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BACKGROUND The advent of immune checkpoint inhibitors (ICIs) has revolutionized the management of several types of solid cancers, including lung cancer, by boosting the body's natural tumor killing response. However, it is undeniable that only a small proportion of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can achieve long-term responses and benefit from immunotherapy. CASE SUMMARY Herein, we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval. In this case report, we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy. CONCLUSION We suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression (defined as ≥ 25%), the L858R mutation, smoking history, or pemetrexed pretreatment may benefit from immunotherapy.

Tropical cyclones (TCs) are strong natural hazards that are important for local and global air–sea interactions. This manuscript briefly reviews the knowledge about the upper ocean responses to TCs, including the current, surface wave, temperature, salinity and biological responses. TCs usually cause upper ocean near-inertial currents, increase strong surface waves, cool the surface ocean, warm subsurface ocean, increase sea surface salinity and decrease subsurface salinity, causing plankton blooms. The upper ocean response to TCs is controlled by TC-induced mixing, advection and surface flux, which usually bias to the right (left) side of the TC track in the Northern (Southern) Hemisphere. The upper ocean response usually recovers in several days to several weeks. The characteristics of the upper ocean response mainly depend on the TC parameters (e.g. TC intensity, translation speed and size) and environmental parameters (e.g. ocean stratification and eddies). In recent decades, our knowledge of the upper ocean response to TCs has improved because of the development of observation methods and numerical models. More processes of the upper ocean response to TCs can be studied by researchers in the future.

Qing-Ping Shao,1,* Chen Wei,2,* Jie Yang,3 Wen-Zhou Zhang1 1Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province 450008, People’s Republic of China; 2Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province 450052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen-Zhou ZhangDepartment of Pharmacy The Affiliated Cancer Hospital of Zhengzhou University, No. 127 Dongming Road,Jinshui District, Zhengzhou City, Henan Province, People’s Republic of ChinaTel/ Fax +86 371 65587240Email wenzhou_zhang2000@aliyun.comBackground: The pregnane X receptor (PXR) not only plays an important role in cellular metabolism processes but also induces the resistance of hepatocellular carcinoma (HCC) cells to molecularly targeted drugs by mediating their metabolism and clearance by these cells. Endothelial PAS domain-containing protein 1 (EPAS-1) acts as a coactivator to regulate the transcription factor activity of PXR. In the present study, a microRNA that potentially targets EPAS-1, namely miR-3609, was identified using the miRDB tool.Methods: The expression of miR-3609 and EPAS-1 was examined by qPCR. Lentiviral particles containing the full-length sequences of miR-3609 (pri-miR-3609) were prepared. The antitumor effect of antitumor agents was examined by the in vitro and in vivo assays.Results: The expression of miR-3609 was negatively correlated with that of EPAS-1 in both HCC clinical specimens and paired non-tumor specimens, and the effect of miR-3609 on the expression of EPAS-1 was confirmed by Western blot experiments. Overexpression of miR-3609 decreased the expression of EPAS-1 and, in turn, repressed the activation of the PXR pathway. miR-3609 decreased the transcription factor activation of PXR, repressed its recruitment to its target gene promoter regions, and decreased the expression of its target genes CYP3A4 and P-GP. In addition, miR-3609 decelerated the metabolism and clearance of sorafenib in HCC cells and enhanced the antitumor effect of sorafenib in HCC cells.Conclusion: Therefore, the results indicate that miR-3609 decreases the expression of EPAS-1 and enhances the sensitivity of HCC cells to sorafenib.Keywords: microRNA-3609, molecular targeting agents, endothelial PAS domain-containing protein 1, pregnane X receptor, hepatocellular carcinoma

The Gulf Stream (GS) transports a massive amount of heat northward to high latitudes and releases sensible and latent heat to the atmosphere, playing an important role in the North Atlantic and European climate change. The change trends of the GS transport and pathway are still uncertain to date. Our analyses of altimeter observations from 1993 to 2016 indicate that the linear trends in surface maximum speed, transport, and latitudinal location of the GS are significant east of 61° W at the 95% level while they are small and not significant between 72° W and 61° W. The weakening trend of the GS during the period from 1993 to 2016 is accompanied with a southward-shifting path, which is associated with the decline of the North Atlantic Oscillation (NAO) and possibly reduction in the Atlantic meridional overturning circulation (AMOC).

Currently, there is no satisfactory treatment available for esophageal squamous cell carcinoma (ESCC), and thus, there is a pressing need to develop effective drugs. Chaetoglobosin E, a cytochalasan alkaloid derived from metabolites ofThe cytotoxic effect of chaetoglobosin E and cisplatin on esophageal cancer KYSE-30, KYSE-150, and TE-1 cells was detected using cell viability or colony formation assays. The cell cycle, apoptosis, autophagy, invasion, and metastasis were assayed by flow cytometry or western blot. The potential target of chaetoglobosin E was assayed by RNA sequencing (RNA-seq) and large loop prediction software analysis and was assessed by western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of its target on cell pyroptosis was assayed using overexpression and silence experiments.Chaetoglobosin E significantly inhibited the proliferation of KYSE-30, KYSE-150, and TE-1 cells, especially KYSE-30 cells. Our results showed that chaetoglobosin E induced the G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and up-regulation of p21. Moreover, chaetoglobosin E also decreased the anti-apoptotic protein expression of Bcl-2, increased apoptotic expression of Bax, increased autophagy protein expressions of beclin1 and LC3, decreased invasion and metastasis protein expression of E-cadherin, and increased expression of vimentin. The RNA-seq and large loop prediction software analysis results indicated that its potential target might be polo-like kinase 1 (PLK1). Moreover, results also showed that chaetoglobosin E can reverse the PLK1 overexpression plasmid-induced up-regulation of the PLK1 protein. Furthermore, we found that chaetoglobosin E induced pyroptosis via the activation of the gasdermin E (GSDME) protein. Further studies showed that the high expression of PLK1 inactivated the GSDME protein, while the knockdown of PLK1 expression activated the GSDME protein, indicating that chaetoglobosin E induced cell pyroptosis by inhibiting PLK1.This study suggested that chaetoglobosin E may be a novel lead compound to the treatment of ESCC patients by targeting PLK1, and elucidated for the first time that PLK1 was involved in a new pyroptosis mechanism.

Targeting autophagy might be a promising anticancer strategy; however, the dual roles of autophagy in cancer development and malignancy remain unclear. NSCLC (non-small cell lung cancer) cells harbour high levels of SQSTM1 (sequestosome 1), the autophagy receptor that is critical for the dual roles of autophagy. Therefore, mechanistic insights into SQSTM1 modulation may point towards better approaches to treat NSCLC. Herein, we used multiple autophagy flux models and autophagy readouts to show that aldo-keto reductase family 1 member C1 (AKR1C1), which is highly expressed in NSCLC, promotes autophagy by directly binding to SQSTM1 in a catalytic-independent manner. This interaction may be strengthened by reactive oxygen species (ROS), important autophagy inducers. Further mechanistic research demonstrated that AKR1C1 interacts with SQSTM1 to augment SQSTM1 oligomerization, contributing to the SQSTM1 affinity for binding cargo. Collectively, our data reveal a catalytic-independent role of AKR1C1 for interacting with SQSTM1 and promoting autophagy. All these findings not only reveal a novel functional role of AKR1C1 in the autophagy process but also indicate that modulation of the AKR1C1-SQSTM1 interaction may be a new strategy for targeting autophagy. [Image: see text]

Combining Argo observations with satellite remote sensing data during the period of 2002–2014, the mean three-dimensional structures of mesoscale eddies on both sides of the Luzon Strait (LS) were obtained via a composite method and analyzed to statistically examine the influences of background marine environment and the Kuroshio current on the eddy structures. The significant signals of temperature and salinity anomalies within the composite eddies extend much deeper in the region east of the LS (zone E) than those in the region west of the strait (zone W) because of stronger eddy intensity and larger vertical gradients of background temperature and salinity in the deep layer in zone E. In the vertical structure of temperature anomaly within the eddies, two cores occur at around 200 and 400 dbar depths, respectively, in zone E and only one core is centered at about 100 dbar in zone W. There is a clear three-core sandwich pattern in the vertical structure of salinity anomaly within the eddies in zone E. The Kuroshio water trapped in the eddy is responsible for abnormally positive salinity anomaly in the surface layer of the anticyclonic eddy center in zone W. On both sides of the LS, an asymmetric dipole structure in the surface layer gradually turns into a monopole one at depths, which resulted from the competition between horizontal advection effect and eddy pumping effect. The Kuroshio current influences the distribution patterns of isotherms and isohalines and enhances background temperature and salinity horizontal gradients on both sides of the LS, determining the orientations of dipole temperature and salinity structures within eddies.

Composite structures of ocean temperature and salinity anomalies caused by tropical cyclones (TCs) or typhoons in the western North Pacific Ocean were obtained from Argo data. These structures were used to analyze ocean responses to typhoons and the dynamic mechanisms inherent in those responses with a particular focus on upwelling. TC-induced cooling is often strongly rightward-biased in the surface layer, and shifts toward the typhoon track at depths exceeding roughly 100 m. In the central water column within approximately 75 km of the typhoon track, subsurface warming predicted by vertical mixing is restrained and replaced by cooling due to upwelling. Upwelling contributes 15% on average to temperature cooling in the near surface layer (10–30 m), 84% in the subsurface layer (30–250 m) and 94% in the deep layer (250–600 m) during the period of 0.5–2.5 days after the typhoon's passage. It is suggested that the sea surface cooling effect of vertical mixing can be enhanced by the upwelling. The effect of upwelling is also prominent in the salinity response to typhoons. The composite results from the Argo data clearly reveal basic ocean responses to typhoons and indicate the important role of upwelling therein.

The variability of chlorophyll a concentration (Chl a) in the open South China Sea (SCS) was examined using observations from two Bio-Argo floats. During the period of September 2014 to August 2015, there was a permanent subsurface Chl a maximum (SCM) in the depth range of 48 to 96 m in the central basin of the SCS. In the northern basin, the SCM disappeared in winter, replaced by enhanced surface layer phytoplankton with high Chl a. The values of the SCM were influenced by the vertical displacement of isotherms. Strong wind forcing and surface cooling were the main physical drivers of high surface Chl a in winter. In the north, stronger wind than in the center, lower sea surface temperature (SST) than in the center, and Kuroshio water intrusion were more favorable for the upward transport of nutrient-rich deep water. A large amount of nitrate could be advected from the Taiwan Strait and shallow continental shelf to the northern basin in winter. A combination of strong wind mixing, surface cooling, Kuroshio water intrusion, and horizontal advection caused the winter surface phytoplankton bloom in the north. This article is protected by copyright. All rights reserved.

Zhuo Chen, Zhengkui Jiang, Wenzhou Zhang, Baoxia He The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou 450008, People’s Republic of China Background: The application of the oral targeted therapeutic agent sorafenib provides new hope for patients suffering from advanced stages of hepatocellular carcinoma (HCC), but the prognosis of such patients remains poor due to the rapid development of the multidrug resistance process in cancer pathogenesis. The present work evaluated whether copine-III, a novel cancer regulator encoded by the CPNE3 gene, would be a potential indicator of sorafenib resistance in HCC treatment.Materials and methods: The endogenous expression of copine-III in clinical specimens was examined by quantitative polymerase chain reaction. Copine-III siRNA was transfected into HCC cells to downregulate copine-III expression. The effect of copine-III on sorafenib’s antitumor activation was identified by in vitro and in vivo experiments (MTT, Transwell, and flow cytometry as well as a nude mice model).Results: High levels of copine-III in clinical specimens are related to poor prognosis of advanced HCC patients on sorafenib treatment. Infection of Ad-siCPNE3 significantly decreased the endogenous expression of copine-III and enhanced the susceptibility of MHCC97-H cells to sorafenib: the IC50 value decreased from 1.15±0.11 to 0.25±0.05 μmol/L. Moreover, silencing copine-III enhanced the effect of sorafenib on apoptosis, in vitro invasion/migration, and subcutaneous or intrahepatic growth of MHCC97-H cells in nude mice.Conclusion: Copine-III is a novel potential indicator of prognosis for patients who received sorafenib for advanced HCC treatment. Keywords: hepatocellular carcinoma, CPNE3, copine-III, molecular targeted agent, sorafenib-resistance

Model output from a Pacific basin-wide three-dimensional physical-biogeochemical model during the period of 1991 to 2008 was used to investigate the impact of Kuroshio water on the source water of the southeastern Taiwan Strait. Based on the characteristic salinities of both Kuroshio water and the South China Sea water, a Kuroshio impact index (KII) was designed to measure the degree of impact. The KII correlates significantly with the northeast-southwest component of wind stress, but the former lags the latter by approximately two months. The correlation coefficient between them increases from 0.267 4 to 0.852 9, with a lag time increasing from 0 to 63 days. The impact of Kuroshio Water is greater in winter and spring than in summer and autumn. At the interannual time scale, El Nino and La Nina events play an important role in impacting the KII. During El Nino events, more Kuroshio water contributes to the source water of the southeastern Taiwan Strait. Conversely, during La Nina events, less Kuroshio water contributes to the source water.

The Taiwan Strait is the only direct passage between the South China Sea (SCS) and the East China Sea. Variations in the intensity of Kuroshio Branch and surface currents in the SCS result in seasonal and inter-annual variability in the hydrography of the SE Taiwan Strait, where the northwardly pointing funnel-like Penghu Channel is located. These currents vary with the intensity and direction of monsoons. The teleconnection between air-sea interaction of the east Pacific and west Pacific reportedly has time differences. The data in this study reveal that the salinity of the seawater in the Penghu Channel is highest during El Nino events with a seven-month lag to the monthly Nino 3.4 index, and lowest during La Nina periods, also with a lag of seven months to the monthly Nino 3.4 index. The chemical parameters also vary with these events. The concentrations of apparent oxygen utilization, nutrients, and hydrogen ions vary with the mixing ratio of SCS water and Kuroshio Branch water. The maximum concentrations of nutrients are significantly higher during the summer, seven months after a La Nina event (La Nina-7), than in other seasons. However, biological activities also affected these chemical parameters. In spring, active photosynthesis consumes more nutrients and hydrogen ion concentrations in La Nina-7 periods than in normal-7 periods.

Mesoscale eddies play a significant role in supplying the nutrients required for phytoplankton blooms and redistributing biomass in the ocean. However, how eddies influence nutrient flux and biomass distribution remains unclear. Here we reveal two important dynamical processes (radial displacement and vertical fluctuations) within an anticyclonic eddy by analyzing observations from Argo floats. The Argo floats in the eddy were displaced toward the eddy edge due to the imbalance of radial momentum. Vertical fluctuations below the mixed layer resulted in alternating upwelling and downwelling in the inner and outer parts of the eddy. High salinity deep water was uplifted tens of meters by the upwelling and further extended to the surface with the aid of wind effects. Vertical motions associated with the fluctuations penetrated to the depths of several hundred meters. These processes represent crucial dynamical mechanisms for the motion of particles in mature anticyclonic eddies.

Volume transport through the Taiwan Strait during 2005–2008 was simulated using a shallow water model forced by high spatio-temporal resolution meteorological data. On average, simulated monthly mean transports ranged from a southward maximum of 0.38 Sv in December to a northward maximum of 2.02 Sv in June, with an annual mean northward transport of 0.78 Sv. These estimates are in agreement with the published results based on bottom-mounted ADCP observations. Several sensitivity experiments were conducted to separately examine possible influence of ignoring air pressure or applying time-averaged wind forcing on the transport estimate. We found that excluding the air pressure component in the model gave rise to an insignificant difference (0.01 Sv) in the mean transport estimate. Using multi-year-averaged monthly mean wind, however, provided markedly different results; it brought about a magnitude change of up to 0.65 Sv for the monthly mean transport and 0.34 Sv for the annual mean transport. The nonlinear parameterization of wind stress was mainly responsible for the distortion. In addition, we found that typhoons, as one kind of synoptic events, had an accumulative influence not only on the monthly mean transport during the typhoon season but also on the annual mean transport. The effect of typhoons reduced the monthly mean transport by up to 0.45 Sv and the annual mean transport by 0.09 Sv (more than 10%). Therefore, high temporal resolution wind data with synoptic scale variability are required to accurately estimate the monthly mean and annual mean transports when using a model.

The Western North Pacific (WNP) is the most favorable area in the world for the generation of tropical cyclones (TCs). As the most intense weather system, TCs play an important role in the change of ocean environment in the WNP. Based on many investigations published in the literature, we obtained a collective and systematic understanding of the influence of TCs on ocean components in the WNP, including sea temperature, ocean currents, mesoscale eddies, storm surges, phytoplankton (indicated by chlorophyll a). Some ocean responses to TCs are unique in the WNP because of the existence of the Kuroshio and special geographical configurations such as the South China Sea.

National Natural Science Foundation of China [41076002, 41276007]; Fundamental Research Funds for the Central Universities [2010121036]; Science Foundation of Fujian Province [2010Y0064]; Public Science and Technology Research Funds Projects of Ocean [200905013-7]

A two-way nested coupled tide-surge prediction model was established and applied in the Taiwan Strait and adjacent sea area in this study. This two-dimensional (2D) model had a fine horizontal resolution and took into account the interaction between storm surges and astronomical tides, which made it suitable for depicting the complicated physical properties of storm surges in the Taiwan Strait. A two-way nesting technique and an open boundary condition developed from Flather's radiation condition and Roed and Smedstad's local mode idea, were successfully implemented in the model. A simulation experiment showed that the open boundary condition could be used in the coupled tide-surge model and that the performance of the two-way nested model was slightly superior in accuracy to that of the one-way nested one. The fluctuations of storm surge residuals with tidal period at Sansha and Pingtan tide stations during the period of typhoon Dan in 1999 were well reproduced by the model, with the coupling effect between storm surges and tides indicating that the effect of astronomical tides upon typhoon surges should be considered in a storm-surge prediction model for the Taiwan Strait. The forecast experiment during typhoon Talim in 2005 showed that the storm surge prediction outputs by the model were better in the early 20 h of the forecast period of each model run than those in the later period due to the prediction accuracy of the typhoon track, maximum winds, and central air pressures.

Arctigenin, a bioactive component of Arctium lappa (Nubang), has anti-inflammatory activity. Here, we investigated the effects of arctigenin on lipopolysaccharide (LPS)-induced acute lung injury. Mice were divided into four groups: control, LPS, LPS + DMSO, and LPS + Arctigenin. Mice in the LPS + Arctigenin group were injected intraperitoneally with 50 mg/kg of arctigenin 1 h before an intratracheal administration of LPS (5 mg/kg). Lung tissues and bronchoalveolar lavage fluids (BALFs) were collected. Histological changes of the lung were analyzed by hematoxylin and eosin staining. Arctigenin decreased LPS-induced acute lung inflammation, infiltration of inflammatory cells into BALF, and production of pro-inflammatory cytokines. Moreover, arctigenin pretreatment reduced the malondialdehyde level and increased superoxide dismutase and catalase activities and glutathione peroxidase/glutathione disulfide ratio in the lung. Mechanically, arctigenin significantly reduced the production of nitric oxygen and inducible nitric oxygen synthase (iNOS) expression, enhanced the expression of heme oxygenase-1, and decreased the phosphorylation of mitogen-activated protein kinases (MAPKs). Arctigenin has anti-inflammatory and antioxidative effects on LPS-induced acute lung injury, which are associated with modulation of MAPK, HO-1, and iNOS signaling.

Science Foundation of Fujian Province [2009J01223]; National High-tech RD Program [2006AA09A302-6]; National Oceanographic Partnership Program [N00014-06-1-0945]

China Postdoctoral Science Foundation [20070420745]; Science Foundation of Fujian Province [2009J01223]; National High-Tech Research and Development [2006AA09A302-6]

The traditional tabletop AR systems general use head mounted display (HMD) that has some shortcomings, such as the imprecise precision and low flexibility. To solve these problems, a new design of video see-through tabletop system based on ADSP-BF561 [1,2] is presented, it can fix the display system on the end of the orientation system, that made up of mechanism and angle sensor, and move in a circular area measured by pole length, observe every orientation. These implemented system registration, image collection, transmission and display.

Network transmission is of great effect to capability of the desktop AR system, so speed and veracity of network transmission is very important. This article introduces hardware and software design about the network transmission system and experimental result shows that both speed and veracity of network transmission can satisfy the requirement of image data transmission in desktop AR system.