Genetic Contribution of Endometriosis to the Risk of Developing Hormone-Related Cancers

Endometriosis is a common gynecological disorder that has been associated with endometrial, breast and epithelial ovarian cancers in epidemiological studies. Since complex diseases are a result of multiple environmental and genetic factors, we hypothesized that the biological mechanism underlying their comorbidity might be explained, at least in part, by shared genetics. To assess their potential genetic relationship, we performed a two-sample mendelian randomization (2SMR) analysis on results from public genome-wide association studies (GWAS). This analysis confirmed previously reported genetic pleiotropy between endometriosis and endometrial cancer. We present robust evidence supporting a causal genetic association between endometriosis and ovarian cancer, particularly with the clear cell and endometrioid subtypes. Our study also identified genetic variants that could explain those associations, opening the door to further functional experiments. Overall, this work demonstrates the value of genomic analyses to support epidemiological data, and to identify targets of relevance in multiple disorders.     

Automatic measurement of volume percentage stroma in endometrial images using texture segmentation

The popularity of digital microscopy and tissue microarrays allow the use of high-throughput imaging for pathology research. To coordinate with this new technique, it is essential to automate the process of extracting information from such high amount of images. In this paper, we present a new model called the Subspace Mumford-Shah model for texture segmentation of microscopic endometrial images. The model incorporates subspace clustering techniques into a Mumford-Shah model to solve texture segmentation problems. The method first uses a supervised procedure to determine several optimal subspaces. These subspaces are then embedded into a Mumford-Shah objective function so that each segment of the optimal partition is homogeneous in its own subspace. The method outperforms a widely used method in bioimaging community called k-means segmentation since it can separate textures which are less separated in the full feature space, which confirm the usefulness of subspace clustering in texture segmentation. Experimental results also show that the proposed method is well performed on diagnosing premalignant endometrial disease and is very practical for segmenting image set sharing similar properties.     

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.     

Changes in the Expression and Functional Activities of C-X-C Motif Chemokine Ligand 13 (CXCL13) in Hyperplastic Prostate

Background: C-X-C motif chemokine ligand 13 (CXCL13), a member of the CXC subtype in chemokine superfamily, affects numerous biological processes of various types of cells and the progress of a great number of clinical diseases. The purpose of the current study was to reveal the internal mechanism between CXCL13 and benign prostatic hyperplasia (BPH). Methods: Human serum, prostate tissues and human prostate cell lines (BPH-1, WPMY-1) were utilized. The effect of recombinant human CXCL13 (rHuCXCL13) protein and the influences of the knockdown/overexpression of CXCL13 on two cell lines were studied. Rescue experiments by anti-CXCR5 were also conducted. In vivo, rHuCXCL13 was injected into the ventral prostate of rats. Additionally, a tissue microarray of hyperplastic prostate tissues was constructed to analyze the correlations between CXCL13 and clinical parameters. Results: CXCL13 was highly expressed in the prostate tissues and upregulated in the BPH group. It was observed that CXCL13 modulated cell proliferation, apoptosis, and the epithelial–mesenchymal transition (EMT) through CXCR5 via AKT and the ERK1/2 pathway in BPH-1, while it contributed to inflammation and fibrosis through CXCR5 via the STAT3 pathway in WPMY-1. In vivo, rHuCXCL13 induced the development of rat BPH. Additionally, CXCL13 was positively correlated with the prostate volume and total prostate specific antigen. Conclusions: Our novel data demonstrated that CXCL13 modulated cell proliferation, cell cycle, the EMT of epithelial cells, and induced the fibrosis of prostatic stromal cells via a variety of inflammatory factors, suggesting that CXCL13 might be rediscovered as a potential therapeutic target for the treatment of BPH.     

植物原料乳酸菌发酵剂增菌培养的研究

对筛自泡菜的嗜酸乳杆菌S1的生长条件和增殖培养基进行了研究,优化确定了乳酸菌的培养条件和增殖培养基:起始pH值为5.5、培养温度为35℃、培养时间为12h,培养基主要组成为麦芽糖2%、牛肉膏1%、缓冲盐(NaAc∶CaCO3)0.5∶0.3。控制培养条件,结合优化培养基,可使培养液活菌数提高一个数量级达到5×109cfu/mL。     

子宫下段受累可能为Ⅰ期内膜癌辅助放疗的不良预后因素

目的　探讨子宫下段受累对Ⅰ期子宫内膜癌术后放疗患者的预后作用。方法　回顾性分析1999年1月至2012年12月在北京协和医院进行术后放疗的Ⅰ期子宫内膜癌患者265例，中位年龄53岁，病理类型主要为子宫内膜样腺癌(226例，85.3％)。根据病理结果是否有子宫下段受累分为两组：子宫下段受累组和子宫下段未受累组，比较两组患者的预后因素和临床治疗结果，并对其中的高危和高中危患者进行亚组分析。主要研究终点包括总生存率、无进展生存率、局部区域复发率、远处转移率和治疗失败率。使用Kaplan-Meier法统计生存率，不同组间生存率的比较使用Log-rank检验，使用Cox比例风险回归模型进行预后因素分析。结果　所有Ⅰ期内膜癌患者的5年总生存率和无进展生存率分别为92.8%和89.7%，5年局部区域复发率、远处转移率和治疗失败率分别为4.5%、6.4%和7.8%。单因素分析显示，子宫下段受累是影响总生存率和无进展生存率的相关因素（P= 0.015,0.035）。Cox比例风险回归模型显示，子宫下段受累组患者的总生存率和无进展生存率更低（P=0.041, RR=0.346, 95% CI: 0.125~0.959; P=0.041, RR=0.411, 95% CI: 0.175~ 0.963）。亚组单因素分析显示，在高危和高中危患者中，子宫下段受累是影响治疗失败率的相关因素（P=0.034）。结论　子宫下段受累可能是影响Ⅰ期内膜癌辅助放疗患者总生存率和无进展生存率的不良预后因素；在高危和高中危患者中，子宫下段受累主要与治疗失败的发生相关。     

The Role of mTOR and eIF Signaling in Benign Endometrial Diseases

Adenomyosis, endometriosis, endometritis, and typical endometrial hyperplasia are common non-cancerous diseases of the endometrium that afflict many women with life-impacting consequences. The mammalian target of the rapamycin (mTOR) pathway interacts with estrogen signaling and is known to be dysregulated in endometrial cancer. Based on this knowledge, we attempt to investigate the role of mTOR signaling in benign endometrial diseases while focusing on how the interplay between mTOR and eukaryotic translation initiation factors (eIFs) affects their development. In fact, mTOR overactivity is apparent in adenomyosis, endometriosis, and typical endometrial hyperplasia, where it promotes endometrial cell proliferation and invasiveness. Recent data show aberrant expression of various components of the mTOR pathway in both eutopic and ectopic endometrium of patients with adenomyosis or endometriosis and in hyperplastic endometrium as well. Moreover, studies on endometritis show that derangement of mTOR signaling is linked to the establishment of endometrial dysfunction caused by chronic inflammation. This review shows that inhibition of the mTOR pathway has a promising therapeutic effect in benign endometrial conditions, concluding that mTOR signaling dysregulation plays a critical part in their pathogenesis.     

基于网络药理学与分子对接技术探究逍遥丸治疗乳腺增生的作用机制（网络首发、推荐阅读）

用网络药理学方法进行逍遥丸治疗乳腺增生过程的机制研究.通过中药系统药理学数据库和分析平台(TCMSP)进行逍遥丸活性成分的搜集和筛选,将纳入的化合物成分通过TCMSP数据库进行成分的靶点预测;在GeneCards数据库,NCBI基因数据库以及OMIM数据库进行乳腺增生疾病靶点筛选;取药物靶点和疾病靶点作韦恩图,并利用共有靶点在String数据库中作PPI网络图,利用拓扑分析和MCODE聚类分析筛选核心靶点和核心基因;在cytoscape 3.8.0软件中进行关键活性成分的筛选;关键靶点使用String数据库进行GO分析和KEGG分析,将相关结果导入Cytoscape3.8.0绘制成分—疾病—通路—靶点网络图.结果表明,筛选得到逍遥丸各药活性成分及靶点,其中与乳腺增生相关的有169个靶点.STAT3、AKT1、MAPK1、JUN、MAPK3等20个靶点为该药治疗乳腺增生的关键靶点,HTR2A、IL2、TOP2A、PCNA、MMP1为该药治疗乳腺增生的核心基因.槲皮素(quercetin)、山奈酚(kaempferol)、叶黄素(luteolin)、柚皮素(naringenin)、甘草酮a(licochalcone a)、7-甲氧基-2-甲基异黄酮(7-Methoxy-2-methyl isoflavone)、芒柄花素(formononetin)、醋栗素(acacetin)等可能是逍遥丸治疗乳腺增生发挥作用的主要活性成分.GO富集分析总共富集到2328条生物过程,160项分子功能相关,47项细胞组成相关.通路富集分析显示与166条通路相关,涉及AGE-RAGE信号通路、TNF信号通路、IL-17信号通路、TH17细胞分化、流体剪切应力与动脉粥样硬化等信号通路.分子对接验证结果说明关键活性成分与核心靶点均对接良好.