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1.
J Cell Commun Signal ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31933275

RESUMO

Pembrolizumab monotherapy has been demonstrated as a first-line therapy for non-small-cell lung cancer (NSCLC) patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥50%; however, the clinical efficacy is limited by the unreasonable threshold of the TPS. A recent study published by Mok et al. (Lancet 393:1819-1830, 2019) showed that pembrolizumab monotherapy could also be extended as an effective first-line therapeutic strategy for NSCLC patients with low TPS. However, this needs to be further evaluated in detail after considering the following issues. In Mok's report, the survival curves were much lower in a pembrolizumab-treated group in the first 6 months of treatment compared with a chemotherapy group. These contradictory findings might have been due to anecdotal occurrences of rapid progression, especially hyperprogressive disease.

2.
Mol Med Rep ; 21(1): 360-370, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939622

RESUMO

The gasdermin (GSDM) superfamily has been demonstrated to consist of several important molecules that modulate multifunctional signal processes, such as cell pyroptosis. In this research, the roles of the GSDM superfamily on the occurrence and prognosis of lung adenocarcinoma (LUAD) were evaluated using integrative bioinformatic analyses and in vitro methods. Here, data from several bioinformatic platforms revealed that GSDMC is significantly upregulated in LUAD tissues and cell lines. Real­time fluorescence quantitative PCR (qPCR) demonstrated that GSDMC was obviously upregulated in radio­resistant LUAD cells, compared with their parental cells. Moreover, upregulated GSDMC expression was confirmed to be an independent indicator of poor first progression (FP) and overall survival (OS) in LUAD patients. DNA methylation analysis showed an evidently negative correlation between GSDMC expression and methylation status of one CpG site (cg05316065) in its DNA sequence. Patients with high methylation values had significantly higher Karnofsky performance scores (KPSs) and prolonged OS rates. Together, we confirmed that overexpression of GSDMC acts as a promising predictive factor for the poor prognosis of LUAD patients.

3.
Langmuir ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31971393

RESUMO

Solid-state nanopores provide a highly versatile platform for rapid electrical detection and analysis of single molecules. Lipid bilayer coating of the nanopores can reduce nonspecific analyte adsorption to the nanopore sidewalls and increase the sensing selectivity by providing possibilities for tethering specific ligands in a cell-membrane mimicking environment. However, the mechanism and kinetics of lipid bilayer formation from vesicles remain unclear in the presence of nanopores. In this work, we used a silicon-based, truncated pyramidal nanopore array as the support for lipid bilayer formation. Lipid bilayer formation in the nanopores was monitored in real time by the change in ionic current through the nanopores. Statistical analysis revealed that a lipid bilayer is formed from the instantaneous rupture of individual vesicle upon adsorption in the nanopores, differing from the generally agreed mechanism that lipid bilayer forms at a high vesicle surface coverage on a planar support. The dependence of the lipid bilayer formation process on the applied bias, vesicle size, and concentration was systematically studied. In addition, the nonfouling properties of the lipid bilayer coated nanopores were demonstrated during long single-stranded DNA translocation through the nanopore array. The findings indicate that the lipid bilayer formation process can be modulated by introducing nanocavities intentionally on the planar surface to create active sites or changing the vesicle size and concentration.

5.
Ann Transl Med ; 7(20): 541, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807523

RESUMO

Background: Gliomas are the most frequently occurring malignant brain cancers. Recently, isocitrate dehydrogenase (IDH) mutations, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and 1p/19q co-deletion have been suggested to indicate a favorable prognosis in gliomas. However, the clinical prognostic value of these genetic tests in human gliomas is not fully understood. Methods: We included glioma patients who accepted genetic testing including IDH, MGMT and 1p/19q at Xiangya Hospital, Central South University in China (Jan 2015 to Jun 2017) and further analyzed the effect of the above gene states in high-grade gliomas. Results: In 103 high-grade glioma patients, IDH mutation, MGMT promoter methylation, and 1p/19q co-deletion had better progression-free survival (PFS) than IDH wild-type (P=0.005), MGMT unmethylated promoter (P=0.002), and without 1p19q co-deletion (P=0.008), respectively. Additionally, we classified the above gliomas into 5 molecular groups, triple-positive, IDH mutation and MGMT methylation, methylation in MGMT only, mutation in IDH only, and triple-negative, according to characteristics of recruited patients. We found that triple-positive gliomas had better PFS than triple-negative cases in high-grade patients (P=0.016). Moreover, the IDH mutation and MGMT methylation groups had prolonged PFS compared to triple-negative (P=0.029). Conclusions: Our study reinforced the clinical value of biomarkers, including 1p/19q co-deletion, IDH mutation, and the most prominent MGMT methylation, as previously described in glioma prognosis. Further, triple-negative patients have poorer PFS, indicating that the states of these genes can be divided into subgroups as a potential prognostic marker for clinical treatment, which requires a larger, multicenter study to testify.

6.
Infect Drug Resist ; 12: 2683-2691, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695444

RESUMO

Purpose: To describe trends and correlation between antibacterial exposure and bacterial resistance from hospitalized patients in a hospital in southern China. Patients and methods: This study used hospital-wide data regarding antimicrobial resistance and consumption between January 1, 2014 and December 31, 2018. Antibacterial consumption was expressed as antimicrobial use density (AUD). The changes in trends and associations between antibacterial utilization and resistance were analyzed using linear regression and time series analysis. Results: The total AUD of all antimicrobials decreased year by year (50.66 in 2014 vs 44.28 in 2018, P=0.03). The annual use of antimicrobials, such as penicillins, monobactams, aminoglycosides, macrolides, and lincosamides, significantly decreased (P<0.05), while the annual use of quinolones and tetracyclines significantly increased (P<0.05). Among the top ten isolated bacteria, antimicrobial resistance trends of Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Staphylococcus aureus, and Staphylococcus epidermidis significantly decreased (P<0.05). Significant positive correlation was found between AUD of carbapenems and resistance rate of Acinetobacter baumannii to imipenem (ß=32.87, P<0.01), as well as the correlation between AUD of quinolones and resistance rate of Enterococcus faecium to levofloxacin (ß=104.40, P<0.01). Conclusion: The consumption of antibiotics and antibiotic resistance has been significantly improved in this tertiary hospital. Additionally, the efforts of China's antibiotic management may be suggested by the relationship between indicated antibiotic resistance and consumption. However, overall AUD levels and poor control of the use of antibiotics, such as quinolones and tetracyclines, still require strengthened management.

7.
Front Cell Dev Biol ; 7: 217, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632968

RESUMO

Background: LncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated. Methods: To elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and in vitro cell lines. Results: Reanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC50 of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC50 of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells. Conclusion: ADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.

8.
Anal Chem ; 91(22): 14597-14604, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31644866

RESUMO

Rectification of ionic current, a frequently observed phenomenon with asymmetric nanopores varying in geometry and/or surface charge, has been utilized for studies of microfluidic circuits, nanopore sensors, and energy conversion devices. However, the physics behind the rectification phenomenon deserves further analysis, and the involved processes need renewed organization; however, the origin is known, and numerous simulations based on the Poisson-Nernst-Planck formalism provide details of the observation. Here, we present an analytical model by identifying the causal chain connecting the key physical factors and processes leading to rectification: the charge present on the pore sidewalls causing the selectivity of ion fluxes through the pore, the selectivity inducing enrichment-depletion of ions around the pore, and the established ion concentration gradient rendering the electric field redistribution in the pore. Our analytical model that considers nanopore geometry, surface charge density, and electrolyte concentration calculates the ionic current and corresponding rectification factor at given bias voltages. The model is validated by numerical simulations, and the model results agree well with experimental data. It is, therefore, a useful tool not only for gaining physical insights into ionic current rectification but also for providing practical guidelines in designing nanopore- and nanopipette-based ion sensors for a range of applications.

9.
Nat Nanotechnol ; 14(11): 1056-1062, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31591525

RESUMO

Solid-state nanopore technology presents an emerging single-molecule-based analytical tool for the separation and analysis of nanoparticles. Different approaches have been pursued to attain the anticipated detection performance. Here, we report the rectification behaviour of protein translocation through silicon-based truncated pyramidal nanopores. When the size of translocating proteins is comparable to the smallest physical constriction of the nanopore, the frequency of translocation events observed is lower for proteins that travel from the larger to the small opening of the nanopore than for those that travel in the reverse direction. When the proteins are appreciably smaller than the nanopore, an opposite rectification in the frequency of translocation events is evident. The maximum rectification factor achieved is around ten. Numerical simulations reveal the formation of an electro-osmotic vortex in such asymmetric nanopores. The vortex-protein interaction is found to play a decisive role in rectifying the translocation in terms of polarity and amplitude. The reported phenomenon can be potentially exploitable for the discrimination of various nanoparticles.

11.
Front Oncol ; 9: 852, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552177

RESUMO

Nafamostat mesylate (NM), a synthetic serine protease inhibitor first placed on the market by Japan Tobacco in 1986, has been approved to treat inflammatory-related diseases, such as pancreatitis. Recently, an increasing number of studies have highlighted the promising effects of NM in inhibiting cancer progression. Alone or in combination treatments, studies have shown that NM attenuates various malignant tumors, including pancreatic, colorectal, gastric, gallbladder, and hepatocellular cancers. In this review, based on several activating pathways, including the canonical Nuclear factor-κB (NF-κB) signaling pathway, tumor necrosis factor receptor-1 (TNFR1) signaling pathway, and tumorigenesis-related tryptase secreted by mast cells, we summarize the anticancer properties of NM in existing studies both in vitro and in vivo. In addition, the efficacy and side effects of NM in cancer patients are summarized in detail. To further clarify NM's antitumor activities, clinical trials devoted to validating the clinical applications and underlying mechanisms are needed in the future.

12.
PeerJ ; 7: e7652, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534865

RESUMO

Objective: Aloperine (ALO), an alkaloid isolated from the leaves of Sophora alopecuroides, has been suggested to exhibit anti-inflammatory and anti-tumor properties and is traditionally used to treat various human diseases, including cancer. However, limited information is available about the mechanisms that determine the anti-tumor activities of ALO. Methods: Herein, through comprehensive bioinformatics methods and in vitro functional analyses, we evaluated the detailed anti-tumor mechanisms of ALO. Results: Using the databases Bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine and PubChem Project, we identified the potential targets of ALO. A protein-protein interaction network was constructed to determine the relationship among these probable targets. Functional enrichment analysis revealed that ALO is potentially involved in the induction of apoptosis. In addition, molecular docking demonstrated that ALO expectedly docks into the active pocket of the Bcl2 protein, suggesting Bcl2 as a direct target of ALO. Moreover, western blot and qPCR analysis showed that ALO downregulated Bcl2 expression in human glioma cell lines, SK-N-AS and U118. Using flow cytometry methods, we further confirmed that ALO significantly promotes apoptosis in SK-N-AS and U118 cell lines, similar to the effect induced by ABT-737, a well-known Bcl2 inhibitor. In addition, Bcl-2 overexpression could rescue ALO-induced Bcl-2 inhibition and suppress pro-apoptotic effects in glioma cells. Conclusion: Taken together, these findings suggest that the natural agent ALO effectively enhances apoptosis by acting as a potential Bcl2 inhibitor in human glioma cells.

13.
Mol Med Rep ; 20(4): 3642-3648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485643

RESUMO

There is increasing evidence that human complement factor H­related protein 1 (CFHR1) plays a crucial role in the development of malignant diseases. However, few studies have identified the roles of CFHR1 in the occurrence and prognosis of lung adenocarcinoma (LADC). In the present study, comprehensive bioinformatic analyses of data obtained from the Oncomine platform, UALCAN and Gene Expression Profiling Interactive Analysis (GEPIA) demonstrated that CFHR1 expression is significantly reduced in both LADC tissues and cancer cells. The patients presenting with downregulation of CFHR1 had significantly lower overall survival (OS) and post progression survival (PPS) times. Through analysis of the datasets from Gene Expression Omnibus database, we found that the compound actinomycin D promoted CFHR1 expression, further displaying the cytotoxic effect in the LADC cell line A549. In addition, the expression level of CFHR1 in the cisplatin­resistant LADC cell line CDDP­R (derived from H460) was also significantly reduced. Our research demonstrated that low levels of CFHR1 are specifically found in LADC samples, and CFHR1 could serve as a potential therapeutic target for this subset of lung cancers. Determination of the detailed roles of CFHR1 in LADC biology could provide insightful information for further investigations.

14.
Nanotechnology ; 30(45): 455303, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31394513

RESUMO

Solid-state nanopores have drawn considerable attention for their potential applications in DNA sequencing and nanoparticle analysis. However, fabrication of nanopores, especially those of diameter below 30 nm, requires sophisticated techniques. Here, a versatile method to controllably reduce the diameter of prefabricated large-size pores down to sub-30 nm without greatly increasing the effective pore depth from the original membrane thickness is shown. This method exploits carbon deposition achieved via hydrocarbon evaporation, induced by an incident beam of electrons, and subsequent dissociation of hydrocarbon to solid carbon deposits. The carbon deposition employs a conventional scanning electron microscope equipped with direct visual feedback, along with a stable hydrocarbon source nearby the sample. This work systematically studies how electron beam accelerating voltage, imaging magnification, initial pore size and membrane composition affect the process of pore size reduction. Secondary electrons generated in the membrane material are confirmed to be the main cause of the dissociation of hydrocarbon. Thicker carbon deposited on one side than on the other of the membrane results in an asymmetric nanopore shape and a rectifying ionic transport. A physico-phenomenological model combined with Monte Carlo simulations is proposed to account for the observed carbon deposition behaviors.

15.
Int J Clin Pharm ; 41(5): 1133-1137, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31468253

RESUMO

This article reviews the current status of the overuse of intravenous (IV) infusions in China and implications to patient safety, and analyzes factors associated with the overuse. Although many factors contribute to the overuse of IV infusions in China, we focus on the construction of an IV infusion management system and tackling cultural problems as the first step to address issues of IV therapy in this commentary.

17.
Clin Ther ; 41(8): 1631-1637.e4, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31174860

RESUMO

This study categorizes the types of inappropriate intravenous prescriptions in hospitalized patients in China. Prescription data from 2016 were retrospectively analyzed based on predefined categories of inappropriateness. Of the 123,521 patients included, 89.2% received intravenous medications, contributing to 80% of the patients' hospital medication costs. Of significant concern, antibiotics and traditional Chinese medicines were administered to 44.3% and 14.5% of hospitalized patients, respectively. Overall, 11.4% of all intravenous prescriptions were classified as inappropriate, with improper diluent and diluent volumes being the primary cause. A team-based collaborative approach is necessary to address this widespread issue in China.

18.
PeerJ ; 7: e7125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31245181

RESUMO

Neurotrophic receptor tyrosine kinase 2 (NTRK2) is a member of the tropomyosin receptor kinase family associated with the tumor development. However, the detailed function of NTRK2 in lung cancer, especially in lung adenocarcinoma (LUAD), is still not fully understood. Here, we investigated the effects of NTRK2 on LUAD biology. Through analyzing bioinformatics data derived from several databases, such as Oncomine, Gene Expression Profiling Interactive Analysis and UALCAN, we found that NTRK2 expression was significantly decreased in LUAD tissues. Clinical data acquired from Wanderer database, which is linked to The Cancer Genome Atlas database, demonstrated that the expression and methylation site of NTRK2 were significantly related to the clinical characteristics and prognosis of LUAD. Furthermore, NTRK2 expression was increased remarkably after treatment with the protein kinase B (AKT) inhibitor MK2206 and the anticancer agent actinomycin D. Functional enrichment analysis of NTRK2-associated coexpression genes was further conducted. Together, our results suggested that downregulated NTRK2 might be used in the diagnostic and prognostic evaluation of LUAD patients, or as a potential therapeutic target for the treatment of LUAD.

19.
World J Gastroenterol ; 25(17): 2099-2109, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31114136

RESUMO

BACKGROUND: The methylated septin 9 (mSEPT9) assay was the first blood-based test approved by the United States Food and Drug Administration as a colorectal screening test. However, the diagnostic and prognostic role of preoperative mSEPT9 for colorectal cancer (CRC) in Chinese patients is still unknown. AIM: To improve the understanding of diagnostic and prognostic factors, serum mSEPT9 was detected in Chinese CRC patients. METHODS: A retrospective analysis of 354 cases, of which 300 had CRC and 54 were normal, was performed in China. Patients' characteristics, treatments, and laboratory data, including age, the date of surgery, Union for International Cancer Control (UICC) stages, distant metastasis (M), and so on, were collected. Methylation levels of SEPT9 were quantified by quantitative, methylation-specific polymerase chain reaction before surgery. In addition, the effects of mSEPT9 on the occurrence and prognosis of 330 CRC cases from The Cancer Genome Atlas (TCGA) database were evaluated using bioinformatics analyses. Potential prognostic factors for overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier univariate analysis. RESULTS: In Chinese CRC patients, positive mSEPT9 was strongly associated with advanced UICC stages, deeper invasion by the primary tumor, and more distant metastasis. Methylation levels of SEPT9 were stage-dependent and showed a stepwise increase in UICC stages (I-IV), primary tumor categories (T1-T4), regional node categories (N0-N2), and distant metastasis categories (M0-M1). The patients with positive mSEPT9 showed a tendency toward lower PFS. After analyzing TCGA clinical data, the high mSEPT9 group was found to be obviously correlated only with more distant metastasis. The patients with high mSEPT9 levels showed a tendency toward lower OS. Besides, nine meaningful mSEPT9 sites were found to provide guidance for the follow-up studies. CONCLUSION: MSEPT9 analysis may add valuable information to current tumor staging. Serum mSEPT9 in Chinese CRC patients appears to offer promising novel prognostic markers and might be considered for monitoring CRC recurrence.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Septinas/metabolismo , Adenoma/sangue , Adenoma/diagnóstico , Adenoma/cirurgia , Idoso , China , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Biologia Computacional , Metilação de DNA , Detecção Precoce de Câncer , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos
20.
Oncol Res ; 27(7): 849-858, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30982492

RESUMO

Over the past decade, natural compounds have been proven to be effective against many human diseases, including cancers. Triptolide (TPL), a diterpenoid triepoxide from the Chinese herb Tripterygium wilfordii Hook F, has exhibited attractive cytotoxic activity on several cancer cells. An increasing number of studies have emphasized the antitumor effects of TPL on non-small cell lung cancer (NSCLC). Here we mainly focused on the key molecular signaling pathways that lead to the inhibitory effects of TPL on human NSCLC, such as mitogen-activated protein kinases (MAPKs) modulation, inhibition of NF-κB activation, suppression of miRNA expression, etc. In addition, the effect of TIG on immune response in cancer patients is summarized for improved immune modulation utilization. However, the clinical use of TPL is often limited by its severe toxicity and water insolubility. Future clinical trials and drug delivery strategies that will evaluate the security and validate the underlying tumor-killing properties of TPL in human NSCLC are also to be discussed.

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