内源性保护蛋白Iduna在抑制大脑神经元parthanatos中的作用

背景 Parthanatos是新近发现的一种与人类多种疾病有关,通过激活多聚腺苷二磷酸(ADP)核糖聚合酶-1[poly(ADP-ribose)polymerase-1,PARP-1]引发,不同于坏死、凋亡和自噬的新的细胞死亡形式.目前发现N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)预处理可诱导产生一种内源性存活蛋白Iduna,通过与多聚ADP核糖聚合物(poly ADP-ribose,PAR)结合,有效干预兴奋毒性引起的神经细胞parthanatos死亡.目的 了解内源性保护蛋白Iduna在抑制大脑神经元parthanatos中的作用.内容 就细胞发生parthanatos的可能机制,以及内源性抑制蛋白Iduna如何作用于PARP-1通路产生脑保护作用最新研究进展作一综述.趋向 随着对Iduna研究的不断深入,临床治疗parthanatos相关疾病的方法也会不断涌现.     

Hepatic ischemia-reperfusion promotes liver metastasis of colon cancer

BACKGROUND: The effects of hepatic ischemia/reperfusion (I/R) on liver metastasis have not been fully examined. We examined hepatic I/R and liver metastasis of colorectal cancer in a rat model; we also quantitated expression of E-selectin (ELAM-1) mRNA after I/R. MATERIALS AND METHODS: Rats underwent 30 or 60 min of 70% partial hepatic ischemia. After 60 min of reperfusion, rat colon adenocarcinoma cells (RCN-H4) were inoculated intrasplenically. The number of tumor nodules on the liver surface was determined 3 weeks later. Expression of E-selectin mRNA was determined at 1, 3, and 6 h after ischemia by quantitative RT-PCR. RESULTS: Hepatic I/R promoted liver metastasis of RCN-H4 and induced the expression of E-selectin mRNA in both clamped and unclamped liver lobes. The number of tumor nodules and the expression of E-selectin mRNA after 60 min of ischemia was greater than that after 30 min. CONCLUSIONS: Hepatic I/R, especially with a long duration of ischemia, induces expression of E-selectin and promotes liver metastasis of colon cancer in rats.     

The effect of UFTM therapy on primary and metastatic colon cancer from the same human xenotransplanted into nude mice

Successful simultaneous transplants of a cancer of the ascending colon from a 60 year old woman, taken from 3 sites: the primary focus, a lymph node metastasis, and a hepatic metastasis, into nude mice yielded KHC (-P,-N,-H) strains. These three strains were compared under uniform conditions of nude mouse transplantation from the standpoints of morphological variation, growth rate, and sensitivity to chemotherapy. The results showed no major differences in morphology or growth rate. However, an effect on chemotherapeutic sensitivity was observed in KHC-P and KHC-N, with reduction rates of 25.8 per cent and 31.4 per cent, respectively, in the MMC only treatment group with large doses, and in KHC-N and KHC-H, with reduction rates of 46.5 per cent and 34.9 per cent, respectively, in the UFTM group. Chemotherapy sensitivity not only exhibited heterogeneity by site, but also differed according to the chemotherapeutic agent used. These results indicate that this method of nude mouse transplantation is a good experimental system for comparing primary foci and metastases under uniform conditions, and also strongly suggest the presence of heterogeneity in sensitivity to chemotherapy.     

多聚ADP核糖聚合酶-1及其依赖性细胞死亡在神经系统疾病中的研究进展

背景多聚ADP核糖聚合酶-1（poly ADP-ribose polymerase-1,PARP-1）作为-种DNA修复酶,具有维持基因组稳定的生理作用,应激条件下介导细胞程序性死亡,即PARP．1依赖性细胞死亡（PARP-1-dependent cell death,PARthanatos）。目的研究PARP-1及其介导的细胞死亡在脑卒中和神经退行性疾病等神经系统疾病中作用,探讨PARP-1阻断对神经细胞的保护作用。内容持续氧化应激可使PARP-1过度活化,促进凋亡诱导因子（apoptosis induced factor,AIF）转位至细胞核,介导PARthanatos。缺血,再灌注以及谷氨酸兴奋性毒性作用均可产生大量氧自由基,是神经系统疾病主要致病物质。脑卒中和神经退行性疾病中存在持续氧化应激和PARP-1活化,其介导的PARthanatos是神经元死亡的主要方式之一。抑制PARP-1活化具有神经保护作用。趋向PARP-1活化介导脑卒中和神经退行性疾病的发生,阻断PARP-1有望成为治疗该类疾病的新靶点。     

结肠癌手术治疗值得关注的若干问题

基于结肠癌手术效果尚不够理想、术后复发率高且常伴有急性肠梗阻,因此结肠癌手术治疗中除遵循一般外科原则外,尚要求有严格无瘤观念和预防肿瘤播散的综合治疗观念。结肠癌手术中应重点关注手术切除范围、肝转移的探查与切除、腹膜播散的预防与治疗、伴有肠梗阻的肠切除与吻合以及术中化疗等问题。     

Thymidylate synthase gene polymorphism as a prognostic factor for colon cancer

The human thymidylate synthase (TS) gene promoter is polymorphic, having either double or triple tandem repeats of a 28-base-pair (bp) sequence. Here, we determined the significance of this polymorphism in predicting the clinical outcomes for patients with colon cancer. We reviewed 121 consecutive patients with stage II or III colon cancer who underwent a curative resection. After DNA extraction from paraffin-embedded tissues, the promoter region of the TS gene was amplified by polymerase chain reaction. In addition to the conventional prognostic factors, patient survivals were compared with regard to the pattern of TS polymorphism. Sixty-eight subjects were homozygotes for the triple-repeat variant (250 bp, group A), and 53 subjects (group B) were either homozygotes for the double-repeat variant (220 bp) or heterozygotes (220 and 250 bp).Wefound a significant difference between groups A and B in survival (53% versus 80%, P = 0.0481). The difference was particularly significant in the patients with stage III disease (41% versus 77%, P = 0.0414). Tumor stage and the TS polymorphism were identified as significant prognostic factors by multivariate analysis. We found the TS polymorphism to be a significant and independent prognostic factor for colon cancer.     

七氟烷对幼鼠不同脑区多聚腺苷二磷酸核糖聚合酶-1表达和远期认知功能的影响

目的 观察七氟烷对幼鼠不同脑区神经元细胞多聚腺苷二磷酸核糖聚合酶-1[Poly(ADP-ribose)polymerase-1,PARP-1]表达、远期学习记忆能力及空间探索能力的影响. 方法 出生后7d的wistar幼鼠105只采用随机数字表法随机分为模拟麻醉组(A组)、1％七氟烷麻醉2h组(B组)、1％七氟烷麻醉4h组(C组)、2％七氟烷麻醉2h组(D组)和2％七氟烷麻醉4h组(E组).麻醉结束后即刻,每组随机选3只,左心室取血进行血气分析.麻醉结束6h后,每组随机选6只幼鼠,分别取大脑皮层和海马组织,用Western blot方法检测PARP-1蛋白表达量.其余实验动物,分别在幼鼠成长至5周、8周、14周时,进行悬崖逃避实验和旷场实验. 结果 各组实验动物无缺氧和明显的CO2蓄积.与A组比较,E组海马PARP-1蛋白表达量明显增加,其他实验组无明显升高:A组(0.32±0.53),B组(0.45±0.11)、C组(0.46±0.15)、D组(0.34±0.14)、E组(0.80±0.34)(P＜0.05),各组皮层PARP-1蛋白表达量差异无统计学意义(P＞0.05).A组(0.34±0.07)、B组(0.33±0.14)、C组(0.28±0.11)、D组(0.29±0.13)、E组(0.38±0.15) (P＞0.05).5周时接受七氟烷麻醉的大鼠在旷场中平面活动及垂直活动均多于模拟麻醉幼鼠(平面活动时间/s):A组(431±32)、B组(463±27)、C组(448±31)、D组(467±23)、E组(473±25)(P＞0.05);垂直面进入时间/s:A组(112±37)、B组(169±46)、C组(152.3±44.3)、D组(150±26)、E组(129±36)(P＞0.05);8周和14周时,各组动物旷场表现差异无统计学意义(P＞0.05).5周、8周及14周时,各组动物悬崖逃避实验表现差异无统计学意义(P＞o.05). 结论 2％七氟烷作用于发育期的幼鼠4h,可导致PARP-1表达增加,诱发海马神经元凋亡;使成长中幼鼠在陌生环境中活动增加,影响其空间探索认知能力.     

Accuracy of radiological staging in identifying high‐risk colon cancer patients suitable for neoadjuvant chemotherapy: a multicentre experience

Aim A pilot study was undertaken to determine the accuracy of computed tomography (CT) staging in identifying patients with high‐risk colon cancers who would be considered as candidates for a neoadjuvant therapy trial (FOxTROT) and those at low risk (T1/T2) who would be excluded. Method Participating radiologists from 19 centres attended workshops for standardization of image interpretation according to previously defined prognostic criteria: good prognosis tumours, including, T1/T2; intermediate prognosis, T3 < 5 mm tumour invasion beyond the muscularis propria (MP); and poor prognosis tumours, including T3 with tumour extension ≥ 5 mm beyond the MP or T4. The CT findings were compared with histopathology as the reference standard. Results Of 94 patients with radiological and pathological data, 71% were categorized by CT as having a poor prognosis. The sensitivity and specificity of CT in identifying these tumours were 87% (95% CI, 74–94) and 49% (95% CI, 33–65). Sensitivity and specificity for tumour infiltration beyond the MP (T3/T4 vs T1/T2) were 95% (95% CI, 87–98) and 50% (95% CI, 22–77), respectively. Including all CT‐staged T3 and T4 patients in the trial would have increased the proportion eligible for entry to 89% (n = 84) without affecting the false‐positive rate of 7%. Some 20% of T3/T4 patients would have been ineligible for FOxTROT because of synchronous metastases. Conclusion In a multicentre setting, CT scanning identified high‐risk (T3/4) colon cancers with minimal overstaging of T1/T2 tumours, thus establishing the feasibility of radiologically guided neoadjuvant chemotherapy.     

结肠癌肝转移外科治疗的临床与病理分析(附25例报告)

目的　探讨结肠癌肝转移的外科治疗方法及其病理因素对预后的影响。方法　本组79例结肠癌肝转移患者中共有 2 5例接受原发灶根治术以及肝转移灶切除术或射频消融术。其中 14例进行了原发灶根治术及肝脏转移灶切除术 ,11例进行了肝脏转移灶射频消融术。结果　本组结肠癌肝转移患者术后 1年、3年生存率分别为 84 %、4 8%。分化程度高以及单个转移灶的患者预后较好。肝脏肿瘤切除与肝脏肿瘤射频消融术后患者生存时间无明显差异。结论　结肠癌肝转移患者原发肿瘤的分化程度、肝脏转移灶的数量对预测患者的预后有一定的作用。手术切除及射频消融术对治疗结肠癌肝转移能够达到较为接近的治疗效果。     

Vitamin E succinate inhibits colon cancer liver metastases

BACKGROUND: Vitamin E succinate (VES) is a promising anti-cancer micronutrient. In this study, we tested the hypothesis that VES will promote colon cancer tumor dormancy and inhibit liver metastases in colon cancer. METHODS: CT-26 colon cancer cells were treated with VES in vitro and in an in vivo model of liver metastases. The impact of VES on cellular proliferation and apoptosis was measured in vitro by MTS assay and sandwich ELISA and in vivo by PCNA staining and TUNEL assay, respectively. Correlation coefficients and independent t tests were used for statistical analysis. RESULTS: VES significantly and specifically inhibited cell proliferation (P = 0.011) and promoted apoptosis (P < 0.0074) of cancer cells in vitro. VES produced a 40% reduction of liver metastases (P = 0.037). Five of the eight mice had an excellent response to VES. Subsequent analysis of these five mice revealed a 75% reduction in the number of liver metastases (P < 0.05). VES significantly promoted tumor cell apoptosis (P < 0.0003) and inhibited cell proliferation (P = 0.0069) in vivo. CONCLUSIONS: VES inhibits the growth of colon cancer cells in vitro and in vivo. This is the first report of VES inhibition of colon cancer tumor metastases. The mechanism of VES anti-tumor and anti-metastatic activity in vivo appears to involve promotion of tumor apoptosis and inhibition of cell proliferation. These findings support further investigation of VES as a micronutrient to promote colon cancer tumor dormancy and prevent metastases.     

睾酮诱导的结肠癌细胞凋亡受PI3K／Racl信号调控

近来,有报道指出睾酮膜信号在结肠肿瘤细胞中调控肌动蛋白重组并诱导凋亡前期反应。本研究分析了膜雄激素受体（mAR）诱导的Racl GTPase活化,以及PI-3K／Racl信号在睾酮处理的Cac02结肠癌细胞中参与控制凋亡反应。与之前的发现一致,mAR睾酮结合活化后,启动了早期的和短暂的肌动蛋白重组,正如处理15分钟和30分钟后的细胞中显著降低的G／总肌动蛋白比值所表明的类似。有趣的是,mAR的刺激快速激活了Racl GTPase。处理15分钟后,就能观察到这一现象,并持续至少24小时。用PI-3K的抑制剂wortmannin预处理Cac02细胞,睾酮诱导的Racl活化被完全阻断,表明了Racl信号作用于PI-3K通路的下游。值得注意的是,当细胞被阻断PI-3K／Racl信号的wortmannin预处理后,凋亡反应被几乎完全抑制。这些发现提示Racl的活化启动了肌动蛋白的重新分配,参与了睾酮诱导的由mAR活化调控的凋亡前期反应,强调了PI-3K／Racl信号在结肠肿瘤中的调控作用。     

结肠癌患者奥沙利铂治疗体验的质性研究

对15例用奥沙利铂治疗的结肠癌患者进行半结构式访谈,归纳其症状体验主要为疲乏,食欲不振和味觉改变,恶心、呕吐及腹泻,四肢麻木和疼痛;情感体验主要是恐惧,抵触和无奈,矛盾,压抑和担忧。护理人员应采取有效措施减轻化疗痛苦,提高患者生命质量。     

大肠癌干细胞研究进展

随着肿瘤下细胞研究的深入,近年来学者提出了大肠癌起源的干细胞学说,并借助干细胞分离技术,将其成功分离.本篇旨在回顾基于肿瘤干细胞概念提出的大肠癌起源假说和大肠癌干细胞在大肠癌进展的作用,大肠癌干细胞分离技术及其在体内和体外的功能特征,与大肠癌干细胞相关的信号通路及大肠癌耐药机制研究.     

Metastatic colon cancer presenting as Pancoast's disease

We report a rare case of metastatic adenocarcinoma of the sigmoid colon that presented as Pancoast's disease.     

Curative resection for locally advanced sigmoid colon cancer using neoadjuvant chemotherapy with FOLFOX plus panitumumab: A case report

IntroductionFOLFOX and panitumumab combined chemotherapy plays an important role for metastatic colorectal cancer. However the usefulness of this regimen for neoadjuvant therapy is unclear.Case reportA 67-year-old man with abdominal pain and pneumaturia was diagnosed with RAS wild-type sigmoid colon cancer with urinary bladder invasion and colovesical fistulas. Because the cancer was considered to be unresectable, a transverse-loop colostomy was performed. Colonoscopy and computed tomography revealed a marked reduction in the size of the primary tumor after six courses of FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) plus panitumumab. Laparoscopic sigmoidectomy and partial cystectomy were then performed. The pathological findings based on the resected specimen showed almost complete replacement of the tumor by fibrous tissue, with only a few degenerated tumor glands persisting in the submucosa. The patient’s postoperative course was uneventful and he was doing well, without disease recurrence, after 36 months of follow up.ConclusionTo our knowledge, this is the first report of a successful curative resection in a patient with initially unresectable, locally advanced colorectal cancer who was treated with FOLFOX4 combined with panitumumab.