胃癌免疫细胞浸润相关预后基因的共表达网络分析鉴定

背景与目的：肿瘤免疫细胞浸润在胃癌（GC）的进展和预后中起到关键作用,然而,目前影响GC预后的免疫细胞浸润调控基因还不清楚。本研究联合共表达网络分析研究和反卷积分法鉴定了GC免疫相关预后基因。  方法：从TCGA数据库中下载GC的mRNA表达数据并使用CIBERSORT反卷积算法来确定每个样品中免疫细胞的比例,并构建共表达网络,结合Kaplan-Meier法确定免疫相关预后基因。 结果：在纳入分析的22种免疫细胞中,有11种免疫细胞在肿瘤组织中显著高于正常组织（均P<0.05）。对上述11种免疫细胞进行生存分析,发现静止记忆性CD4 T细胞和调节型T细胞的浸润情况与GC患者生存率呈明显相关（均P<0.05）。基于上结果论进行共表达网络分析,得绿松石模块中的基因与上述两种类型的细胞相关性最显著,并鉴定得到了3个与记忆性CD4 T细胞相关（CGB5、LINC00106、LINC00392）和1个与调节型T细胞相关（UPK1B）的预后基因（均P<0.05)。 结论：本研究鉴定的4个胃癌免疫细胞浸润相关预后基因可能在GC的进展和预后中起到重要作用,这些基因可能会通过影响肿瘤免疫过程而作为潜在的胃癌免疫治疗靶点。      

PIK3C3与SMAD4在胰腺癌中的表达及作用

背景与目的 III型磷脂酰肌醇3-激酶（PIK3C3）及SMAD家族成员4（SMAD4）参与的信号通路与胰腺癌（PAAD）关系密切,但两者与PAAD发生及预后是否有关尚不十分清楚。本研究初步探究两者在PAAD中的表达及其对患者预后的影响。方法 利用UALCAN在线网站分析PIK3C3 mRNA和SMAD4 mRNA在PAAD中的表达及两者各自对PAAD患者预后的影响;从TCGA数据库下载PAAD患者PIK3C3 mRNA和SMAD4 mRNA的表达数据和相应临床病理资料,基于PIK3C3和SMAD4联合的mRNA表达水平,用一致性聚类分析将PAAD患者分为两个聚类,用Kolmogorov-Smirnov检验及Kaplan-Meier法分析两个聚类患者PIK3C3与SMAD4的mRNA表达模式、临床病理因素和总体生存率的差异;用免疫组化的方法检测PAAD和癌旁组织组织芯片中PIK3C3及SMAD4蛋白表达水平,并用独立样本t检验及ROC曲线下面积（AUC）评估两个蛋白在癌和癌旁组织中的差异;采用Kaplan-Meier的方法分析PIK3C3和SMAD4的蛋白水平单独及联合对PAAD患者生存的影响。结果 分析结果表明,PIK3C3 mRNA或SMAD4 mRNA水平在PAAD中均无明显变化,并且两者单独均不影响PAAD患者的预后（均P>0.05）。PAAD中与PIK3C3 mRNA与SMAD4 mRNA具有较高的共表达相关性。两个聚类的PAAD患者之间,两基因的mRNA水平及年龄有明显差异（均P<0.05）,其中,PIK3C3 mRNA及SMAD4 mRNA均高表达聚类的PAAD患者预后较好（P=0.006）。PAAD组织中PIK3C3和SMAD4的蛋白表达水平均明显低于癌旁组织（均P<0.001）,AUC分别为0.7417及0.7991。PIK3C3和SMAD4蛋白之一阳性患者比两蛋白均阴性的患者预后更好（P=0.0359）。结论 PIK3C3和SMAD4蛋白可作为PAAD潜在的诊断标志物,PIK3C3和SMAD4联合分析可成为PAAD患者预后评估的新指标。     

Gasdermin基因家族在胃癌中的表达及功能的生物信息学分析

背景与目的 Gasdermin（GSDM）家族由6个重要分子组成,主要负责调控细胞焦亡等多种生物学过程。近来不断有研究表明GSDM家族的表达失调参与多种癌症进程,然而GSDM家族成员在胃癌中的表达、预后、功能和潜在机制研究尚待阐明。本研究旨在通过生物信息学方法系统性的分析GSDM基因家族各成员在胃癌中的作用。方法 使用ONCOMINE、GEPIA2、UALCAN、Kaplan-Meier Plotter、cBioPortal、TIMER 2.0、DiseaseMeth等多个数据库对GSDM家族分子在胃癌患者中的表达差异、预后价值、功能富集、基因改变、免疫浸润相关性、甲基化改变等方面进行了综合分析。结果 GSDM家族中仅DFNA5在胃癌中明显高表达,表达水平较正常组织升高2.479倍。DFNA5在TNM 2、3、4期的表达明显升高,同时在肿瘤分级2、3级的表达明显升高。GSDM家族中仅DFNA5在胃癌中有预后价值,高表达的DFNA5提示较差的总生存期。GSDM家族中GSDMD的基因变异率最高（19%）,GSDMA、GSDMB、GSDMC次之（14%）,DFNA5（8%）和PJVK最低（6%）。在胃癌中筛选出186个GSDM相关的共表达基因,这些分子可能通过炎症细胞凋亡、趋化因子反应、急性炎症反应相关的信号通路参与胃癌进程。多数GSDM家族成员的表达与CD4⁺ T细胞、CD8⁺ T细胞、B细胞、中性粒细胞、巨噬细胞、树突细胞的浸润存在不同程度的显著正相关,仅PJVK在巨噬细胞和树突细胞浸润中呈负相关。GSDMA、GSDMD在胃癌组织中处于低甲基化水平。结论 GSDM家族成员在胃癌中存在表达及功能紊乱。GSDM家族特别是DFNA5分子可能成为胃癌诊断和预后评估的重要肿瘤标志物,为开发新的胃癌治疗靶点提供思路。     

Ⅱ型糖尿病运动疗法的生物学分析

通过文献资料法对Ⅱ型糖尿病的发病机理及Ⅱ型糖尿病运动疗法进行生物学分析，剖析运动对Ⅱ型糖尿病胰岛素的敏感性、加速脂肪分解及降低血脂和控制肥胖、改善心肺功能的生物学作用，为Ⅱ型糖尿病的运动疗法提供理论指导。     

UFH-001 cells: A novel triple negative,CAIX-positive,human breast cancer model system

Human cell lines are an important resource for research, and are often used as in vitro models of human diseases. In response to the mandate that all cells should be authenticated, we discovered that the MDA-MB-231 cells that were in use in our lab, did not validate based on the alleles of 9 different markers (STR Profile). We had been using this line as a model of triple negative breast cancer (TNBC) that has the ability to form tumors in immuno-compromised mice. Based on marker analysis, these cells most closely resembled the MCF10A line, which are a near diploid and normal mammary epithelial line. Yet, the original cells express carbonic anhydrase IX (CAIX) both constitutively and in response to hypoxia and are features that likely drive the aggressive nature of these cells. Thus, we sought to sub-purify CAIX-expressing cells using Fluorescence Activated Cell Sorting (FACS). These studies have revealed a new line of cells that we have name UFH-001, which have the TNBC phenotype, are positive for CAIX expression, both constitutively and in response to hypoxia, and behave aggressively in vivo. These cells may be useful for exploring mechanisms that underlie progression, migration, and metastasis of this phenotype. In addition, constitutive expression of CAIX allows its evaluation as a therapeutic target, both in vivo and in vitro.     

Emergence of KRAS-mutation in liver metastases after an anti-EGFR treatment in patient with colorectal cancer: Are we aware of the therapeutic impact of intratumor heterogeneity?

Tumors represent a dynamic system where the genomic plasticity permits to adapt to the perturbation induced by environmental pressures, supporting the importance of longitudinal tumor sampling strategies to deciphering the temporal acquisition of driver event that could impact treatment outcome. We describe the case of a metastatic colorectal cancer (mCRC) patient, RAS wild-type, who responded to anti-EGFR therapy and underwent liver surgery, revealing a KRAS mutations in the metastatic lesion, not detectable prior to initiation of therapy in the colonic biopsy. After liver surgery, the patient received chemotherapy alone, then underwent left colectomy and the final pathological report confirmed the KRAS wild-type status. We can speculate the existence of two distinct populations of KRAS wild-type and mutant CRC cells sharing the same genetic origin. The anti-EGFR treatment represented a selective pressure which allowed the selection of KRAS mutant subclones. The prognostic and /or predictive role of intratumor heterogeneity has not been assessed prospectively. Our case report is of clinical relevance because patients with mCRC who respond to anti-EGFR antibodies often develop resistance within several months of initiating therapy, thus outlining the importance to better ascertain the molecular landscape of tumors to design better therapeutic strategies.     

The Auger Effect in biology and medicine. Looking back

Abstract

Purpose: The Auger Effect entered biology in 1967 in a quantal step leading to a burst of experimental work on basic and applied cell- and molecular biology and medicine, which is briefly described.

Conclusion: The relevance of this work again appears in the agenda of the 7th International Symposium on Physical, Cellular, Molecular and Medical Aspects of Auger Processes, held in Jülich, Germany, in 2011.