發(fā)布時間：2018-04-28 11:09

  本文選題：MiRNA + 子宮內(nèi)膜異位癥惡變��； 參考：《北京協(xié)和醫(yī)學院》2017年博士論文

【摘要】：第一部分子宮內(nèi)膜異位癥惡變而來的卵巢透明細胞癌miRNA表達譜研究目的:本研究通過miRNA微陣列基因芯片技術(shù)(microarray)對子宮內(nèi)膜異位癥(以下簡稱為內(nèi)異癥)惡變?yōu)槁殉餐该骷毎?ovarian clear cell carcinoma,OCCC)過程中各級病變,包括在位內(nèi)膜、卵巢內(nèi)異癥、不典型內(nèi)異癥、癌,以及對照組的miRNA表達譜進行比較,并與并進行生物信息學分析,篩選出具有差異的miRNA及其可能靶基因。旨在尋找提示內(nèi)異癥惡變的生物標志,并為進一步研究內(nèi)異癥惡變基因通路和靶向治療提供依據(jù)。方法:運用microarray芯片技術(shù),對4例內(nèi)異癥惡變的卵巢透明細胞癌病例及其對照組石蠟切片進行miRNA表達譜研究,篩選出差異表達miRNA。對差異表達miRNA進行基因功能的富集分析(GO-enrichment Analysis),Pathway的富集分析(Pathway-enrichment Analysis),miRNA 與基因的調(diào)控網(wǎng)絡(luò)(miRNA-Gene-Network),miRNA與pathway的調(diào)控網(wǎng)絡(luò)(miRNA-pathway-Network)等生物信息學分析,篩選出候選miRNA。在6例驗證組病理石蠟切片中采用實時熒光定量PCR(RT-PCR)驗證基于芯片篩查的差異miRNA,以驗證芯片表達譜的可靠性。結(jié)果:內(nèi)異癥惡變的OCCC的在位內(nèi)膜、內(nèi)異癥、不典型內(nèi)異癥和癌四級病變對比,miR-199b-5p從在位內(nèi)膜到癌一直下降,且不典型內(nèi)異癥到癌有顯著下降;miR-200a-3p和miR-200b-3p的表達呈雙向型的改變,以在位內(nèi)膜為對照,在內(nèi)異癥和不典型內(nèi)異癥中下降,在癌組織中上升。內(nèi)異癥惡變的OCCC、符合內(nèi)異癥相關(guān)的卵巢癌但非內(nèi)異癥惡變的OCCC和與內(nèi)異癥無關(guān)的OCCC三組相比,后兩組miR-20a-5p,93-5p,203a和328表達相近,均低于試驗組癌。結(jié)論:內(nèi)異癥惡變的卵巢透明細胞癌研究中,miR-199b-5p,miR-200a-3p,miR-200b-3p,miR-20a-5p,miR-20b-5p,miR-106a-5p,miR-93-5p,miR-203a 和miR-328可能成為研究的關(guān)鍵miRNA。第二部分卵巢透明細胞癌的臨床病理學特點與預(yù)后分析目的:卵巢透明細胞癌與子宮內(nèi)膜異位癥聯(lián)系密切,本研究旨在研究卵巢透明細胞癌的臨床病理特點,探究內(nèi)異癥是否為可能的預(yù)后因素。方法:回顧性分析對2000年到2016年在北京協(xié)和醫(yī)院就診的卵巢透明細胞癌患者的病歷及病理資料,進行統(tǒng)計學數(shù)據(jù)處理。結(jié)果:共納入264名卵巢透明細胞癌的患者,84(31.8%)名為內(nèi)異癥相關(guān)的卵巢癌(endometriosis associated ovarian cancer,EAOC),EAOC 組中根據(jù)是否符合Sampson和Scott標準又分為兩個亞組,內(nèi)異癥惡變組(n=42,50%)和非惡變組(n=42,50%)。EAOC組發(fā)病年齡更小,多在絕經(jīng)前診斷,無癥狀盆腔包塊更多,早期(Ⅰ,Ⅱ)病例更多,更多合并子宮腺肌癥,更易達到滿意的腫瘤細胞減滅術(shù);不合并內(nèi)異癥的對照組腹脹癥狀更多,更多合并腹水、LVSI陽性,復(fù)發(fā)率、死亡率更高;EAOC中兩個亞組相比,非內(nèi)異癥惡變組復(fù)發(fā)率和死亡率更高,其他指標均無統(tǒng)計學差異。單變量生存分析中內(nèi)異癥與OS和DFS都相關(guān),多變量分析中不是獨立預(yù)后因素;多變量生存分析顯示OS和DFS的獨立預(yù)后因素一致,均為FIGO分期、殘余腫瘤和LVSI。結(jié)論:合并內(nèi)異癥的卵巢透明細胞癌有其獨特的臨床病理特征,OS和DFS的獨立預(yù)后因素均為FIGO分期、殘余腫瘤和LVSI,內(nèi)異癥不是OS或DFS的獨立預(yù)后因素。第三部分卵巢畸胎瘤合并抗N-甲基-D-天冬氨酸受體腦炎例臨床病例分析目的:總結(jié)卵巢畸胎瘤合并抗N-甲基D-天冬氨酸受體(NMDAR)腦炎患者的臨床特征。方法:收集北京協(xié)和醫(yī)院和北京天壇醫(yī)院2011年6月至2016年10月收治的21例卵巢畸胎瘤合并抗NMDAR腦炎患者的臨床資料,對其臨床表現(xiàn)、輔助檢查、治療及預(yù)后進行回顧性總結(jié)。結(jié)果:13例患者發(fā)病前有上呼吸道感染的前驅(qū)癥狀。臨床多表現(xiàn)為典型精神癥狀、癇性發(fā)作和不自主運動。19例患者血清和腦脊液抗NMDAR抗體均為陽性,1例僅腦脊液抗NMDAR抗體陽性,1例血清和腦脊液抗NMDAR抗體均為陰性。卵巢畸胎瘤平均直徑4cm,2例為雙側(cè)卵巢畸胎瘤,其余均為單側(cè);僅1例為未成熟畸胎瘤Ⅰ級,其余均為成熟畸胎瘤。經(jīng)過卵巢畸胎瘤切除及免疫治療,20例患者癥狀得到明顯緩解。隨訪期間3例患者出現(xiàn)精神癥狀復(fù)發(fā)或腫瘤復(fù)發(fā),無死亡病例。結(jié)論:卵巢畸胎瘤合并抗NMDAR腦炎常以神經(jīng)及精神癥狀起病,容易被誤診為精神心理疾病,病毒性腦炎,或癲癇等;手術(shù)切除卵巢畸胎瘤結(jié)合免疫治療多數(shù)預(yù)后良好。
[Abstract]:Part I study of miRNA expression profiles in ovarian hyaline cell carcinoma with malignant transformation of endometriosis: the purpose of this study was to use miRNA microarray gene chip technology (microarray) to treat endometriosis (hereinafter referred to as endometriosis) to ovarian clear cell carcinoma (ovarian clear cell carcinoma, OCCC) at all levels, including the pathological changes of endometriosis (microarray). The miRNA expression profiles of the intima, endometriosis, atypical endometriosis, atypical endometriosis, cancer, and the control group were compared, and the bioinformatics analysis was used to screen out the different miRNA and its possible target genes. The purpose was to find the biomarkers for the malignancy of the disease, and to further study the gene pathway and target therapy of the disease. Methods: microarray chip technology was used to study the miRNA expression profiles of 4 cases of ovarian hyaline cell carcinoma with malignant endometriosis and its control group. The enrichment analysis (GO-enrichment Analysis) of differential expression miRNA. for differentially expressed miRNA (GO-enrichment Analysis) and Pathway enrichment analysis (Pathway-enrichme) were screened. NT Analysis), miRNA and gene regulatory network (miRNA-Gene-Network), miRNA and pathway regulatory network (miRNA-pathway-Network) and other bioinformatics analysis, screening candidate miRNA. in 6 cases of verifying group pathological paraffin sections using real-time fluorescent quantitative PCR (RT-PCR) verification based on chip screening differential miRNA, in order to verify the chip expression profile Results: OCCC in endometriosis, endometriosis, atypical endometriosis and four stages of cancer, miR-199b-5p decreased from the eutopic endometrium to cancer, and the atypical endometriosis to cancer decreased significantly, and the expression of atypical endometriosis and cancer decreased significantly; the expression of miR-200a-3p and miR-200b-3p was bidirectional, with the eutopic endometrium as the control, and in the endometriosis and not A decrease in typical endometriosis and a rise in the cancer tissue. OCCC, a malignant transformation of endometriosis, conforms to ovarian cancer associated with endometriosis, but the OCCC in non endometriosis and OCCC three that are not associated with endometriosis, the latter two groups are similar in the expression of miR-20a-5p, 93-5p, 203A and 328, all lower than those in the experimental group. MiR-199b-5p, miR-200a-3p, miR-200b-3p, miR-20a-5p, miR-20b-5p, miR-106a-5p, miR-93-5p, miR-203a, and miR-328 may be the key miRNA. second part of the study of the clinicopathological features and prognostic analysis of ovarian clear cell carcinoma: ovarian clear cell carcinoma is closely associated with endometriosis. This study aims to study ovarian permeability. The clinicopathological features of the cancer of the clear cell and the possible prognostic factors of endometriosis. Methods: a retrospective analysis of the medical records and pathological data of ovarian clear cell carcinoma patients in Peking Union Medical College Hospital from 2000 to 2016. Results: 264 patients with ovarian clear cell carcinoma were admitted to 84 (31.8%) names. Endometriosis associated ovarian cancer (EAOC) was associated with endometriosis. The EAOC group was divided into two subgroups according to the Sampson and Scott standards. The onset age of the group (n=42,50%) and the non malignant group (n=42,50%).EAOC group was smaller, more before the menopause, more in the asymptomatic pelvic masses, and in the early (I, II) disease. More patients with adenomyosis, more likely to achieve satisfactory tumor cell reduction, more abdominal distention in the control group without endometriosis, more amalgamated ascites, LVSI positive, a higher recurrence rate, and higher mortality; the relapse rate and mortality rate in the two subgroups of EAOC were higher, and the other indexes were not statistically different. In the variable survival analysis, the disease was related to both OS and DFS. Multivariate analysis was not an independent prognostic factor. Multivariate survival analysis showed that the independent prognostic factors of OS and DFS were consistent with FIGO staging, residual tumor and LVSI. conclusion: ovarian clear cell carcinoma with endometriosis had its unique clinicopathological features, independent prognosis of OS and DFS. All factors are FIGO staging, residual tumor and LVSI, and endometriosis is not an independent prognostic factor for OS or DFS. Third ovarian teratoma combined with anti N- methyl -D- aspartic receptor encephalitis Objective: To summarize the clinical characteristics of ovarian teratoma with anti N- methyl D- aspartic acid receptor (NMDAR) encephalitis patients. Methods: collect Beijing The clinical data of 21 cases of ovarian teratoma with anti NMDAR encephalitis treated from June 2011 to October 2016 in Union Hospital and Beijing Tiantan Hospital were reviewed. The clinical manifestations, auxiliary examination, treatment and prognosis were reviewed. Results: 13 patients had premonitory symptoms of upper respiratory tract infection. The clinical manifestations were typical mental symptoms. Both serum and cerebrospinal fluid anti NMDAR antibody were positive in.19 patients with epileptic seizures and involuntary movement, 1 cases of cerebrospinal fluid anti NMDAR antibody positive, 1 cases of serum and cerebrospinal fluid anti NMDAR antibody negative. The average diameter of ovarian teratoma was 4cm, 2 cases were bilateral ovarian teratoma and the rest were unilateral; only 1 cases were immature teratoma grade I, the rest were all For the mature teratoma. After the resection of ovarian teratoma and immunotherapy, the symptoms of 20 patients were obviously relieved. During the follow-up period, 3 patients had recurrent mental symptoms or tumor recurrence and no death. Conclusion: ovarian teratoma combined with anti NMDAR encephalitis often occurs with neurological and mental symptoms and is easily misdiagnosed as psycho psychological disease and viral Encephalitis, or epilepsy, etc., surgical resection of ovarian teratoma combined with immunotherapy has a good prognosis.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R711.71;R737.31

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