PhaseⅡstudy of induction chemotherapy followed by concurrent chemoradiotherapy with raltitrexed and cisplatin in locally advanced nasopharyngeal carcinoma

Objective:For locally advanced nasopharyngeal carcinoma(LA-NPC)patients,high incidences of distant metastases and severe treatment related toxicities are the main obstacles needed to be overcome.Raltitrexed,a specific thymidylate synthase inhibitor with a convenient administration schedule,has an acceptable and manageable toxicity,and possesses radio-sensitizing properties.To investigate the efficacy and safety of raltitrexed and cisplatin induction chemotherapy and concurrent chemoradiotherapy(IC+CCRT)in patients with LA-NPC,a phaseⅡclinical study was conducted.Methods:Sixty eligible patients with LA-NPC were enrolled into this study.A raltitrexed-cisplatin combination was used as part of an IC+CCRT regimen.Raltitrexed-cisplatin IC was given once every 3 weeks(q3 w)for two cycles,followed by raltitrexed-cisplatin based CCRT q3 w for two cycles.Intensity-modulated radiotherapy(IMRT)was given for all enrolled patients.Results:All patients were included in survival analysis according to the intent-to-treat principle.The objective response rate(ORR)3 months after treatment was 98%.The 2-year overall survival(OS)rate was 92%.The median relapse-free survival(RFS)time was 30.5[95%confidence interval(95%CI),28.4-32.3]months.The 2-year RFS rate was 85%.The 2-year local failure-free survival(LFFS)rate was 97%and the 2-year distant metastasis-free survival(DMFS)rate was 88%.Acute toxicities were mostly grade 2 and 3 reactions in bone marrow suppression,gastrointestinal side effect and oropharyngeal mucositis.Only two patients occurred grade 4 acute toxicities,one was bone marrow suppression and the other was dermatitis radiation.Conclusions:The combination of raltitrexed and cisplatin has a comparable efficacy to those in standard firstline therapy.

Single-cell RNA sequencing of meiocytes and microspores reveals the involvement of the Rf4 gene in redox homeostasis of CMS-C maize

Normal microsporogenesis is determined by both nuclear and mitochondrial genes. In maize C-type cytoplasmic male sterility, it is unclear how the development of meiocytes and microspores is affected by the mitochondrial sterility gene and the nuclear restorer gene. In this study, we sequenced the transcriptomes of single meiocytes(tetrad stage) and early mononucleate microspores from sterile and restorer lines. The numbers of expressed genes varied in individual cells and fewer than half of the expressed genes were common to the same cell types. Four comparisons revealed 3379 differentially expressed genes(DEGs), with 277 putatively associated with mitochondria, 226 encoding transcription factors,and 467 possibly targeted by RF4. KEGG analysis indicated that the DEGs in the two lines at the tetrad stage were involved predominantly in carbon metabolism and in amino acid biosynthesis and metabolism, whereas the DEGs during the transition from the tetrad stage to the early mononucleate stage were associated mostly with regulation of protein metabolism, fatty acid metabolism, and anatomical structure morphogenesis. Thus, meiocyte and microspore development was affected by the surrounding cells and the restorer gene, and the restorer gene helped restore the redox homeostasis of microspores and the normal cellular reconstruction during the transition.

Correlation between miR-564, TGF-β1, and radiation-induced lung injury

Objective Our study aimed to analyze the expression of miR-564 and TGF-β1 in cancer tissues and the serum of patients with radiation-induced lung injury,and to investigate the relationship between them and radiation-induced lung injury.Methods In situ hybridization and real-time fluorescence quantitative method were used to detect the expression of miR-564.Additionally,immunohistochemistry and enzyme-linked immunosorbent assay(ELISA)were performed to detect the expression of TGF-β1.Results The overall incidence of acute radiation pneumonia was 55.9%(100/179).The incidence of≥grade 2 radioactive pneumonia was 24.0%(43/179)and that of grade 1 was 31.8%(57/179).The expression of miR-564 in grade≥2 was slightly higher than that in patients without or with grade 1,but there was no statistical difference(P=0.86).The serum level and ratio of miR-564 in patients with grade≥2 were significantly higher than those without or with grade 1(P=0.005,P=0.025,respectively).The expression of TGF-β1 in grade≥2 was significantly higher than that of patients without or with grade 1(P=0.017).The serum levels of TGF-β1 in grade≥2 were significantly higher than those in patients without or with grade 1(P=0.038).Although the ratio of TGF-β1 in radiation pneumonia of grade≥2 was significantly higher than that of without or with grade 1,there was no significant difference(P=0.24).Moreover,patients with higher expression of miR-564 and lower expression of TGF-β1 had better prognosis.Conclusion MiR-564 and TGF-β1 are predictors of radiation-induced lung injury.Monitoring its changing trend can improve the accuracy of predicting radiation-induced lung injury.The levels and ratio of serum miR-564 and TGF-β1 in patients with radiation-induced lung injury are related to the severity of radiationinduced lung injury.

Research on Surface Roughness of Supersonic Vibration Auxiliary Side Milling for Titanium Alloy

The processed surface contour shape is extracted with the finite element simulation software.The difference value of contour shape change is used as the parameters of balancing surface roughness to construct finite element model of supersonic vibration milling in cutting stability domain.The surface roughness trial scheme is designed in the orthogonal test design method to analyze the surface roughness test result in the response surface methodology.The surface roughness prediction model is established and optimized.Finally,the surface roughness finite element simulation prediction model is verified by experiments.The research results show that,compared with the experiment results,the error range of the finite element simulation model is 27.5%–30.9%,and the error range of the empirical model obtained by the response surface method is between 4.4%and 12.3%.So,the model in this paper is accurate and will provide the theoretical basis for the optimization study of the auxiliary milling process of supersonic vibration.

Multifaceted functions of STING in human health and disease:from molecular mechanism to targeted strategy

Since the discovery of Stimulator of Interferon Genes(STING)as an important pivot for cytosolic DNA sensation and interferon(IFN)induction,intensive efforts have been endeavored to clarify the molecular mechanism of its activation,its physiological function as a ubiquitously expressed protein,and to explore its potential as a therapeutic target in a wide range of immune-related diseases.With its orthodox ligand 2’3’-cyclic GMP–AMP(2’3’-cGAMP)and the upstream sensor 2’3’-cGAMP synthase(cGAS)to be found,STING acquires its central functionality in the best-studied signaling cascade,namely the cGAS–STING–IFN pathway.However,recently updated research through structural research,genetic screening,and biochemical assay greatly extends the current knowledge of STING biology.A second ligand pocket was recently discovered in the transmembrane domain for a synthetic agonist.On its downstream outputs,accumulating studies sketch primordial and multifaceted roles of STING beyond its cytokine-inducing function,such as autophagy,cell death,metabolic modulation,endoplasmic reticulum(ER)stress,and RNA virus restriction.Furthermore,with the expansion of the STING interactome,the details of STING trafficking also get clearer.After retrospecting the brief history of viral interference and the milestone events since the discovery of STING,we present a vivid panorama of STING biology taking into account the details of the biochemical assay and structural information,especially its versatile outputs and functions beyond IFN induction.We also summarize the roles of STING in the pathogenesis of various diseases and highlight the development of small-molecular compounds targeting STING for disease treatment in combination with the latest research.Finally,we discuss the open questions imperative to answer.

人类衰竭心脏中髓系细胞的全面描述

Heart failure(HF)remains a rising global epidemic worldwide[1,2].It is widely recognized that immune cells play important roles in the pathogenesis of HF.The hearts of HF patients are characterized by persistent low-grade inflammation,which has been linked to adverse ventricular remodeling as it promotes interstitial fibrosis and cardiomyocyte dysfunction and loss.

单列毛壳菌通过促进秸秆降解并调控激素响应基因表达促进玉米生长

为探究生防真菌单列毛壳菌(Chaetomium uniseriatum)对秸秆降解和玉米(Zea mays)生长的影响,将单列毛壳菌接种到玉米盆栽土壤中,其它条件不变,以保证单一变量。于拔节期和抽雄期进行采样,通过测定土壤有机碳、土壤可溶性碳/氮、微生物量碳/氮以及酶活性,探究接种单列毛壳菌对土壤生物化学指标的影响。在抽雄期对秸秆降解率、地上部生物量、叶片SPAD值、玉米根系激素含量及根系转录组进行分析,探究接种单列毛壳菌对秸秆降解和玉米植株生长发育的影响。结果表明,接种单列毛壳菌后,土壤养分含量未出现显著性变化, β-葡萄糖苷酶(β-GC)活性显著降低;抽雄期玉米地上部生物量、叶片SPAD值以及秸秆降解率均显著高于对照组;玉米根系生长激素(IAA)和玉米素(ZR)含量均显著低于对照组。不同处理下玉米根系转录组分析筛选得到990个差异表达基因(383个基因表达上调,607个基因表达下调);对差异基因进行GO富集分析,得到5个植物激素相关的条目;KEGG富集分析得到1个与植物激素相关的通路(Pvalue<0.05,Q value<0.05)。综上,单列毛壳菌通过促进秸秆降解以及调控作物根系激素响应基因的表达,进而促进玉米生长。

Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Experimental Ulcerative Colitis Mice

Ulcerative colitis(UC)is a chronic inflammatory bowel disease caused by many factors including colonic inflammation and microbiota dysbiosis.Previous studies have indicated that celastrol(CSR)has strong anti-inflammatory and immune-inhibitory effects.Here,we investigated the effects of CSR on colonic inflammation and mucosal immunity in an experimental colitis model,and addressed the mechanism by which CSR exerts the protective effects.We characterized the therapeutic effects and the potential mechanism of CSR on treating UC using histological staining,intestinal permeability assay,cytokine assay,flow cytometry,fecal microbiota transplantation(FMT),16S rRNA sequencing,untargeted metabolomics,and cell differentiation.CSR administration significantly ameliorated the dextran sodium sulfate(DSS)-induced colitis in mice,which was evidenced by the recovered body weight and colon length as well as the decreased disease activity index(DAI)score and intestinal permeability.Meanwhile,CSR down-regulated the production of pro-inflammatory cytokines and up-regulated the amount of anti-inflammatory mediators at both mRNA and protein levels,and improved the balances of Treg/Th1 and Treg/Th17 to maintain the colonic immune homeostasis.Notably,all the therapeutic effects were exerted in a gut microbiota-dependent manner.Furthermore,CSR treatment increased the gut microbiota diversity and changed the compositions of the gut microbiota and metabolites,which is probably associated with the gut microbiota-mediated protective effects.In conclusion,this study provides the strong evidence that CSR may be a promising therapeutic drug for UC.

The Environmental Right to Water

Fresh water is an indispensable part of the environment for being one of the three media of abiotic environment,as well as for its essential function and vital role to biotic environment.The failure of the human beings and their communities to satisfy the environment for appropriate water requirement has been leading to significant,unnecessary and preventable sufferings on both the environment and the human beings.This paper discusses that the environment for appropriate water requirement is a right implicitly or explicitly by international law,international documents and state practice.Individuals and their communities at various levels should work to provide people with appropriate water and guarantee the environmental right to water as a lawful right.By acknowledging the environmental right to water and willingness to meet this right for the environment deprived of it,the human beings and their communities should have a valuable tool for addressing the crisis of water resources and sustainable development.

Drilling process of indexable drill bit based on Coupled Eulerian-Lagrangian method:A simulation study

42CrMo steel has the characteristics of high strength,high wear resistance,high impact resistance,and fatigue resistance.Therefore,drilling 42CrMo steel has always been a challenging task.The indexable drill bit has the advantages of high processing efficiency and low processing cost and has been widely used in the field of aerospace hole processing.To better understand the machining mechanism of the indexable drill bit,this paper uses the Coupled EulerianLagrangian method(CEL)to simulate the three-dimensional drilling model for the first time.The simulation results of the drilling force obtained by the CEL method and Lagrangian method are compared with the experimental results.It is verified that the CEL method is easy to converge and can avoid the problem of program interruption caused by mesh distortion,and the CEL simulation value is more consistent with the actual value.Secondly,the simulation results of cutting force and blade cutting edge node temperature under different process parameters are extracted.The variation of time domain cutting force,frequency domain cutting force and tool temperature with process parameters are obtained.This study provides a new method for the prediction of cutting performance and the optimization of process parameters of indexable drills.

北部湾盆地涠西南凹陷天然气地球化学特征及来源探讨

北部湾盆地涠西南凹陷油气勘探活动长期以来集中在原油领域,随着时间推移,原油发现难度逐渐增大。天然气是油气增储上产的重要驱动力,但勘探研究程度低,其地球化学特征及来源尚不清楚,制约了下一步勘探进程。基于天然气组成、轻烃组成和稳定碳同位素等数据,对北部湾盆地涠西南凹陷天然气的地球化学特征、成因类型及来源进行探讨,结果表明:①天然气组成以烃类气体为主,其中甲烷含量最高,介于53.73%~95.80%之间,平均为74.80%;重烃(C_(2-5))含量相对较高,平均为19.80%,干燥系数普遍小于0.95,为典型的湿气;非烃类气体含量低,主要为N_(2)和CO_(2);②在C_(7)轻烃化合物中,正庚烷含量相对较高,平均为37.18%(21.74%~51.02%),其次为甲基环己烷,含量平均为34.46%,各种结构的二甲基环戊烷含量略低,平均为28.36%,反映其母质来源复杂,以偏腐泥型干酪根为主,部分为混合型,少量为腐殖型;③δ^(13)C_(1)值和δ^(13)C_(2)值分别为-54.8‰~-34.4‰和-35.2‰~-25.6‰,烷烃气碳同位素总体呈正序分布特征,仅部分井区天然气碳同位素发生一定程度倒转,可能与同源不同期气或同型不同源气的混合作用有关;④天然气主要为油型气,且与原油同源共生,为偏腐泥型干酪根在成熟—高成熟阶段裂解的产物,主要来源于流沙港组二段下层序油页岩,部分有流沙港组三段上层序泥页岩的贡献。研究成果明确了北部湾盆地涠西南凹陷天然气地球化学特征及来源,对下一步天然气勘探部署决策具有重要的指导意义。