A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

张掖市户外运动旅游发展现状的调查研究

为进一步挖掘张掖市户外运动旅游的潜力,促进张掖市体育旅游示范区建设,针对张掖市户外运动旅游现状采用问卷调查、实地考察等方法进行调查研究。结果显示:张掖市户外运动旅游资源丰富,其产品转化率很高;张掖市户外运动旅游市场需求广泛,牵动着许多领域经济的发展;张掖市户外运动旅游产品供需关系相对不平衡,满足不了游客深层次的旅游体验需求。为了进一步促进张掖市户外运动旅游的发展,提出了明确户外运动旅游产品的主题,突出旅游产品的特色;准确把握户外运动旅游产品的定位,拓展旅游产品的营销渠道;增强游客间的互动性,提升游客旅游体验的层次等对策和建议。

Plasticizing Effect of Camellia oleifera Seed-Oil-Based Plasticizer on PVC Material Modification

In this study,as the plasticizer,Camellia oleifera seed-oil-based cyclohexyl ester(COSOCE)was prepared by the reaction of cyclohexene oxide and refined C.oleifera seed oil(RCOSO)obtained by acidification hydrolysis after saponification.In addition,the structure of the target product was confirmed by Fourier transform infrared(FTIR)spectroscopy,nuclear magnetic resonance(NMR)spectroscopy,and Raman spectroscopy.COSOCE was used as plasticizer-modified polyvinyl chloride(PVC)membranes.The structure of the COSOCE-modified PVC membranes were characterized by Raman spectroscopy and scanning electron microscopy(SEM).The properties of the COSOCE-modified PVC membrane were characterized by contact angle measurements,universal testing machine,thermogravimetric analysis(TGA),and differential scanning calorimetry(DSC).The results revealed that(1)The COSOCE-modified PVC membranes exhibit a good microscopic morphology.Combined with energy-dispersive X-ray spectroscopy(EDS)and contact angle measurement results,the COSOCE-modified PVC membranes are confirmed to be a hydrophilic material.(2)The modified PVC membrane with 60%COSOCE exhibited the best mechanical properties.The tensile strength reached 23.56±2.94 MPa.(3)COSOCE-modified PVC material exhibited better thermal stability,with a loss rate of less than 75%at the end of the first decomposition stage.Compared with that of the dioctyl-phthalate(DOP)-modified PVC membrane,the initial decomposition temperature of PVC was increased by 1.17°C–8.17°C,and the residual rate was increased by 0.67%–5.75%.The carbon–carbon double bond in the COSOCE molecular structure can remove the free radicals generated during the degradation of PVC material and slow down the decomposition rate of PVC.In addition,the double bond can be cross-linked partially with the PVC molecular chain containing the conjugated polyene structure,thereby increasing the movement resistance of the PVC molecular chain segment.Hence,COSOCE can replace DOP as a PVC plasticizer.

电极界面浓差极化对锂金属沉积的影响

锂金属作为下一代高能量密度电池的理想负极材料受到研究人员广泛关注。然而,锂枝晶生长引起的安全隐患和循环寿命短等问题严重影响了锂金属电池的实用化进程。本文以电化学现象和理论为依据,从浓差极化角度详细分析锂金属电沉积过程中枝晶生长、死锂形成和全电池失效机制,并对目前研究较多的多孔宿主电极中的浓差极化及枝晶抑制进行分析,提出锂金属界面浓差电池现象。本文得到的结论为研究人员更深入地探究锂金属保护策略提供了理论依据。

户外运动与裕固族传统体育融合发展研究

先分析了户外运动和裕固族传统体育融合的可行性,随后介绍了裕固族传统体育项目的内容和特征,最后介绍了户外运动和裕固族传统体育有机结合的具体措施,包括形成多元融合的体育产业格局、创建特色精品赛事、构建裕固族传统体育和户外活动有机结合的运动基地,希望能给相关人士提供有效参考。

Re-Os geochronology of Cu and W-Mo deposits in the Balkhash metallogenic belt,Kazakhstan and its geological significance

The Central Asian metallogenic domain （CAMD） is a multi-core metallogenic system controlled by boundary strike-slip fault systems. The Balkhash metallogenic belt in Kazakhstan, in which occur many large and super-large porphyritic Cu--Mo deposits and some quartz vein- and greisen-type W-Mo deposits, is a well-known porphyritic Cu--Mo metallogenic belt in the CAMD. In this paper 11 molybdenite samples from the western segment of the Balkhash metallogenic belt are selected for Re--Os compositional analyses and Re--Os isotopic dating. Molybdenites from the Borly porphyry Cu deposit and the three quartz vein-greisen W--Mo deposits--East Kounrad, Akshatau and Zhanet--all have relatively high Re contents （2712--2772 μg/g for Borly and 2.267--31.50 μg/g for the other three W-Mo deposits）, and lower common Os contents （0.670-2.696 ng/g for Borly and 0.0051--0.056 ng/g for the other three）. The molybdenites from the Borly porphyry Cu--Mo deposit and the East Kounrad, Zhanet, and Akshatau quartz vein- and greisen-type W-Mo deposits give average model Re--Os ages of 315.9 Ma, 298.0 Ma, 295.0 Ma, and 289.3 Ma respectively. Meanwhile, molybde- nites from the East Kounrad, Zhanet, and Akshatan W-Mo deposits give a Re--Os isochron age of 297.9 Ma, with an MSWD value of 0.97. Re--Os dating of the molybdenites indicates that Cu-W-Mo metallogenesis in the western Balkhash metallogeuic belt occurred during Late Carboniferous to Early Permian （315.9--289.3 Ma）, while the porphyry Cu--Mo deposits formed at ~316 Ma, and the quartz vein-greisen W--Mo deposits formed at ~298 Ma. The Re--Os model and isochron ages thus suggest that Late Carboniferous porphyry granitoid and pegmatite magmatism took place during the late Hercy- nian movement. Compared to the Junggar-East Tianshan porphyry Cu metallogenic belt in northwestern China, the formation of the Cu-Mo metallogenesis in the Balkhash rnetallogenic belt occurred between that of the Tuwu-Yandong in East Tianshan and the Baogutu porphyry Cu deposits in West Junggar. Collectively, the large-scale Late Carboniferous porphyry Cu-Mo metallogenesis in the Central Asian metallogenic domain is related to Hercynian tectono-magmatic activities.

Mapping epistasis and environment × QTX interaction based on four-omics genotypes for the detected QTX loci controlling complex traits in tobacco

Using newly developed methods and software, association mapping was conducted for chromium content and total sugar in tobacco leaf, based on four-omics datasets. Our objective was to collect data on genotype and phenotype for 60 leaf samples at four developmental stages, from three plant architectural positions and for three cultivars that were grown in two locations. Association mapping was conducted to detect genetic variants at quantitative trait SNP(QTS) loci, quantitative trait transcript(QTT) differences,quantitative trait protein(QTP) variability, and quantitative trait metabolite(QTM) changes,which can be summarized as QTX locus variation. The total heritabilities of the four-omics loci for both traits tested were 23.60% for epistasis and 15.26% for treatment interaction.Epistasis and environment × treatment interaction had important impacts on complex traits at all-omics levels. For decreasing chromium content and increasing total sugar in tobacco leaf, six methylated loci can be directly used for marker-assisted selection, and expression of ten QTTs, seven QTPs and six QTMs can be modified by selection or cultivation.

Ion association tailoring SEI composition for Li metal anode protection

Electrolyte additives play an important role in suppressing lithium dendrites through tailoring the composition/property of the SEI,however lacking of additives can achieve high performances both in ether and carbonate electrolytes hinders further enhancement of the high voltage lithium^-metal batteries.Here,lithium perchlorate(LiClO4)has been presented as an excellent additive to meet the above requirements.An optimized chemical composition of SEI can be achieved through the formation of ionic association.Our results indicate that the LiClO4 behaves like a catalyst,which promotes LiTFSI to form a better SEI to inhibit further reaction.Superior coulombic efficiencies and cycling performances were obtained both in ether and carbonate electrolytes.This study paves a new pathway for designing bi-soluble additives for safe lithium metal batteries.

Role of serum lactate dehydrogenase levels in evaluating efficacy of interventional therapy for hepatocellular carcinoma

Objective The aim of the study was to investigate the role of serum lactate dehydrogenase(LDH) levels in evaluating the efficacy of transcatheter arterial chemoembolization(TACE) for primary liver cancer.Methods A total of 52 patients with liver cancer admitted in our hospital(Huangzhou District People's Hospital, Huanggang, China) from June 2015 to December 2017 were selected and divided into control group(LDH of ≤ 450 U/L, n = 26) and observation group(LDH of > 450 U/L, n = 26), based on the pretreatment level of LDH. Based on the changes in serum LDH levels before and after treatment, patients were classified into two groups: LDH increased group(22 cases) and LDH decreased group(30 cases). The relationship between LDH levels and efficacy of TACE treatment was analyzed in the four groups retrospectively. Results No significant difference was seen in the clinical characteristics(gender, median age, performance status Eastern Cooperative Oncology Group, and staging system) between the control and observation groups. The efficacy rate in the control group was 57.7%, whereas that in the observation group was 42.3%(P > 0.05). The 1-year survival rate in the observation group was 53.8% and that in the control group was 84.6%(P < 0.05).Conclusion Serum LDH levels may be of clinical value in evaluating the efficacy of TACE in patients with hepatocellular carcinoma.

杜仲叶对芦花鸡生长性能及肉质的影响

本试验旨在研究饲粮中不同添加量杜仲叶粉对芦花鸡生长性能、屠宰指标、血液生化指标以及肉品质等影响,探讨其在养鸡行业的应用效果。试验选取4周龄健康、体重约为300 g/羽的芦花鸡160羽,随机分成4组,每组40羽。对照组饲喂基础饲粮,试验组在其基础上分别添加1%、3%和5%杜仲叶粉,试验期70天。结果表明:与对照组相比,试验组芦花鸡平均日增重降低,料重比升高(P <0.01);各试验组中,芦花鸡末重减小(P <0.05),腹脂率和低密度脂蛋白胆固醇含量降低(P <0.01),并且蛋白质含量明显提高(P <0.01);另外不同添加量的杜仲叶粉也会引起黄酮、硒和氨基酸含量等成分的变化。综合考虑,饲粮中添加3%杜仲叶粉更适合芦花鸡生长性能及肉质的改善。

Determining the in vitro Anti-Aging Effect of the Characteristic Components from Eucommia ulmoides

To evaluate the potential anti-aging ability of Eucommia ulmoides,four characteristic components(chlorogenic acid,geniposidic acid,aucubin,quercetin)were selected to assess their effects on H_(2)O_(2)-induced oxidative damage model of human umbilical vein endothelial cell(HUVEC).Oxidative damage indexes,inflammatory factors,cell cycle,cell apoptosis,cell senescence,and their related proteins were analyzed by methyl thiazolyl tetrazolium(MTT)assay,enzyme-linked immunosorbent assay(ELISA),propidium iodide(PI)staining,annexin V-FITC/PI double staining,SAβ-galactosidase staining,and western blotting(WB).The results showed that H_(2)O_(2)-induced cell growth inhibition rate decreased as supplementation with characteristic components when compared to H_(2)O_(2) group.Meanwhile,the contents of antioxidant indexes(reactive oxygen species,lactate dehydrogenase,molondialdehyde,superoxide dismutase,glutathione),inflammatory factors(nuclear factor kappa-B,intercellular cell adhesion molecule-1,vascular cell adhesion protein 1),and functional factors(NO,Endothelin-1)in characteristic components treated groups improved if comparison with H_(2)O_(2) group,suggesting the characteristic components of E.ulmoides could alleviate H_(2)O_(2)-induced oxidative damage.Moreover,cell cycle,cell apoptosis,cell senescence,and their related proteins under characteristic components treatment exhibited a better effect than under H_(2)O_(2) treatment,implying the characteristic components could participate in anti-aging via multiple pathways.These results manifested that the characteristic components of E.ulmoides posses the capacity of anti-aging,which provided a basis for investigating the anti-aging ability of E.ulmoides itself.

Free Vibration Analysis of Elastic Bodies for Six-Axis Force Sensor

Now the six-axis force sensor (6-AFS) is used widely, and as the core components, mechanical properties of its elastic bodies are significant. With the increase of dynamic loads, studies on dynamic characteristics of the 6-AFS become more and more important. In this paper, the study focuses on the free vibration problem of a novel 6-AFS. The research approach is to decompose the sensor into several separate elastic bodies (four lamellas and upper and lower membranes) and research these elastic bodies respectively. The free vibration of the lamella is studied based on Rayleigh-Ritz method and the separation of variables. The analytical solutions of free vibration of the membranes are deduced according to the nature of Bessel functions. Both the analytical results are simulated with MATLAB. Compared the simulated diagrams with actual situations, they are very close. The mode shapes obtained play a major role in solving the forced vibration of the sensor.

A Plant Image Compression Algorithm Based on Wireless Sensor Network

This paper designs and implements an image transmission algorithm applied to plant information collection based on the wireless sensor network. It can effectively reduce the volume of transmitted data, low-energy, high-availability image compression algorithm. This algorithm mainly has two aspects of improvement measures: the first is to reduce the number of pixels that transmit images, from interlaced scanning to interlaced neighbor scanning;the second is to use JPEG image compression algorithm [1], changing the value of the quantization table in the algorithm [2]. After image compression, the image data volume is greatly reduced;the transmission efficiency is improved;and the problem of excessive data volume during image transmission is effectively solved.

High-Affinity Decoy PD-1 Mutant Screened from an Epitope-Specific Cell Library

Immunotherapy with anti-programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PDL1)monoclonal antibodies has become routine in the treatment of many kinds of human cancers,such as lung cancer,intestinal cancer,and melanoma.The PD-1/PD-L1 pathway inhibits T cell activation in the micro-environment,making it an attractive target against cancer.Wild-type(WT)PD-1 ectodomain has been shown to have difficulty blocking PD-1/PD-L1 mixture formation due to its low affinity.The present work uses three-dimensional(3D)crystal complex structures to analyze the interaction by which PD-1 binds to PD-L1 or PD-L2.It also reports on a theoretical study of the binding mode between PD-1 and its clinical antibody Opdivo.Based on the theoretical binding analysis of PD-1 and its ligands(i.e.,PD-L1 and PD-L2)or antibody(Opdivo),a small-content,epitope-oriented mammalian cell library was established for PD-1.After three rounds of cell sorting,the decoy PD-1 mutant 463,which presented a higher affinity than WT PD-1 to the PD-L1(the affinity has increased by almost three orders of magnitude)was screened out.It exhibited an inhibitory effect against PD-1 to prevent it from forming mixtures with PD-L1,which was similar to the effect of the commercial anti-PD-L1 antibody atezolizumab(ATE).The median effective concentration(EC50)value of the decoy mutant was 0.031 μg·mL^(-1) in comparison with 0.063 μg·mL^(-1) for ATE;both values were much lower than that of WT PD-1,at 2.571 μg·mL^(-1).The 463 decoy mutant reversed the inhibitory function of PD-1 in T cell activation;furthermore,10 mg·kg^(-1) of 463 inhibited about 75%of tumor growth in vivo in a MC38 transgenic xenograft mice model,which was similar to the activity of ATE.More interestingly,an even lower dose of 463(2 mg·kg^(-1))showed a better effect than 10 mg·kg^(-1) of WT PD-1.This work offers the decoy 463 with an improved curative effect,which holds potential to become a good option against PD-1/PD-L1-related cancers.

Lunasin protease inhibitor concentrate decreases pro-infl ammatory cytokines and improves histopathological markers in dextran sodium sulfate-induced ulcerative colitis

Lunasin protease inhibitor concentrate(LPIC)is a novel combination of soy bioactive peptide lunasin,Kunitz and Bowman-Birk protease inhibitors.The reported anti-inflammatory and anticancer properties of each one of them suggest LPIC as a promising candidate for the treatment of infl ammatory-related diseases.Our objective was to assess the in vivo anti-infl ammatory properties of LPIC.First,an in vitro test was performed in lipopolysaccharide(LPS)-activated RAW264.7 murine macrophages by measuring the production of nitric oxide(NO),interleukin-6(IL-6),and tumor necrosis factorα(TNF-α)as infl ammatory markers.For the in vivo model,ulcerative colitis(UC)was induced in mice via oral administration of dextran sodium sulfate(DSS).LPIC treatment was performed via daily intraperitoneal injection of 50 mg/kg body weight.Body weight,visible blood in stool and stool consistency were scored daily as macroscopic indicators of disease progression.Occult blood was evaluated by the presence of hemoglobin in stool every third day.Colon length,caecum weight,colonic myeloperoxidase activity(MPO),presence of pro-inflammatory cytokines in blood and colon,changes in the architecture,and expression of inducible nitric oxide synthase(i NOS)in colonic tissue were evaluated.In vitro,LPIC induced production of NO and maintained cytokine levels in comparison to activated untreated macrophages.In vivo,LPIC increased colonic bleeding and did not improve macroscopic markers of the disease,but reduced colonic IL-1βand IL-6,decreased systemic circulation of TNF-α,attenuated neutrophils infi ltration and i NOS expression in colonic tissue,and diminished the damage in colonic architecture.Our results suggest that combinations of peptides in LPIC may counteract the antiinfl ammatory properties in vitro;while in vivo,LPIC can signifi cantly reduce the histopathological damage,hence is a possible therapeutic strategy to attenuate UC.

In Vitro Study of Ultrasound on Multidrug Resistance in MDR Human Hepatoma HepG_2 Cells

OBJECTIVE The aim of the study was to examine the reversal effects of ultrasound （US） on the MDR in HepG2/ADM, a HepG2 cell line resistant to Adriamycin （ADM）, and to study the mechanism of US action.METHODS Using the MTT assay, the effects of US on MDR in HepG2/ADR cells were studied. Before and after the treatment with 0.5 W/cm^2 low intensity ultrasound （LIUS）, the expression of the MDR-related genes, mdrl, mrp and lrp was assayed with the reverse transcriptase polymerase chain reaction （RT-PCR） and the levels of their respective protein expression determined by flow cytometry. By using confocal laser scanning microscopy （CLSM）, we examined the intracellular daunorubicin （DNR） distribution, and the effects on the cells of treatment with US or DNR.RESULTS LIUS significantly reversed MDR in HepG2/ADR cells. After treatment with LIUS at 0.5 W/cm^2, chemosensitivity to ADM and DNR increased 3.35-fold and 2.81-fold, respectively. The reversal activity by LIUS plus verapamil （VER） was stronger than with either US or VER alone. After treatment with 0.5 W/cm^2, the expression of both the MDR1 and the MRP mRNA genes began to decline （P 〈 0.01 and P 〈 0.05, respectively）; the expression of LRP showed no significant changes. Changes in the expression of the P-glycoprotein （P-gp） and MRP were similar to those of their mRNA expressions. Results of the CLSM showed that administration of US （0. 5 W/cm^2） or VER （15.7 uM） with DNR to HepGa/ADM cells showed a significant change in the distribution of DNR in the cells.CONCLUSION Our results show that LIUS can reverse MDR. The reversal effects are stronger than those of either US or VER alone, when combined with VER administration. As LIUS is noninvasive causing no toxicity, it might have potential for clinical application. The reversal mechanism needs further study.

Experimental Study of Ultrasound on MDR in a Human Tumor in Vivo

OBJECTIVE To evaluate the potential efficacy of low-intensity ultrasound （US） in combination with anticancer drugs to reverse multidrug resistance （MDR）in nude mice. METHODS A total of 40 male and female athymic nude mice were inoculated subcutaneously with 5×10^6 HepG2/ADM and HepG2 cells. Ultrasound with pulsed irradiation at an average intensity of 0.5 W/cm^2 was given to the tumor area 10 rain after administration of adriamycin （ADM）. The tumor 3 dimensional diameters were measured by calipers before and after treatment, and the tumor growth indexes （TGI） calculated. RT-PCR was used to detect the gene levels of the HepG2/ADM cells. Immunohistochemical analyses for MDR proteins were conducted on the tumor tissues. RESULTS The ultrasonic treatment resulted in an average reduction in the tumor volume of 62% one month later. The relative mRNA levels of MDR1 and MRP were significantly different among the following 4 groups： untreated group as control, ADM treated; US treated; and ADM plus US treated. The mRNA levels of mdrl and mrp were down-regulated in the US groups compared to those of the non-ultrasound groups by multiple comparisons. The relative mRNA levels of Irp expression were not significantly changed. The results of immunohistochemistry indicated that tumor tissue from animals treated with US had remarkably low mdrl and mrp expression. CONCLUSION The results showed that low-intensity US can effectively reduce the size of adriamycin-resistant human hepotacarcinoma in a nude mouse model, and support the efficacy of US to overcome multiple mechanisms of drug resistance.

水泥半终粉磨系统磨头喂料不稳定的解决措施

对Ф3.2 m×13 m水泥磨进行技术升级改造,配置180-120辊压机+V型选粉机+动态选粉机组成开路半终粉磨系统。技改后,三分离选粉机下游空气斜槽与管磨机进料溜子落差15 m,物料进入管磨机的冲量大,料量极不稳定。在空气斜槽与管磨机进料溜子之间增设稳流仓及转子计量秤,实现管磨机喂料的定量控制,解决了冲料问题。