Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment

Vascular abnormality is a hallmark of most solid tumors and facilitates immune evasion. Targeting the abnormal metabolism of tumor endothelial cells (TECs) may provide an opportunity to improve the outcome of immunotherapy. Here, in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer (CRC), TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Then an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in TECs. Low-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor, which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of GAPDH. Moreover, osimertinib and anti-PD-1 blockade synergistically retarded tumor growth. This study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.     

The impact of spleen volume on the survival of metastatic pancreatic adenocarcinoma patients receiving nanoliposomal irinotecan

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (NalFL) comprises the current standard for gemcitabine-failed metastatic pancreatic ductal adenocarcinoma (PDAC). As liposomes generally accumulate in the spleen, we evaluated the impact of spleen volume on prognosis. We enrolled patients with metastatic PDAC who failed gemcitabine-based therapy and were initiated on NalFL between August 2018 and November 2020. The spleen volume before NalFL administration was evaluated. They were stratified into dose subgroups (i.e. low, < 48 mg/m²; intermediate, 48 - < 64 mg/m²; high, ≥ 64 mg/m²) by the average nal-IRI dose during the entire treatment, and multivariate analysis of overall survival (OS) was performed. We included 547 patients with a median age of 63 years (range, 27-89 years) and a median of 1 (range, 0-7) palliative chemotherapy regimen. The median spleen volume was 245 mL (range, 82-817 mL). Among patients with splenomegaly (≥ 245 mL), the low-dose subgroup had the worst median time to treatment failure (TTF, 1.8 months vs. 2.5 months vs. 2.5 months, P = 0.020) and OS (3.3 months vs. 5.9 months vs. 6.6 months, P = 0.018) as against no prognostic impact in patients without splenomegaly. In the multivariate analysis of patients with splenomegaly, performance status (PS) ≥ 2, body surface area (BSA) < 1.6 m², prior fluoropyrimidine use, liver metastasis, and low-dose subgroup were independent poor prognostic factors. A low average nal-IRI dose was significantly associated with poor prognosis, especially among patients with splenomegaly. Further pharmacological studies should validate the relevance of spleen volume on the treatment outcomes of nal-IRI.     

经皮肾镜钬激光碎石与双导管超声碎石的比较研究

目的：比较经皮肾镜钬激光碎石与双导管超声碎石的疗效及安全性。方法回顾性分析2012年10月~2014年12月我院泌尿外科采用经皮肾镜碎石术治疗136例肾结石患者的临床资料,按碎石取石方式不同分为钬激光碎石组(A组66例)和双导管超声碎石组(B组70例),比较两组患者手术时间、失血量、术后感染发生率、Ⅰ期清石率的差异。结果A组手术时间为(85.36±21.52)皂蚤灶,术中出血量为(154.18±33.25)皂蕴,术后感染发生率为13.64豫,Ⅰ期清石率为90.91豫;月组手术时间为(76.15±20.36)皂蚤灶,术中出血量为(85.66±27.68)皂蕴,术后感染发生率为2.86%,Ⅰ期清石率为92.86%。两组手术时间、失血量、术后感染发生率比较差异有统计学意义(孕<0.05),Ⅰ期清石率比较差异无统计学意义(孕>0.05)。结论经皮肾镜双导管超声碎石术治疗肾结石手术时间短,术后感染、出血并发症少,疗效及安全性优于经皮肾镜钬激光碎石术。     

用低浓度过氧化氢建立心肌细胞氧化损伤模型

目的　观察低浓度 (10 0μm ol· L- 1 )过氧化氢对心肌细胞的时间损伤效应 ,探讨在细胞水平建立心肌氧化损伤模型 .方法　胰酶消化法分离培养心肌细胞 ,随机分为两组 :H2 O2 处理组和对照组 .在处理后不同的时间点 ,倒置显微镜下观察心肌细胞每分钟搏动频率 ;硫代巴比妥酸法检测心肌细胞脂质过氧化代谢产物丙二醛 (MDA) ;生化分析仪检测培养液中乳酸脱氢酶 (L DH) ;台盼蓝排斥试验检测细胞的存活率 .结果　 H2 O2 处理后细胞搏动频率先有一个增加过程 ,而后迅速下降直至停止搏动 ;细胞 MDA的含量随作用时间的延长逐渐升高 ,30 min开始与对照组均差异显著 (P<0 .0 1) ;L DH漏出量也逐渐增加 ,40 min后与对照组均差异显著 (P<0 .0 1) ;H2 O2 处理 30 min后细胞存活率就开始下降 ,与对照组相比组间差异显著 (P<0 .0 1) .结论　 10 0 μmol· L- 1的H2 O2 随着时间的延长表现出明显的细胞损伤效应 ,可以用它建立模型来研究心肌细胞氧化损伤     

Evaluation of the High- and Low-Temperature Performance of Asphalt Mortar Based on the DMA Method

Asphalt mortar is a typical temperature-sensitive material that plays a crucial role in the performance of asphalt mixture. This study evaluates the high- and low-temperature performance of asphalt mortar based on the dynamic mechanical analysis (DMA) method. Temperature-sweep tests of asphalt mortars were conducted using the DMA method under fixed strain level, frequency, and heating rate conditions. The dynamic mechanical response curves, characteristic temperature, and other indices were obtained and used to investigate the high- and low-temperature performance of asphalt mortar. The results showed that the phase transition temperatures T₁, T₀, and T_g can be used to evaluate the low-temperature performance of asphalt mortar. Additionally, they had a good linear relationship, and the evaluation results were consistent. Meanwhile, T₂, E₆₀, and tan(δ)_max indicators can effectively evaluate the high-temperature performance of asphalt mortar. Asphalt plays a key role in the performance of asphalt mortar. Mortars with neat asphalt A70 and modified asphalt AR had the worst and best high- and low-temperature performances, respectively. Furthermore, the finer gradation improved the low-temperature performance of asphalt mortar, while the coarser gradation improved the high-temperature properties of modified asphalt mortars but had the opposite effect on neat asphalt A70.     

男性服刑罪犯中的精神分裂症MMPI测试分析

目的：探讨男性服刑罪犯中精神分裂症患的人格特征。方法：比较52例男性服刑罪犯中的精神分裂症与48例普通医院中的男性精神分裂症的MMPI量表分。结果：罪犯组精神分裂症MMPI测试的L、Hs、D、Pd、Pa、Si量表分明显高于罪犯组精神分裂症患。结论：服刑罪犯中精神分裂症患更加表现为掩饰、消极沮丧、诸多躯体不适、多疑及敌对等，应关注这部分人的心理健康。     

Effects of IL-17 on expression of GRO-α and IL-8 in fibroblasts from nasal polyps

Recent studies indicated that interleukin（IL）-17, growth-related oncogene（GRO）-α and IL-8 play an important role in the pathogenesis of nasal polyps. However, the effects of the increased amount of IL-17 and the production of GRO-α and IL-8 in human nasal polyp fibroblasts are not completely understood. This study aimed to determine the effects of the increased IL-17 on the changes of GRO-α and IL-8 expression in human nasal polyp fibroblasts and further investigate the mechanism of neutrophil infiltration in nasal polyps. Nasal polyp fibroblasts were isolated from six cases of human nasal polyps, and the cells were stimulated with five different concentrations of IL-17. Real-time fluorescence quantitative polymerase chain reaction（RT-PCR） was used to detect the mRNA expression of GRO-α and IL-8. The mRNA of GRO-α and IL-8 was expressed in unstimulated controls and remarkably increased by stimulation with IL-17. Moreover, the levels of GRO-α and IL-8 produced by fibroblasts were increased gradually with the increases in IL-17 concentrations. The present study showed that nasal fibroblasts can produce GRO-α and IL-8, and their production is remarkably enhanced by IL-17 stimulation, thereby clarifying the mechanism of the IL-17 mediated neutrophil infiltration in nasal polyps. These findings might provide a rationale for using IL-17 inhibitors as a treatment for nasal inflammatory diseases such as nasal polyps.     

利用IGF-1基因敲除鼠乳腺癌模型研究IGF-1对血管生成的影响

目的探讨在低血清胰岛素样生长因子-1（IGF-1）水平与正常IGF-1水平的小鼠乳腺癌模型中应用血管生长抑制剂——人参皂甙（GS）Rg3后，IGF-1对血管生成的影响。方法应用7，12-二甲基苯蒽（DMBA）诱导肝脏特异性IGF-1基因敲除鼠（IAD鼠）及对照鼠建立原发乳腺癌模型，应用GSRg3进行干预治疗，利用免疫组化法检测乳腺癌组织中血管内皮生长因子（VEGF）和Ⅷ因子相关抗原（F8-RAg）表达水平，同时利用基因芯片技术检测小鼠乳腺癌及正常乳腺组织中相关基因的表达情况。结果LID鼠乳腺癌的发生率低于对照鼠（P〈0．05）；LID鼠乳腺癌组织中VEGF表达水平与微血管密度均低于对照组（P〈0．05）。LID鼠乳腺癌组织中IGF-1、成纤维细胞生长因子（FGF）1、肝细胞生长因子（HGF）和转化生长因子（TGF）-β1基因较对照组上调，成纤维细胞生长因子受体（FGFR）-2、血小板源性生长因子（PDGF）-A和PDGF-B基因较对照组下调；应用GSRg3后，LID鼠乳腺癌组织中VEGFa、表皮生长因子（EGF）、表皮生长因子受体（EGFR）、PDGF—A和FGFR-2基因较对照组上调，而IGF1和TGF-β1基因较对照组下调。结论IGF1促进小鼠乳腺癌的发生、发展，且与血管生长密切相关。血管生长抑制剂可能通过IGF-1及TGF-β1发挥抗肿瘤作用。