Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Non-small-cell lung cancer(NSCLC)remains the leading cause of cancer-related death in both men and women in the United States.Platinum-based doublet chemotherapy has been a standard for patients with advanced stage disease.Improvements in overall survival and quality of life have been modest.Improved knowledge of the aberrant molecular signaling pathways found in NSCLC has led to the development of biomarkers with associated targeted therapeutics,thus changing the treatment paradigm for many NSCLC patients.In this review,we present a summary of many of the currently investigated biologic targets in NSCLC,discuss their current clinical trial status,and also discuss the potential for development of other targeted agents.

Review of the current targeted therapies for non-small-cell lung cancer

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer(NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor(EGFR), and crizotinib which targets anaplastic lymphoma kinase(ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790 Mtargeted agents CO-1686 and AZD9291, and the ALKtargeted agents ceritinib(LDK378), AP26113, alectinib(CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

Treatment of non-small cell lung cancer in the era of targeted therapy

Lung cancer, mostly non-small cell carcinoma (NSCLC), is still a major global problem with devastating outcomes. The majority presents at late stages, in which the chance of cure is minimal. With the better understanding of lung cancer biology, there have been several novel targeted approaches against NSCLC. Anti-angiogenesis has been proven to be an important approach in combination with systemic chemotherapy treatment in NSCLC at the first-line setting. The prototypic monoclonal antibody against vascular endothelial growth factor (VEGF), be- vacizumab, is now approved for clinical use in combination with platinum-based chemotherapy in first-line treatment of advanced non-squamous NSCLC, associated with improved response and survival compared with chemotherapy alone. The most notable example of targeted therapy for lung cancer is epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI). There have been extensive evidences supporting the superiority of EGFR TKI (like gefitinib or erlotinib) over standard platinum-based doublet chemotherapy in first-line treatment of advanced NSCLC carrying EGFR activating mutations. Almost following the same path as EGFR TKI, a novel target (anaplastic lymphoma kinase, ALK) has been identified recently with a very promising targeted agent (crizotinib) that has already been approved for clinical use in NSCLC carrying ALK rearrangements. Over the past decade, there have been undoubtedly growing armamentaria in the treatment of NSCLC, focusing on personalized and targeted approach.

Safety Evaluation of Myricetin and Crude Extract from Myrica rubra Leaves on Non-target Organisms

[ Objective] The study aimed to supply important basis for developing environment-friendly pesticides with myricetin and crude extract of Myrica rubra leaves as effective components. [ Method] According to ＂Test guidelines for environmental safety evaluation on chemical pesticides＂, the toxicity of myricetin and crude extract of M. rubra leaves on non-target organisms was determined and the safety evaluation was carried out. [Result] MyriceUn and crude extract of M. rubra leaves had low toxicity on non-target organisms, such as earthworm, silkworm and soil microbes. Myricetin showed low toxicity and the crude extract of M. rubra leaves showed middle toxicity on tadpole. The high-concentration crude extract of M. rubra leaves had some antifeedant effect on silkworm. [ Conclusion] Myricetin and crude extract of M. rubra leaves had low toxicity on non-tar- get organisms in environment and they were relatively safe.

Effects of Transgenic Bt+CpTI Cotton on Field Abundance of Non-Target Pests and Predators in Xinjiang, China

Transgenic insect-resistant cotton is being increasingly planted in Xinjiang cotton-planting regions, where geographical climate conditions and species composition of pests and natural enemies are greatly unique in China. Limited studies have been conducted on the ecological impacts of transgenic insect-resistant cotton, especially for transgenic double genes （Bt＋CpTI） cotton, in this region. In this study, the potential effects of transgenic Bt＋CpTI cotton on the seasonal abundance of non-target pests and predators were assessed from 2009 to 2011 in Korla, Xinjiang. The results showed that species composition and seasonal abundance of 5 groups of pests and 5 groups of predators were not significantly different between transgenic Bt＋CpTI cotton and non-transgenic cotton every year. It suggests that transgenic Bt＋CpTI cotton per se does not affect the population dynamics of non-target pests and predators on this crop in Xinjiang.

Robust detector for range-spread targets in non-Gaussian background

Based on the target scatterer density, the range-spread target detection of high-resolution radar is addressed in additive non-Gaussian clutter, which is modeled as a spherically invariant random vector. Firstly, for sparse scatterer density, the detection of target scatterer in each range cell is derived, and then an M/K detector is proposed to detect the whole range-spread target. Se- condly, an integrating detector is devised to detect a range-spread target with dense scatterer density. Finally, to make the best of the advantages of M/K detector and integrating detector, a robust detector based on scatterer density （DBSD） is designed, which can reduce the probable collapsing loss or quantization error ef- fectively. Moreover, the density decision factor of DBSD is also determined. The formula of the false alarm probability is derived for DBSD. It is proved that the DBSD ensures a constant false alarm rate property. Furthermore, the computational results indi- cate that the DBSD is robust to different clutter one-lag correlations and target scatterer densities. It is also shown that the DBSD out- performs the existing scatterer-density-dependent detector.

Design of a Non-cooperative Target Capture Mechanism

A passive compliant non-cooperative target capture mechanism is designed to maintain the non-cooperative target on-orbit. When the relative position between capture mechanism and satellite is confirmed,a pair of four-bar linkages lock the docking ring,which is used for connecting the satellite and the rocket. The mathematical model of capture mechanism and capture space is built by the Denavit-Hartenberg(D-H)method,and the torque of each joint is analyzed by the Lagrange dynamic equation. Besides,the capture condition and the torque of every joint under different capture conditions are analyzed by simulation in MSC. Adams. The results indicate that the mechanism can capture the non-cooperative target satellite in a wide range. During the process of capture,the passive compliant mechanism at the bottom can increase capture space,thereby reducing the difficulty and enhance stability of the capture.

Non-target-site and target-site resistance to AHAS inhibitors in American sloughgrass(Beckmannia syzigachne)

American sloughgrass(Beckmannia syzigachne(Steud.) Fernald) is one of the most competitive and malignant weeds in rice-wheat rotation fields in China. American sloughgrass populations in the Jiangsu Province of China became less sensitive to acetohydroxyacid synthase(AHAS) inhibitors after repeated application for many years in these areas. Two suspected resistant American sloughgrass populations(R1 and R2) collected in the field were detected the resistance to inhibitors of AHAS in whole-plant dose-response assays, compared to the susceptible(S) population. These assays indicated that R1 showed low resistance to mesosulfuron-methyl(3.32-fold), imazapic(2.84-fold) and pyroxsulam(1.55-fold), moderate resistance to flazasulfuron(4.67-fold) and pyribenzoxim(7.41-fold), and high resistance to flucarbazone(11.73-fold). However, using a combination of the cytochrome P450 inhibitor, malathion, with mesosulfuron-methyl resulted in a reduction in R1 resistance relative to mesosulfuron-methyl alone. Furthermore, R2 was highly resistant to flazasulfuron(34.90-fold), imazapic(11.30-fold), flucarbazone(49.20-fold), pyribenzoxim(12.94-fold), moderately resistant to mesosulfuron-methyl(9.77-fold) and pyroxsulam(6.26-fold), and malathion had no effect on R2 resistance to mesosulfuron-methyl. The fulllength of AHAS genes was sequenced and the AHAS enzymes were assayed in vitro in order to clarify the mechanism of resistance to AHAS inhibitors in R1 and R2 populations. The results demonstrated that R2 had a Pro-197-Ser mutation in the AHAS gene, and the sensitivity of R2 to the five AHAS inhibitors was decreased, which may result in R2 resistance to AHAS inhibitors. There was no mutation in the AHAS gene of R1, and there were no significant differences in enzyme sensitivity between susceptible(S) and resistant(R1) populations. An enhanced metabolism may be the main mechanism of R1 resistance to AHAS inhibitors.

Non-fluctuating target detection in low-grazing angle with MIMO radar

The non-fluctuating target detection in low-grazing angle using multiple-input multiple-output(MIMO) radar systems was studied, where the multipath effects are very abundant. The performance of detection can be improved via utilizing the multipath echoes. First, the reflection coefficient considering the curved earth effect is derived. Then, the general signal model for MIMO radar is introduced for non-fluctuating target in low-grazing angle. Using the generalized likelihood ratio test(GLRT) criterion, the detector of non-fluctuating target with multipath was analyzed. The simulation results demonstrate that the MIMO radar outperforms the conventional radar in non-fluctuating target detection and show that the performance can be enhanced markedly when the multipath effects are considered.

Impact Assessments of Transgenic cry1Ab Rice on the Population Dynamics of Five Non-Target Thrips Species and Their General Predatory Flower Bug in Bt and Non-Bt Rice Fields Using Color Sticky Card Traps

A 2-yr field study was conducted to assess the effects of transgenic japonica rice（KMD1 and KMD2） with a synthetic cry1 Ab gene from Bacillus thuingiensis Berliner on population dynamics and seasonal average densities of five thrips species including Stenchaetothrips biformis（Bagnall）,Frankliniella intonsa（Trybom）,F.tenuicornis（Uzel）,Haplothrips aculeatus（Fabricius）,Haplothrips tritici（Kurd） and their general predatory flower bug,Orius similis Zheng as compared to the parental control rice line using the white,blue and yellow sticky card traps.Population dynamics and seasonal average densities of these five thrips species and their general predatory flower bug were not significantly affected by rice type.Additionally,the white sticky card trap was suggested to be the most suitable for monitoring the population of these five thrips species and their general predator.These results show that our tested Bt rice lines do not interrupt the population of non-target thrips species and their general predatory flower bug in the field,and also cannot result in more occurrence of these thrips species in the rice ecosystem.

Non-target Screening and Quantitation of Organic Chlorides in Oilfield Chemicals with Comprehensive Two Dimensional Gas Chromatography Coupled with Time of Flight Mass Spectrometry

Advanced analytical methodology based on comprehensive two-dimensional gas chromatography-time of flight mass spectrometry(GC×GC-TOFMS) is proposed for investigation of organic chlorides in different oilfield chemicals.The target screening was initially carried out on 8 suspected organic chlorides by evaluating the capability of the enhanced separation and reliable identification at a trace concentration. GC×GC-TOFMS allowed for the fast and automated analysis of organic chlorides at a level of 200 μg/L. This method was subsequently applied for non-target screening of organic chlorides in different oilfield chemicals at various locations across China. 22 organic chlorides were identified and verified by comparison with pure standards in the mixed sample. Finally, this method was used to determine the content of the organic chlorides in individual samples. The result showed that the organic chloride levels in 19 of the 39 tested oilfield chemicals were above the threshold limit of 1.0 mg/L.

Targeted therapies for patients with advanced NSCLC harboring wild-type EGFR:what's new and what's enough

Historically,non-small cell lung cancer(NSCLC) is divided into squamous and nonsquamous subtypes based on histologic features.With a growing number of oncogenic drivers being identified in squamous and nonsquamous NSCLC,this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations.This new paradigm has substantially highlighted the treatment of advanced NSCLC,shifting it from standard chemotherapy according to specific histologic subtypes to targeted therapy according to specific oncogenic drivers.The application of epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs) in NSCLC patients harboring activating EGFR mutations has been a representative model of precise medicine in the treatment of NSCLC.As the role of EGFR-TKIs in routine management of patients with advanced NSCLC has been well established,this review provides an overview of alternative targeted therapy in the treatment of NSCLC,including EGFR-TKIs for patients with wild-type EGFR NSCLC,as well as other targeted agents either clinical available or in early- to late-stage development.

A RGD-Containing Oligopeptide (K)_(16)GRGBSPC: A Novel Vector for Integrin-Mediated Targeted Gene Belivery

A 23 amino acid, bifunctional integrin-targeted synthetic oligopeptide was evaluated for ex vivo gene delivery to rabbit bone marrow stromal cells （BMSCs）. Synthesis of the peptide （K）16GRGDSPC was performed on a solid-phase batch peptide synthesizer. BMSCs were transfected with plasmid DNA coding for luciferase by （K）j6GRGDSPC and the transfection efficiency was assayed. The influences of chloroquine and polyethyleneimine on the transfection efficiency were also examined. The target specificity of （K）16GRGDSPC to mediate exogenous gene into BMSCs was analyzed using cell attachment test and gene delivery inhibition test. The results showed that the transfection efficiency of the oligopeptide vector was lower than that of Lipofectamine. But in the presence of endosomal buffer chloroquine or endosomal disrupting agent polyethyleneimine, the transfection efficiency of the vector was greatly enhanced. In addition, RGD-containing peptides inhibited BMSCs＇ attachment to the 96-well plates pretreated with fibronectin or vitronecfin and significantly decreased the transfection efficiency of the oligopeptide vector. These studies demonstrated that oligopeptide （K）16GRGDSPC was an ideal novel targeted non-viral gene delivery vector, which was easy to be synthesized, high efficient and low cytotoxicity. The vector could effectively deliver exogenous gene into rat BMSCs.

Advances in treatment strategies for non–clear cell renal cell carcinoma

Renal cell carcinoma is the sixth most commonly diagnosed cancer in men and the tenth in women,with clear cell renal cell carcinoma accounting for nearly 75%of cases.The remaining 25%consists of non–clear cell renal cell carcinoma,a diverse and less prevalent group.Although current treatments for clear cell types are well-defined,progress in treating non–clear cell renal cell carcinoma has been limited owing to its heterogeneity and rarity,relying primarily on findings from small-scale phase Ⅱ clinical trials.This review examined recent advancements in the treatment of non–clear cell renal cell carcinoma,particularly in the areas of immunotherapy and targeted therapy.

Non-Detection Probability of a Diffusing Target by a Stationary Searcher in a Large Region

We revisit one of the classical search problems in which a diffusing target encounters a stationary searcher. Under the condition that the searcher’s detection region is much smaller than the search region in which the target roams diffusively, we carry out an asymptotic analysis to derive the decay rate of the non-detection probability. We consider two different geometries of the search region: a disk and a square, respectively. We construct a unified asymptotic expression valid for both of these two cases. The unified asymptotic expression shows that the decay rate of the non-detection probability, to the leading order, is proportional to the diffusion constant, is inversely proportional to the search region, and is inversely proportional to the logarithm of the ratio of the search region to the searcher’s detection region. Furthermore, the second term in the unified asymptotic expansion indicates that the decay rate of the non-detection probability for a square region is slightly smaller than that for a disk region of the same area. We also demonstrate that the asymptotic results are in good agreement with numerical solutions.

Thrips-mediated impacts from transgenic rice expressing Cry1Ab on ecological fitness of non-target predator Orius tantilus(Hemiptera:Anthocoridae)

Various rice lines have been genetically modified with genes from Bacillus thuringiensis（Bt） to continuously produce Bt insecticidal proteins against lepidopteran larvae. The Bt insecticidal protein constantly expresses in the plants to create an opportunity for non-target herbivores to acquire and convey the protein to their predators or parasitoids across trophic levels. This paper evaluates the effects of Bt rice（namely, Kemindao 1（KMD1） and Kemindao 2（KMD2）） expressing Cry1 Ab as compared to its non-Bt control line, Xiushui 11 on non-target predator Orius tantilus（a generalist predatory anthocorid of thrips） under laboratory and field conditions. To measure several biological parameters such as total nymphal duration and fecundity of this bug, it was reared on thrips and pollens of KMD1 and KMD2 as compared to their control under laboratory conditions. By comparison with the control, Bt rice did not significantly affect main life-history characteristics（total nymphal duration, female adult longevity, oviposition period and fecundity） of this anthocorid preying on Bt rice-fed thrips along with Bt rice pollens, except that the fecundity of this predator for KMD1 was distinctly lower as compared with KMD2 or the control. Enzyme-linked immunosorbent assay（ELISA） results showed that no Cry1 Ab protein was detected in this predator fed on thrips or rice pollen from Bt rice but was in Bt rice pollens. With the beat plate, plastic bag and color trap sampling methods, two-year field monitoring of O. tantilus abundance demonstrated that Bt rice had no significant detrimental effects on the population dynamics and seasonal average densities of this predatory anthocorid as compared with the control. Thus, it is suggested that growing our tested Bt rice（KMD1 and KMD2） producing Cry1 Ab will pose a negligible risk to the anthocorid, O. tantilus.

ISAR target recognition based on non-negative sparse coding

Aiming at technical difficulties in feature extraction for the inverse synthetic aperture radar （ISAR） target recognition, this paper imports the concept of visual perception and presents a novel method, which is based on the combination of non-negative sparse coding （NNSC） and linear discrimination optimization, to recognize targets in ISAR images. This method implements NNSC on the matrix constituted by the intensities of pixels in ISAR images for training, to obtain non-negative sparse bases which characterize sparse distribution of strong scattering centers. Then this paper chooses sparse bases via optimization criteria and calculates the corresponding non-negative sparse codes of both training and test images as the feature vectors, which are input into k neighbors classifier to realize recognition finally. The feasibility and robustness of the proposed method are proved by comparing with the template matching, principle component analysis （PCA） and non-negative matrix factorization （NMF） via simulations.

剁辣椒源益生菌筛选及其在发酵剁辣椒中的应用

为开发风味优良且具有一定营养健康功效的益生菌发酵剁辣椒,本研究以湖南传统发酵剁辣椒为原料,筛选耐受胃肠消化的益生菌进行剁辣椒发酵,通过理化分析、感官评价及非靶向代谢组学技术,探究益生菌发酵对剁辣椒理化性质、安全性和感官特性的影响。结果表明,筛选得到3株耐受胃肠消化菌株,鉴定为植物乳植杆菌(Lactiplantibacillus plantarumJEB2)、短乳杆菌(Lactobacillus brevisJEB7)和酿酒酵母(Saccharomyces cerevisiae JEE2)。其中L.plantarum JEB2和L.brevis JEB7在24 h内将0.25 mg/mL亚硝酸钠全部降解,S.cerevisiae JEE2在24 h内胆固醇同化率达50.79%;筛选菌种发酵制备的剁辣椒pH<4.2、滴定酸度>0.6%,样品亚硝酸盐含量及大肠菌群明显低于自然发酵剁辣椒;L.plantarum JEB2和L.brevis JEB7复配发酵制备的剁辣椒样品感官得分最高为19.50(满分20),非靶向代谢组学结果显示该剁辣椒样品刺激性物质(4-乙酰氨基-2-氨基丁酸和巴豆苷)表达量下调,芳香物质(4-甲基苯甲醛、黄铜酸乙烯酯、D-山梨醇等)和活性物质(笑脸素、鹅膏苷F5、白花丹等)表达量上调。因此,利用L.plantarum JEB2和L.brevis JEB7发酵剁辣椒,可以降低产品刺激性、增加风味,并提高产品安全性和益生特性,可进一步开发利用作为发酵产品的生产发酵剂。

A Method to Obtain the Moving Speed of Uncooperative Target Based on Only Two Measurements

The existing research results show that a fixed single station must conduct three consecutive frequency shift measurements and obtain the target’s moving speed by constructing two frequency difference equations. This article proposes a new method that requires only two consecutive measurements. While using the azimuth measurement to obtain the angular difference between two radial distances, it also conducts two consecutive Doppler frequency shift measurements at the same target azimuth. On the basis of this measurement, a frequency difference equation is first constructed and solved jointly with the Doppler frequency shift equation. By eliminating the velocity variable and using the measured angular difference to obtain the target’s lead angle, the target’s velocity can be solved by using the Doppler frequency shift equation again. The new method avoids the condition that the target must move equidistantly, which not only provides an achievable method for engineering applications but also lays a good foundation for further exploring the use of steady-state signals to achieve passive positioning.

基于改进YOLOv5的红花目标检测算法研究

为实现农业非结构环境下采摘机器人对红花的准确识别,提出了一种基于改进YOLOv5的红花目标检测算法。将CBAM注意力机制嵌入到YOLOv5网络,提高了小尺寸目标物在高层次特征中的表现力;建立一种Alpha-IoU目标位置损失函数对原损失函数GIOU存在的梯度消失问题进行改进,提高了被遮挡红花的预测率,并通过在目标检测网络中增加分割检测模块,提高宽和高小于最低像素的小目标物检测精度,利用图像扩增数据集对改进后的YOLOv5算法进行训练,再分别与改进前后YOLOv5网络和Faster R-CNN网络在不同红花品种、不同自然光照情况、不同天气条件和不同遮挡情况下进行对比。试验结果表明:改进后的YOLOv5算法P值、R值分别为90.45%和0.90,对非结构环境下盛开期的未采摘红花mAP值达到94.48%,在不同影响因素下都可以准确识别出红花且置信度较高,可为红花采摘机器人自动化作业中的红花识别提供技术支持。