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Curcumin Inhibits Viability of Clear Cell Renal Cell Carcinoma by Down-Regulating ADAMTS18 Gene Methylation through NF-κB and AKT Signaling Pathway

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Chinese Journal of Integrative Medicine 2022年第5期28卷 419-424页

作者： XU Ben PENG Yi-ji ZHU Wei-jie Department of Urology Peking University First Hospital and Institute of UrologyPeking UniversityNational Urological Cancer CenterBeijing(100034)China

Objective:To investigate the effect of curcumin on viability of clear cell renal cell carcinoma(cc RCC)and analyze its possible mechanism.Methods:In cell lines of A498 and 786-O,the effects of curcumin(1.25,2.5,5 and 10μmol/L)on the viability of cc RCC were analyzed at 24,48 and 72 h by MTT assay.The protein expression levels of ADAMTS18 gene,p65,phosphorylation p65(pp65),AKT,phosphorylation AKT(p AKT)and matrix metallopeptidase 2(MMP-2)before and after curcumin(10μmol/L)treatment were examined by Western blotting.Real-time PCR and methylation specific PCR(MSP)were applied to analyze the expression and methylation level of ADAMTS18 gene before and after curcumin treatment(10μmol/L).Results:Curcumin significantly inhibited the viability of A498 and 786-O cell lines in a dose-and time-dependent manner(P<0.01).Up-regulation of ADAMTS18 gene expression with down-regulation of ADAMTS18 gene methylation was reflected after curcumin treatment,accompanied by down-regulation of nuclear factorκB(NF-κk B)related protein(p65 and pp65),AKT related protein(AKT and p AKT),and NF-κB/AKT common related protein MMP-2.With ADAMTS18 gene overexpressed,the expression levels of p65,AKT and MMP2 were downregulated,of which were conversely up-regulated in silenced ADAMTS18(sh-ADAMTS18).The expression of pp65,p AKT and MMP2 in sh-ADAMTS18 was down-regulated after being treated with PDTC(NF-κB inhibitor)and LY294002(AKT inhibitor).Conclusion:Curcumin could inhibit the viability of cc RCC by down-regulating ADAMTS18 gene methylation though NF-κB and AKT signaling pathway.

关键词： curcumin clear cell renal cell carcinoma ADAMTS18 gene methylation signaling pathway

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Robotic urologic surgery using the KangDuo-Surgical Robot-01 system:A single-center prospective analysis

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Chinese Medical Journal 2023年第24期136卷 2960-2966页

作者： Shengwei Xiong Shubo Fan Silu Chen Xiang Wang Guanpeng Han Zhihua Li Wei Zuo Zhenyu Li Kunlin Yang Zhongyuan Zhang Cheng Shen Liqun Zhou Xuesong Li Department of Urology Peking University First HospitalBeijing 100034China Institute of Urology Peking UniversityBeijing 100034China National Urological Cancer Center Beijing 100034China

Background:The KangDuo-Surgical Robot-01(KD-SR-01)system is a new surgical robot recently developed in China.The aim of this study was to present our single-center experience and mid-term outcomes of urological procedures using the KD-SR-01 system.Methods:From August 2020 to April 2023,consecutive urologic procedures were performed at Peking University First Hospital using the KD-SR-01 system.The clinical features,perioperative data,and follow-up outcomes were prospectively collected and analyzed.Results:A total of 110 consecutive patients were recruited.Among these patients,28 underwent partial nephrectomy(PN),41 underwent urinary tract reconstruction(26 underwent pyeloplasty,3 underwent ureteral reconstruction and 12 underwent ureterovesical reimplantation[UR]),and 41 underwent radical prostatectomy(RP).The median operative time for PN was 112.5 min,157.0 min for pyeloplasty,151.0 min for ureteral reconstruction,142.5 min for UR,and 138.0 min for RP.The median intraoperative blood loss was 10 mL for PN,10 mL for pyeloplasty,30 mL for ureteral reconstruction,20 mL for UR,and 50 mL for RP.All procedures were successfully completed without conversion,and there were no major complications in any patient.The median warm ischemia time of PN was 17.3 min,and positive surgical margin was not noted in any patient.The overall positive surgical margin rate of RP was 39%(16/41),and no biochemical recurrence was observed in any RP patient during the median follow-up of 11.0 months.The surgical success rates of pyeloplasty and UR were 96%(25/26)and 92%(11/12)during the median follow-up of 29.5 months and 11.5 months,respectively.Conclusion:The KD-SR-01 system appears feasible,safe,and effective for most urological procedures,based on our single-center experience.

关键词： Robotics KangDuo-Surgical Robot-01 Partial nephrectomy Urinary tract reconstruction Radical prostatectomy

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The evolution of cancer genomic medicine in Japan and the role of the national cancer center Japan

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cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno Department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan Department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan Department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan national cancer center Research Institute Tokyo 104-0045Japan Department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the national cancer center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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Palliative chemotherapy for gastroesophageal cancer in old and very old patients: A retrospective cohort study at the national center for Tumor Diseases, Heidelberg

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World Journal of Gastroenterology 2015年第16期21卷 4911-4918页

作者： Anne Katrin Berger Stefanie Zschaebitz Christine Komander Dirk Jger Georg Martin Haag national center for Tumor Diseases Heidelberg University Hospital NCT Clinical cancer Registry German Cancer Research Center

AIM:To investigate the outcome of palliative chemotherapy in old patients with gastroesophageal cancer at the national center for Tumor Diseases,Heidelberg.METHODS:Using a prospectively generated database,we retrospectively analyzed 55 patients≥70years under palliative chemotherapy for advanced gastroesophageal cancer at the outpatient clinic of the national center for Tumor Diseases Heidelberg,Germany between January 2006 and December2013.Further requirements for inclusion were(1)histologically proven diagnosis of gastroesophageal cancer;(2)advanced(metastatic or inoperable)disease;and(3)no history of radiation or radiochemotherapy.The clinical information included Eastern Cooperative Oncology Group performance status(ECOG PS),presence and site of metastases at diagnosis,date of previous surgery and perioperative chemotherapy,start and stop date of first-line treatment,toxicities and consecutive dosage reductions of first-line treatment,response to first-line therapy,date of progression,usage of second-line therapies and date and cause of death.Survival times[progression-free survival(PFS),overall survival(OS)and residual survival(RS)]were calculated.Toxicity and safety were examined.Prognostic factors including ECOG PS,age and previousperioperative treatment were analyzed.RESULTS:Median age of our cohort was 76 years.86%of patients received a combination of two cytotoxic drugs.76 percent of patients had an oxaliplatin-based first-line therapy with the oxaliplatin and 5-fluorouracil regimen being the predominantely chosen regimen(69%).Drug modifications due to toxicity were necessary in 56%of patients,and 11%of patients stopped treatment due to toxicities.Survival times of our cohort are in good accordance with the major phaseⅢtrials that included mostly younger patients:PFS and OS were 5.8 and 9.5 mo,respectively.Survival differed significantly between patient groups with low(≤1)and high(≥2)ECOG PS(12.7 mo vs 3.8 mo,P<0.001).Very old patients(≥75 years)did not show a worse outcome in terms of survival.Patients

关键词： Gastroesophageal cancer Old patients Palliative chemotherapy Toxicity Eastern CooperativeOncology Group performance status

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The application of internal suspension technique in retroperitoneal robot-assisted laparoscopic partial nephrectomy with a new robotic system KangDuo Surgical Robot-01:Initial experience

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Asian Journal of Urology 2023年第4期10卷 482-487页

作者： Silu Chen Shubo Fan Hua Guan Kunlin Yang Zhihua Li Shengwei Xiong Xiang Wang Zhenyu Li Cheng Shen Liqun Zhou Xuesong Li Department of Urology Peking University First HospitalInstitute of UrologyPeking UniversityNational Urological Cancer CenterXicheng DistrictBeijingChina

Objective To assess the feasibility of internal suspension technique in retroperitoneal robot-assisted laparoscopic partial nephrectomy(rRAPN)with a new robotic platform called KangDuo Surgical Robot-01(KD-SR-01)system(Suzhou KangDuo Robot Co.,Ltd.,Suzhou,China)and discuss its surgical technique.Methods A 44-year-old male patient was admitted with a 2.5 cm tumor on dorsolateral upper pole of the left kidney.The R.E.N.A.L.nephrometry score of this patient was 4x.This patient underwent rRAPN with KD-SR-01.The perinephric fat between the tumor and Gerota's fascia was preserved,which was used for internal suspension traction during tumor resection.Postoperative follow-up data were collected.Results The surgery was successfully carried out with a duration of 127 min,in which the docking time was 6 min 25 s and console time was 60 min.The warm ischemia time was 19 min 53 s,and the estimated blood loss was 0 mL.The pathological histology showed a pathological tumor stage 1a clear cell renal cell carcinoma,with a negative surgical margin.The World Health Organization/International Society of urological Pathology(WHO/ISUP)grade of this patient was Grade 2.No recurrence was observed during the 6-month follow-up.Conclusion Internal suspension in rRAPN is feasible and effective with use of the new robotic system KD-SR-01.

关键词： KangDuo Surgical Robot-01 Internal suspension Partial nephrectomy Retroperitoneal approach

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Mission of the national cancer center Hospital in Japan to promote clinical trials for precision medicine

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cancer Biology & Medicine 2024年第1期21卷 1-3页

作者： Kazuaki Shimada Kenichi Nakamura Noboru Yamamoto Department of Hepatobiliary and Pancreatic Surgery National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce National Cancer Center HospitalTokyo 104-0045Japan Department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan

Precision medicine is a growing field worldwide.Despite its potential benefit to many patients,several major obstacles must be overcome before precision medicine can be more widely used in clinical practice.The main o... 详细信息

关键词： clinical cancer overcome

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A preliminary study on rectal dose reduction associated with hyaluronic acid implantation in brachytherapy for prostate cancer

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Asian Journal of Urology 2024年第2期11卷 286-293页

作者： Tairo Kashihara Yuka Urago Hiroyuki Okamoto Mihiro Takemori Hiroki Nakayama Shohei Mikasa Tetsu Nakaichi Kotaro Iijima Takahito Chiba Junichi Kuwahara Satoshi Nakamura Weishan Chang Yoshiyuki Matsui Hiroshi Igaki Department of Radiation Oncology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Radiation Safety and Quality Assurance Division National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Department of Radiological Sciences Graduate School of Human Health SciencesTokyo Metropolitan University7-2-10 Higashi-OguArakawa-kuTokyoJapan Department of Radiological Technology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan Department of urological Oncology National Cancer Center Hospital5-1-1 TsukijiChuo-kuTokyoJapan

Objectives: Hydrogel spacer (HS) was developed to reduce rectal toxicities caused by radiotherapy, but has been reported to cause major adverse events. Our institute has attempted to introduce a hyaluronic acid (HA) as an alternative spacer. This study aimed to compare rectal doses and geometric distributions between the HS and HA implantation in prostate cancer.Methods: HS and HA were inserted in 20 and 18 patients undergoing high-dose brachytherapy, respectively. The rectum spacer volumes injected were 10 mL and 22 mL, respectively. In the treatment planning system, 13.5 Gy was administered with common catheter positions. The rectal dose indices were assessed between the spacer groups for dosimetry evaluation. Distances between the prostate and rectum and configurations of the spacers were compared.Results: The mean doses irradiated to 0.1 and 2 mL of the rectum were 10.45 Gy and 6.71 Gy for HS, and 6.73 Gy and 4.90 Gy for HA (p<0.001). The mean minimum distances between the prostate and rectum were 1.23 cm and 1.79 cm for HS and HA, respectively (p<0.05). Geometrical configuration comparisons revealed that HA has a higher ability to expand the space than HS.Conclusion: The rectal dose reduction ability of HA is significantly greater than that of HS, suggesting its potential as a new spacer.

关键词： Brachytherapy Hyaluronicacid Hydrogel Prostaticneoplasm Radiotherapy

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Curcumin Interferes with TGF-β1-Induced Fibrosis in NRK-49F Cells by Reversing ADAMTS18 Gene Methylation

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Chinese Journal of Integrative Medicine 2024年第7期 600-607页

作者： XU Ben ZHANG Jia-en YE Lin YUAN Chang-wei Department of Urology Peking University First Hospital and Institute of Urology National Urological Cancer Center

Objective: To explore the molecular mechanism by which curcumin affects renal interstitial fibrosis(RIF) progression by regulating ADAM metallopeptidase with thrombospondin type 1 motif 18(ADAMTS18) methylation. Methods: NRK-49F cells RIF model were induced with transforming growth factor β1(TGF-β1). Effects of different concentrations of curcumin(0, 10, 20, and 30 μmol/L) on cell proliferation, cell cycle, cell apoptosis as well as cyclin D1 expression were analyzed by cell counting kit-8, flow cytometry and Western blot, respectively. ADAMTS18 methylation levels were determined by methylation-specific polymerase chain reaction. ADAMTS18, fibronectin(FN), type Ⅰ collagen(Col-Ⅰ) and alpha-smooth muscle actin(α-SMA) mRNA and protein expressions were analyzed by real-time PCR(RT-PCR) and Western blot, respectively. Meanwhile, cells were treated with 50 mmol/L 5-aza-2’-deoxycytidine(5-aza-dC, demethylation agent) for 72 h. Effect of curcumin on extracellular matrix(ECM) deposition was evaluated by immunochemical staining and Western blot. NRK-49F cells were transfected with ADAMTS18 small interfering RNA and grouped into a normal control, ADAMTS18-knock-out(KO), and ADAMTS18-KO+ 30 μmol/L curcumin groups, and whether curcumin can reverse the effect of ADAMTS18 knockdown on RIF was evaluated. Results: Compared with the control group, TGF-β1 significantly inhibited the proliferation of NRK-49F cells, blocked the G1/G0phase, promoted cell apoptosis and inhibited cyclin D1 expression(P<0.01). Among the different concentrations of curcumin, 30 μmol/L curcumin significantly reversed these processes(P<0.01). Immunochemical staining and Western blot results showed that curcumin significantly inhibited the deposition of FN, Col-Ⅰ and α-SMA(P<0.01). Curcumin and 5-zaz-dC had synergistic effects, promoting ADAMTS18 expression, removing ADAMTS18 methylation, and reducing ECM deposition. ADAMTS18 knockdown promoted ECM accumulation, and curcumin reversed this process(P<0.01). Conclusion: TGF-β1 induced fibrosis in NRK-49F cells.

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Validation of the Pretreatment Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor in a Large Cohort of Chinese Patients with Upper Tract Urothelial Carcinoma

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Chinese Medical Journal 2017年第17期130卷 2063-2068页

作者： Zhen-Peng Cao Bao Guan Guang-Zhi Zhao Dong Fang Geng-Yan Xiong Xue-Song Li Li-Qun Zhou Department of Urology Peking University First Hospital Institute of Urology Peking University National Urological Cancer Centre Beijing 100034 China

Background：The pretreatment neutrophil-to-lymphocyte ratio （NLR） has been reported to be a prognostic factor in various types of carcinomas.The aim of this study was to investigate the prognostic value of pretreatment NLR in a large cohort of Chinese patients with upper tract urothelial carcinoma （UTUC）.Methods：We retrospectively analyzed the medical data of 656 UTUC patients who underwent radical nephroureterectomy （RNU） from 2001 to 2011 at Peking University First Hospital.Receiver operating characteristic （ROC） curve analysis was performed to calculate the optimal cutoffpoint of pretreatment NLR.Uni-and multi-variate analyses were used to identify the prognostic factors for cancer-specific survival （CSS） and intravesical recurrence-free survival （IVRFS）.Results：The optimal cutoff point of pretreatment NLR was 2.40 by ROC curves,by which patients with high NLR （NLR 〉2.40） and low NLR （NLR 〈2.40） accounted for 314 （47.9%） and 342 （52.1%） patients,respectively.Patients with a high pretreatment NLR tended to have high tumor grades （x2 =15.725,P〈 0.001）,high tumor stages （x2 =25.416,P〈 0.001）,tumor sizes 〉5 cm （x2 =8.213,P=0.005）,ipsilateral hydronephrosis （x2 =4.624,P =0.033）,and concomitant carcinoma in situ （CIS）（x2 =9.517,P =0.003）.A high pretreatment NLR （hazard ratio [HR] =1.820,P=0.001）,main tumor diameter 〉5 cm （HR =1.789,P =0.009）,lymph node metastasis （HR =1.863,P =0.024）,and high tumor stage （HR =1.745,P 〈 0.001） independently predicted poor CSS after surgery,while only concomitant carcinoma in situ （CIS）（HR =2.164,P =0.034）,ureteroscopy before surgery （HR =1.701,P =0.015）,and high tumor grade （HR =1.645,P =0.018） were independent predictors of IVRFS after RNU.Conclusions：The pretreatment NLR was related to some adverse clinicopathological features and was an independent predictor of CSS,although not IVRFS,in Chinese UTUC patients.

关键词： Neutrophil-to-Lymphocyte Ratio Prognosis Upper Tract Urothelial Carcinoma

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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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