Modulatory effects of adiponectin on the polarization of tumor‐associated macrophages

The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor‐associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft‐tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn^?/? mice versus WT controls. The accumulation of TAMs in apn^?/? mice was also reduced which correlated to downregulated serum levels of MCP‐1. Likewise, TAMs in apn^?/? mice exhibited a M1‐like phenotype, characterized by increase in MHC II^high population and M1 phenotypic markers, such as iNOS gene and serum TNF‐α accompanied by a decrease in M2 markers, namely YM1 gene and serum IL‐10. In addition, APN deficiency increased the number of CD4⁺ T cells, CD8⁺ T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn^?/? mice was associated with a marked decrease in phospho‐p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN‐mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth.     

Hematologic toxicity assessment in solid tumor patients treated with cetuximab: A pooled analysis of 18 randomized controlled trials

The role of cetuximab in treatment‐related hematologic toxicity is not clear. We performed a meta‐analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as abstracts presented at American Society of Clinical Oncology conferences and ClinicalTrials.gov were searched to identify relevant studies. Eligible studies included RCTs in which cetuximab in combination with chemotherapy or chemoradiotherapy was compared with chemotherapy or chemoradiotherapy alone. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects models. A total of 11,234 patients with a variety of advanced solid tumors from 18 RCTs were included in the meta‐analysis. Compared with chemotherapy alone, the addition of cetuximab was associated with increased risks of ≥grade 3 leucopenia/neutropenia and anemia events in colorectal cancer, with RRs of 1.16 (95% CI 1.05–1.27, p = 0.002; incidence, 21.0 vs. 18.0%) and 2.67 (95% CI 1.53–4.65, p = 0.01; incidence, 4.0 vs. 2.0%), respectively. Cetuximab was also associated with an increased risk of leucopenia/neutropenia in nonsmall cell lung cancer (NSCLC) (RR: 1.15; 95% CI 1.08–1.22, p < 0.01). Additionally, K‐ras wild type in the case of colorectal cancer patients was more vulnerable to ≥grade 3 leucopenia or neutropenia events in cetuximab group (RR: 1.31; 95% CI 1.11–1.54, p = 0.001). With present evidence, cetuximab in conjunction with chemotherapy or chemoradiotherapy, compared with chemotherapy or chemoradiotherapy alone, was associated with increased slight risk of ≥grade 3 HTEs, especially in colorectal cancer and NSCLC.     

Comparison of clonogenic assay with premature chromosome condensation assay in prediction of human cell radiosensitivity

AIM: To determine whether the number of non-rejoining G2-chromatid breaks can predict the radiosensitivity of human cell lines. METHODS: Cell lines of human ovary carcinoma cells (HO8910), human hepatoma cells (HepG2) and liver cells (L02) were irradiated with a range of doses and assessed both of cell survival and non-rejoining G2-chromatid breaks at 24 h after irradiation. Cell survival was documented by a colony assay. Non-rejoining G2-chromatid breaks were measured by counting the number of non-rejoining G2 chromatid breaks at 24 h after irradiation, detected by the prematurely chromosome condensed (PCC) technique. RESULTS: A linear-quadratic survival curve was observed in three cell lines, and HepG2 was the most sensitive to y-radiation. A dose-dependent linear increase was observed in radiation-induced non-rejoining G2-PCC breaks measured at 24 h after irradiation in all cell lines, and HepG2 was the most susceptible to induction of non-rejoining G2-PCC breaks. A close correlation was found between the clonogenic radiosensitivity and the radiation-induced non-rejoining G2-PCC breaks (r=0.923). Furthermore, survival-aberration correlations for two or more than two doses lever were also significant. CONCLUSION: The number of non-rejoining G2 PCC breaks holds considerable promise for predicting the radiosensitivity of normal and tumor cells when two or more than two doses lever is tested.     

Triple labeling with three thymidine analogs reveals a well-orchestrated regulation of hepatocyte proliferation during liver regeneration

Aim: After a two‐thirds partial hepatectomy (PHx) in rodents, the remaining cells will proliferate and restore the lost liver mass within 7 days. Previous studies have proved that the residual hepatocytes proliferate in a synchronous manner. However, the existing data can not reflect the chronicle of individual hepatocytes proliferation during liver regeneration. Methods: In this study, a combination of pulse and continuous labeling using three thymidine analogs, Bromodeoxyuridine (BrdU), Chlorodeoxyuridine (CldU) and Iododeoxyuridine (IdU), were used to analyze the cell proliferation of rat liver after PHx. This strategy allows us to follow an individual cell for more than one cell cycle and to define how many cells and which cells undergo multiple divisions. Results: The residual hepatocytes clustered into three subpopulations to initiate the proliferation sequentially, and the corresponding percentage of each was 32%, 17%, and 36%. Meanwhile, the remaining 15% of hepatocytes never proliferated. In addition, the periportal hepatocytes were the first to respond to PHx stimulation and re‐proliferated synchronously at 54 h. Furthermore, at least 11% of residual hepatocytes were identified to divide thrice or more. Conclusion: Based on the present analysis, we concluded a sequential model of the initial proliferation in residual hepatocytes, and for the first time, quantitatively elucidated the proliferation manner of three subpopulations during liver regeneration.     

Hyperpolarization-activated Cyclic nucleotide-gated Channel and Cardiac Biological Pacemaker： Part Ⅰ

Hyperpolarization-activated cyclic-nucleotide-gated （HCN） channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current （ named If, Ib, or Iq ）. Recent studies have unveiled the molecular identity of HCN （HCN1-4） channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ib and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models, local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.     

门脉高压症时脾静脉的病理改变及其临床意义

目的 探讨门脉高压症时脾静脉类粥样硬化改变的发生率、形态及其临床意义。 方法 对尸检正常脾静脉和门脉高压症切除脾静脉各20例进行光镜观察。后者5例斑块进行电镜观察。 结果 正常脾静脉有瓣膜样结构。门脉高压症时脾静脉内膜结节性斑块及弥漫性增厚;中膜显著增厚;外膜多见急慢性炎。斑块以平滑肌细胞增生为主。 结论 门脉高压症时脾静脉皆有类粥样硬化改变,但与动脉粥样硬化有区别。了解脾静脉的病理改变及程度,对脾肾分流术选择合适的术式及吻合口部位以减少吻合口栓塞有一定意义。     

核磁共振波谱法测定安立生坦对照品的含量

摘 要 目的： 建立测定安立生坦对照品含量的方法。 方法: 采用核磁共振波谱法,使用Bruker AscendTM 400超导核磁共振谱仪,以氘代DMSO为溶剂,在脉冲宽度10.0 μs, 延迟时间5 s和扫描次数16的条件下采集试样氢谱。结果:以化学位移分别为6.16 ppm和6.28 ppm的安立生坦和顺丁烯二酸的氢质子峰作为定量峰,其峰面积比与其质量比的线性回归方程为Y=0.140 7X+0.034 8,相关系数为0.999 4,含量测定重复性试验的RSD为0.2%（n=6）。测得安立生坦对照品的绝对含量为99.9%。结论: 分析结果表明,在没有对照品的情况下,该方法可行,且具有快速、准确、简便的优点。