Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

Computed tomography imaging features for amyloid dacryolith in the nasolacrimal excretory system: A case report

BACKGROUNDNasolacrimal duct obstruction leading to epiphora is a common ophthalmologic complaint, and it may derive from amyloidosis in rare cases. There are a few reports about localized amyloidosis, and amyloidosis with involvement and obstruction of the nasolacrimal duct is exceedingly rare. CASE SUMMARYA 54-year-old male presented with a 2-year history of a lump overlying the left lacrimal sac that had grown rapidly for nearly half a year. Physical examination touched a firm lump in the left lacrimal sac. Nasal endoscopy discovered lesions in appearance of sediments with easy bleeding at the entry of the nasolacrimal duct of the left inferior nasal meatus. Computerized tomography scan revealed speckle high density in the left lacrimal sac and the dilated nasolacrimal duct. During an endoscopic exploration and excision, a large number of dacryoliths were exposed. Pathology indicated amorphous pink material and multinucleated giant cell reaction in the fibrous tissue.CONCLUSIONThis case showed amyloidosis in localized form mimicking dacryolith with nasolacrimal duct obstruction. In clinical practice, we should be aware of the possibility of localized amyloidosis in the nasolacrimal excretory system.     

动态对比增强磁共振成像纹理多参数联合分析预测P53表达状态对直肠癌鉴别诊断的价值

目的探讨动态对比增强磁共振成像(dynamic contrast-enhanced MRI,DCE-MRI)纹理分析在术前预测直肠癌患者P53表达状态的价值.材料与方法回顾性收集行DCE-MRI扫描且有P53免疫组化检测结果的原发直肠癌患者91例(P53高表达组50例、低表达组41例).由GenIQ后处理软件获取Ktrans、Kep、Ve后处理图像并导入ITK-SNAP软件,由两位观察者分别使用AK软件提取12个纹理特征参数,采用组内相关系数ICC对数据的一致性进行检验,采用独立样本t检验或Mann-Whitney U检验比较两组纹理参数,应用ROC曲线分析纹理参数的鉴别效能,应用Logistics回归分析联合纹理特征参数进行效能分析,通过Delong检验比较各单一参数模型及联合模型与各单一参数模型AUC间的差异.结果P53高表达组纹理参数Cluster ProminenceKtrans(23.00±50.84)×106、CorrelationKtrans(1.49±1.42)×10-2、InertiaKep(13.52±22.31)×104值均大于低表达组Cluster ProminenceKtrans(4.89±5.92)×106、CorrelationKtrans(0.16±0.17)×10-2、InertiaKep(50.52±61.27)×103,差异均具有统计学意义(P<0.05),AUC值分别为0.712、0.838、0.638.P53两组间有差异的纹理参数联合诊断效能更高,AUC为0.914,敏感度为80％,特异度为95％.经Delong检验,P53两组间有组间差异纹理参数联合模型的AUC大于单一参数模型,差异有统计学意义(P<0.05).结论纹理特征参数Cluster Prominence、Correlation、Inertia能有效预测直肠癌P53表达状态,纹理分析特征参数的联合分析可获得更高的鉴别诊断效能.     

High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.     

食管癌患者化疗联合细胞免疫治疗前后外周血淋巴细胞亚群变化的分析

目的:探讨肿瘤分期和治疗对食管癌患者外周血淋巴细胞亚群的影响及其相应的临床意义。方法:选取在我院治疗的113例食管癌患者，其中45例中晚期患者接受了化疗联合细胞免疫治疗。对113例患者进行了治疗前外周血淋巴细胞亚群检测，对45例患者进行了联合治疗前后外周血淋巴细胞亚群、肿瘤标志物检测。分析细胞免疫治疗周期、疗效与外周血淋巴细胞亚群的相关性以及治疗前肿瘤血清学标志物与疗效的相关性。结果:早期食管癌患者CD8+/CD28+T细胞(Tc)比例高于中晚期患者，CD4+/CD25+T细胞(Treg)比例低于中晚期患者（P=0.011、P=0.015）。45例患者治疗后CD3+T细胞(TT)、Tc、髓系树突状细胞(mDCs)比例明显升高（P=0.003、P=0.039、P=0.007）。细胞免疫治疗1个周期14例（A组），2个周期16例（B组），3个周期及以上15例（C组）。A组患者治疗后TT比例明显升高，Treg比例明显下降；B组患者治疗后TT、Tc比例明显升高；C组患者发现了三组淋巴细胞亚群的变化，其中TT、Treg比例变化较A、B两组更为显著（P=0.003 7、P=0.002）。30例获得客观缓解的患者治疗后TT、Tc、自然杀伤T细胞(NKT)和mDCs比例较治疗前明显升高，而Treg比例则较前明显下降。治疗前鳞状上皮细胞癌相关抗原（SCC）正常的患者客观缓解率要好于升高的患者（P=0.029）。结论:中晚期食管癌患者较早期患者免疫失衡更为明显，细胞免疫治疗联合化疗可以改善食管癌患者的免疫状态，治疗效果与患者的免疫功能改善程度有关，SCC升高可能影响食管癌患者的近期疗效。     

输尿管支架管结壳患者尿液菌群的分布特点

目的探讨输尿管支架管结壳患者尿液菌群的分布特点。方法选取2018年10月至2019年3月在山东省立第三医院、山东大学齐鲁医院、济南市中心医院和济南市济钢医院就诊的35例输尿管支架管置入术后患者。纳入标准:年龄18~65岁;输尿管镜碎石术后留置内支架管4周。排除标准:尿液细菌培养阳性;严重肉眼血尿;近期口服抗生素;存在明显残石患者。本研究采用横断面研究方法(临床研究注册号为ChiCTR1800020025),根据有无支架管结壳将患者分为结壳组23例和无结壳组12例。收集拔管当日患者尿液行细菌16s DNA检测。使用UPARSE、UCHIME和RDP calssifier等软件分析两组患者尿液菌群分布特点,明确两组患者尿液中细菌种类总数、细菌丰度,以及丰度占比较大的细菌类别,比较两组患者尿液细菌种类、数量及细菌丰度的差异,明确结壳组患者尿液中丰度占比较大的细菌菌属。结果两组患者的年龄、性别、体质指数、置管侧别、内支架管型号及结石成分差异均无统计学意义(P>0.05)。16s DNA检测结果显示,结壳组丰度占比>1%的菌属数量为11个,丰度占比>0.01%的菌属数量为74个;无结壳组丰度占比>1%的菌属数量为7个,丰度占比>0.01%的菌属数量为11个,两组丰度占比>1%的菌属数量比较差异有统计学意义(t=5.12,P=0.000)。结壳组中菌属丰度占比前3位分别为乳杆菌属(23.1%)、拟杆菌属(18.8%)和未分级拟杆菌属(17.1%),非结壳组中菌属丰度占比前3位分别是为埃希菌-志贺菌属(32.2%)、肠球菌属(24.9%)和假单胞菌属(18.2%)。两组间差异最大的3种细菌是乳杆菌属(P=0.010),拟杆菌属(P=0.004)和未分级拟杆菌属(P=0.004)。结论支架管结壳患者尿液中细菌种类和数量都明显多于非支架管结壳患者。拟杆菌属细菌在支架管结壳患者尿液中的细菌种类丰度较大。     

常见植物药对结肠癌的防治作用及其作用机制

植物药对结肠癌具有良好的防治作用。姜黄素、多糖(苹果多糖、香菇多糖)、皂苷(重楼皂苷、人参皂苷)、白藜芦醇、槲皮素等植物药可通过不同信号通路抑制结肠癌细胞的增殖,促进细胞凋亡。此外,植物药还具有抗炎、抗氧化、抗血管生成、减轻化疗药物不良反应、逆转肿瘤细胞耐药等作用。了解植物药对结肠癌的防治作用及其可能的作用机制,能为结肠癌的临床防治提供更多的理论依据及治疗思路。     

Aloe‐emodin: A review of its pharmacology,toxicity, and pharmacokinetics

Aloe‐emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe‐emodin exhibits many pharmacological effects, including anticancer, antivirus, anti‐inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe‐emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe‐emodin has a poor intestinal absorption, short elimination half‐life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe‐emodin reported to date with an emphasis on its biological properties and mechanisms of action.     

长链非编码RNA TUG1调控miR-138-5p对骨肉瘤细胞增殖、凋亡、侵袭和迁移的影响

目的:探讨长链非编码RNA(LncRNA)牛磺酸调节基因1(TUG1)调控miR-138-5p对骨肉瘤细胞增殖、凋亡、侵袭和迁移的影响。方法:在骨肉瘤细胞U-2OS中转染TUG1 siRNA和siRNA control，qRT-PCR测定干扰效果，MTT测定增殖，流式细胞术测定凋亡，Transwell小室测定细胞侵袭和迁移。starBase预测TUG1与miR-138-5p有结合位点，双荧光素酶报告载体鉴定靶向调控关系。将miR-138-5p抑制物和TUG1 siRNA共转染至骨肉瘤细胞中，测定干扰miR-138-5p对下调TUG1的骨肉瘤细胞增殖、凋亡、侵袭和迁移的影响。结果:转染TUG1 siRNA后的骨肉瘤细胞中TUG1表达水平明显低于转染siRNA control后的细胞（P<0.05）。下调TUG1后的骨肉瘤细胞增殖、侵袭和迁移能力降低，细胞凋亡率升高（P<0.05）。野生型TUG1荧光素酶报告载体与miR-138-5p共转染后细胞荧光素酶活性降低（P<0.05）。与转染TUG1 siRNA的细胞比较，miR-138-5p抑制物和TUG1 siRNA共转染后的细胞增殖、侵袭和迁移能力升高，细胞凋亡率降低（P<0.05）。结论:下调LncRNA TUG1表达通过调控miR-138-5p表达抑制骨肉瘤细胞增殖、侵袭、迁移能力并诱导细胞凋亡。