs as the most potential candidates for next-generation displays.

12.
J Biotechnol ; 307: 29-34, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31689467

RESUMO

Yeast has been widely used for large-scale production of terpenoids. In yeast, modifications of terpenoid biosynthetic pathways have been intensively studied. tHMG1 (encoding the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase of yeast) and UPC2-1 (the G888D mutant of UPC2 encoding a transcription factor) were integrated into yeast chromosome, and ERG9 (the squalene synthase gene of yeast) was knocked down to yield the chassis strain DH02. A F96C mutation in ERG20 (farnesyl diphosphate synthase of yeast) was conducted to obtain mERG20 which can function as a geranylgeranyl diphosphate synthase (GGPS). Then, three fused genes, including BTS1 (the yeast innate GGPS)-ERG20, ERG20-mERG20 and mERG20-ERG20, were constructed, and expressed either by the pESC-based plasmids in DH02, or by being integrated into DH02 chromosome. The highest geranylgeraniol (GGOH) content was observed in the extracts of DH12 integrated with ERG20-mERG20, corresponding to 3.2 and 2.3 folds of those of the strains integrated with BTS1 and mERG20, respectively. Finally, three genes encoding nor-copalyl diphosphate synthase (nor-CPS), ent-CPS and syn-CPS were integrated into the chromosome of DH12, respectively, to construct yeasts for producing corresponding copalyl diphosphates (CPPs). Thus, a yeast-based platform was built for characterizing all types of diterpene synthases using GGPP or various CPPs as their substrates.

13.
Molecules ; 24(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801248

RESUMO

The overexpression of ABC transporters induced by anticancer drugs has been found to be the main cause of multidrug resistance. It is actually also a strategy by which cancer cells escape being killed. Tetrandrine is a natural product extracted from the stem of Tinospora crispa. In this study, tetrandrine showed synergistic cytotoxic activity in combinational use with chemotherapeutic drugs, such as Doxorubicin, Vincristine, and Paclitaxel, in both drug-induced and MDR1 gene-transfected cancer cells that over-expressed ABCB1/P-glycoprotein. Tetrandrine stimulated P-glycoprotein ATPase activity, decreased the efflux of [3H]-Paclitaxel and increased the intracellular accumulation of [3H]-Paclitaxel in KB-C2 cells. Furthermore, SW620/Ad300 and KB-C2 cells pretreated with 1 µM tetrandrine for 72 h decreased P-glycoprotein expression without changing its cellular localization. This was demonstrated through Western blotting and immunofluorescence analysis. Interestingly, down-regulation of P-glycoprotein expression was not correlated with gene transcription, as the MDR1 mRNA level exhibited a slight fluctuation in SW620/Ad300 and KB-C2 cells at 0, 24, 48, and 72 h treatment time points. In addition, molecular docking analysis predicted that tetrandrine had inhibitory potential with the ABCB1 transporter. Our results suggested that tetrandrine can antagonize MDR in both drug-selected and MDR1 gene-transfected cancer cells by down regulating the expression of the ABCB1 transporter, followed by increasing the intracellular concentration of chemotherapeutic agents. The combinational therapy using tetrandrine and other anticancer drugs could promote the treatment efficiency of drugs that are substrates of ABCB1.

14.
Genomics ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31809797

RESUMO

Promoter is an important functional elements of DNA sequences, which is in charge of gene transcription initiation. Recognizing promoter have important help for understanding the relative life phenomena. Based on the concept that promoter is mainly determined by its sequence and structure, a novel statistical physics model for predicting promoter in Escherichia coli K-12 is proposed. The total energies of DNA local structure of sequence segments in the three benchmark promoter sequence datasets, the sole prediction parameter, are calculated by using principles from statistical physics and information theory. The better results are obtained. And a web-server PhysMPrePro for predicting promoter is established at http://202.207.14.87:8032/bioinformation/PhysMPrePro/index.asp, so that other scientists can easily get their desired results by our web-server.

15.
J Thorac Oncol ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31843683

RESUMO

INTRODUCTION: Blood-based tumor mutational burden (bTMB) has been studied to differentiate non-small cell lung cancer (NSCLC) patients who would benefit from anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of NSCLC patients treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N=211 and OAK, N=462) and further validated in the third National Cancer Center cohort (NCC, N=64). RESULTS: bTMB-H (bTMB≥cut-off point) was not associated with favorable OS following immunotherapy regardless of the cut-off points in either the POPLAR and OAK or the NCC cohorts (P>0.05) due to its correlation with the circulating tumor DNA (ctDNA) amount, which was associated with poor OS. In the POPLAR and OAK cohorts, upon allele frequency (AF) adjustment, a high allele frequency bTMB (HAF-bTMB, mutation counts with an AF>5%) was strongly correlated with the ctDNA amount (Pearson's r=0.65), while a low allele frequency bTMB (LAF-bTMB, mutation counts with an AF≤5%) was not (Pearson's r=0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [[HR], 0.70; 95% confidence interval [CI], 0.52-0.95; P=0.02), progression-free survival (PFS) (HR, 0.62; 95% CI, 0.47-0.80; P<0.001), and the objective response rate (ORR) (P<0.001) following immunotherapy but not chemotherapy, with a cut-off point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR, 0.20; 95% CI, 0.05-0.84; P=0.02), PFS (HR, 0.30; 95% CI, 0.13-0.70; P=0.003), and the ORR (P=0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and the ORR following anti-PD-1/PD-L1 therapies in NSCLC patients, which needs to be prospectively validated.

16.
Nat Chem Biol ; 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844301

RESUMO

Chloramphenicol (CHL) and linezolid (LZD) are antibiotics that inhibit translation. Both were thought to block peptide-bond formation between all combinations of amino acids. Yet recently, a strong nascent peptide context-dependency of CHL- and LZD-induced translation arrest was discovered. Here we probed the mechanism of action of CHL and LZD by using single-molecule Förster resonance energy transfer spectroscopy to monitor translation arrest induced by antibiotics. The presence of CHL or LZD does not substantially alter dynamics of protein synthesis until the arrest-motif of the nascent peptide is generated. Inhibition of peptide-bond formation compels the fully accommodated A-site transfer RNA to undergo repeated rounds of dissociation and nonproductive rebinding. The glycyl amino-acid moiety on the A-site Gly-tRNA manages to overcome the arrest by CHL. Our results illuminate the mechanism of CHL and LZD action through their interactions with the ribosome, the nascent peptide and the incoming amino acid, perturbing elongation dynamics.

17.
Biopharm Drug Dispos ; 40(9): 341-349, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31693190

RESUMO

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 µmol min/L, Cmax 6.46 ± 0.74 µmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 µmol/min/L, Cmax 6.10 µmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.

18.
Zhongguo Zhen Jiu ; 39(11): 1149-53, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31724347

RESUMO

OBJECTIVE: To explore the clinical therapeutic effect and mechanism of acupuncture on headache in the recovery phase of ischemic stroke. METHODS: A total of 97 patients with headache in the recovery phase of ischemic stroke were randomized into an acupuncture group (57 cases) and a western medication group (40 cases). In the western medication group, flunarizine hydrochloride capsule was taken orally 5 mg each time, once a day. In the acupuncture group, acupuncture was applied at Qiuxu (GB 40), Zulinqi (GB 41), Xuanli (GB 6), Shuaigu (GB 8), Fengchi (GB 20) and Baihui (GV 20) for migraine; Chongyang (ST 42), Neiting (ST 44), Jiexi (ST 41), Zusanli (ST 36), Hegu (LI 4), Cuanzhu (BL 2) and Baihui (GV 20) for forehead pain; Jinggu (BL 64), Kunlun (BL 60), Tianzhu (BL 10), Fengchi (GB 20), Baihui (GV 20) and Sishencong (EX-HN 1) for occipital headache; Taichong (LR 3), Yongquan (KI 1), Sanyinjiao (SP 6), Fengchi (GB 20), Baihui (GV 20) and Sishencong (EX-HN 1) for parietal headache. The needles were retained for 30 min each time, once a day and 5 times a week. Both of the two groups were given consecutive treatment for 14 days. The visual analogue scale (VAS) and the headache scores before and after treatment and the recurrence rate 1 month after treatment were observed to evaluate the therapeutic effect, before and after treatment, the contents of substance P (SP), dopamine (DA), serotonin (5-HT), alpha-endorphin (α-EP) and beta-endorphin (ß-EP) in plasma were determined by ELISA in the two groups. RESULTS: Compared before treatment, the VAS scores, the headache scores and the contents of SP, DA and 5-HT in plasma were reduced and the contents ofα-EP andß-EP in plasma were increased in the two groups (all P<0.01). After treatment, the changes of the VAS score, the headache score and the contents of pain-related factors and endogenous opioid peptides in plasma in the acupuncture group were larger than the western medication group (all P<0.05). The total effective rate in the acupuncture group was 84.2% (48/57), which was superior to 62.5% (25/40) in the western medication group, and the recurrence rate in the acupuncture group was lower than the western medication group (both P<0.01). CONCLUSION: The therapeutic effect of acupuncture on headache in the recovery phase of ischemic stroke is superior to flunarizine hydrochloride capsule, and the mechanism may relate to down-regulate the pain-related factors and up-regulate endogenous opioid peptides in plasma.


Assuntos
Terapia por Acupuntura , Cefaleia/terapia , Acidente Vascular Cerebral , Pontos de Acupuntura , Terapia por Acupuntura/métodos , Isquemia Encefálica , Flunarizina/uso terapêutico , Humanos , Acidente Vascular Cerebral/complicações , Resultado do Tratamento , Vasodilatadores/uso terapêutico
19.
Genes (Basel) ; 10(11)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739500

RESUMO

While methods for detecting SNVs and indels in circulating tumor DNA (ctDNA) with hybridization capture-based next-generation sequencing (NGS) have been available, copy number variations (CNVs) detection is more challenging. Here, we present a method enabling CNV detection from a 150-gene panel using a very low amount of ctDNA. First, a read depth-based CNV estimation method without a paired blood sample was developed and cfDNA sequencing data from healthy people were used to build a panel of normal (PoN) model. Then, in silico and in vitro simulations were performed to define the limit of detection (LOD) for EGFR, ERBB2, and MET. Compared to the WES results of the 48 samples, the concordance rate for EGFR, ERBB2, and MET CNVs was 78%, 89.6%, and 92.4%, respectively. In another cohort profiled with the 150-gene panel from 5980 lung cancer ctDNA samples, we detected the three genes' amplification with comparable population frequency with other cohorts. One lung adenocarcinoma patient with MET amplification detected by our method reached partial response to crizotinib. These findings show that our ctDNA CNV detection pipeline can detect CNVs with high specificity and concordance, which enables CNV calling in a non-invasive way for cancer patients when tissues are not available.

20.
ACS Cent Sci ; 5(9): 1614-1624, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31572788

RESUMO

The drug discovery and development process is greatly hampered by difficulties in translating in vitro potency to in vivo efficacy. Recent studies suggest that the long-neglected drug-target residence time parameter complements classical drug affinity parameters (K I, K d, IC50, or EC50) and is a better predictor of in vivo efficacy. Compounds with a long drug-target residence time are often more efficacious in vivo. The impact, however, of the drug-target residence time on in vivo efficacy remains controversial due to difficulties in experimentally determining the in vivo target occupancy during drug treatment. To tackle this problem, an in vivo displacement assay was developed using soluble epoxide hydrolase as a biological model. In this report, we experimentally demonstrated that drug-target residence time affects the duration of in vivo drug-target binding. In addition, the drug-target residence time plays an important role in modulating the rate of drug metabolism which also affects the efficacy of the drug.

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