Selective organ specific inflammation in offspring harbouring microchimerism from strongly alloreactive mothers

The origins of autoimmunity are not yet understood despite significant advances in immunology. The trafficking of maternal cells to the offspring represents the very first immunological event in foetal life and is reinforced during lactation. The persistence of maternal cells in offspring's tissues and circulation has been associated with several autoimmune disorders. However a direct causal effect has never been demonstrated. Maternal T cells specifically targeting foetal insulin producing cells have been shown to generate islet inflammation without directly participating in this process. Our objective was to evaluate if alloreactive maternal cells could directly trigger a graft-versus host like reaction or indirectly influence the development of the offspring's regulatory T cells favouring autoimmunity. We adopted a breeding strategy comparing genetically identical offspring from either strongly alloreactive transgenic mothers compared to immunodeficient mothers. We detected maternal alloreactive T cells in the offspring and early signs of inflammation in small intestine of 6 weeks old offspring. Interestingly, CD4⁺ Foxp3⁺ regulatory T cell frequency was diminished in mesenteric lymph nodes from eight months old offspring born of alloreactive mothers compared to offspring of immunodeficient mothers. Our study favours a hypothesis where highly alloreactive maternal cell microchimerism indirectly predisposes offspring to autoimmunity.     

VEGF在SD大鼠Walker-256肝转移瘤模型建立中的应用

 目的：探讨采用血管内皮细胞生长因子（VEGF）缩短SD大鼠Walker-256肝转移瘤成模时间的安全性与可行性,为抗VEGF靶向药物的研究提供更实用的模型。方法：将SD大鼠随机分为3组,每组各15只。生理盐水（NS）模型组：于建模前1周开始尾静脉注射生理盐水0.1 mL/d; 20 mg/L VEGF模型组：于建模前1周开始尾静脉注射20 mg/L VEGF（0.1 mL/d）; 40 mg/L VEGF模型组于建模前1周开始尾静脉注射40 mg/L　VEGF（0.1 mL/d）。各组均注射至建模当天。建模方法：暴露大鼠肝脏,将瘤块种植于肝包膜下。分别于建模后3 d、1周和2周用磁共振成像（MRI）观察肿瘤生长情况,并记存活时间。结果：建模成功,肝内肿块HE染色符合恶性肿瘤特点。大鼠肝脏MRI表现：肿块呈结节状,T2WI呈稍高信号,显示更为清楚,腹水于T2WI呈高信号。NS模型组和20 mg/L VEGF模型组各有1只动物于建模后1 d死亡,40 mg/L VEGF模型组有3只于建模1周后死亡。建模后3 d各组可观察到肿块的大鼠数分别为：NS模型组0只,20 mg/L VEGF模型组7只,40 mg/L VEGF模型组10只;建模后1周各组可观察到肿块的大鼠数分别为：NS模型组3只,20 mg/L VEGF模型组14只,40 mg/L VEGF模型组13只;建模后2周各组可观察到肿块的大鼠数分别为：NS模型组12只,20 mg/L VEGF模型组14只,40 mg/L VEGF模型组10只。20 mg/L VEGF模型组和40 mg/L VEGF模型组分别与NS模型组相比,3 d可观察到成瘤的老鼠数目差异均有统计学意义（P<0.05）。NS模型组与20 mg/L VEGF模型组大鼠存活时间差异无统计学意义（P＞0.05）,40 mg/L VEGF模型组存活时间短于NS模型组（P<0.01）。结论:20 mg/L VEGF能缩短SD大鼠肝转移瘤成模时间,对其存活时间无显著影响,且相较于传统模型,更适合应用于抗VEGF靶向药物的研究。     

PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine

Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co‐occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal‐specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild‐type (WT) mice and mice with a predisposition to adenoma development (Apc^fl/+). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life‐span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk     

三维细胞模型在肿瘤研究中的应用

三维细胞模型借助特殊材料或载体在体外培养不同种类的细胞,使细胞在三维环境中生长、迁移和分化。三维细胞模型为细胞提供接近体内生存的体外环境,使细胞的基因表达、信号传递更具生理学相关性。本文从三维细胞模型的概念与分类入手,综述了近几年三维细胞模型在肿瘤微环境、肿瘤转移与抗肿瘤药物研发的应用与进展。基于三维细胞模型目前存在的不足,对其在肿瘤治疗中的应用提出了设想与展望。     

CT纹理分析与淋巴结阴性结直肠癌患者伴同时性远处转移的相关性分析

目的 探讨CT纹理指标与淋巴结阴性的结直肠癌患者同时性远处转移的相关性。方法 回顾性分析82例淋巴结阴性结直肠癌患者的术前CT图像,12例患者伴同时性远处转移,70例不伴同时性远处转移,使用TexRAD软件对平扫及门脉期CT图像上病灶的最大层面进行分析,空间缩放因子(SSF)取0和2~6时获得6个纹理参数,比较两组之间各纹理参数值的差异性,计数资料使用卡方检验进行分析,计量资料使用曼-惠特尼检验进行分析。结果 同时性远处转移组和无同时性转移组间CT平扫图像上,SSF=3时的偏度值差异有统计学意义(P=0.031);CT增强图像上,SSF=2、3、5、6时的熵值差异有统计学意义(P分别为0.048、0.027、0.016、0.017),SSF=2的峰度值差异有统计学意义(P=0.026)。综合分析这6组有组间差异的纹理指标,当界值取0.636时,诊断同时性远处转移的敏感性为75%、特异性为89%。结论 CT纹理分析技术与淋巴结阴性结直肠癌患者伴同时性远处转移的诊断具有一定相关性。     

前哨淋巴结活检与乳腺癌分子分型的关系

目的 探讨前哨淋巴结活检结果与乳腺癌分子分型的关系。方法 选取2015 年1 月—2018 年 12 月于东莞市松山湖中心医院接受全乳切除术或保乳术加前哨淋巴结活检的302 例早期乳腺癌患者作为 研究对象,采用免疫组织化学法检测肿瘤组织中雌激素受体（ER）、孕激素受体（PR）、人体表皮生长因 子受体-2（Her-2）、Ki-67 的表达,并将患者划分为Luminal A 型、Luminal B 型、HER-2 阳性型及三阴 性型。分析前哨淋巴结转移与患者分型的关系。结果 患者中Luminal A 型134 例、Luminal B 型91 例、 Her-2 阳性型32 例及三阴性型45 例,各亚型中前哨淋巴结阳性者分别有31、37、7 及6 例。前哨淋巴结 阳性组年龄≤ 52 岁、T2 期、Luminal B 型占比均高于阴性组（P <0.05）,TNM 分期是前哨淋巴结阳性的危 险因素[Ol ^ R=3.531（95% CI ：1.936,6.438）,P =0.000],Luminal A 型[Ol ^ R=0.242（95% CI ：0.121,0.483）, P =0.000]、年龄[Ol ^ R=0.202（95% CI ：0.101,0.405）,P =0.000] 是其保护因素。前哨淋巴结阳性组年龄≤ 52 岁、T2 期、Luminal B 型占比均高于阴性组（P <0.05）, 年龄[Ol ^ R=0.250（95% CI ：0.063,0.987）, P =0.000] 是前哨淋巴结阳性数的保护因素。检出组年龄≤ 52 岁、T2 期、阳性前哨淋巴结数量≥ 2 枚、前哨 淋巴结宏转移者占比均高于未检出组（P <0.05）,前哨淋巴结阳性数量≥ 2 枚[Ol ^ R=27.926（95% CI ：6.433, 121.222）,P =0.000]、前哨淋巴结宏转移[Ol ^ R=10.662（95% CI ：1.620,70.177）,P =0.014] 是非前哨淋巴结转 移的危险因素。结论 分子分型与前哨淋巴结阳性有一定关系,其中Luminal A 型患者前哨淋巴结阳性风险 低于Luminal B 型患者,但分子分型与是否伴非前哨淋巴结转移无关。