Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy

With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.

COPD中MicRNA-320c-5p调节SERPINA1基因表达的研究

目的通过双荧光素酶报告系统验证miR-320c-5p对SERPINA1基因的靶向调控关系。方法从人正常肺上皮细胞基因组库中获取SERPINA1基因的3′UTR序列,并通过序列匹配拟定候选miRNA。利用3%香烟烟雾提取物(cigarette smoke extract,CSE)诱导人支气管上皮细胞(BEAS-2b细胞)建立慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)细胞模型作为实验组,正常培养的BEAS-2b细胞作为对照组,使用实时荧光定量聚合酶链反应(real time flurocent qualitative polymerase chain reaction,RT-qPCR)法检测两组SERPINA1和候选miRNA的表达水平。构建野生型及突变型双荧光素酶报告基因载体,分别将双荧光素酶报告质粒(psiCHECK-2-SERPINA1-3′UTR和psiCHECK-2-SERPINA1-3′UTR mut)和miRNA质粒(miR-320-5p mimic)共转染到293T细胞,进行荧光活性测定。结果通过序列匹配,拟候选miR-26、miR-210、miR-320c和miR-96为目标miRNA。与对照组相比,实验组SERPINA1基因mRNA表达水平显著上调(P<0.05),四个候选miRNA表达水平均显著下调(P<0.01),其中miR-320c和miR-96更为显著(P<0.001),基于文献miR-320c与COPD的预后相关,挑选miR-320c用于后续双荧光素酶实验。携带micR-320c-5p mimic和SERPINA1野生型3,UTR的构建体的相对荧光素酶活性明显下降(P<0.001),SERPINA1突变型3′UTR的构建体的相对荧光素酶活性无明显下降(P>0.05)。结论SERPINA1在3%CSE诱导的BEAS-2b细胞中表达上调,miR-320c-5p表达下调,miR-320c-5p可能通过负向调控SERPINA1的表达,在COPD的发生发展过程中起重要作用。

Hydration Characteristics and Microstructure of Alkali-Activated Slag Concrete: A Review

Alkali-activated slag concrete (AASC) is a new green building material. The amount of CO_(2) produced by AASC is 1/5th of that produced by ordinary Portland cement concrete (OPCC). In addition, AASC promotes the reuse of slag and other wastes and saves resources. Furthermore, the scope of use of slag has been expanded. The progress of the research on the hydration characteristics, microstructure, interfacial transition zone, and pore structure of AASC based on the relevant literatures was analyzed and summarized in this study. The influences of the slag composition, the type and dosage of the alkali activator, and the curing conditions on the hydration characteristics and the microstructure of the AASC were discussed. Relatively few research results on the microstructure of AASC are available, and the relevant conclusions are not completely consistent. Moreover, there are many constraints on the development of AASC (e.g., complex composition of raw materials of slag, large shrinkage deformation, and low fluidity). Therefore, further research is required.

MICR反应器处理乳品废水的运行特性研究

研究了多相串联内循环厌氧反应器(MICR)处理乳品废水的运行特性,结果表明MICR对乳品废水有很好的处理效果。当HRT为8 h,进水CODCr为2 000 mg/L,相应的CODCr容积负荷为6.0 kg/(m3.d)时,CODCr去除率可稳定在85.6%左右。MICR对pH骤变有较强的抗冲击能力,对SS的去除率较高,当HRT>8 h时,SS去除率保持在78.8%～88.7%之间。MICR存在明显的产酸相与甲烷相分离的现象,1﹟反应室以产酸菌为主,2﹟、3﹟反应室以产甲烷菌为主。

基于步进子时段MICR方法的毛管质量预报

无缝钢管穿孔生产是利用穿孔机将实心管坯斜轧穿孔成空心毛管的生产过程。斜轧穿孔中毛管质量与许多工艺参数,如辊型、送进角、顶头前伸量及温度,以及设备性能参数如穿孔机刚度、加工精度和顶杆振动等有关。由于其具有复杂的金属流动状态,传统的轧制理论难以解决其质量预报问题。本文通过对斜轧穿孔过程的分析,提出了步进子时段MICR(multiway independent component regression)算法,利用现场采集的多根毛管生产数据建立了预测毛管质量的数学模型。经仿真证明该模型具有较高的可靠性和精度,可以用于毛管质量的在线预报和优化。

Studied microRNA gene expression in human hepatocellular carcinoma by micro RNA microarray techniques

AIM: To achieve a better understanding of the molecular mechanisms of micro RNA expression changes involved in hepatocellular carcinoma.METHODS: In this research process, patients were not treated with antivirals, immunosuppressants or immunomodulators for at least 6 mo before collecting serum. The study population was composed of 35 outpatient hepatitis B virus(HBV) cases and 12 healthy control cases from the Affiliated Hospital of Inner Mongolia Medical University(Inner Mongolia, China) from July 2013 to April 2014. The 35 HBV cases were divided into two groups: a hepatocirrhosis group with 20 cases and a liver cancer group with 15 cases. All 35 cases carried HBs Ag. The diagnostic criteria followed the European Association for the Study of the Liver 2012(EASL2012) standards. Micro RNA(mi RNA) was extracted from a control group of patients, a group with hepatocirrhosis and a group with liver cancer and its quality was analyzed using the human V2 micro RNA expression beadchip. Cluster analysis and a radar chart were then applied to the mi RNA changes.RESULTS: The mi RNA-qualified rate of human serum samples was 93%. The concentration of a single sample was > 200 ng/μL and the volume was > 5 μL.All mi RNA serum samples were uncontaminated by the genome. The Mann-Whitney test showed significant differences in mi RNA between each group, with a detection P-value of < 0.05. Illumina software was set up with Diff Score set to ± 13, meaning that P = 0.001.There were significant changes in mi RNA expression between the three groups. mi RNA-183 was the most up-regulated, followed by mi RNA-373. mi RNA-129 and mi RNA-188 were both strongly down-regulated and mi RNA-378 was down-regulated a small amount. The liver cancer group had greater changes, which indicated that changes in mi RNA expression levels were caused by hepatocirrhosis. The liver cancer disease course then further increased these changes. In the pentagon created by these five mi RNAs, three groups showed significant deviation. The liver cancer group had a bigger deviation trend. The chart indicated that mi RNA expression changes occurred in the hepatocirrhosis group, which increased in the liver cancer disease course and were irreversible.CONCLUSION: There was a significant relationship between the irreversible up-regulation of mi RNA-183/373 and down-regulation of mi RNA-129/188/378 and incidences of hepatocirrhosis and liver cancer.

MICR反应器处理淀粉废水的启动实验研究

采用淀粉废水对多相串联内循环厌氧反应器(MICR,multi-internal-circle reactor)的启动特性进行实验研究,旨在为该反应器的实际应用和工艺优化提供理论依据。结果表明,经过58 d的启动,当进水的化学需氧量(CODCr)浓度为3 500 mg/L、水力停留时间(HRT)为24 h、相应的容积负荷为3.5 kgCOD/(m3.d)时,CODCr去除率稳定在94.5%左右,1﹟、2﹟、3﹟反应室CH4容积产气率分别为0.15、0.23、0.08 m3/(m3.d),反应器启动成功。系统出水pH值稳定在7.5左右,碱度保持在1 370 mg/L左右,具有较强的缓冲能力。反应器底部污泥颗粒化良好,粒径在2.0～3.5 mm,沉降性好。

AB Micro850在逻辑无环流可逆直流调速系统实验教学中的应用

将AB Micr0850 PLC应用于逻辑无环流可逆直流调速系统的本科实验教学环节，引导学生通过理论学习、实物测试和结果分析等过程，自主完成对无环流逻辑控制器（DLC）的梯形图程序设计与调试，并最终实现对直流调速系统的逻辑无环流控制。

急性髓系白血病患者PD-L1和MicroRNA-138-5p的表达及其临床意义

目的:探讨PD-L1和MicroRNA-138-5p(miR-138)在急性髓系白血病(AML)患者外周血单个核细胞(PBMNCs)中的表达特点及其临床意义。方法:应用SYBR GreenⅠreal-time PCR方法分别检测20例初治AML患者、9例复发/难治AML患者和8例完全缓解患者PBMNCs中PD-L1 mRNA和miR-138的表达水平,并选择20例健康体检者外周血样本作为对照组。结果:初治AML组和复发/难治AML组患者PD-L1的表达水平均显著高于健康对照组(P<0.01),而且复发/难治AML组患者PD-L1的表达水平显著高于初治AML组患者(P<0.01);初治AML组和复发/难治AML组患者miR-138的表达水平均显著低于健康对照组(P<0.01);在20例初治AML患者中共收集了8例完全缓解期标本,完全缓解组mi R-138的表达水平高于初治AML组(P<0.05),而缓解组PD-L1的表达水平与初治AML组差异无统计学意义(P>0.05);初治AML患者中PD-L1 mRNA与mi R-138表达呈负相关(P<0.05)。结论:AML患者PBMC中PD-L1表达增加、miR-138表达下调,且两者间有相关性。

Biodiversity and Screening of Moderately Halophilic Bacteria with Hydrolytic and Antimicrobial Activities from Yuncheng Salt Lake,China

1 Introduction Yuncheng Salt Lake is an old lake with a history of more than 5000 years,which locates in the margins of the central plains of China,with an area of about 130 km.It was an important resource of salt for human consumption from early times.Major chemicals in Yuncheng Salt Lake contain Na Cl,Na2SO4 and Mg SO4(Gao et al.2007).In recent years,some halophilic bacteria and archaea were

Fuelwood assessment at micro-watershed level in Northeast Himalaya:a case study in Manipur,India

Fuelwood is one of the major sources of energy in the domestic sector across the rural areas,especially in the developing regions across the world.The Northeastern Himalayan state of Manipur is dominated by the tribal population that largely depends on fuelwood from the nearby forest area.The entire dependence on forests for energy resources is affecting the sustainability of the forest ecosystem in the region,thus indicating the livelihood conditions.Since land-use land-cover change is the key driver to the change in resource availability of a region,the present study has tried to analyze the landcover changes over a period 28 years.The second major component affecting resource availability is the increasing population pressure that leads to changes in the land dynamics,which directly affect the resource production.Based on the existing consumption pattern,the total consumption of fuelwood in the watershed ranges fiom a minimum of 289.992 tons/year to a maximum of 3545.719 tons/year with an average of 1561.956 tons/year in the year 2009 and simulated fuelwood consumption for the year 2021 is around 1469.260 tons/year.Nine different probable scenarios of resource are proposed to calculate the stress value that can be used by the policy-makers and planners for suitable policy implementation at the micro level with a complex social system.

Evaluation on the Nutritive Value of Micro-storage Wheat Straw Using Gas Production Technique in vitro

[ Objective] The research aimed to improve the utilization ratio of wheat strew in Qinghai Province. [ Method] During wheat straw microstorage, the pH, crude protein （CP）, crude fiber （CF）, ether extract （EE） and water content in wheat strew at different micro-storage periods were determined. The effects of micro-storage time on the quality of wheat strew were studied and evaluated by using gas production technique in vitro. [Result] pH in each test group gradually decreased with the micro-storege time, which was all significantly lower than that in control group （P 〈0.01 ）. CP content in all test groups increased with the micro-storage time, which was all higher than that in control group. CF content in all test groups decreased with the h^icro-storage time, significantly lower than that in control group （ P 〈 0.01 ）. EE content in all experimental groups showed a gradual increase trend with the micro-storege time, which was all higher than that in control group, without significant difference compared with control group （P〉0.05）. Water content in test groups went down with the micro-storage time. With the increase of micro-storage time, net gas production, dry matter degradability, organic matter degradability, digestible energy and metabolizable energy went up gradually. [ Conclusion] Comprehensively considering the micro-storege effect of wheat strew in each period and actual production application, we suggest that 22-day micro-storege for wheat straw could meet the demand of actual production.

In situ injectable hydrogel encapsulating Mn/NO-based immune nano-activator for prevention of postoperative tumor recurrence

Postoperative tumor recurrence remains a predominant cause of treatment failure. In this study, we developed an in situ injectable hydrogel, termed MPB-NO@DOX + ATRA gel, which was locally formed within the tumor resection cavity. The MPB-NO@DOX + ATRA gel was fabricated by mixing a thrombin solution, a fibrinogen solution containing all-trans retinoic acid (ATRA), and a Mn/NO-based immune nano-activator termed MPB-NO@DOX. ATRA promoted the differentiation of cancer stem cells, inhibited cancer cell migration, and affected the polarization of tumor-associated macrophages. The outer MnO2 shell disintegrated due to its reaction with glutathione and hydrogen peroxide in the cytoplasm to release Mn2+ and produce O2, resulting in the release of doxorubicin (DOX). The released DOX entered the nucleus and destroyed DNA, and the fragmented DNA cooperated with Mn2+ to activate the cGAS-STING pathway and stimulate an anti-tumor immune response. In addition, when MPB-NO@DOX was exposed to 808 nm laser irradiation, the Fe-NO bond was broken to release NO, which downregulated the expression of PD-L1 on the surface of tumor cells and reversed the immunosuppressive tumor microenvironment. In conclusion, the MPB-NO@DOX + ATRA gel exhibited excellent anti-tumor efficacy. The results of this study demonstrated the great potential of in situ injectable hydrogels in preventing postoperative tumor recurrence.

lncRNA717对胃癌细胞生物学行为的影响及调控机制研究

目的探讨长链非编码RNA(lncRNA)717对胃癌细胞增殖、转移等生物学行为的影响及其调控机制。方法收集2021年1至12月宁波大学附属第一医院手术切除或活检的31例胃癌组织及配对癌旁组织,以及胃癌细胞系AGS、HGC-27和人正常胃黏膜细胞系GES-1。采用qRT-PCR法检测lncRNA717在胃癌组织及癌旁组织、各细胞系中的表达水平。采用细胞增殖和毒性检测(CCK-8)法、Transwell法和划痕试验分别评估lncRNA717对细胞增殖、侵袭和迁移中的影响。采用荧光素酶报告基因测定、qRT-PCR法和Western blot法检测各组标本和细胞中lncRNA717、miR-762和干扰素调节因子(IRF)7表达水平。结果与癌旁组织相比,lncRNA717在胃癌组织中显著下调,与正常细胞相比,lncRNA717在胃癌细胞中显著下调。过表达lncRNA717抑制了胃癌细胞的增殖、迁移和侵袭。lncRNA717可以吸附miR-762,上调miR-762能抑制IRF7的表达,促进胃癌细胞的增殖、迁移和侵袭,而过表达lncRNA717后逆转了miR-762对细胞的增殖、迁移和侵袭的促进作用。结论lncRNA717可抑制胃癌细胞的增殖和转移,这可能与调控miR-762/IRF7有关。提示lncRNA717可作为胃癌的潜在生物标志物和治疗靶点。

机械应力对成骨细胞影响的研究进展

成骨细胞(OB)是骨形成的主要功能细胞,负责机体骨基质的合成、分泌以及矿化。机械应力(MS)是指物体受到外力而发生变形时,在物体内各部分之间产生相互作用的内力。随着世界人口老年化的加剧,老年性骨病已经成为全球性的医疗卫生问题,同时伴随着科技的进步,生物组织工程学、航空航天等领域对MS对于成骨细胞影响的研究也提出了更高要求。本文将阐述OB在流体剪切应力、压缩应力、牵张力和微重力不同MS刺激下的反应。

溶液电导率对LY12铝合金微弧氧化陶瓷层的生长速度和致密度的影响

探讨了微弧氧化溶液体系电导率对陶瓷层生长速度的影响 ,并以击穿场强作为反映陶瓷层致密度的物理参量 ,测定了实验条件下电导率与击穿场强的关系。结果表明 ,陶瓷层的生长速度与溶液电导率之间有近似线性的正比增长关系 ;

金属橡胶材料基于微弹簧组合变形的细观本构模型

研究了金属橡胶材料细观本构模型。依据金属橡胶材料变形的主要特征,分析了微弹簧沿轴向和径向变形的规律,分别推导了应力应变关系的解析表达式,由两种微弹簧的组和变形构造了代表性体积单元-微元体。为了反映因铺层引起的工艺各向异性,本构方程中引入了一个新的材料参数铺层比例系数iβ,该参数可以较好地表征细观结构中微弹簧取向的分布状况。在大量试验的基础上,提出了确定铺层系数的实验方法,进而建立了包含金属橡胶材料细观结构信息的本构方程。理论与实验结果比较表明,本文建立的本构模型能较好的反映材料的力学行为。

康复新结肠靶向微丸的制备工艺

目的:将康复新制备成pH依赖和酶依赖2种结肠靶向微丸,使其在结肠定位释放,发挥局部治疗作用。方法:采用泛丸法制备素丸,流化床包衣技术对素丸进行包衣,分别对泛丸工艺和包衣参数进行了研究,筛选出最佳成型及包衣工艺。结果:微丸制备为干浸膏加125%淀粉+2%羧甲基纤维素钠,以30%乙醇为黏合剂,应用泛丸法制得素丸;制备得由Eudragit S100包衣得到的pH依赖及由果胶-羟丙基甲基纤维素(HPMC)包衣制得的酶依赖结肠靶向微丸。结论:制备得到了pH依赖和酶依赖2种康复新结肠靶向微丸。

盐酸小檗碱致大鼠肝脏代谢相关基因表达变化的基因芯片研究

目的 研究小檗碱对大鼠肝脏基因表达谱的影响。方法 大鼠予以盐酸小檗碱灌胃 6d ,摘取肝脏提取总RNA。用Cy3和Cy5两种荧光物质分别标记阴性对照组和盐酸小檗碱组肝组织cDNA ,制备成探针与表达谱芯片进行杂交 ,获得的荧光信号图像用计算机扫描后进行数据分析 ,计算每点的Cy5和Cy3信号强度比值。结果 在被检测的 4 0 96个基因中 ,盐酸小檗碱组差异表达基因 2 36个 ,与代谢相关的差异表达基因共 32个 ,其中表达上调的代谢相关基因 8个 ,包括大鼠环核苷酸磷酸二酯酶、异柠檬酸脱氢酶 3、心肌黄酶和葡萄糖 6 磷酸酶等。表达下调的代谢相关基因 2 4个 ,包括尿苷二磷酸 葡糖醛酰转移酶、细胞色素P4 5 0 2E1、谷胱甘肽S 转移酶 1、16 α 碳腈孕烯醇酮诱导的细胞色素P4 5 0酶和S 腺苷 L 甲硫氨酸脱羧酶等。结论 小檗碱的降血糖。

微型飞行器测量天平设计与风洞试验

用三梁式、四梁式结构分别设计了用于测量微型飞行器气动性能的单分量、二分量和三分量应变天平4台。通过天平的地面静态校准给出了每台天平的使用公式,在专门设计建造的微型飞行器实验装置中,用软模型、硬模型、翼型进行了模型静态气动性能试验,用微型扑翼飞行器进行了单分量和二分量天平动态吹风试验,结果表明,所设计的天平具有较高的精准度和灵敏度,试验曲线光滑连续,实验数据可靠,为微型飞行器的研究提供了非常有效的测量手段。