Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and cons...Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.展开更多
Objective:Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignancy.CD8^(+)T cells,cancer stem cells(CSCs),and tumor budding(TB)have been significantly correlated with the outcome of patients with PDAC,but the...Objective:Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignancy.CD8^(+)T cells,cancer stem cells(CSCs),and tumor budding(TB)have been significantly correlated with the outcome of patients with PDAC,but the correlations have been independently reported.In addition,no integrated immune-CSC-TB profile for predicting survival in patients with PDAC has been established.Methods:Multiplexed immunofluorescence and artificial intelligence(AI)-based comprehensive analyses were used for quantification and spatial distribution analysis of CD8^(+)T cells,CD133^(+)CSCs,and TB.In vivo humanized patient-derived xenograft(PDX)models were established.Nomogram analysis,calibration curve,time-dependent receiver operating characteristic curve,and decision curve analyses were performed using R software.Results:The established‘anti-/pro-tumor’models showed that the CD8^(+)T cell/TB,CD8^(+)T cell/CD133^(+)CSC,TB-adjacent CD8^(+)T cell,and CD133^(+)CSC-adjacent CD8^(+)T cell indices were positively associated with survival of patients with PDAC.These findings were validated using PDX-transplanted humanized mouse models.An integrated nomogram-based immune-CSC-TB profile that included the CD8^(+)T cell/TB and CD8^(+)T cell/CD133^(+)CSC indices was established and shown to be superior to the tumor-nodemetastasis stage model in predicting survival of patients with PDAC.Conclusions:‘Anti-/pro-tumor’models and the spatial relationship among CD8^(+)T cells,CSCs,and TB within the tumor microenvironment were investigated.Novel strategies to predict the prognosis of patients with PDAC were established using AI-based comprehensive analysis and machine learning workflow.The nomogram-based immune-CSC-TB profile can provide accurate prognosis prediction for patients with PDAC.展开更多
Background: Pancreatic ductal adenocarcinoma(PDAC) is the most deadly type of tumor, and its pathogenesis remains unknown. Circular RNAs(circRNAs) may be functional and bind to micro RNAs and consequently, influence t...Background: Pancreatic ductal adenocarcinoma(PDAC) is the most deadly type of tumor, and its pathogenesis remains unknown. Circular RNAs(circRNAs) may be functional and bind to micro RNAs and consequently, influence the activity of targeted mRNAs. Recent researches indicate that one circRNA, ciRS-7, acts as a sponge of miR-7 and thus, inhibits its activity. It is well known that miR-7 is a cancer suppressor in many cancers. However, the relationship between ciRS-7 and miR-7, and the role of ciRS-7 in PDAC, remains to be elucidated. Methods: miR-7 and ciRS-7 expression in 41 pairs of PDAC tumors and their paracancerous tissues were detected by quantitative reverse transcription polymerase chain reaction(qRT-PCR). The relationships between their expression levels and clinicopathological features in PDAC tissues were assessed. The relationship between miR-7 and ciRS-7 was also assessed by Spearman’s correlation. We also used cell lines to evaluate the role of ciRS-7 in cell line behavior. The ciRS-7 interfere RNA(si RNA) and its empty vector were transfected into PDAC cells. PDAC cells proliferation and invasion abilities were detected by MTT assay and invasion analysis. The expression of proteins was assessed by Western blotting. Results: ciRS-7 expression was significantly higher in PDAC tissues than paracancerous tissues( P = 0.002). However, miR-7 expression showed the opposite trend( P = 0.048). Moreover, ciRS-7 expression was inversely correlated with miR-7 in PDAC( r s =-0.353, P = 0.023). ciRS-7 expression was also significantly elevated in venous invasion(3.72 ± 2.93 vs. 2.14 ± 1.26;P = 0.028) and lymph node metastasis(4.19 ± 2.75 vs. 2.32 ± 1.90;P = 0.016) in PDAC patients. Furthermore, ciRS-7 knockdown suppressed cell proliferation and invasion of PDAC cells( P < 0.05), and the downregulation of ciRS-7 resulted in miR-7 overexpression and subsequent inhibition of epidermal growth factor receptor(EGFR) and signal transducer and activator of transcription 3(STAT3). Conclusions: Circular RNA ciRS-7 plays an oncogene role in PDAC, partly by targeting miR-7 and regulating the EGFR/STAT3 signaling pathway.展开更多
Authors introduction： Qian Zhan, female, who was born in Sept, 1979. She studied in the Shanghai Second Medical University during 1998 to 2005. She majored in Clinical Medicine, and earned her master degree in 2005. ...Authors introduction： Qian Zhan, female, who was born in Sept, 1979. She studied in the Shanghai Second Medical University during 1998 to 2005. She majored in Clinical Medicine, and earned her master degree in 2005. In 2005, she went to the Beaujon Hospital of Paris 7th Universit3. in France, as a foreign intern. Later, she came to postgraduate work and residencies in the general surgery department of Shanghai Ruijin Hospital. Her clinical work is focused on multidisciplinary especially postoperative management for the patients with pancreatic cancer. In addition, she is a lead researcher in the pancreatic cancer group for nano based drug delivery, systems. Chenghong Peng, male, who was born in Apr, 1957. He worked in the 2nd Affiliated Hospital of Zhejiang University School of Medicine during 1989 to 2002. In 2002, Chenghong Peng came m Shanghai Ruiiin Hospital and began to take charge of general surgery department. As a pioneer in the hepatobifiopancreatic field, Chenghong Peng devoted himself in the basic and clinical research of pancreatic tmnors. He brings forth new ideas by creating ＂Pancreatic multiple treatment collaborating groups＂, which integrate the advantages of gasn＇oenterology, department, endoscopy department, radiology department, pathology deparnnent and SICU. He constantly strives for excellence in pancreatic surgery. In the previous five years, he performed more than 300 cases of pancreatectomy each year, and has accomplished more than 2,000 cases of pancreatectomy altogether, among which the resectable rate is 74%. Besides, he is also committed to laparoscopic surgery and robotic surgeD,. He has achieved more than 200 laparoscopic hepatectomies, 150 laparoscopic pancreatectomies and 500 robotic hepatobiliopancreatic surgeries （350 robotic pancreatic surgeries included）, which keeps leading position in China. In 2011, Chenghong Peng has won the first prize in 3rd international congress of CRSA, which marked that our achievement in robotic surgery was recognized by oversea peers.Background： To explore the effectiveness, safety, and efficacy of the robot-assisted surgery in the radical resection of pancreatic ductal adenocarcinoma （PDAC）. Methods： The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed. Results： Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3±118.8 min, and the mean intra-operative blood loss was 447.3±269.9 mL. Among 31 patients who underwent the distal pancreatectomy （DP）, the average operative time was 185.5±74.1 min, and the mean intra-operative blood loss was 267.1±305.3 mL. In two patients who received the middle pancreatectomy （NIP）, the average operative time was 225 rain and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2±2.6 lymph nodes were dissected, with an average hospital stay of 22.6±10.7 days. Complications were observed in 18 patients, which included pancreatic fistula （n=11）, bile leak （n=5）, anastomotic bleeding （n：2）, pancreatic fistula complicated with portal vein thrombosis （n=1）, and anastomotic bleeding complicated with acute renal failure （n=l）. Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 （15.6±5.8） months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis. Conclusions- Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post-operative recovery, and therefore can achieve the lymph node dissection scope and tumor resection margin required by the standards of radical resection for pancreatic cancer. Nevertheless, its long-term efficacy requires further validation.展开更多
文摘Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.
基金supported by The Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2017KJ198)。
文摘Objective:Pancreatic ductal adenocarcinoma(PDAC)is an aggressive malignancy.CD8^(+)T cells,cancer stem cells(CSCs),and tumor budding(TB)have been significantly correlated with the outcome of patients with PDAC,but the correlations have been independently reported.In addition,no integrated immune-CSC-TB profile for predicting survival in patients with PDAC has been established.Methods:Multiplexed immunofluorescence and artificial intelligence(AI)-based comprehensive analyses were used for quantification and spatial distribution analysis of CD8^(+)T cells,CD133^(+)CSCs,and TB.In vivo humanized patient-derived xenograft(PDX)models were established.Nomogram analysis,calibration curve,time-dependent receiver operating characteristic curve,and decision curve analyses were performed using R software.Results:The established‘anti-/pro-tumor’models showed that the CD8^(+)T cell/TB,CD8^(+)T cell/CD133^(+)CSC,TB-adjacent CD8^(+)T cell,and CD133^(+)CSC-adjacent CD8^(+)T cell indices were positively associated with survival of patients with PDAC.These findings were validated using PDX-transplanted humanized mouse models.An integrated nomogram-based immune-CSC-TB profile that included the CD8^(+)T cell/TB and CD8^(+)T cell/CD133^(+)CSC indices was established and shown to be superior to the tumor-nodemetastasis stage model in predicting survival of patients with PDAC.Conclusions:‘Anti-/pro-tumor’models and the spatial relationship among CD8^(+)T cells,CSCs,and TB within the tumor microenvironment were investigated.Novel strategies to predict the prognosis of patients with PDAC were established using AI-based comprehensive analysis and machine learning workflow.The nomogram-based immune-CSC-TB profile can provide accurate prognosis prediction for patients with PDAC.
基金supported by grants from the Key Research and Development Program Projects in Anhui Province(1804h08020277)the Programs for Science and Technology Development of An-hui Province(1606c08234)
文摘Background: Pancreatic ductal adenocarcinoma(PDAC) is the most deadly type of tumor, and its pathogenesis remains unknown. Circular RNAs(circRNAs) may be functional and bind to micro RNAs and consequently, influence the activity of targeted mRNAs. Recent researches indicate that one circRNA, ciRS-7, acts as a sponge of miR-7 and thus, inhibits its activity. It is well known that miR-7 is a cancer suppressor in many cancers. However, the relationship between ciRS-7 and miR-7, and the role of ciRS-7 in PDAC, remains to be elucidated. Methods: miR-7 and ciRS-7 expression in 41 pairs of PDAC tumors and their paracancerous tissues were detected by quantitative reverse transcription polymerase chain reaction(qRT-PCR). The relationships between their expression levels and clinicopathological features in PDAC tissues were assessed. The relationship between miR-7 and ciRS-7 was also assessed by Spearman’s correlation. We also used cell lines to evaluate the role of ciRS-7 in cell line behavior. The ciRS-7 interfere RNA(si RNA) and its empty vector were transfected into PDAC cells. PDAC cells proliferation and invasion abilities were detected by MTT assay and invasion analysis. The expression of proteins was assessed by Western blotting. Results: ciRS-7 expression was significantly higher in PDAC tissues than paracancerous tissues( P = 0.002). However, miR-7 expression showed the opposite trend( P = 0.048). Moreover, ciRS-7 expression was inversely correlated with miR-7 in PDAC( r s =-0.353, P = 0.023). ciRS-7 expression was also significantly elevated in venous invasion(3.72 ± 2.93 vs. 2.14 ± 1.26;P = 0.028) and lymph node metastasis(4.19 ± 2.75 vs. 2.32 ± 1.90;P = 0.016) in PDAC patients. Furthermore, ciRS-7 knockdown suppressed cell proliferation and invasion of PDAC cells( P < 0.05), and the downregulation of ciRS-7 resulted in miR-7 overexpression and subsequent inhibition of epidermal growth factor receptor(EGFR) and signal transducer and activator of transcription 3(STAT3). Conclusions: Circular RNA ciRS-7 plays an oncogene role in PDAC, partly by targeting miR-7 and regulating the EGFR/STAT3 signaling pathway.
文摘目的在大规模表达谱芯片中寻找与胰腺导管腺癌(PDAC)相关的RNA分子,并探讨其分子机制。方法基于RNA的表达谱数据,构建"转录因子-miRNA-mRNA"调控关系网络,挖掘与PDAC相关的mRNA及miRNA。结果 6个miR let-7家族miRNA成员(hsa-let-7i、hsa-let-7d、hsa-let-7b、hsa-let-7g、hsa-let-7c、hsa-let-7e)参与一个核心调控网络,其网络中涉及的基因和其他miRNA均为与PDAC发生发展相关的分子。其中处于网络核心位置的基因ALDH1A1、ZEB1、HMGA2、EGR1和TGFB1,与PDAC的发展及预后直接相关。网络中的hsa-mir-200b、hsa-mir-200a可与ZEB1基因相互调控,通过Notch信号通路影响PDAC的发展及转移。结论 miR let-7家族miRNA分子可能与ALDH1A1、ZEB1与HMGA2等分子相互调控,并与PDAC的发生发展密切相关。
文摘Authors introduction： Qian Zhan, female, who was born in Sept, 1979. She studied in the Shanghai Second Medical University during 1998 to 2005. She majored in Clinical Medicine, and earned her master degree in 2005. In 2005, she went to the Beaujon Hospital of Paris 7th Universit3. in France, as a foreign intern. Later, she came to postgraduate work and residencies in the general surgery department of Shanghai Ruijin Hospital. Her clinical work is focused on multidisciplinary especially postoperative management for the patients with pancreatic cancer. In addition, she is a lead researcher in the pancreatic cancer group for nano based drug delivery, systems. Chenghong Peng, male, who was born in Apr, 1957. He worked in the 2nd Affiliated Hospital of Zhejiang University School of Medicine during 1989 to 2002. In 2002, Chenghong Peng came m Shanghai Ruiiin Hospital and began to take charge of general surgery department. As a pioneer in the hepatobifiopancreatic field, Chenghong Peng devoted himself in the basic and clinical research of pancreatic tmnors. He brings forth new ideas by creating ＂Pancreatic multiple treatment collaborating groups＂, which integrate the advantages of gasn＇oenterology, department, endoscopy department, radiology department, pathology deparnnent and SICU. He constantly strives for excellence in pancreatic surgery. In the previous five years, he performed more than 300 cases of pancreatectomy each year, and has accomplished more than 2,000 cases of pancreatectomy altogether, among which the resectable rate is 74%. Besides, he is also committed to laparoscopic surgery and robotic surgeD,. He has achieved more than 200 laparoscopic hepatectomies, 150 laparoscopic pancreatectomies and 500 robotic hepatobiliopancreatic surgeries （350 robotic pancreatic surgeries included）, which keeps leading position in China. In 2011, Chenghong Peng has won the first prize in 3rd international congress of CRSA, which marked that our achievement in robotic surgery was recognized by oversea peers.Background： To explore the effectiveness, safety, and efficacy of the robot-assisted surgery in the radical resection of pancreatic ductal adenocarcinoma （PDAC）. Methods： The clinical data of 72 patients with PDAC who underwent radical resection using the da Vinci Surgical System from April 2010 to December 2014 were retrospectively analyzed. Results： Among these 72 patients, three were converted to conventional laparotomy due to the vascular invasion or due to the difficulties in tissue isolation from the surrounding organs. Among 39 patients who underwent the pancreatoduodenectomy, the average operative time was 395.3±118.8 min, and the mean intra-operative blood loss was 447.3±269.9 mL. Among 31 patients who underwent the distal pancreatectomy （DP）, the average operative time was 185.5±74.1 min, and the mean intra-operative blood loss was 267.1±305.3 mL. In two patients who received the middle pancreatectomy （NIP）, the average operative time was 225 rain and mean intra-operative blood loss was 100 mL. Among all the 72 patients, an average of 4.2±2.6 lymph nodes were dissected, with an average hospital stay of 22.6±10.7 days. Complications were observed in 18 patients, which included pancreatic fistula （n=11）, bile leak （n=5）, anastomotic bleeding （n：2）, pancreatic fistula complicated with portal vein thrombosis （n=1）, and anastomotic bleeding complicated with acute renal failure （n=l）. Except that one patient died due to post-operative bleeding and acute renal failure, all the other patients were cured after conservative treatment. These 72 patients were followed for 1-45 （15.6±5.8） months, during which 10 patients died. Eleven patients suffered from recurrence or metastasis, among which 6 had local recurrence, 4 had liver metastasis, and 1 had ascites accompnaied with incision site tumor metastasis. Conclusions- Radical resection of PDAC by robotic surgical system is safe and feasible. It has less surgical trauma and enables faster post-operative recovery, and therefore can achieve the lymph node dissection scope and tumor resection margin required by the standards of radical resection for pancreatic cancer. Nevertheless, its long-term efficacy requires further validation.
