大肠癌发病地理特征的趋势面分析

了解嘉善县大肠癌发病的地理分布特征及地理趋势,为研究大肠癌的病因提供一些线索,嘉善县大肠癌发病率有地域差异,应进一步研究各地区地理环境、生活习惯、经济状况等因素的差异及其与大肠癌的关系,对于存在异常残差值的地区,应作为重点研究对象。探讨这些地区可能存在的某种保护或危险因素。     

结合CA-125, PA, 腹水，卵巢癌偏侧性建立人工神经网络模型对上皮性卵巢癌结直肠转移进行预测诊断

摘要 目的：基于上皮性卵巢癌患者的最优临床指标建立人工神经网络模型（ANN''s Model）,预测卵巢癌患者结直肠转移情况,以期在降低诊断成本的同时,能够更好地进行结直肠转移风险预估,为个体化治疗方案的制定提供参考。方法：采用回顾性研究对2015年1月至2019年11月期间由哈尔滨医科大学附属第一医院、哈尔滨医科大学附属第二医院和哈尔滨医科大学附属肿瘤医院收治的801例确诊为上皮性卵巢癌患者的血清肿瘤标志物等临床常用血液指标进行分析,其中2015年1月至2017年12月所收集的附属肿瘤医院病例资料做建模组（534例）, 2018年1月至2019年11月所收集的附属一院及附属二院病例资料做外部验证组（267例）。利用Medcalc V15.2.0.0软件计算建模组534例卵巢癌患者包括血常规、尿常规、肝肾功、肿瘤标记物、凝血象等临床指标曲线下面积（area under the curve, AUC）,筛选出结直肠转移相关指标;Graphpad Prism V6.0软件计算结直肠转移相关指标共线性,进一步获得结直肠转移相关优势指标来构建ANN模型,并用最优ANN模型对267例外部验证组卵巢癌患者结直肠转移进行预测,验证其能效。结果：血液学指标AUC结果显示CA-125和血清前蛋白（Prealbumin, PA）AUC值分别为0.68、0.67（P均<0.0001）,为人工神经网络模型优势参数,纳入CA125、PA建立ANN I模型AUC值为0.716（P<0.0001）,其对卵巢癌结直肠转移预测的敏感性及特异性分别为69.81%、62.50%。在ANNI模型基础上进而结合术中卵巢癌发生偏侧性（单侧卵巢受累或双侧卵巢受累）、有无腹水情况所建立ANN II模型AUC值为0.745（P<0.0001）,其对卵巢癌结直肠转移预测的敏感度及特异性分别为65.38%、78.24%。结论：1).卵巢癌伴结直肠转移患者其血清CA-125升高更明显,PA降低更明显。伴有腹水及双侧卵巢受累的上皮性卵巢癌患者,更易出现结直肠转移。2).根据卵巢癌患者治疗前CA-125、PA所建立的人工神经网络模型ANN I及在ANNI基础上进一步结合卵巢癌偏侧性及腹水情况所建立的人工神经网络模型ANN II,其二者对上皮性卵巢癌结直肠转移有一定预测能效,且预测性能较单独的CA-125及PA更为理想,为上皮性卵巢癌结直肠转移临床预测提供参考。     

Morusin induces apoptosis and suppresses NF-kappaB activity in human colorectal cancer HT-29 cells

Morusin is a pure compound isolated from root bark of Morusaustralis (Moraceae). In this study, we demonstrated that morusin significantly inhibited the growth and clonogenicity of human colorectal cancer HT-29 cells. Apoptosis induced by morusin was characterized by accumulation of cells at the sub-G₁ phase, fragmentation of DNA, and condensation of chromatin. Morusin also inhibited the phosphorylation of IKK-α, IKK-β and IκB-α, increased expression of IκB-α, and suppressed nuclear translocation of NF-κB and its DNA binding activity. Dephosphorylation of NF-κB upstream regulators PI3K, Akt and PDK1 was also displayed. In addition, activation of caspase-8, change of mitochondrial membrane potential, release of cytochrome c and Smac/DIABLO, and activation of caspase-9 and -3 were observed at the early time point. Downregulation in the expression of Ku70 and XIAP was exhibited afterward. Caspase-8 or wide-ranging caspase inhibitor suppressed morusin-induced apoptosis. Therefore, the antitumor mechanism of morusin in HT-29 cells may be via activation of caspases and inhibition of NF-κB.     

Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APC(Min/+) mice

The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H₂ (PGH₂) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APC^Min/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH₂ into PGE₂, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE₂ related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE₂ levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH₂ derived prostanoids were generally enhanced, being most prominent for TxA₂ and PGD₂. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE₂ during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer.     

IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells

IL-4-induced Stat6 signaling is active in a variety of cell types and plays a role in cell proliferation/growth and resistance to apoptosis. Using EMSA, we identified differential IL-4/Stat6 activities in colorectal cancer cell lines, HT-29 being active Stat6^high phenotype and Caco-2 being defective Stat6^null phenotype, respectively. Active Stat6^high HT-29 cells exhibited resistance to apoptosis by flowcytometry and aggressive metastasis by Transwell assay compared with defective Stat6^null Caco-2 cells. Comparing one another using RT-PCR, Stat6^high HT-29 cells expressed more mRNA of anti-apoptotic and pro-metastatic genes Survivin, MDM2, and TMPRSS4, while Stat6^null Caco-2 cells expressed more mRNA of pro-apoptotic and anti-metastatic genes BAX, CAV1, and P53, respectively. This is the first study describing correlations of IL-4/Stat6 activities with apoptosis and metastasis in colon cancer. These findings, together with the observation of constitutive Stat6 activation in many human malignancies, suggest that Stat6 activities could be a biomarker for cancer cell’s invasive/metastatic capability.     

Oncogenic KRAS suppresses store-operated Ca2+ entry and ICRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines

The KRAS GTPase plays a fundamental role in transducing signals from plasma membrane growth factor receptors to downstream signalling pathways controlling cell proliferation, survival and migration. Activating KRAS mutations are found in 20% of all cancers and in up to 40% of colorectal cancers, where they contribute to dysregulation of cell processes underlying oncogenic transformation. Multiple KRAS-regulated cell functions are also influenced by changes in intracellular Ca²⁺ levels that are concurrently modified by receptor signalling pathways. Suppression of intracellular Ca²⁺ release mechanisms can confer a survival advantage in cancer cells, and changes in Ca²⁺ entry across the plasma membrane modulate cell migration and proliferation. However, inconsistent remodelling of Ca²⁺ influx and its signalling role has been reported in studies of transformed cells. To isolate the interaction between altered Ca²⁺ handling and mutated KRAS in colorectal cancer, we have previously employed isogenic cell line pairs, differing by the presence of an oncogenic KRAS allele (encoding KRAS^G13D), and have shown that reduced Ca²⁺ release from the ER and mitochondrial Ca²⁺ uptake contributes to the survival advantage conferred by oncogenic KRAS. Here we show in the same cell lines, that Store-Operated Ca²⁺ Entry (SOCE) and its underlying current, I_CRAC are under the influence of KRAS^G13D. Specifically, deletion of the oncogenic KRAS allele resulted in enhanced STIM1 expression and greater Ca²⁺ influx. Consistent with the role of KRAS in the activation of the ERK pathway, MEK inhibition in cells with KRAS^G13D resulted in increased STIM1 expression. Further, ectopic expression of STIM1 in HCT 116 cells (which express KRAS^G13D) rescued SOCE, demonstrating a fundamental role of STIM1 in suppression of Ca²⁺ entry downstream of KRAS^G13D. These results add to the understanding of how ERK controls cancer cell physiology and highlight STIM1 as an important biomarker in cancerogenesis.     

Population-level cure of colorectal cancer in Malta: An analysis of patients diagnosed between 1995 and 2004

AimThe aim of this study was to estimate the population-level ‘cure’ of Maltese colorectal cancer patients diagnosed between 1995 and 2004, and to estimate the median survival time for the ‘uncured’ patients.Methods and study populationAnalysis was conducted on 1470 cases registered by the Malta National Cancer Register between 1995 and 2004 and followed up to end of 2010. The mean age of the patients was 66.4 (95%CI 65.8–67.1), and the number of men and women were equal. Background mortality for 1995–2010 was extracted from publicly available life tables. A mixture model with Weibull survival distribution and identity link was used to model ‘cure’.ResultsThe overall ‘cured’ proportion for the patients diagnosed in 1995–1999 was 45.3% (95%CI 40.2–50.5) while the ‘cured’ proportion for the patients diagnosed in 2000–2004 was 52.3% (95%CI 47.2–57.5). Median survival time for the ‘uncured’ patients increased in the second calendar period from 1.25 years (95%CI 1.04–1.45) to 1.42 years (95%CI 1.15–1.76).ConclusionIn Malta, as in the rest of Europe, improvements have been made in short- and long-term survival over the 15-year period under study. To continue this improvement, differences by age that still persist must be investigated and efforts focused to reduce any gaps between Malta and other European countries.     

Interleukin-12 increases bispecific-antibody-mediated natural killer cell cytotoxicity against human tumors

 The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK) cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin’s lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin’s disease and colorectal carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca²⁺ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment. Received: 26 July 1995 / Accepted: 16 November 1995