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Patient Assessment and Therapy Planning Based on Homologous Recombination Repair Deficiency

Genomics, Proteomics & Bioinformatics 2023年第5期21卷 962-975页

作者： Wenbin Li Lin Gao Xin Yi Shuangfeng Shi Jie Huang Leming Shi Xiaoyan Zhou lingying wu Jianming Ying Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Geneplus–Shenzhen Shenzhen 518000China Institute of Microbiology Chinese Academy of SciencesBeijing 100101China Geneplus–Beijing Beijing 102206China National Institutes for Food and Drug Control Beijing 100050China State Key Laboratory of Genetic Engineering Human Phenome InstituteSchool of Life SciencesFudan UniversityShanghai 200438China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Defects in genes involved in the DNA damage response cause homologous recombination repair deficiency(HRD).HRD is found in a subgroup of cancer patients for several tumor types,and it has a clinical relevance to cancer prevention and therapies.Accumulating evidence has identified HRD as a biomarker for assessing the therapeutic response of tumor cells to poly(ADP-ribose)polymerase inhibitors and platinum-based chemotherapies.Nevertheless,the biology of HRD is complex,and its applications and the benefits of different HRD biomarker assays are controversial.This is primarily due to inconsistencies in HRD assessments and definitions(gene-level tests,genomic scars,mutational signatures,or a combination of these methods)and difficulties in assessing the contribution of each genomic event.Therefore,we aim to review the biological rationale and clinical evidence of HRD as a biomarker.This review provides a blueprint for the standardization and harmonization of HRD assessments.

关键词： DNA damage response Homologous recombination repair deficiency Poly(ADP-ribose)polymerase inhibitor Biomarker Harmonization

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外国文学经典之中国化研究范例——中国内地近十年弥尔顿三部曲研究述评(2013—2022)

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中南大学学报（社会科学版） 2024年第2期30卷 183-193页

作者：吴玲英李未雪中南大学外国语学院湖南长沙410083

自1832年弥尔顿进入中国至2012年,中国内地研究弥尔顿三部曲的论文与著作数目逾百,而近十年来(2013—2022)相关研究发展更为迅速:一是研究内容得到纵深性开拓,特别在弥尔顿多重思想之主题探微、恶魔与英雄之人物探讨、多元文化影响之风... 详细信息

自1832年弥尔顿进入中国至2012年,中国内地研究弥尔顿三部曲的论文与著作数目逾百,而近十年来(2013—2022)相关研究发展更为迅速:一是研究内容得到纵深性开拓,特别在弥尔顿多重思想之主题探微、恶魔与英雄之人物探讨、多元文化影响之风格探索等三个维度;二是研究方法取得开拓式创新,尤其是跨学科交叉探究方法和跨文化研究路径。通过将弥尔顿研究作为外国文学经典之中国化研究范例展开分析和探讨,并指出当下研究存在的拓进空间,希望能为中国内地未来的弥尔顿三部曲研究指明方向,或能为中国的外国文学经典研究提供一定的方法论指引。

关键词：约翰·弥尔顿弥尔顿三部曲外国文学经典之中国化研究中国内地共同体

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Nomograms based on HPV load for predicting survival in cervical squamous cell carcinoma: An observational study with a longterm follow-up

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Chinese Journal of Cancer Research 2019年第2期31卷 389-399页

作者： Jing Zuo Ying Huang Jusheng An Xi Yang Ning Li Manni Huang lingying wu Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Women's Health Integrated Research Center the Henry Jackson Foundation

Objective: To investigate the prognostic value of pretreatment human papillomavirus(HPV) viral load for cervical cancer, and to develop nomograms based on HPV load and other clinicopathological factors for long-term survival.Methods: We conducted a prospective study on cervical squamous cell carcinoma(SCC) patients diagnosed between January 2003 and December 2008. Cervical samples were tested for HPV viral load by the Hybrid Capture II(HCII) assay before treatment and 6 months after treatment. Clinical characteristics and follow-up information were also collected. A multivariable Cox proportional hazards model was used to adjust covariates in both the radical hysterectomy(RH) treatment group and concurrent chemoradiotherapy(CCRT) treatment group to identify relevant covariates, and then nomograms were constructed and used for internal validation.Results: A total of 520 SCC patients enrolled in this study with a median follow-up of 127 months, 360 patients received RH, whereas 160 patients received CCRT. The median HPV viral load in RH and CCRT groups was356.10 and 294.29, respectively. Tumor size was positively correlated with high pretreatment HPV load in both groups. In CCRT group, the advanced International Federation of Gynecology and Obstetrics(FIGO) stage and enlarged retroperitoneal lymph node status determined by computed tomography(LNSCT) were correlated with low HPV load group. Initial HPV viral load, FIGO stage and lymph node metastasis were prognostic factors for RH group, whereas HPV viral load, squamous cell carcinoma antigen(SCC-Ag) level and LNSCT were identified as prognostic factors for CCRT group. Nomograms incorporating these predictors for 10-year progression-free survival(PFS) were constructed [concordance index(C-index): 0.756, 0.749].Conclusions: A low pretreatment HPV viral load is an independent prognostic factor for poor prognosis of cervical SCC and is related to other clinicopathological factors. The survival nomogram based on HPV viral load could predict the long-term prognosis.

关键词： Cervical squamous cell carcinoma human papillomavirus viral load survival nomogram

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Prognostic evaluation of postoperative adjuvant therapy for operable cervical cancer:10 years'experience of National Cancer Center in China

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Chinese Journal of Cancer Research 2017年第6期29卷 510-520页

作者： Tong Shu Dan Zhao Bin Li Yating Wang Shuanghuan Liu Pingping Li Jing Zuo Ping Ba i RongZhang lingying wu Department of Gynecologic Oncology National Cancer Center/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Objective： The aim of this study was to investigate the prognostic factors and to evaluate the impact of adjuvant therapy on clinical outcome for early-stage cervical cancer. Methods： The clinical-pathological data of all 1,335 patients with the International Federation of Gynecology and Obstetrics （FIGO） Ib-[Ia cervical cancer treated with primary radical surgery at the Chinese National Cancer Center between May 2007 and Dec 2013 were retrospectively reviewed. The median follow-up was 70 months. Results： Of all the patients, 61.6% of the cases received adjuvant therapy, with 5-year disease-free survival （DFS） of 92.1% and 5-year overall survival （OS） of 95.0%. In multivariate analysis, differentiation of G3 （P〈0.05）, lymph node metastasis （LNM, P〈0.05） and lymphovascular space invasion （LVSI, P〈0.05） were independent predictors for OS, while LNM （P〈0.05）, deep stroma invasion （DSI, P〈0.05） and LVSI （P〈0.05） were independent factors for DFS. The samples were stratified by histologic type, and cervical squamous cell carcinoma （SCC） was found to share the same independent factors except for differentiation of OS. As to patients with cervical adenocarcinoma/adenosquamons carcinoma （AC/ASC）, differentiation was the independent predictor of OS （P〈0.05）; and LVSI of DFS （P〈0.05）. Of 236 patients with high-risk factors, there was no significant difference in survival between concurrent chemoradiotherapy （CCRT, n=195）, radiotherapy （RT, n=24）, and chemotherapy （CT, n=17）. Among the 190 patients with LNM who underwent CCRT, 124 cases showed improved DFS after sequential CT （P=0.118）, with a recurrence rate decrease of 14%, though the difference was not statistically significant. Patients with single intermediate-risk factors like DSI or LVSI were found to partially benefit from adjuvant therapy, but the difference was not statistically significant. Conclusions： LNM, LVSI, DSI and differentiation were found to be independent prognostic factors for operable cervical cancer. Aggressive postoperative adjuvant therapy based on

关键词： Cervical neoplasm adjuvant therapy prognostic factors DFS OS

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A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors

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Signal Transduction and Targeted Therapy 2023年第6期8卷 3070-3086页

作者： Chao Zhang Qiang Guo Lifeng Chen Zheming wu Xiao-Jian Yan Chengyang Zou Qiuxue Zhang Jiahong Tan Tian Fang Qunxian Rao Yang Li Shizhen Shen Min Deng Liewei Wang Huanyao Gao Jia Yu Hu Li Cheng Zhang Somaira Nowsheen Jake Kloeber Fei Zhao Ping Yin Chunbo Teng Zhongqiu Lin Kun Song Shuzhong Yao Liangqing Yao lingying wu Yong Zhang Xiaodong Cheng Qinglei Gao Jian Yuan Zhenkun Lou Jin-San Zhang Beijing Institute of Basic Medical Sciences 100850BeijingChina Department of Oncology Mayo ClinicRochesterMN55905USA School of Pharmaceutical Sciences Wenzhou Medical University325035WenzhouZhejiangChina Key Laboratory of Endocrine Gland Diseases of Zhejiang Province Zhejiang Provincial People’s Hospital310014HangzhouZhejiangChina Department of Gynecology Zhejiang Provincial People’s Hospital310014HangzhouZhejiangChina Department of Gynecology the First Affiliated Hospital of Wenzhou Medical University325000WenzhouZhejiangChina wuhan Kingwise Biotechnology Co. Ltd.430206WuhanHubeiChina Cancer Biology Research Center(Key Laboratory of the Ministry of Education) Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology430030WuhanHubeiChina Department of Gynecological Oncology Sun Yat-sen Memorial HospitalSun Yat-sen University510120GuangzhouGuangdongChina Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Reproductive Health Research 310006HangzhouZhejiangChina Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases 310006HangzhouZhejiangChina Department of Molecular Pharmacology and Experimental Therapeutics Mayo ClinicRochesterMN55905USA Department of Dermatology University of California San DiegoSan DiegoCA92122USA Key Laboratory of Saline-alkali Vegetation Ecology Restoration Ministry of EducationCollege of Life ScienceNortheast Forestry University150040HarbinChina Division of Gynecology Oncology Department of Obstetrics and GynecologyQilu HospitalShandong University250012JinanShandongChina Department of Obstetrics and Gynecology the First Affiliated HospitalSun Yat-Sen University510080GuangzhouGuangdongChina Department of Gynecologic Oncology Obstetrics and Gynecology Hospital of Fudan University200090ShanghaiChina Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of

Poly(ADP-ribose)polymerase(PARP)inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination(HR)deficiency.However,many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin.The biomarker responsible for this mechanism remains unclear.Here,we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients.PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage(ATM)signaling-induced pro-apoptotic ribosomal stress,which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage.Therefore,the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin.The gene panel as an independent biomarker was validated by multiple published clinical datasets,as well as by an ovarian cancer organoids library we established.More importantly,its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data.Furthermore,we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines.These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance.Together,our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

关键词： drugs BRCA panel

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从《失乐园》看弥尔顿的早期生态女性主义观

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外语与翻译 2024年第1期31卷 88-93页

作者：吴玲英李未雪中南大学

面对十七世纪女性意识觉醒与生态破坏两大剧变,约翰·弥尔顿省思这些挑战并在其史诗《失乐园》中,将相关思想融入对夏娃与自然的刻画。本文揭示弥尔顿的观点,包括承认女性与自然之相似性、尊重存在物之差异性并构建地球共同体。其观点... 详细信息

面对十七世纪女性意识觉醒与生态破坏两大剧变,约翰·弥尔顿省思这些挑战并在其史诗《失乐园》中,将相关思想融入对夏娃与自然的刻画。本文揭示弥尔顿的观点,包括承认女性与自然之相似性、尊重存在物之差异性并构建地球共同体。其观点具有革命性与前瞻性,本质上可界定为“早期生态女性主义观点”,因而对后来的生态女性主义思想有先驱性贡献。本研究不仅有助于读者理解英国早期现代的社会剧变,亦揭示弥尔顿的早期生态女性主义观对当代社会的重要启示。

关键词：约翰·弥尔顿《失乐园》早期生态女性主义观共同体

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闭关止渴汤加味治疗2型糖尿病酮症酸中毒(阴虚热盛证)的临床观察

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中国中医急症 2024年第1期33卷 82-84页

作者：但玲英孙霞吴静浙江中医药大学附属丽水中医院浙江丽水323020

目的观察闭关止渴汤加味对2型糖尿病酮症酸中毒(DKA)(阴虚热盛证)患者的疗效。方法将104例2型DKA阴虚热盛证患者随机分为观察组与对照组各52例。两组均予常规治疗措施,对照组予胰岛素和补液,观察组在对照组基础上给予闭关止渴汤加味... 详细信息

目的观察闭关止渴汤加味对2型糖尿病酮症酸中毒(DKA)(阴虚热盛证)患者的疗效。方法将104例2型DKA阴虚热盛证患者随机分为观察组与对照组各52例。两组均予常规治疗措施,对照组予胰岛素和补液,观察组在对照组基础上给予闭关止渴汤加味治疗。两组连续观察1周。比较两组2型DKA常规指标和酸中毒指标改善情况、治疗效果、氧化应激反应。结果观察组血糖复常、酮体消失、酸中毒纠正的时间均短于对照组(P<0.05);治疗1周后,两组氢离子浓度指数(p H值)、二氧化碳结合力(CO_(2)CP)显著升高,血乳酸、β-羟丁酸(β-HB)明显减少,并且观察组上述指标改善更优(P<0.05);治疗1周后,观察组病例总有效率为96.15%,明显高于对照组的80.77%(P<0.05);治疗1周后,两组病例血清超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、总抗氧化能力(TAC)水平显著升高,并且观察组升高更显著(P<0.05)。结论闭关止渴汤加味对2型DKA(阴虚热盛证)患者的疗效显著,可促进病情好转,纠正酸中毒,以及减轻氧化应激损伤。

关键词：糖尿病酮症酸中毒闭关止渴汤阴虚热盛证氧化应激

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Primary Malignant Amelanotic Melanoma in the Female Genital Tract:A Report of Six Cases and a Review of the Literature

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Chinese Journal of Clinical Oncology 2008年第5期5卷 383-386页

作者： Jusheng An lingying wu Bin Li Haizhen Lu Ning Li Shaokang Ma Department of Gynecological Oncology Cancer Hospital Peking Union Medical College Beijing 100021 China Department of Pathology Cancer Hospital Peking Union Medical College Beijing 100021 China

OBJECTIVE To analyze the clinical characteristics,pathologic diagnosis,treatment and prognosis of amelanotic melanoma in the female genital tract(AMFGT).METHODS The medical records of 6 patients with AMFGT between 1991 and 2006 in our hospital were reviewed.RESULTS Of these cases,4 were preliminarily misdiagnosed as chorioepithelioma,sarcoma,adenocarcinoma or lymphoma.Two patients were determined to have AMFGT preoperatively after positive immunohistochemical staining for both S-100 protein and HMB-45.Specimens removed from all 6 cases were tested for immunohistochemical staining,as well as H&E histochemical stains.S-100 and vimentin were both positive in all patients,and HMB-45 was positive in 3 out of 5 patients.Four patients recurred(at 6,6,12 and 19 months) a er primary treatments.Three patients died(at 13,18 and 19 months) a er the initial diagnosis.CONCLUSION Because of an absence of pigmentation AMFGT is extremely difficult to diagnose.Combined immunohistochemical staining,such as the S-100 protein,HMB-45 and vimentin etc,is important in the evaluation of AMFGT.Correct diagnosis plays a crucial role in the treatment of this disease.

关键词：黑素瘤女性生殖道诊断临床分析

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Down-Modulation of Notch1 Expression in Cervical Cancer Is Associated with HPV-Induced Carcinogenesis

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Clinical oncology and cancer resexreh 2009年第6期6卷 401-405页

作者： Li Sun Yongmei Song Tong Tong lingying wu Wenhua Zhang Qimin Zhan Department of Gynecological Oncology Cancer Hospital and Institute State Key Laboratory of Molecular Oncology Cancer Hospital and Institute Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 China

OBJECTIVE Notch1 signaling has been implicated intumorigenesis. The purpose of this study was to investigate theputative role of the Notch1 receptor in carcinogenesis and in theprogression of the cervical cancer. Since human papillomavirus(HPV) is a causative agent in cervical carcinoma, the interactionbetween Notch1 and HPV infection was examined.METHODS Forty cervical cancer samples and 30 normalcervical tissue specimens were examined using Western blot andRT-PCR to detect Notch1 protein and mRNA levels. HPV16 DNAwas examined in all samples using PCR.RESULTS The level of Notch1 protein expression wassignificantly lower in cervical cancer tissue than in normal tissue.Levels of Notch1 mRNA were found to be substantially downregulatedin cancer tissue. Notch1 protein expression levelswere significantly higher in carcinomas without HPV DNAthan that in carcinomas with HPV infection (55.5% vs. 3.3%, P <0.05). Down-modulation of Notch1 mRNA levels in carcinomawas demonstrated to be associated with HPVE6 transcription.Moreover, levels of Notch1 expression were shown to besignificantly higher in early stage disease than in advanced stagedisease (P = 0.001).CONCLUSION Down-modulation of Notch1 expressionprobably plays an important role in the late stages of HPVinducedcervical cancer.

关键词：人乳头瘤病毒16型子宫颈癌癌变诱发调制 mRNA水平乳头状瘤病毒 PCR检测

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Papillary serous carcinoma of the uterine cervix:a clinicopathological analysis of 4 cases and a literature review

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Oncology and Translational Medicine 2017年第5期3卷 197-202页

作者： Li Ge Hongwen Yao Rong Zhang Xiaoguang Li lingying wu Department of Gynecologic Oncology National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021 China

Objective To investigate the clinicopathological characteristics and clinical treatment outcomes of patients with papillary serous carcinoma of the uterine cervix(PSCC).Methods In this study, 4 patients with histologically confirmed papillary serous carcinoma of the uterine cervix were retrospectively investigated. Pap smears, human papillomavirus(HPV) screening, tumor marker status, biopsy analysis, and relevant imaging examinations were conducted for the confirmation of primary diagnosis and recurrence. Patients underwent surgery, chemotherapy, or radiotherapy, and survival were the main endpoint.Results The 4 patients were diagnosed with IB1, IB1, IIA, or IIIB disease. Two patients(2/4) presented with recurrence within 18 months after primary therapy. Compared with chemotherapy alone(progressionfree survival(PFS): 11 months), radiotherapy combined with adjuvant chemotherapy showed favorable PFS rates(PFS: 20, 36, 13 months in 3 cases), although valid statistical analysis was not feasible because of the small sample size. The 5-year survival rate was 0%, and the 3-year survival rate was 75%. Our data, in agreement with the literature evidence, showed that the number of moderate-risk and high-risk factors in patients diagnosed with PSCC at an early stage was higher than that in patients diagnosed with common adenocarcinoma/squamous carcinoma of the uterine cervix.Conclusion PSCC has a poor clinical prognosis, and compared with chemotherapy alone, radiotherapy combined with adjuvant chemotherapy may lead to improved PFS.

关键词： papillary serous carcinoma of uterine cervix (PSCC) clinicopathological features prognosis analysis

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