VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.     

黄土丘陵沟壑区农林草地土壤热量状况及植被生长响应——以燕沟流域为例

利用CoupModel模型模拟了黄土丘陵沟壑区燕沟流域刺槐(Robinia pseudoacacia)林地、辽东栎(Quercus liaotungensis)林地、荒草地、农地等7种土地类型的土壤热量状况,分析了不同植被类型的潜热通量、感热通量、土壤热通量以及植被生长对土壤热量的响应.结果表明,农地潜热通量较小,林地和荒草地潜热通量较大,各地类潜热通量季节变化规律基本一致.潜热通量是黄土丘陵区土壤-植被-大气系统能量的主要支出项,占总净辐射的72.1%～81.4%以上;感热通量变化振幅相对较小,占总净辐射的16.4%～26.4%;土壤热通量仅占总净辐射的1.4%～2.4%,但直接影响土壤温度的变化速度和变化时间.试验地各地类地表温度随季节的变化趋势均呈单峰曲线型.2～7月份0～20cm平均土壤温度随累积土壤热通量的增大而升高,9月到翌年1月份0～20cm平均土壤温度随累积土壤热通量的减小而降低,但累积土壤热通量的变化滞后于土壤温度变化.同一植被类型条件下,阳坡土壤温度年变幅显著高于阴坡.在阴坡,0cm、10cm、20cm深土壤温度年变幅农地＞阴坡荒草地＞阴坡辽东栎林地＞阴坡刺槐林地;在阳坡,阳坡荒草地＞阳坡刺槐林地＞阳坡辽东栎林地.阴坡刺槐林地、阴坡荒草地和农地0～20cm土壤温度达到5℃以上的时间比阳坡刺槐林和阳坡荒草地推迟1周左右,根系开始生长活动的时间也推迟1周左右;而阴坡辽东栎林地则晚于阳坡辽东栎林地5d左右,根系开始生长活动的时间也较阳坡辽东栎林晚5d左右.出叶时间阳坡刺槐林和阳坡荒草地植物比阴坡刺槐林、阴坡荒草地和阳坡辽东栎林的早1周左右,比阴坡辽东栎林早12d左右.     

Attention allocation on mobile app interfaces when human interacts with them

With the popularity of smartphones and the pervasion of mobile apps, people spend more and more time to interact with a diversity of apps on their smartphones, especially for young population. This raises a question: how people allocate attention to interfaces of apps during using them. To address this question, we, in this study, designed an experiment with two sessions (i.e., Session1: browsing original interfaces; Session 2: browsing interfaces after removal of colors and background) integrating with an eyetracking system. Attention fixation durations were recorded by an eye-tracker while participants browsed app interfaces. The whole screen of smartphone was divided into four even regions to explore fixation durations. The results revealed that participants gave significantly longer total fixation duration on the bottom left region compared to other regions in the session (1) Longer total fixation duration on the bottom was preserved, but there is no significant difference between left side and right side in the session2. Similar to the finding of total fixation duration, first fixation duration is also predominantly paid on the bottom area of the interface. Moreover, the skill in the use of mobile phone was quantified by assessing familiarity and accuracy of phone operation and was investigated in the association with the fixation durations. We found that first fixation duration of the bottom left region is significantly negatively correlated with the smartphone operation level in the session 1, but there is no significant correlation between them in the session (2) According to the results of ratio exploration, the ratio of the first fixation duration to the total fixation duration is not significantly different between areas of interest for both sessions. The findings of this study provide insights into the attention allocation during browsing app interfaces and are of implications on the design of app interfaces and advertisements as layout can be optimized according to the attention allocation to maximally deliver information.     

A secreted ribonuclease effector from Verticillium dahliae localizes in the plant nucleus to modulate host immunity

The arms race between fungal pathogens and plant hosts involves recognition of fungal effectors to induce host immunity. Although various fungal effectors have been identified, the effector functions of ribonucleases are largely unknown. Herein, we identified a ribonuclease secreted by Verticillium dahliae (VdRTX1) that translocates into the plant nucleus to modulate immunity. The activity of VdRTX1 causes hypersensitive response (HR)‐related cell death in Nicotiana benthamiana and cotton. VdRTX1 possesses a signal peptide but is unlikely to be an apoplastic effector because its nuclear localization in the plant is necessary for cell death induction. Knockout of VdRTX1 significantly enhanced V. dahliae virulence on tobacco while V. dahliae employs the known suppressor VdCBM1 to escape the immunity induced by VdRTX1. VdRTX1 homologs are widely distributed in fungi but transient expression of 24 homologs from other fungi did not yield cell death induction, suggesting that this function is specific to the VdRTX1 in V. dahliae. Expression of site‐directed mutants of VdRTX1 in N. benthamiana leaves revealed conserved ligand‐binding sites that are important for VdRTX1 function in inducing cell death. Thus, VdRTX1 functions as a unique HR‐inducing effector in V. dahliae that contributes to the activation of plant immunity.     

Depression compromises antiviral innate immunity via the AVP-AHI1-Tyk2 axis

Depression is a serious public-health issue. Recent reports have suggested higher susceptibility to viral infections in depressive patients. However, how depression affects antiviral innate immune signaling remains unknown. Here, we revealed a reduction in expression of Abelson helper integration site 1 (AHI1) in the peripheral blood mononuclear cells (PBMCs) and macrophages from the patients with major depressive disorder (MDD), which leads to attenuated antiviral immune response. We found that depression-related arginine vasopressin (AVP) induces reduction of AHI1 in macrophages. Further studies demonstrated that AHI1 is a critical stabilizer of basal type-I-interferon (IFN-I) signaling. Mechanistically, AHI1 recruits OTUD1 to deubiquitinate and stabilize Tyk2, while AHI1 reduction downregulates Tyk2 and IFN-I signaling activity in macrophages from both MDD patients and depression model mice. Interestingly, we identified a clinical analgesic meptazinol that effectively stimulates AHI1 expression, thus enhancing IFN-I antiviral defense in depression model mice. Our study promotes the understanding of the signaling mechanisms of depression-mediated antiviral immune dysfunction, and reveals meptazinol as an enhancer of antiviral innate immunity in depressive patients.Subject terms: Innate immunity, Ubiquitylation, Cell signalling     

湘潭锰矿废弃地不同林龄栾树人工林碳储量变化趋势

对湘潭锰矿区废弃地植被恢复区的3年生、5年生和9年生栾树林,进行了不同时间序列栾树林生物量和碳储量的时空变化研究。结果表明:随着林龄的增长,林木和各器官生物量增加,树干生物量所占比例逐渐增大,林下植被层生物量随林龄增长而增加,且以草本植被为主;不同林龄栾树人工林乔木层碳含量在0.51—0.53gC/g之间,并高于林下植被层碳含量;不同林龄林地土壤层碳含量变化范围为0.01—0.03gC/g,同一林龄不同深度土层碳含量没有显著差异,相同深度不同林龄土层碳含量存在差异;3年生、5年生和9年生栾树碳储量分别为:1.66、18.32和49.87t/hm2,随林龄增长而增加,其中树干碳储量贡献率最大,所占比例由3年生的27.71%增长到9年生的43.43%;不同林龄栾树林生态系统总碳储量分别为77.76、101.63和149.86t/hm2,其中土壤层碳储量变化范围为76.09—99.93t/hm2,占总储量的66.68%—97.85%,死地被物层碳储量为0.01—0.04t/hm2,占总储量0.001%—0.02%,植被层碳储量为1.67—49.89t/hm2,占总碳储量的2.15%—33.29%,植被层中乔木层为1.66—49.87t/hm2,占植被层碳储量的99%以上。各林龄栾树林生态系统碳储量空间分布序列为土壤层植被层死地被物层。研究结果可为我国矿区植被恢复地的森林资源和碳汇管理提供科学依据。     

湘南某矿区蔬菜中Pb、Cd污染状况及健康风险评估

通过采集湘南某矿区周边农田中种植的蔬菜和对应耕作层土壤样品,探究了农田蔬菜Pb、Cd的污染状况,蔬菜和土壤重金属含量之间的相关性,蔬菜中重金属对人体的健康风险。结果表明:(1)污染区土壤重金属污染非常严重,叶菜类蔬菜重金属超出了食品卫生标准限值,但是果菜类蔬菜中重金属没有超出食品卫生标准限值。(2)不同蔬菜不同器官所含Pb、Cd有明显差异;不同种类蔬菜Pb、Cd含量不同,一般是叶菜类果菜类;同种蔬菜不同部位重金属含量的顺序也不同,一般为根茎叶果,或根叶茎果。(3)二类蔬菜中重金属Pb、Cd的富集系数顺序为叶菜类果菜类。(4)蔬菜中Pb、Cd含量与土壤中相对应元素含量均无显著相关性。(5)就农产品安全性而言,果菜类蔬菜比叶菜类蔬菜更适合在此矿区栽培。