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1.
Invest New Drugs ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32008178

RESUMO

Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). The results of this study showed that the inhibitory effect of proxalutamide on PCa cell proliferation was better than that of bicalutamide and enzalutamide, and proxalutamide preferentially affected AR-positive PCa cells over AR-negative cells. The metabolic composition of PCa cells changed significantly after proxalutamide administration, and these changes in response to proxalutamide were significantly different from those in the presence of the two other AR antagonists. In AR-positive cells, proxalutamide significantly decreased the intracellular levels of glutamine, glutamate, glutathione, cysteine, glycine, aspartate, uridine, cytidine and thymidine. However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide.

2.
Biom J ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080888

RESUMO

This paper discusses regression analysis of the failure time data arising from case-cohort periodic follow-up studies, and one feature of such data, which makes their analysis much more difficult, is that they are usually interval-censored rather than right-censored. Although some methods have been developed for general failure time data, there does not seem to exist an established procedure for the situation considered here. To address the problem, we present a semiparametric regularized procedure and develop a simple algorithm for the implementation of the proposed method. In addition, unlike some existing procedures for similar situations, the proposed procedure is shown to have the oracle property, and an extensive simulation is conducted and it suggests that the presented approach seems to work well for practical situations. The method is applied to an HIV vaccine trial that motivated this study.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32078223

RESUMO

In hunting for safe and cost-effective materials for post lithium-ion energy storage systems, design and synthesis of high-performance solid electrolytes (SEs) are currently bottlenecks for all-solid-state batteries. Many issues need to be addressed, such as chemical stability during processing, storing and using in ambient condition. Therefore, we investigate the effect of water as well as oxyhdryl group (▪OH) on NaBi 3 O 4 Cl 2 through evaluating ionic conductivity. It is noted that presence of water and ▪OH results in an increase in ionic conductivity of NaBi 3 O 4 Cl 2 due to the diffusion of H 2 O into NaBi 3 O 4 Cl 2 and partially forming binding ▪OH through oxygen vacancy repairing. Furthermore, Ab intio calculation reveals that the electrons significantly accumulate around ▪OH and induce a more negative charge center which can promote Na + hopping. This finding provides a fundamental for understanding the essential role of H 2 O in halide-based SEs and hence provides possible roles in designing water-insensitive SEs through defects control.

4.
Acta Pharmacol Sin ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937930

RESUMO

Etimicin (ETM), a fourth-generation aminoglycosides (AGs), is now widely clinically used in China due to its high efficacy and low toxicity. However, the mechanisms underlying its low nephrotoxicity and ototoxicity remain unclear. In the present study we compared the antibacterial and toxicity profiles of etimicin, gentamicin (GM, a second-generation AG), and amikacin (AMK, a third-generation AG), and investigated their pharmacokinetic properties in the toxicity target organs (kidney and inner ear) and subcellular compartments. We first demonstrated that ETM exhibited superior antibacterial activities against clinical isolates to GM and AMK, and it exerted minimal nephrotoxicity and ototoxicity in rats following multi-dose administration. Then, we conducted pharmacokinetic studies in rats, showed that the three AGs accumulated in the kidney and inner ear with ETM being distributed to a lesser degree in the two toxicity target organs as compared with GM and AMK high-dose groups. Furthermore, we conducted in vitro experiments in NRK-52E rat renal tubular epithelial cells and HEI-OC1 cochlear hair cells, and revealed that all the three AGs were distributed predominantly in the mitochondria with ETM showing minimal accumulation; they not only directly inhibited the activity of mitochondrial complexes IV and V but also inhibited mitochondrial function and its related PGC-1α-NRF1-TFAM pathway; ETM caused minimal damage to the mitochondrial complex and mitochondrial biogenesis. Our results demonstrate that the minimal otonephrotoxicity of ETM results from its lesser accumulation in mitochondria of target cells and subsequently lesser inhibition of mitochondrial function. These results provide a new strategy for discovering novel AGs with high efficacy and low toxicity.

5.
Acta Pharmacol Sin ; 41(1): 22-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31431734

RESUMO

Long non-coding RNAs (lncRNAs) have been identified as essential mediators in neurological dysfunction. Our previous study shows that berberine (BBR) hampers the nuclear-to-cytosolic translocation of high-mobility group box 1 (HMGB1) in the process of poststroke inflammation. In this study, we explored the role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) in the process of BBR-induced inhibition of HMGB1 in ischemic brain. Before the 60-min MCAO surgery, the mice were pretreated with BBR (50 mg· kg-1 per day, ig) for 14 days or ICV injected with specific lentiviral vector or shRNA. We showed that MCAO caused marked increase in the expression Malat1 and HMGB1 in the ipsilateral cortex, which was significantly attenuated by pretreatment with BBR. Knockdown of Malat1 attenuated the inflammatory injury after brain ischemia, whereas overexpression of Malat1 exacerbated ischemic brain inflammation. Overexpression of Malat1 also reversed BBR-induced reduction of HMGB1 and proinflammatory cytokines. The above results suggested a potential correlation between Malat1 and stroke inflammation. Based on informatics analysis we predicted that HMGB1 was a direct downstream target of miR-181c-5p, whereas Malat1 acted as a competitive endogenous RNA (ceRNA) for miR-181c-5p targeted the 3'-UTR of HMGB1 to promote inflammation after ischemic stroke. Knockdown of Malat1 significantly decreased HMGB1 level, which could be abrogated by transfection with miR-181c-5p inhibitors. Taken together, our results demonstrate for the first time that Malat1/miR-181c-5p/HMGB1 axis may be a key pathway of BBR-induced antiinflammation effects in stroke, and they may provide a novel avenue for targeted therapy.

6.
ACS Nano ; 13(12): 14208-14216, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31790591

RESUMO

Most issues with Li-S batteries are caused by the slowness of the multielectron sulfur electrochemical reaction resulting in the loss of sulfur as soluble polysulfides to the electrolyte and the redox shuttling of polysulfides between the cathode and anode during battery charge and discharge. The acceleration of the polysulfide conversion reaction to their end products via electrocatalysis has the appeal of a root-cause solution. However, the polysulfide electrocatalysts developed to date have rarely considered polysulfide conversion as a multistep reaction and, as such, were not optimized to target specific steps in the overall S8 ↔ Li2Sn ↔ Li2S conversion. The targeting approach is however beneficial, as it can be used to design multicatalyst systems to reduce as many rate-limiting steps in the overall catalysis as effectively possible. This article demonstrates the concept and implementation of stepwise electrocatalysis in polysulfide conversion, using Fe-N and Co-N co-doped carbons to selectively catalyze the long-chain polysulfide conversion (S8 ↔ Li2S4) and the short-chain polysulfide conversion reactions (Li2S4 ↔ Li2S), respectively. The two electrocatalysts were deployed in the sulfur cathode as a dual layer, using an ordered spatial separation to synergize their catalytic effects. A sulfur electrode designed as such could utilize ∼90% of the sulfur theoretical specific capacity and support a high areal capacity of ∼8.3 mAh cm-2 and a low electrolyte/sulfur ratio of 5 µL mg-1.

7.
Onco Targets Ther ; 12: 8873-8877, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802899

RESUMO

A new progression pattern, hyperprogressive disease (HPD), has been recently acknowledged in cancer patients accepted immune checkpoint inhibitors (ICIs). We report a unique case of cervical small cell carcinoma which showed primary resistance to pembrolizumab and was with a rapid radiological progression after the initiate of ICIs treatment. However, the detection results of multiple predictive biomarkers suggested that the patient was eligible for ICIs treatment. The whole exome sequencing showed that AKT1 E17K mutation was high (26.316%) in tumor tissue, and dynamic monitoring of circulating tumor DNA indicated that AKT1 E17K mutation rate was increasing successively and highly consistent with tumor growth in peripheral blood. Therefore, the correlation between AKT1 E17K mutation and HPD, and the role of AKT1 E17K mutation in identifying patients who might not benefit from ICIs treatment need to be further studied.

8.
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 identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration. METHODS: Three independent cohorts of patients with NSCLC 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 (NCC) cohort (N = 64). RESULTS: bTMB-H (bTMB ≥ cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF ≤ 5%) was not (Pearson 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 objective response rate (ORR) (p < 0.001) after immunotherapy but not chemotherapy, with a cutoff 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 ORR (p = 0.001). CONCLUSIONS: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31593603

RESUMO

Interfacing magnetic particles with ordered mesoporous materials is an effective direction for the development of functional porous composite materials with rationally designed core-shell structure. Due to the combined properties of magnetic nanoparticles and mesoporous silica (high surface area, large pore volume, porosity, and biocompatibility), core-shell magnetic mesoporous silica materials have emerged as a research hotspot and attracted tremendous interests of various disciplines including chemistry, materials, bioengineering, and biomedicine in the past decade. Interfacial assembly methods and strategies enable a rational construction of magnetic mesoporous silica materials with well-defined core-shell structure and precise adjustment of morphology, pore parameters and surface wettability, which can decisively influence the physical and chemical properties, and thus improve their application performances. This minireview aims to summarize the recent progress about core/yolk-shell magnetic mesoporous silica, especially in synthesis methodology and key parameters adjustment including pore size, morphology, and pore orientation control. The synthesis principles and interface assembly mechanisms detailed in this review help to guide researchers to design high-quality core-shell magnetic mesoporous materials with desired physical parameters and properties.

11.
Clin Cancer Res ; 25(23): 6967-6975, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31413010

RESUMO

PURPOSE: Preclinical and retrospective studies suggested a role for metformin in sensitizing patients who have diabetes with non-small cell lung cancer (NSCLC) to EGFR tyrosine kinase inhibitors (TKIs). We therefore examined its effects in combination with gefitinib in patients without diabetes harboring EGFR mutations (EGFRm). PATIENTS AND METHODS: A total of 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFRm NSCLC were randomly assigned in a 1:1 ratio to receive gefitinib plus either metformin or placebo. The primary endpoint was progression-free survival (PFS) rate at 1 year and secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), and safety. Serum levels of IL6 were also examined in an exploratory analysis. RESULTS: The median duration of follow-up was 19.15 months. The estimated 1-year PFS rates were 41.2% [95% confidence interval (CI), 30.0-52.2] with gefitinib plus metformin and 42.9% (95% CI, 32.6-52.7) with gefitinib plus placebo (P = 0.6268). Median PFS (10.3 months vs. 11.4 months) and median OS (22.0 months vs. 27.5 months) were numerically lower in the metformin group, while ORRs were similar between the two arms (66% vs. 66.7%). No significant treatment group differences were detected across all subgroups with respect to PFS, including those with elevated levels of IL6. Metformin combined with gefitinib resulted in a remarkably higher incidence of diarrhea compared with the control arm (78.38% vs. 43.24%). CONCLUSIONS: Our study showed that addition of metformin resulted in nonsignificantly worse outcomes and increased toxicity and hence does not support its concurrent use with first-line EGFR-TKI therapy in patients without diabetes with EGFRm NSCLC.

12.
J Opt Soc Am A Opt Image Sci Vis ; 36(6): 950-963, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31158126

RESUMO

As a precision instrument, the microscope is typically used by researchers in criminal investigation, information forensics, biology, metallography, etc. However, the traditional microscope has a dilemma in that if it uses higher magnification, its field of view is smaller and its depth of field is more limited. Hence, it seriously challenges the endurance and brain of the observer to observe an object thoroughly. This paper proposes a wide-field and full-focus imaging method for solving the above problem. First, a high-precision multi-focus image acquisition platform is improved, and its motion displacement is used directly for image calculation, which greatly reduces the amount of calculation. Second, the focus area of each image is segmented by the mask generation algorithm based on a graph cut. Third, a fusion algorithm, whose contrast pyramid is based on the mask region, is proposed, which utilizes the position of the clear area on the mask pyramid to guide the fusion of the contrast pyramid. Finally, a fast and fault-tolerant stitching algorithm based on mechanical and optical parameters is proposed, which effectively eliminates the interference of the cumulative error and successfully completes hundreds of image-stitching tasks. The experimental results demonstrate that the proposed imaging system is obviously superior to the traditional image fusion algorithms and image-stitching approaches. Both the imaging effect and execution time are satisfactory.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Microscopia/métodos , Imagem Óptica/instrumentação , Algoritmos , Animais , Artefatos , Dispositivos Ópticos
13.
Molecules ; 24(11)2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159257

RESUMO

GC20, a novel soluble bis-chelated gold(I)-diphosphine compound, has been reported as a promising anticancer candidate. Assessing the pharmacokinetic properties of GC20 is critical for its medicinal evaluation. First, a sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and well validated to determine GC20 in rat plasma and rat tissue homogenate after one step protein precipitation. Chromatographic separation was achieved on an Angilent ZORBAX-C18 column (3.5 µm, 2.1 × 50 mm) with gradient elution and mass spectrometry was performed on a triple quadrupole in positive ion mode using an electrospray ionization source. This method was then applied to investigate the pharmacokinetics and tissue distribution of GC20 in rats after intravenous administration. The results showed that the plasma exposure of GC20 in vivo increased with increasing doses after a single dose. However, after multiple doses, a significant accumulation and a saturation at elimination were observed for GC20 in rats. Moreover, after intravenous administration, GC20 was widely distributed in various tissues, with the highest levels in the lung, spleen, liver, and pancreas, followed by the kidney and heart, while the lowest level was found in the brain. This is the first report on the pharmacokinetic properties of GC20.


Assuntos
Quelantes/farmacocinética , Ouro , Fosfinas/farmacocinética , Animais , Quelantes/química , Cromatografia Líquida , Ouro/química , Estrutura Molecular , Fosfinas/química , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Distribuição Tecidual
14.
Oncol Lett ; 17(6): 5590-5600, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31186781

RESUMO

The prognosis of non-small cell lung cancer (NSCLC) is poor, particularly for patients with metastatic disease. Numerous efforts have been made to improve the prognosis of these patients; however, only a small number of studies have explored the occurrence rate and prognostic value of different patterns of distant metastasis (DM) in NSCLC systematically. To investigate these, information from patients diagnosed with NSCLC between 2010 and 2014 was collected from the Surveillance, Epidemiology and End Results database. Survival rate comparisons were performed using Kaplan-Meier analysis and log-rank tests. A Cox proportional hazard model was established to determine factors associated with improved overall survival (OS) and cancer-specific survival (CSS). The present study revealed that the most common site of single metastasis occurrence was bone, and the least common was the liver for NSCLC. As for multi-site metastases, the most common two-site metastasis involved bone and lung, and the most common three-site metastasis involved bone, liver and lung. As for NSCLC subtypes, large cell carcinoma (LCC) exhibited more specific metastatic features. The most common single metastatic site was the brain for patients with LCC, and the most common two-site metastatic combination was bone and liver. Patients with isolated liver metastasis exhibited the worst OS and CSS among patients with single metastasis. Furthermore, for patients with multi-site metastases, metastases involving the liver were associated with the worst OS and CSS among various combinations. To the best of our knowledge, the present study is the first to investigate the occurrence rate and prognostic value of different metastatic patterns of site-specific DM for NSCLC using a large population-based dataset. The findings of the present study may have vital implications for classifying patients with advanced NSCLC, thus laying a foundation for individualized precise treatment.

15.
Scand Stat Theory Appl ; 46(2): 414-431, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31223184

RESUMO

This paper discusses regression analysis of panel count data with dependent observation and dropout processes. For the problem, a general mean model is presented that can allow both additive and multiplicative effects of covariates on the underlying point process. In addition, the proportional rates model and the accelerated failure time model are employed to describe possible covariate effects on the observation process and the dropout or follow-up process, respectively. For estimation of regression parameters, some estimating equation-based procedures are developed and the asymptotic properties of the proposed estimators are established. In addition, a resampling approach is proposed for estimating covariance matrix of the proposed estimator and a model checking procedure is also provided. Results from an extensive simulation study indicate that the proposed methodology works well for practical situations and it is applied to a motivating set of real data.

16.
Oncologist ; 24(8): 1031-e612, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31040256

RESUMO

LESSONS LEARNED: This single-arm, phase II study shows that concurrent EGFR-tyrosine kinase inhibitor plus thoracic radiotherapy as the first-line treatment for stage IV non-small cell lung cancer harboring EGFR active mutations provides long-term control for the primary lung lesion, and 1-year progression-free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients. BACKGROUND: Studies show effective local control by EGFR-tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression-free survival (PFS) in local disease during EGFR-TKI treatment. However, no prospective study has been reported on concurrent EGFR-TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first-line EGFR-TKI combined with thoracic radiotherapy in treating stage IV non-small cell lung cancer (NSCLC) harboring EGFR active mutations. METHODS: We conducted a single-arm, phase II clinical trial. Each patient received EGFR-TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54-60 Gy/27-30 F/5.5-6 w) within 2 weeks of beginning EGFR-TKI therapy until either disease progression or intolerable adverse events (AEs) appeared. RESULTS: From January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40-75) and median follow-up of 19.8 months (5.8-34). The 1-year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse. CONCLUSION: Concurrent EGFR-TKI plus thoracic radiotherapy as the first-line treatment for stage IV NSCLC harboring EGFR active mutations shows a long-term control of primary lung lesion. The 1-year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.

17.
J Cell Biochem ; 120(8): 13694-13705, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31081974

RESUMO

Glycolysis and glycogenesis are known to be tightly associated with cancer cell migration. However, their roles in bladder cancer have not been reported. In this study, ALDOLASE A (ALDOA) was identified in a coexpression network generated using glycolysis- and glycogenesis-related genes in Kyoto Encyclopedia of Genes and Genomes. ALDOA was located in the central region in the network, and the cancer genome atlas (TCGA) data suggest that ALDOA expression levels are associated with viability in patients with cancer at the middle and late stages. Bladder cancer cell lines, T24 and RT4, were used to knockdown (sh) or overexpress (OE) ALODA to analyze its role. The sh-ALDOA reduced cell viability, colony formation rate, and invasion cell number; while OE had an opposite effect compared with sh-ALDOA. Further, the sh-ALDOA expression induced E-cadherin level while reduced N-cadherin and vimentin levels. The OE cells reduced E-cadherin and induced N-cadherin and vimentin levels. In addition, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and AKT serine/threonine kinase (AKT) phosphorylation levels are all reduced in sh-ALODA while activated in OE cells compared with the control group. But either sh-ALODA or OE did not change total protein levels of EGFR, MAPK, and AKT. To further analyze E-cadherin function in ALDOA regulation on bladder cancer cells, sh-ALDOA and sh-E-cadherin were cotransfected in T24 and RT4 cells. The results indicated that sh-ALDOA and sh-E-cadherin expressions eliminated sh-ALDOA function, resulting similar cell viability, colony formation rate, and invasion cell number with control group. Also, sh-ALDOA and shE-cadherin expressions increased EGFR, MAPK, and AKT phosphorylation levels; and the levels were similar to the control group. But, sh-ALDOA and sh-E-cadherin expressions did not change N-cadherin and vimentin levels, which maintain similar levels with sh-ALDOA-expressing cells. Taken together, these results suggest that ALDOA might play an important function in bladder cancer and its action may be though E-cadherin-EGFR signaling.

18.
Lifetime Data Anal ; 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31115745

RESUMO

Doubly censored failure time data occur when the failure time of interest represents the elapsed time between two events, an initial event and a subsequent event, and the observations on both events may suffer censoring. A well-known example of such data is given by the acquired immune deficiency syndrome (AIDS) cohort study in which the two events are HIV infection and AIDS diagnosis, and several inference methods have been developed in the literature for their regression analysis. However, all of them only apply to limited situations or focus on a single model. In this paper, we propose a marginal likelihood approach based on a general class of semiparametric transformation models, which can be applied to much more general situations. For the implementation, we develop a two-step procedure that makes use of both the multiple imputation technique and a novel EM algorithm. The asymptotic properties of the resulting estimators are established by using the modern empirical process theory, and the simulation study conducted suggests that the method works well in practical situations. An application is also provided.

19.
ACS Appl Mater Interfaces ; 11(23): 20895-20904, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31117464

RESUMO

All-solid-state lithium metal batteries (ASSLiMB) have been considered as one of the most promising next-generation high-energy storage systems that replace liquid organic electrolytes by solid-state electrolytes (SSE). Among many different types of SSE, NASICON-structured Li1+ xAl xGe2- x(PO3)4 (LAGP) shows high a ionic conductivity, high stability against moisture, and wide working electrochemical windows. However, it is unstable when it is in contact with molten Li, hence largely limiting its applications in ASSLiMB. To solve this issue, we have studied reaction processes and mechanisms between LAGP and molten Li, based on which a failure mechanism is hence proposed. With better understanding the failure mechanism, a thin thermosetting Li salt polymer, P(AA- co-MA)Li, layer is coated on the bare LAGP pellet before contacting with molten Li. To further increase the ionic conductivity of P(AA- co-MA)Li, LiCl is added in P(AA- co-MA)Li. A symmetric cell of Li/interface/LAGP/interface/Li is prepared using molten Li-Sn alloy and galvanically cycled at current densities of 15, 30, and 70 µA cm-2 for 100 cycles, showing stable low overpotentials of 0.036, 0.105, and 0.257 V, respectively. These electrochemical results demonstrate that the interface coating of P(AA- co-MA)Li can be an effective method to avoid an interfacial reaction between the LAGP electrolyte and molten Li.

20.
Onco Targets Ther ; 12: 3019-3030, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114245

RESUMO

Background: Cancer metastasis is the leading cause of cancer-related death in breast cancer. However, our understanding of its mechanisms is still limited. At this study, the biological roles and clinical significance of NRF3 (NFE2L3, nuclear factor, Erythroid 2 Like 3) in breast cancer are evaluated for the first time. Methods: NRF3 expression in breast cancer cell lines and clinical specimens was determined by western blot and immunohistochemistry, respectively. Cell proliferation, cell cycle distribution, cell migration, and invasion were detected by MTT, colony formation, flow cytometry, and transwell assays, respectively. All other proteins were measured by western blot. The clinical significance of NRF3 was analyzed using the data from tissue microarray. Results: We found that NRF3 expression was obviously suppressed in breast cancer tissues, and negatively associated with the Lymph node metastasis status and tumor stages. Our data also indicated NRF3 expression was much higher in MCF-7 cells than that in MDA-MB-231 and SKBR3 cells which were more malignant. Silence of NRF3 in MCF-7 cells could significantly promote cell proliferation by reducing the cell number in the G0/G1 phase. Exogenous expression of NRF3 in SKBR3 and MDA-MB-231 cells effectively inhibited both cell growth and metastasis with epithelial-mesenchymal transition and MMPs expression suppressed. NRF3 overexpression also impaired the ID3 expression by inactivating the AKT signaling pathway. Exogenous expression of ID3 could not only effectively promote breast cancer cell invasion by inhibiting E-cadherin expression and upregulating MMP-2 expression, but also attenuated the inhibitory function of NRF3 on the breast cancer cell invasion. Conclusion: Our findings suggested that NRF3 inhibited breast cancer cell proliferation and metastasis via inhibiting AKT/ID3 axis at least partially, and potentially to be a valuable clinic marker in breast cancer prognosis.

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