1.The expression and clinical significance of S100A9 protein in gastric cancer of intestinal type
Rongjian ZHOU ; Heng ZHANG ; Ping SHU ; Hongshan WANG ; Zhenbin SHEN ; Fenglin LIU ; Jing QIN
Chinese Journal of General Surgery 2019;34(1):53-57
Objective To investigate the expression and clinical significance of pro-inflammation S100A9 protein in intestinal type gastric cancer.Methods We retrospectively analyzed the clinicopathological materials of the 278 patients who were diagnosed as Lauren classification intestinal gastric cancer and underwent surgical treatment between January and December 2008 at the Department of General Surgery,Zhongshan Hospital Fudan University.Immunohistochemistry was used to analyze the expression of S100A9 protein in tumor tissues and para-tumor tissues.Results High expression of S100A9 protein was associated with the depth of tumor invasion (P =0.013),lymph node metastasis (81.4%,53.9%,47.3% vs.84.7%,69.3%,60.7%,x2 =4.220,P =0.041) and TNM stage (P =0.010).The overall survival rate of these patients with high expression of S100A9 protein was significantly lower than those with low expression of S100A9 protein.In stage Ⅲ/Ⅳ patients,the overall survival rate of these patients with high expression of S100A9 protein was significantly lower than those with low expression of S100A9 protein.Moreover,for those patients who received postoperative chemotherapy,the prognosis of the patients with high expression of S100A9 protein was poorer than those with low expression.By multivariable analysis,the expression of S100A9 protein was not an independent risk factor for the prognosis of intestinal gastric cancer patients.Conclusions High expression of S100A9 protein in intestinal gastric cancer was associated with poor prognosis.
2.Prognostic factors of radical gastrectomy for stage Ⅲ gastric cancer and predictive value of metastatic lymph node ratio for prognosis: a report of 995 cases
Rongjian ZHOU ; Heng ZHANG ; Ping SHU ; Hongshan WANG ; Zhenbin SHEN ; Fenglin LIU ; Jing QIN
Chinese Journal of Digestive Surgery 2019;18(3):250-258
Objective To investigate the prognostic factors of radical gastrectomy for stage Ⅲ gastric cancer and predictive value of metastatic lymph node ratio for prognosis.Methods The retrospective case-control study was conducted.The clinicopathological data of 995 patients with stage Ⅲ gastric cancer who were admitted to the Zhongshan Hospital of Fudan University between January 2003 and December 2014 were collected.There were 690 males and 305 females,aged from 20 to 75 years,with an average age of 61 years.After clinical staging according to results of preoperative accessory examinations,patients with early gastric cancer underwent D1+ lymphadenectomy,patients with advanced gastric cancer underwent D2 lymphadenectomy and patients with serosa invasion underwent D2+ lymphadenectomy.Observation indicators:(1) treatment situations;(2) follow-up and survival situations;(3) prognostic factors analysis after operation;(4) stratified analysis:① stratified analysis of tumor pathological N staging;② stratified analysis of number of lymph node dissected;③ stratified analysis of tumor pathological TNM staging;(5) receiver operating characteristic (ROC) curve.Patients were followed up using outpatient examination and telephone interview to detect postoperative survival up to January 2016.The overall survival time was from the operation data to last follow-up or time of death.Measurement data with normal distribution were represented as Mean±SD.The survival rate and curve were respectively calculated and drawn by the Kaplan-Meier method and Log-rank test was used for survival analysis.The COX proportional hazard model was used for univariate and multivariate analysis.The ROC curve and area under curve (AUC) were used to check the accuracy of number of positive lymph nodes and metastatic lymph node ratio for prognosis.Comparison of the AUC was analyzed by the Z test.Results (1) Treatment situations:of 995 patients underging gastrectomy,677 underwent distal gastrectomy,85 underwent proximal gastrectomy,233 underwent total gastrectomy.There were 117 undergoing D1+ lymphadenectomy and 878 undergoing D2 lymphadenectomy or D2+ lymphadenectomy.The number of lymph node dissected,number of positive lymph nodes,metastatic lymph node ratio were 27± 12,10± 9 and 0.41±0.28,respectively.(2) Follow-up and survival situations:995 patients were followed up for (35± 32)months.During the follow-up,the 1-,3-,5-year overall survival rates were 77.9%,47.8%,36.2%.(3) Prognostic factors analysis after operation:results of univariate analysis showed that sex,tumor histological type,vascular embolus,degree of tumor invasion,tumor pathological N staging,number of lymph node dissected,metastatic lymph node ratio,tumor pathological TNM staging were related factors affecting prognosis of radical gastrectomy for stage Ⅲ gasteric cancer (hazard ratio =0.817,1.486,1.268,2.173,1.957,1.737,3.357,2.169,95% confidence interval:0.686-0.973,1.059-2.086,1.074-1.497,1.195-3.954,1.480-2.588,1.390-2.170,2.476-4.602,1.740-2.704,P<0.05).Results of multivariate analysis showed that sex,tumor histological type,tumor pathological N staging,number of lymph node dissected,metastatic lymph node ratio,tumor pathological TNM staging were independent factors affecting prognosis of radical gastrectomy for stage Ⅲ gastric cancer (hazard ratio =0.805,1.476,0.237,1.475,3.811,3.600,95% confidence interval:0.673-0.963,1.049-2.087,0.083-0.678,1.140-1.909,2.259-6.428,1.317-9.839,P<0.05).(4) Stratified analysis:of the 995 patients,the postoperative l-,3-,5-year overall survival rates were 93.7%,69.6%,60.5% in the patients with metastatic lymph node ratio ≤ 0.1,86.9%,60.6%,44.3% in the patients with 0.1 < metastatic lymph node ratio ≤0.4 and 64.3%,28.9%,21.0% in the patients with metastatic lymph node ratio > 0.4,showing a statistically significant difference (x2 =121.300,P<0.05).There were statistically significant differences between patients with metastatic lymph node ratio ≤0.1 and patients with 0.1< metastatic lymph node ratio ≤0.4,between patients with metastatic lymph node ratio ≤0.1 and patients with metastatic lymph node ratio >0.4 (x2=7.580,65.320,P<0.05).There was a statistically significant difference between patients with 0.1 < metastatic lymph node ratio ≤0.4 and patients with metastatic lymph node ratio>0.4 (x2 =80.806,P<0.05).① Stratified analysis of tumor pathological N staging:the average metastatic lymph node ratio was 0.09 in the 132 stage N1 patients,who were divided into the patients with metastatic lymph node ratio ≤ 0.1 and > 0.1.The postoperative 1-,3-,5-year overall survival rates were 92.2%,68.6%,59.1% in the 108 patients with metastatic lymph node ratio ≤ 0.1 and 79.2%,32.8%,21.9% in the 24 patients with metastatic lymph node ratio >0.1,respectively,showing a statistically significant difference (x2 =14.499,P<0.05).The average metastatic lymph node ratio was 0.23 in the 265 stage N2 patients,who were divided into the patients with metastatic lymph node ratio ≤0.2 and >0.2.The postoperative 1-,3-,5-year overall survival rates were 92.3%,73.8%,61.0% in the 138 patients with metastatic lymph node ratio ≤0.2 and 76.5%,40.1%,22.2% in the 127 patients with metastatic lymph node ratio >0.2,respectively,showing a statistically significant difference (x2 =42.536,P<0.05).The average metastatic lymph node ratio was 0.56 in the 598 stage N3 patients,who were divided into the patients with metastatic lymph node ratio ≤0.4 and >0.4.The postoperative 1-,3-,5-year overall survival rates were 88.5%,62.8%,47.0% in the 194 patients with metastatic lymph node ratio ≤ 0.4 and 64.3%,29.8%,21.0% in the 404 patients with metastatic lymph node ratio >0.4,respectively,showing a statistically significant difference (x2 =51.860,P< 0.05).② Stratified analysis of number of lymph node dissected:7 of 117 patients with the number of lymph node dissected < 15 had metastatic lymph node ratio ≤0.1,who were divided into patients with metastatic lymph node ratio ≤0.4 and >0.4.The postoperative 1-,3-,5-year overall survival rates were 78.2%,40.0%,28.6% in the 44 patients with metastatic lymph node ratio ≤0.4 and 78.1%,18.7%,12.9% in the 73 patients with metastatic lymph node ratio>0.4,respectively,showing a statistically significant difference (x2 =4.727,P<0.05).③ Stratified analysis of tumor pathological TNM staging:of 262 patients with stage Ⅲa gastric cancer,the postoperative 1-,3-,5-year overall survival rates were 88.5%,65.0%,54.3% in the 230 patients with metastatic lymph node ratio ≤0.4 and 77.5%,35.4%,29.5% in the 32 patients with metastatic lymph node ratio >0.4,respectively,showing a statistically significant difference (x2 =6.132,P<0.05).Of 296 patients with stage Ⅲb gastric cancer,the postoperative 1-,3-,5-year overall survival rates were 84.4%,60.7%,42.7% in the 200 patients with metastatic lymph node ratio ≤ 0.4 and 59.9%,26.8%,21.7% in the 96 patients with metastatic lymph node ratio >0.4,respectively,showing a statistically significant difference (x2 =23.699,P<0.05).Of 437 patients with stage Ⅲ c gastric cancer,the postoperative 1-,3-,5-year overall survival rates were 84.7%,59.9%,38.7% in the 133 patients with metastatic lymph node ratio ≤0.4 and 64.0%,27.9%,18.3% in the 304 patients with metastatic lymph node ratio >0.4,respectively,showing a statistically significant difference (x2=36.215,P< 0.05).(5) ROC curve:ROC curves of postoperative overall survival rates in patients with stage Ⅲ gastric cancer were drawn using the number of positive lymph nodes and metastatic lymph node ratio,of which AUC were 0.619 (95% confidence interval:O.588-0.649) and 0.706 (95% confidence interval:0.677-0.734),showing a statistically significant difference (Z=8.842,P<0.05).Conclusions Sex,tumor histological type,tumor pathological N staging,number of lymph node dissected,metastatic lymph node ratio,tumor pathological TNM staging are independent factors affecting prognosis of radical gastrectomy for stage Ⅲ gastric cancer.There is different prognosis of patients with different metastatic lymph node ratios in the subgroup of the same tumor pathological TNM staging,number of lymph node dissected,tumor pathological TNM staging.Compared with tumor pathological N staging,metastatic lymph node ratio has a more accurate predictive value for prognosis.
3.Establishment of risk evaluation model of peritoneal metastasis in gastric cancer and its predictive value.
Junjie ZHAO ; Rongjian ZHOU ; Qi ZHANG ; Ping SHU ; Haojie LI ; Xuefei WANG ; Zhenbin SHEN ; Fenglin LIU ; Weidong CHEN ; Jing QIN ; Yihong SUN
Chinese Journal of Gastrointestinal Surgery 2017;20(1):47-52
OBJECTIVETo establish an evaluation model of peritoneal metastasis in gastric cancer, and to assess its clinical significance.
METHODSClinical and pathologic data of the consecutive cases of gastric cancer admitted between April 2015 and December 2015 in Department of General Surgery, Zhongshan Hospital of Fudan University were analyzed retrospectively. A total of 710 patients were enrolled in the study after 18 patients with other distant metastasis were excluded. The correlations between peritoneal metastasis and different factors were studied through univariate (Pearson's test or Fisher's exact test) and multivariate analyses (Binary Logistic regression). Independent predictable factors for peritoneal metastasis were combined to establish a risk evaluation model (nomogram). The nomogram was created with R software using the 'rms' package. In the nomogram, each factor had different scores, and every patient could have a total score by adding all the scores of each factor. A higher total score represented higher risk of peritoneal metastasis. Receiver operating characteristic (ROC) curve analysis was used to compare the sensitivity and specificity of the established nomogram. Delong. Delong. Clarke-Pearson test was used to compare the difference of the area under the curve (AUC). The cut-off value was determined by the AUC, when the ROC curve had the biggest AUC, the model had the best sensitivity and specificity.
RESULTSAmong 710 patients, 47 patients had peritoneal metastasis (6.6%), including 30 male (30/506, 5.9%) and 17 female (17/204, 8.3%); 31 were ≥ 60 years old (31/429, 7.2%); 38 had tumor ≥ 3 cm(38/461, 8.2%). Lauren classification indicated that 2 patients were intestinal type(2/245, 0.8%), 8 patients were mixed type(8/208, 3.8%), 11 patients were diffuse type(11/142, 7.7%), and others had no associated data. CA19-9 of 13 patients was ≥ 37 kU/L(13/61, 21.3%); CA125 of 11 patients was ≥ 35 kU/L(11/36, 30.6%); CA72-4 of 11 patients was ≥ 10 kU/L(11/39, 28.2%). Neutrophil/lymphocyte ratio (NLR) of 26 patients was ≥ 2.37(26/231, 11.3%). Multivariate analysis showed that Lauren classification (HR=8.95, 95%CI:1.32-60.59, P=0.025), CA125(HR=17.45, 95%CI:5.54-54.89, P=0.001), CA72-4(HR=20.06, 95%CI:5.05-79.68, P=0.001), and NLR (HR=4.16, 95%CI:1.17-14.75, P=0.032) were independent risk factors of peritoneal metastasis in gastric cancer. In the nomogram, the highest score was 241, including diffuse or mixed Lauren classification (54 score), CA125 ≥ 35 kU/L (66 score), CA72-4 ≥ 10 kU/L (100 score), and NLR ≥ 2.37 (21 score), which represented a highest risk of peritoneal metastasis (more than 90%). The AUC of nomogram was 0.912, which was superior than any single variable (AUC of Lauren classification: 0.678; AUC of CA125: 0.720; AUC of CA72-4: 0.792; AUC of NLR: 0.613, all P=0.000). The total score of nomogram increased according to the TNM stage, and was highest in the peritoneal metastasis group (F=49.1, P=0.000). When the cut-off value calculated by ROC analysis was set at 140, the model could best balanced the sensitivity (0.79) and the specificity (0.87). Only 5% of patients had peritoneal metastasis when their nomogram scores were lower than 140, while 58% of patients had peritoneal metastasis when their scores were ≥ 140(χ=69.1, P=0.000).
CONCLUSIONThe risk evaluation model established with Lauren classification, CA125, CA72-4 and NLR can effectively predict the risk of peritoneal metastasis in gastric cancer, and provide the reference to preoperative staging and choice of therapeutic strategy.
Antigens, Tumor-Associated, Carbohydrate ; blood ; Area Under Curve ; CA-125 Antigen ; blood ; CA-19-9 Antigen ; blood ; Female ; Humans ; Leukocyte Count ; statistics & numerical data ; Logistic Models ; Lymphocytes ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; diagnosis ; Neutrophils ; pathology ; Nomograms ; Peritoneal Neoplasms ; secondary ; Prognosis ; ROC Curve ; Retrospective Studies ; Risk Assessment ; methods ; Risk Factors ; Sensitivity and Specificity ; Stomach Neoplasms ; blood ; classification ; diagnosis ; pathology
4.Improving the repairing effect of thoracodorsal artery perforator flap through ultra-thin flap technology
Xiang XU ; Tao LI ; Zhenbin CHEN ; Wei LEI ; Pan ZHOU ; Wei JI
Chinese Journal of Microsurgery 2017;40(5):438-440
Objective To discuss the application of ultra-thin flap technology in the thoracodorsal artery per forator flap,and appraise the effectiveness in clinical practice.Methods From May,2013 to December,2015,10 patients with soft-tissue defects of the four limbs were treated with ultra-thin thoracodorsal artery perforator flap.The classification of the perforating vessels was done by Kimura method.The flap blood supply was measured and the patients' satisfaction of the appearance of flap was investigated through questionnaires.Results The flap of 8 cases (5 cases of type Ⅰ and 3 cases of type Ⅱ) could be evenly thinned,and the flap of 2 cases (type Ⅲ) could only be thinned at the edge beyond the part with perforator as the center and a radius of 3 centimeters.The flap of 9 cases completely lived.While in 1 case (type Ⅲ),a small part of the edge of the flap was necrosed(2 cm×1 cm),and coalesced well after change dressing.The donor site was sutured directly in 7 cases and covered with skin graft in 1 case.Eight patients were followed-up from 6 to 12 months.The treatment effect was satisfied.And there were no side effects on the functioning of donor sites.Seven patients were highly satisfied with the appearance of the flap (satisfaction rate was 87.5%).Conclusion Ultra-thin flap technology can be adopted to cut thin thoracodorsal artery perforator flap,and can remarkably improve the effect in clinical practice.
5.Practice guideline for patients with ankylosing spondylitis/spondyloarthritis
Ya XIE ; Kehu YANG ; Qing LYU ; Yi ZHENG ; Cibo HUANG ; Zhenbin LI ; Shengyun LIU ; Linkai FANG ; Xiaoqin WANG ; Yuqi ZHOU ; Biling LIANG ; Zhengang ZHA ; Bo JIANG ; Jie ZHOU ; Zhivko YANKOV ; Jieruo GU
Chinese Journal of Internal Medicine 2020;59(7):511-518
In recent years, the clinical experts consensuses or guidelines of ankylosing spondylitis (AS)/spondyloarthritis (SpA) have been constantly updated, but to better understand and practice, patient self-participation management is one of the key points to improve the level of diagnosis and treatment. Through questionnaire survey of these patients, we screened out the most concerned issues, and established the AS/SpA patient practice guideline working group with multidisciplinary physicians and patients. Fifteen opinions, as the AS/SpA patient practice guidelines, are proposed in accordance with the relevant principles of the "WHO guidelines development manual" , and with the international normative process.
6.A multicenter study of costs of drugs in rheumatoid arthritis in China
Xiuru WANG ; Yin SU ; Yuan AN ; Yunshan ZHOU ; Lizhi WANG ; Caihong WANG ; Xiaofeng LI ; Lina CHEN ; Ping ZHU ; Xin LU ; Guochun WANG ; Hongtao JIN ; Rong YANG ; Yongfu WANG ; Guangtao LI ; Zhuoli ZHANG ; Lin SUN ; Xiangyuan LIU ; Jiemei TAO ; Fengxiao ZHANG ; Jing YANG ; Zhenbin LI ; Meiqiu WEI ; Jinying LIN ; Rong SHU ; Liufu CUI ; Dan KE ; Xiaomin LIU ; Cong YE ; Shaoxian HU ; Hao LI ; Xiuyan YANG ; Bei LAI ; Ming GAO ; Cibo HUANG ; Lijun SONG ; Xingfa LI ; Zhanguo LI
Chinese Journal of Rheumatology 2010;14(6):368-372
Objective To describe the distribution of medication costs of rheumatoid arthritis patients, and to analyze the factors that may affect the costs. Methods Data were obtained from a 12-month retrospective investigation of patients with rheumatoid arthritis (RA) across China. Department of Rheuma-tology of 18 hospitals were randomly selected. The data about their social conditions, clinical conditions, medications associated with RA such as disease-modifying antirheumatic drugs (DMARDs), non -steroidal anti -inflammtory drugs (NSAIDs), steroids, biologic agents were collected, and the costs of drugs were calculated. A non-parameter test and multivariate logistic regression analysis were performed. Results Six hundred and forty six patients were enrolled into the study, 435 completed data were chosen for analysis. The results demonstrated that the average costs per patient for medications in the past year was 8018 . The total medication costs were further subdivided into the following parts: DMARDs, (represented 20% of the total costs), biologic drugs (49%), NSAIDs (4%), herbal drugs (22%), steroids (1%). Data analysis showed that patients with higher education and higher incomes, with medical insurance,better health function status and outpatients paid more on DMARDs. Extra-articular manifestations increased the odds of the high-cost group (OR: 2.180, 95%CI: 1.335~3.558, P=0.002), while poor health function status increased the probability of paying high costs (OR: 1.373, 95%CI: 1.012~1.863, P=0.041). Conclusion High medication costs in RA do exist in RA patients. The costs of medication is associated with health function status and the presence of extra-articular manifestations.
7.A multicenter study of fracture in patients with rheumatoid arthritis in China
Lizhi WANG ; Caihong WANG ; Xiaofeng LI ; Xiangcong ZHAO ; Wenpeng ZHAO ; Xiuru WANG ; Yin SU ; Yuan AN ; Yunshan ZHOU ; Ping ZHU ; Lina CHEN ; Guochun WANG ; Xin LU ; Hongtao JIN ; Yongfu WANG ; Rong YANG ; Zhuoli ZHANG ; Guangtao LI ; Xiangyuan LIU ; Lin SUN ; Fengxiao ZHANG ; Jiemei TAO ; Zhenbin LI ; Jing YANG ; Jinying LIN ; Meiqiu WEI ; Liufu CUI ; Rong SHU ; Xiaomin LIU ; Dan KE ; Shaoxian HU ; Cong YE ; Xiuyan YANG ; Hao LI ; Cibo HUANG ; Ming GAO ; Bei LAI ; Xingfu LI ; Lijun SONG ; Zhanguo LI
Chinese Journal of Rheumatology 2012;16(2):102-106
ObjectiveTo examine the clinical features of fractures and related risk factors in patients with rheumatoid arthritis(RA) in China.MethodsSix hundred and eighty-one RA patients were randomly selected from department of rheumatology of 18 hospitals of China.Data were obtained from the questionnaire,including age,sex,disease duration,the involvement of joints,treatment regimen,features of fractures etc.The possible risk factors of fracture in patients with RA were analyzed with a multi-variate Logistic regression analysis.Results① In 681 RA patients of the survey,48 patients had 54 fractures,and the incidence of fractures was about 8%.② Fractures occurred at various sites.Foot/ankle,femur,spine and wrist were the mostfrequent sites.③ The Logistic regression analysis showed that several factors increased the risk of fracture in RA patients,including long disease duration (OR:1.245,95%CI:0.987-1.570,P=0.065),male gender(OR:0.433,95%CI:0.199-0.942,P=0.035),more deformed joints(OR:1.042,95%CI:1.006-1.079,P=0.023),family history of RA (OR:2.201,95%CI:0.984-4.923,P=0.055),and high scores of SF-36(OR:1.017,95%CI:1.002-1.033,P=0.028).④ According to the degree of correlation from strong to weak,the risk factors of fracture were disease duration,SF-36,sex,number of deformed joints and family history of rheumatoid arthritis.ConclusionThe incidence of fracture is high in patients with rheumatoid arthritis.Several factors could increase the risk of fractures in RA patients,including long disease duration,male gender,more deformed joints,and family history of RA.In order to prevent the occurrence of fractures,cautions should be taken to prevent the development of fractures and treat the disease aggressively to suppress the disease activity of RA.
8.Methodological Evaluation of Advantages of Traditional Chinese Medicine Treatment of Sjögren's Syndrome
Wenjing LIU ; Shiya WU ; Ruihua LIU ; Xinyao ZHOU ; Juan JIAO ; Ying LIU ; Zeguang LI ; Zhenbin LI ; Huadong ZHANG ; Xiaopo TANG ; Quan JIANG
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(1):192-197
Screening and evaluating the diseases responding specifically to traditional Chinese medicine (TCM) will help to highlight the advantages of TCM treatment, and the evaluation method should be standardized with consideration to the unique characteristics of the diseases. The incidence of Sjögren's Syndrome (SS) is increasing year by year, while the pathogenesis of this disease remains unclear. Modern therapies for this disease include biological agents and immunosuppressants, which generally have unsatisfactory efficacy. The TCM treatment of SS focuses on the harmony of the physical and mental health. The Rheumatology Branch of the China Association of Chinese Medicine organizes experts in TCM, Western medicine, and evidence-based medicine to form working groups. Delphi method and bibliometric method were used for analysis, and SS was selected as a disease responding specifically to TCM. Furthermore, the evaluation system was established for this disease, and the consensus regarding this disease was reached after seminar discussion. This paper summarized the whole process of the evaluation of the advantages of TCM treatment of SS. First, because TCM atomization is widely used in clinical practice and enriches TCM administration methods, this therapy is included after other non-drug therapies were taken as characteristic therapies. Second, the evaluation indicators of therapeutic effect should be determined with consideration to international acceptance and the current research status. Third, the expression method should be accurate, standardized, and objective, highlight the natural advantages of TCM, and avoid arbitrary extension. This paper provides a reference for clinicians to explore other diseases responding specifically to TCM.
9.Characterization of the depsidone gene cluster reveals etherification, decarboxylation and multiple halogenations as tailoring steps in depsidone assembly.
Jiafan YANG ; Zhenbin ZHOU ; Yingying CHEN ; Yongxiang SONG ; Jianhua JU
Acta Pharmaceutica Sinica B 2023;13(9):3919-3929
Depsides and depsidones have attracted attention for biosynthetic studies due to their broad biological activities and structural diversity. Previous structure‒activity relationships indicated that triple halogenated depsidones display the best anti-pathogenic activity. However, the gene cluster and the tailoring steps responsible for halogenated depsidone nornidulin ( 3) remain enigmatic. In this study, we disclosed the complete biosynthetic pathway of the halogenated depsidone through in vivo gene disruption, heterologous expression and in vitro biochemical experiments. We demonstrated an unusual depside skeleton biosynthesis process mediated by both highly-reducing polyketide synthase and non-reducing polyketide synthase, which is distinct from the common depside skeleton biosynthesis. This skeleton was subsequently modified by two in-cluster enzymes DepG and DepF for the ether bond formation and decarboxylation, respectively. In addition, the decarboxylase DepF exhibited substrate promiscuity for different scaffold substrates. Finally, and interestingly, we discovered a halogenase encoded remotely from the biosynthetic gene cluster, which catalyzes triple-halogenation to produce the active end product nornidulin ( 3). These discoveries provide new insights for further understanding the biosynthesis of depsidones and their derivatives.