The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
Prostate cancer is initially androgen-dependent but, over time, usually develops hormone- and chemo-resistance. The present study investigated a role for p21-activated kinase 4 (PAK4) in prostate ...cancer progression. PAK4 activation was markedly inhibited by H89, a specific protein kinase A (PKA) inhibitor, and PAK4 was activated by the elevation of cAMP. The catalytic subunit of PKA interacted with the regulatory domain of PAK4, and directly phosphorylated PAK4 at serine 474 (S474). Catalytically active PAK4 enhanced the transcriptional activity of CREB independent of S133 phosphorylation. Stable knockdown of PAK4 in PC-3 and DU145 prostate cancer cells inhibited tumor formation in nude mice. Decreased tumorigenicity correlated with decreased expression of CREB and its targets, including Bcl-2 and cyclin A1. Additionally, in androgen-dependent LNCap-FGC cells, PAK4 regulated cAMP-induced neuroendocrine differentiation, which is known to promote tumor progression. Finally, PAK4 enhanced survival and decreased apoptosis following chemotherapy. These results suggested that PAK4 regulates progression toward hormone- and chemo-resistance in prostate cancer, and this study identified both a novel activation mechanism and potential downstream effector pathways. Therefore, PAK4 may be a promising therapeutic target in prostate cancer.
Nanobiotechnology raises fascinating possibilities for new analytical assays in various fields such as bioelectronic assembly, biomechanics and sampling techniques, as well as in chips or ...micromachined devices. Recently, nanotechnology has greatly impacted biotechnological research with its potential applications in smart devices that can operate at the level of molecular manipulation. Micro total analysis system (micro-TAS) offers the potential for highly efficient, simultaneous analysis of a large number of biologically important molecules in genomic, proteomic and metabolic studies. This review aims to describe the present state-of-the-art of microsystems for use in biotechnological research, medicine and diagnostics.
This work demonstrates the first molecular-level conversion pathway of NO oxidation over a novel SrO-clusters@amorphous carbon nitride (SCO-ACN) photocatalyst, which is synthesized via copyrolysis of ...urea and SrCO3. The inclusion of SrCO3 is crucial in the formation of the amorphous carbon nitride (ACN) and SrO clusters by attacking the intralayer hydrogen bonds at the edge sites of graphitic carbon nitride (CN). The amorphous nature of ACN can promote the transportation, migration, and transformation of charge carriers on SCO-ACN. And the SrO clusters are identified as the newly formed active centers to facilitate the activation of NO via the formation of Sr-NOδ(+), which essentially promotes the conversion of NO to the final products. The combined effects of the amorphous structure and SrO clusters impart outstanding photocatalytic NO removal efficiency to the SCO-ACN under visible-light irradiation. To reveal the photocatalytic mechanism, the adsorption and photocatalytic oxidation of NO over CN and SCO-ACN are analyzed by in situ DRIFTS, and the intermediates and conversion pathways are elucidated and compared. This work presents a novel in situ DRIFTS-based strategy to explore the photocatalytic reaction pathway of NO oxidation, which is quite beneficial to understand the mechanism underlying the photocatalytic reaction and advance the development of photocatalytic technology for environmental remediation.
Earth-abundant insulators are seldom exploited as photocatalysts. In this work, we constructed a novel family of insulator-based heterojunctions and demonstrated their promising applications in ...photocatalytic NO purification, even under visible light irradiation. The heterojunction formed between the insulator SrCO3 and the photosensitizer BiOI, via a special SrCO3–BiOI core–shell structure, exhibits an enhanced visible light absorbance between 400–600 nm, and an unprecedentedly high photocatalytic NO removal performance. Further density functional theory (DFT) calculations and X-ray photoelectron spectroscopy (XPS) analysis revealed that the covalent interaction between the O 2p orbital of the insulator (SrCO3, n-type) and the Bi 6p orbital of photosensitizer (BiOI, p-type) can provide an electron transfer channel between SrCO3 and BiOI, allowing the transfer of the photoexcited electrons from the photosensitizer to the conduction band of insulator (confirmed by charge difference distribution analysis and time-resolved fluorescence spectroscopy). The •O2 – and •OH radicals are the main reactive species in photocatalytic NO oxidation. A reaction pathway study based on both in situ FT-IR and molecular-level simulation of NO adsorption and transformation indicates that this heterojunction can efficiently transform NO to harmless nitrate products via the NO → NO+ and NO2 + → nitrate or nitrite routes. This work provides numerous opportunities to explore earth-abundant insulators as visible-light-driven photocatalysts, and also offers a new mechanistic understanding of the role of gas-phase photocatalysis in controlling air pollution.
We search for energetic electron recoil signals induced by boosted dark matter (BDM) from the galactic center using the COSINE-100 array of NaI(Tl) crystal detectors at the Yangyang Underground ...Laboratory. The signal would be an excess of events with energies above 4 MeV over the well-understood background. Because no excess of events are observed in a 97.7 kg·yr exposure, we set limits on BDM interactions under a variety of hypotheses. Notably, we explored the dark photon parameter space, leading to competitive limits compared to direct dark photon search experiments, particularly for dark photon masses below 4 MeV and considering the invisible decay mode. Furthermore, by comparing our results with a previous BDM search conducted by the Super-Kamionkande experiment, we found that the COSINE-100 detector has advantages in searching for low-mass dark matter. This analysis demonstrates the potential of the COSINE-100 detector to search for MeV electron recoil signals produced by the dark sector particle interactions.
This paper empirically assesses the wage effects of the Job Corps program, one of the largest federally funded job training programs in the U.S. Even with the aid of a randomized experiment, the ...impact of a training program on wages is difficult to study because of sample selection, a pervasive problem in applied microeconometric research. Wage rates are only observed for those who are employed, and employment status itself may be affected by the training program. This paper develops an intuitive trimming procedure for bounding average treatment effects in the presence of sample selection. In contrast to existing methods, the procedure requires neither exclusion restrictions nor a bounded support for the outcome of interest. Identification results, estimators, and their asymptotic distribution are presented. The bounds suggest that the program raised wages, consistent with the notion that the Job Corps raises earnings by increasing human capital, rather than solely through encouraging work. The estimator is generally applicable to typical treatment evaluation problems in which there is nonrandom sample selection/attrition.
A new approach to more accurately monitor and evaluate transboundary particulate matter (PM) pollution is introduced based on aerosol optical products from Korea's Geostationary Ocean Color Imager ...(GOCI). The area studied is Northeast Asia (including eastern parts of China, the Korean peninsula and Japan), where GOCI has been monitoring since June 2010. The hourly multi-spectral aerosol optical data that were retrieved from GOCI sensor onboard geostationary satellite COMS (Communication, Ocean, and Meteorology Satellite) through the Yonsei aerosol retrieval algorithm were first presented and used in this study. The GOCI-retrieved aerosol optical data are integrated with estimated aerosol distributions from US EPA Models-3/CMAQ (Community Multi-scale Air Quality) v4.5.1 model simulations via data assimilation technique, thereby making the aerosol data spatially continuous and available even for cloud contamination cells. The assimilated aerosol optical data are utilized to provide quantitative estimates of transboundary PM pollution from China to the Korean peninsula and Japan. For the period of 1 April to 31 May, 2011 this analysis yields estimates that AOD as a proxy for PM2.5 or PM10 during long-range transport events increased by 117–265% compared to background average AOD (aerosol optical depth) at the four AERONET sites in Korea, and average AOD increases of 121% were found when averaged over the entire Korean peninsula. This paper demonstrates that the use of multi-spectral AOD retrievals from geostationary satellites can improve estimates of transboundary PM pollution. Such data will become more widely available later this decade when new sensors such as the GEMS (Geostationary Environment Monitoring Spectrometer) and GOCI-2 are scheduled to be launched.
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