新辅助免疫治疗在局部晚期直肠癌中应用循证证据

错配修复功能缺陷(deficient mismatch repair,dMMR)是目前公认的预测免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)疗效的生物标志物,国内外指南已推荐dMMR实体瘤患者一线治疗选择免疫治疗。在直肠癌中,仅5%患者为dMMR/高度微卫星不稳定(microsatellite instability-high,MSI-H),绝大多数为“免疫沙漠型”或错配修复功能完整(mismatch repair proficient,pMMR)/微卫星稳定(microsatellite stabilization,MSS),即对ICIs反应欠佳。因此免疫药物与新辅助放化疗的协同作用是近些年基础和临床研究的热点,并且有较多Ⅱ/Ⅲ期免疫全新辅助治疗(immuno-total neoadjuvant therapy,iTNT)相关临床试验涌现,局部进展期直肠癌(locally advanced rectal cancer,LARC)管理模式也开始进入非手术治疗时代。dMMR/MSI-H型LARC患者新辅助免疫疗法效果显著,有望让患者在后续治疗中豁免手术和放化疗从而选择观察等待策略;对于pMMR/MSS型LARC,目前初步认定ICIs从初始作为后线姑息方案前移到一线选择策略以及继续开展大型临床试验。但iTNT在LARC中应用最佳模式尚无定论,但短程放疗序贯新辅助化疗联合免疫药物可能获得良好短期疗效。寻找其它新的生物标志物,可能会鉴定出部分对iTNT敏感的pMMR/MSS型患者(尤其是低位直肠癌)。未来LARC治疗策略需结合患者临床复发危险度分层和器官保留意愿两方面考虑,实现分层精准治疗。本文将对LARC中iTNT的相关研究背景、基础和临床研究进展以及存在问题等进行综述。

Protective efficacy evaluation of immunogenic protein AHA_3793 of Aeromonas hydrophila as vaccine candidate for largemouth bass Micropterus salmoides

Aeromonas hydrophila is a Gram-negative pathogen that can infect various fish,including largemouth bass(Micropterus salmoides),which have caused huge economic losses.In present study,largemouth bass anti-A.hydrophila antibodies were produced,then a highly immunogenic outer membrane proteins,AHA_3793,was identified by combined western blotting and mass spectrometry analysis.Moreover,AHA_3793 was expressed,and its immunogenicity was further verified by western blotting.Subsequently,the protective efficacy of AHA_3793 were evaluated in largemouth bass.The results showed that rAHA_3793 could produce a relative percentage survival(RPS)of 61.76% for largemouth bass against A.hydrophila challenge.ELISA analysis showed the specific serum antibodies of largemouth bass against rAHA_3793 and A.hydrophila in vaccinated group in weeks 4 and 5 after immunization were significantly higher than those in control group,which suggested that rAHA_3793 induced production of specific serum antibodies against rAHA_3793 and A.hydrophila.The qRT-PCR analysis showed that expressions of CD4-2 and MHC Ⅱα were also significantly up-regulated after immunization.These results collectively demonstrated that rAHA_3793 could induce a strong humoral immune response of largemouth bass,and then produce high immune protection ef fects against A.hydrophila infection.

A novel mutation in ROR2 led to the loss of function of ROR2 and inhibited the osteogenic differentiation capability of bone marrow mesenchymal stem cells(BMSCs)

Receptor tyrosine kinase-like orphan receptor 2(ROR2)has a vital role in osteogenesis.However,the mechanism underlying the regulation of ROR2 in osteogenic differentiation is still poorly comprehended.A previous study by our research group showed that a novel compound heterozygous ROR2 variation accounted for the autosomal recessive Robinow syndrome(ARRS).This study attempted to explore the impact of the ROR2:c.904C>T variant specifically on the osteogenic differentiation of BMSCs.Methods:Coimmunoprecipitation(CoIP)-western blotting was carried out to identify the interaction between ROR2 and Wnt5a.Double-immunofluorescence staining was used for determining the expressions and co-localization of ROR2 and Wnt5a in bone marrow mesenchymal stem cells(BMSCs).Western blot(WB)analysis and quantitative reverse transcription polymerase chain reaction(RT-qPCR)were conducted to identify the expression levels of ROR2 in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T.The alkaline phosphatase(ALP)activity was detected,and Alizarin Red S staining was done for evaluating the osteogenic differentiation of BMSCs.RT-qPCR was employed to identify the expression of the sphingomyelin synthase 1(SMS1)mRNA in the BMSCs transfected with LV-shROR2 or LV-ROR2-c.904C>T and the mRNA expression levels of Runt-related transcription factor 2(RUNX2),osteocalcin(OCN),and osteopontin(OPN).WB was performed to confirm the protein expressions of extracellular regulated protein kinases1(ERK),P-ERK,Smad family member1/5/8(Smad1/5/8),P-Smad1/5/8,P-P38,P38,RUNX2,OCN,and OPN in the BMSCs transfected with LV-shROR2/LV-ROR2-c.904C>T and sphingomyelin(SM).Results:The ROR2:c.904C>T mutant altered the subcellular localization of the ROR2 protein,which caused an impaired interaction between ROR2 and Wnt5a.The depletion of ROR2 restricted the osteogenic differentiation capability of BMSCs and downregulated the expression of SMS1.SM treatment could reverse the inhibition of osteoblastic differentiation in ROR2-depleted BMSCs.Conclusion:The findings of this work revealed that the ROR2:c.904C>T variant led to the loss of function of ROR2,which impaired the interaction between ROR2 and Wnt5a and also controlled the osteogenic differentiation capability of BMSCs.Furthermore,SM was revealed to be engaged in the osteoblastic differentiation of BMSCs regulated by ROR2,which renders SM a potential target in the therapy for ARRS.

畅享自然——让老年人乐享幸福生活的生态社区公园设计

为了更好地照顾老年人,护理模式正在一步步由家庭护理向社区护理转变。该项目以自然恢复、低影响发展、自我维持的生态社区为设计理念,旨在创造一个健康舒适的户外空间,为老年人提供互动、娱乐和教育服务,加强老年人与家人之间的联系,并完善社区内外的社交网络。项目地址位于安徽省合肥市中心的仙桥社区。该社区占地0.46平方公里,有6个相对独立的居民区。原有社区景观设计陈旧,建筑密度高,仅有一个公共广场和一个袖珍公园,区域内居民很少有接触到绿色和自然的机会。

Autophagy: a double-edged sword for neuronal survival after cerebral ischemia

Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether acti- vation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects.

Vapour–Liquid Equilibrium for N,N-Dimethylformamide + Benzene + Thiophene via Gibbs Ensemble Molecular Simulation

The selection and design of an optimal solvent for extractive distillation require reliable vapour-liquid phase equilibrium data and knowledge of extraction mechanisms.Compared with time-consuming experiments,molecular simulation presents great potential in research on the properties of fluids.Therefore,in this work,Gibbs ensemble Monte Carlo was applied to successfully predict the vapour-liquid phase equilibrium data of binary and ternary systems containing benzene,thiophene and N,Ndimethylformamide(DMF) at P=101.3 kPa.The explicit hydrogen version of the transferable potentials for phase equilibria potential model was chosen for benzene and thiophene,whereas the OPLS potential model was selected for DMF.The predicted phase diagrams were compared with experimental data and the UNIQUAC thermodynamic model.A good agreement was obtained,which corroborated the validity of the potential models.In addition,the extraction mechanism was explored by radial distribution function(RDF) of the liquid-phase structure.The RDFs showed that thiophene and benzene shared a similar liquidphase structure because of the intermolecular interaction.The distinct difference between the RDFs of DMF/benzene and those of DMF/thiophene is that the oxygen atom of DMF is more associated with hydrogen atoms of thiophene than that of benzene,which may be responsible for the extraction effect of DMF.

Regulation of PM_(2.5)on mitochondrial damage in H9c2 cells through miR-421/SIRT3 pathway and protective effect of miR-421 inhibitor and resveratrol

Fine particulate matter(PM_(2.5))exposure is associated with cardiovascular disease(CVD)morbidity and mortality.Mitochondria are sensitive targets of PM_(2.5),and mitochondrial dysfunction is closely related to the occurrence of CVD.The epigenetic mechanism of PM_(2.5)-triggered mitochondrial injury of cardiomyocytes is unclear.This study focused on the mi R-421/SIRT3 signaling pathway to investigate the regulatory mechanism in cardiac mitochondrial dynamics imbalance in rat H9c2 cells induced by PM_(2.5).Results illustrated that PM_(2.5)impaired mitochondrial function and caused dynamics homeostasis imbalance.Besides,PM_(2.5)up-regulated mi R-421 and down-regulated SIRT3 gene expression,along with decreasing p-FOXO3a(SIRT3 downstream target gene)and p-Parkin expression and triggering abnormal expression of fusion gene OPA1 and fission gene Drp1.Further,mi R-421 inhibitor(mi R-421i)and resveratrol significantly elevated the SIRT3 levels in H9c2 cells after PM_(2.5)exposure and mediated the expression of SOD2,OPA1 and Drp1,restoring the mitochondrial morphology and function.It suggests that mi R-421/SIRT3 pathway plays an epigenetic regulatory role in mitochondrial damage induced by PM_(2.5)and that mi R-421i and resveratrol exert protective effects against PM_(2.5)-incurred cardiotoxicity.

Synthetic rubbers prepared by lanthanide coordination catalysts

China is rich in rare earth resources. Rare earth elements, also named lanthanides, are number 58 to number 81 elements in the elemental periodic table. They have unique electronic structures and may form various coordination compounds. In the early 1960s, researchers at the Changchun Institute of Applied Chemistry, Chinese Academy of Sciences (CIAC) found the catalytic activities of lanthanide compounds in stereospecific polymerization of conjugated dienes, and published the first paper on this topic in 1964. On the basis of this finding, CIAC launched extensive research activities on lanthanide compounds as diene polymerization catalysts, from a series of fundamental research to the efforts of industrializing the rare earth catalyzed cis-1,4-polybutatine rubber and cis-1,4-polyisoprene rubber. This review aims to summarize the progress in this field in the past half century.