维生素B12和叶酸干预对绝经后骨质疏松症妇女的骨代谢及同型半胱氨酸水平的影响

目的观察叶酸和维生素B12对绝经后骨质疏松症妇女的骨代谢及同型半胱氨酸水平的影响。方法 80例绝经后骨质疏松症妇女参加研究。所有参与者随机接受叶酸和维生素B12(n=40)或安慰剂(n=40)治疗。在干预前的基线及干预后3个月和6个月,测量两组患者血清同型半胱氨酸、维生素B12和骨代谢标志物的水平。结果治疗前,两组患者血清同型半胱氨酸、维生素B12和骨代谢标志物水平比较差异无统计学意义(P0.05)。治疗后,两组患者同型半胱氨酸均下降,但比较差异无统计学意义(P0.05)。6个月后各组间血清维生素B12、骨钙素、CTX的变化均有显著改变且差异有统计学意义(P0.05)。结论绝经后骨质疏松症妇女补充叶酸和维生素B12可以一定程度改善同型半胱氨酸及骨代谢指标水平。     

术前血清CA125、HE4和中性粒细胞与淋巴细胞比值联合检测在子宫内膜癌诊断中的作用

目的:探讨血清糖类抗原125（carbohydrate antigen 125，CA125）、人附睾蛋白4（human epididymis protein 4，HE4）、中性粒细胞与淋巴细胞比值（neutrophil-lymphocyte ratio，NLR）联合检测在子宫内膜癌诊断中的作用。方法:选取42例子宫内膜癌患者、50例子宫内膜良性疾病患者和50例健康体检人群。采用SYSMEX XN550全自动血液分析仪计数术前外周血中性粒细胞和淋巴细胞，计算NLR；采用Maglumi4000全自动化学发光仪检测术前血清CA125、HE4水平。采用ROC曲线分析CA125、HE4、NLR和三者联合指标在诊断子宫内膜癌中的作用。结果:外周血NLR在健康组、良性组和子宫内膜癌组中逐渐增高，且差异有统计学意义（P<0.05）；子宫内膜癌组HE4表达量显著高于良性组与健康组（P<0.05），而良性组与健康组之间差异无统计学意义（P>0.05）；CA125表达量在三组中差异无统计学意义（P>0.05）。CA125、HE4、NLR及三者联合标记物的AUC分别为0.530、0.733、0.795、0.823，当分别取它们的临界值时，特异性分别为70.8%、85.1%、61.7%、83.0%，敏感性分别为40.0%、63.3%、86.7%、73.3%。单项指标NLR的敏感性最高，HE4的特异性最高，联合指标的特异性和敏感性都很高。结论:术前血清CA125、HE4和NLR联合检测具有较高的特异性和敏感性，联合检测可以互为补充，提高子宫内膜癌的诊断准确率，对子宫内膜癌的诊断具有指导意义。     

Molecular simplification of lipid A structure: TLR4-modulating cationic and anionic amphiphiles

A growing body of data suggests that therapies based on Toll-like receptors (TLR) targeting, in particular TLR4, holds promise in curing autoimmune and inflammatory pathologies still lacking specific treatment, included several rare diseases. While TLR4 activators (agonists) have already found successful clinical application as vaccine adjuvants, the use of TLR4 blockers (antagonists) as antisepsis agents or as agents against inflammatory diseases (including arthritis, multiple sclerosis, neuroinflammations) and cancer is still at a preclinical phase of development. This minireview focuses on recent achievements on the development of TLR4 modulators based on lipid A structure simplification, in particular on compounds having disaccharide or monosaccharide structures. As the TLR4 activity of natural TLR4 ligands (lipopolysaccharide, LPS and its biologically active part, the lipid A) depends on both the structure of endotoxin aggregates in solution and on single-molecule interaction with MD-2 and CD14 receptors, the rational design of TLR4 modulators should in principle take into account both these factors. In the light of the most recent advances in the field, in this minireview we discuss the structure–activity relationship in simplified lipid A analogs, with cationic or anionic amphiphilic structures.     

miR-503靶向TLR4对前列腺癌多西他赛耐药的影响

背景与目的：在前列腺癌标准化疗方案中，多西他赛（docetaxel，DTX）引起的化疗耐药是引起患者死亡的重要原因之一，然而DTX引起的化疗耐药相关机制尚未知。探讨前列腺癌DTX耐药的作用机制。方法：收集2016年6月—2019年6月在武汉市第三医院进行化疗的40例患者，包括20例DTX耐药和20例DTX敏感患者。人前列腺癌细胞系PC-3在一系列逐渐增加的DTX浓度梯度处理下形成耐药株PC-3/DTX。采用实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction，RTFQ-PCR）检测miR-503和TLR4 mRNA的表达，采用蛋白质印迹法（Western blot）检测TLR4蛋白的水平，采用双荧光素酶报告基因检测miR-503和TLR4的相互作用，采用四甲基偶氮唑蓝（methyl thiazolyl tetrazolium，MTT）法检测细胞活力，采用流式细胞术检测细胞凋亡。结果：前列腺癌耐药患者组织和耐药细胞系中miR-503的表达较敏感组显著降低（P=0.013），而TLR4显著增加（P=0.005 6）。过表达miR-503显著抑制耐药细胞的增殖，促进凋亡，同时抑制耐药相关蛋白MDR-1的表达，而过表达TLR4则促进细胞的增殖，抑制凋亡，促进耐药相关蛋白MDR-1的表达。结论：miR-503通过靶向调控TLR4的表达影响前列腺癌的DTX耐药。     

Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome–lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.Electronic supplementary materialThe online version of this article (10.1007/s12264-020-00518-2) contains supplementary material, which is available to authorized users.     

Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

Anisotropic Bladder Planning Target Volume in Bladder Radiation Therapy

Purpose

This study aimed to investigate 3 planning target volume (PTV) margin expansions and determine the most appropriate volume to be used in bladder preservation therapy when using daily cone beam computed tomography (CBCT). We aimed to establish whether a smaller PTV expansion is feasible without risking geographical miss.

PERK信号通路介导结肠癌细胞对5-氟尿嘧啶耐药机制的研究

目的:观察PERK蛋白对结肠癌细胞药物敏感性的影响，并进一步探讨其相关作用机制。方法:结肠癌细胞系HCT116分为三组:空白对照（Control）组、下调PERK表达（si-PERK）组、阴性对照（si-NC）组；采用免疫荧光及RT-PCR验证转染效率；利用CCK-8实验检测下调PERK表达后结肠癌细胞对化疗药物5-FU的敏感性变化；Annexin V-FITC凋亡实验检测下调PERK表达对结肠癌细胞凋亡的影响；利用RT-PCR及Western Blot实验检测PERK信号通路中关键分子eIF2α、ATF4、CHOP、XIAP的mRNA及蛋白表达变化。结果:RT-PCR实验表明:与正常对照组相比，si-PERK 组mRNA的表达显著下降（P＜0.05）,免疫荧光提示转染效率达80%以上；CCK-8实验发现与si-NC组相比，5-FU对 si-PERK组细胞的半数抑制浓度（IC50）明显降低（P＜0.01）；Annexin V-FITC凋亡实验发现与si-NC组相比，si-PERK组细胞的凋亡发生率显著升高（P＜0.05）；RT-PCR及Western Blot实验发现与si-NC组相比，si-PERK组细胞中PERK信号通路下游关键分子eIF2α、ATF4、CHOP的mRNA及蛋白表达均明显降低（P＜0.05）。结论:在结肠癌细胞中，抑制PERK表达后，其可能通过下调eIF2α、ATF4、CHOP的表达促进细胞发生凋亡，从而促进细胞对化疗药物5-FU的敏感性。