本文選題：胰腺癌的早期診斷 + 新發(fā)糖尿病�。� 參考：《浙江大學(xué)》2016年博士論文

【摘要】：背景:胰腺癌惡性程度高,預(yù)后極差。由于缺乏早期癥狀及預(yù)測(cè)的標(biāo)記物,致使胰腺癌的早期診斷十分困難。手術(shù)治療是胰腺癌僅有的根治手段,但由于該病在確診時(shí)通常已是晚期,導(dǎo)致可行手術(shù)治療的患者不足20%。因此,早期診斷已成為提高胰腺癌手術(shù)切除率、進(jìn)而有效改善其預(yù)后的關(guān)鍵。許多研究表明新發(fā)糖尿病可以作為胰腺癌的早期并發(fā)癥,此型糖尿病又被稱(chēng)為胰腺癌相關(guān)性新發(fā)糖尿病。因此,新發(fā)糖尿病可以用于胰腺癌的早期篩查。然而,我國(guó)新發(fā)糖尿病的發(fā)病率要遠(yuǎn)高于胰腺癌,如何將少量的胰腺癌相關(guān)性新發(fā)糖尿病患者從眾多的普通新發(fā)糖尿病患者中篩選出來(lái)仍是個(gè)難題。我們課題組在前期研究中發(fā)現(xiàn),重組人血管非炎性因子1(Vanin-1,VNN1)在胰腺癌相關(guān)性新發(fā)糖尿病患者的癌組織及外周血細(xì)胞內(nèi)呈特異性高表達(dá),其可用于普通新發(fā)糖尿病與胰腺癌相關(guān)性新發(fā)糖尿病之間的鑒別,進(jìn)而可用于胰腺癌的早期篩查。然而,VNN1引起胰腺癌相關(guān)性新發(fā)糖尿病發(fā)生的具體機(jī)制仍不十分明確。在此研究中,我們探究了胰腺癌細(xì)胞內(nèi)VNN1的高表達(dá)對(duì)癌旁原代胰島的影響及其分子機(jī)制。同時(shí),我們還使用臨床標(biāo)本檢測(cè)了 VNN1的下游產(chǎn)物是否也可用于胰腺癌的早期診斷。此外,我們?cè)诒菊n題組前期研究的基礎(chǔ)上合成了 VNN1功能化的超順磁性氧化鐵納米顆粒(USPIO-VNN1),還使用磁共振成像技術(shù)觀(guān)察了 USPIO-VNN1對(duì)VNN1高表達(dá)胰腺癌細(xì)胞系的靶向示蹤作用,并進(jìn)一步探討了USPIO-VNN1是否可對(duì)早期胰腺癌進(jìn)行特異性成像。方法:使用VNN1基因過(guò)表達(dá)載體轉(zhuǎn)染PANC-1和CFPAC-1兩株胰腺癌細(xì)胞系,建立VNN1高表達(dá)的穩(wěn)轉(zhuǎn)胰腺癌細(xì)胞系PANC-VNN1和CFPAC-VNN1。從C57BL/6J(B6)小鼠胰腺內(nèi)分離出原代胰島,并使用6孔板專(zhuān)用的transwell小室(0.4μm徑)構(gòu)建了胰腺癌細(xì)胞與小鼠原代胰島的共培養(yǎng)體系。小鼠原代胰島與胰腺癌細(xì)胞共培養(yǎng)24小時(shí)后,使用臺(tái)盼藍(lán)染色檢測(cè)原代胰島的活性;使用流式技術(shù)檢測(cè)原代胰島的活性及其內(nèi)部活性氧簇(reactiveoxygenspecies,ROS)的含量;使用胰島素釋放實(shí)驗(yàn)檢測(cè)原代胰島細(xì)胞的功能;將200或400胰島當(dāng)量(isletequivalent,IEQ)的原代胰島移植到B6rag1-/-(免疫缺陷)1型糖尿病小鼠腎包膜下,采用尾靜脈取血法連續(xù)監(jiān)測(cè)小鼠血糖水平變化;使用免疫組織化學(xué)染色法檢測(cè)原代胰島內(nèi)胰島素(insulin)的含量及胰腺癌患者組織標(biāo)本內(nèi)VNN1的含量;使用谷胱甘肽(glutathione,GSH)測(cè)定試劑盒檢測(cè)原代胰島細(xì)胞內(nèi)GSH的含量;使用western blot法檢測(cè)原代胰島內(nèi)促凋亡蛋白cleaved caspase-3、cleaved caspase-9及抗氧化蛋白過(guò)氧化物酶體增殖物激活受體 γ(peroxisome proliferator-activated receptor ganma,PPARy)的含量。我們還使用高效液相色譜(high performance liquid chromatography,HPLC)法檢測(cè)了胰腺癌細(xì)胞條件培養(yǎng)基內(nèi)、原代胰島細(xì)胞內(nèi)及胰腺癌患者血清標(biāo)本內(nèi)半胱胺(cysteamine)的含量。我們采用三乙酰丙酮鐵作為前體制備超小超順磁性氧化鐵納米顆粒(USPIO)的鐵核心,然后使用高分子聚合物—聚乙二醇(polyethylene glycol,PEG)對(duì)USPIO進(jìn)行包被后合成水溶性良好的PEG-USPIO,并使用透射電子顯微鏡、納米激光粒度儀、低溫磁場(chǎng)測(cè)試和試樣制備系統(tǒng)、傅里葉變換紅外光譜儀等設(shè)備檢測(cè)PEG-USPIO的理化性質(zhì)。使用N-羥基丁二酰亞胺(N-hydroxysuccinimide,NHS)和二乙基二乙氨丙酯(ethyldiethylaminopropylcarbodiimide,EDC)將PEG-USPIO 和VNN1單克隆抗體連接后合成USPIO-VNN1。將PANC-VNN1及對(duì)照細(xì)胞分別與含有PEG-USPIO(鐵濃度為40 ug/ml)或USPIO-VNN1(鐵濃度為40 ug/ml)的培養(yǎng)基共孵育24h后,使用普魯士藍(lán)染色及3.0 T臨床磁共振成像系統(tǒng)分別檢測(cè)PEG-USPIO、USPIO-VNN1對(duì)胰腺癌細(xì)胞的標(biāo)記效率。使用PANC-VNN1及對(duì)照細(xì)胞建立裸鼠皮下瘤模型,并通過(guò)尾靜脈分別注射PEG-USPIO溶液(鐵濃度為20 mg/kg)或USPIO-VNN1溶液(鐵濃度為20 mg/kg)24小時(shí)后,行磁共振掃描檢測(cè)USPIO-VNN1對(duì)VNN1高表達(dá)胰腺癌細(xì)胞系的靶向示蹤作用。結(jié)果:臺(tái)盼藍(lán)染色和流式分析顯示,與未處理組(未與胰腺癌細(xì)胞共培養(yǎng)的胰島)和對(duì)照細(xì)胞組(與對(duì)照細(xì)胞共培養(yǎng)的胰島)相比,經(jīng)PANC-VNN1和CFPAC-VNN1細(xì)胞共培養(yǎng)24小時(shí)后的原代胰島(PANC-VNN1和CFPAC-VNN1細(xì)胞組)的存活率明顯下降。Western blot結(jié)果顯示PANC-VNN1和CFPAC-VNN1細(xì)胞組的原代胰島內(nèi)促凋亡蛋白cleaved caspase-3及cleaved caspase-9的含量明顯增加,免疫組化染色顯示該組原代胰島結(jié)構(gòu)的完整性也受到了明顯的破壞。與未處理組和對(duì)照細(xì)胞組相比,PANC-VNN1和CFPAC-VNN1細(xì)胞組的原代胰島的胰島素基礎(chǔ)釋放量顯著降低。分別將未處理組、對(duì)照細(xì)胞組及PANC-VNN1細(xì)胞組的原代胰島移植到B6 rag1-/-(免疫缺陷)1型糖尿病小鼠腎包膜下。移植200或400 IEQ原代胰島后,與未經(jīng)胰腺癌細(xì)胞共培養(yǎng)組及對(duì)照細(xì)胞共培養(yǎng)組的糖尿病小鼠相比,PANC-VNN1細(xì)胞共培養(yǎng)組的糖尿病小鼠更晚達(dá)到正常血糖水平。HPLC法分析顯示,使用完全培養(yǎng)基培養(yǎng)胰腺癌細(xì)胞24小時(shí)后,PANC-VNN1和CFPAC-VNN1細(xì)胞分泌至胞外條件培養(yǎng)基內(nèi)cysteamine(VNN1的下游產(chǎn)物)的量明顯高于對(duì)照細(xì)胞。與未處理組及對(duì)照組相比,PANC-VNN1和CFPAC-VNN1細(xì)胞組的胰島細(xì)胞內(nèi)cysteamine和ROS的濃度顯著增高、GSH和PPARγ的表達(dá)量明顯下降。分別使用濃度為10μM的抗氧化劑GSH和1OμM的PPARγ激動(dòng)劑噻唑烷二酮(thiazolidinedione,TZD)預(yù)孵育原代胰島2小時(shí),再將這些原代胰島與胰腺癌細(xì)胞共培養(yǎng)24小時(shí),結(jié)果顯示PANC-VNN1細(xì)胞組的原代胰島內(nèi)ROS的含量明顯下降,此外,該組原代胰島的存活率和胰島素釋放能力均顯著升高.我們使用臨床組織標(biāo)本再次發(fā)現(xiàn)胰腺癌相關(guān)性新發(fā)糖尿病患者癌組織內(nèi)的VNN1蛋白呈特異性高表達(dá)。此外,我們還使用HPLC法檢測(cè)了臨床患者及健康人群血清內(nèi)cysteamine的含量,結(jié)果發(fā)現(xiàn)與不伴有新發(fā)糖尿病的胰腺癌患者、新發(fā)2型糖尿病患者及健康人群相比,胰腺癌相關(guān)性新發(fā)糖尿病患者血清內(nèi)cysteamine的濃度明顯增高。經(jīng) ROC 曲線(xiàn)(receiver operating characteristic curve)分析后,我們發(fā)現(xiàn)檢測(cè)血清內(nèi)cysteamine的濃度從新發(fā)2型糖尿病患者中鑒別胰腺癌相關(guān)性新發(fā)糖尿病患者的曲線(xiàn)下面積(Area Under Curve,AUC)為0.828 ± 0.039(P0.05)。電子顯微鏡掃描顯示USPIO的氧化鐵核心直徑約為3-7nm,分布均勻。USPIO經(jīng)高分子聚合物PEG包被后合成PEG-USPIO,納米激光粒度儀分析結(jié)果顯示PEG-USPIO在水溶液中的平均粒徑約為20nm。采用震動(dòng)樣品磁強(qiáng)計(jì)測(cè)試后發(fā)現(xiàn),PEG-USPIO在室溫下的飽和磁力為35 emu/g。使用NHS/EDC法將PEG-USPIO和VNN1單克隆抗體連接后合成USPIO-VNN1。將PANC-VNN1和對(duì)照細(xì)胞分別與鐵濃度為40 ug/ml的PEG-USPIO及USPIO-VNN1共孵育24h后,普魯士藍(lán)染色顯示經(jīng) USPIO-VNN1 共培養(yǎng)的 PANC-VNN1 細(xì)胞(USPIO-VNN1 +PANC-VNN1細(xì)胞組)內(nèi)出現(xiàn)細(xì)小的藍(lán)色鐵顆粒,而其它3組(PEG-USPIO +對(duì)照細(xì)胞組、PEG-USPIO + PANC-VNN1細(xì)胞組、USPIO-VNN1 +對(duì)照細(xì)胞組)細(xì)胞內(nèi)未見(jiàn)明顯的藍(lán)色鐵顆粒。MRI掃描顯示,USPIO-VNN1+PANC-VNN1細(xì)胞組可見(jiàn)T2信號(hào)(橫向弛豫時(shí)間加權(quán)信號(hào))減低,而其它3組未見(jiàn)明顯信號(hào)改變。通過(guò)尾靜脈將PEG-USPIO溶液(鐵濃度為20 mg/kg)或USPIO-VNN1溶液(鐵濃度為20 mg/kg)分別注射入PANC-VNN1或?qū)φ占?xì)胞荷瘤鼠體內(nèi)24小時(shí)后,MRI掃描顯示尾靜脈注射USPIO-VNN1溶液的PANC-VNN1細(xì)胞荷瘤鼠瘤塊內(nèi)可見(jiàn)信號(hào)減低,而其它3組荷瘤鼠瘤塊內(nèi)未見(jiàn)明顯信號(hào)改變。將瘤塊的組織切片進(jìn)行普魯士藍(lán)染色后發(fā)現(xiàn),在USPIO-VNN1 + PANC-VNN1細(xì)胞組瘤塊內(nèi)可見(jiàn)散在的鐵顆粒沉積,而其它3組則未見(jiàn)此現(xiàn)象。此外,我們還發(fā)現(xiàn)USPIO-VNN1在小鼠體內(nèi)具有良好的生物相容性,未見(jiàn)明顯細(xì)胞毒性。結(jié)論:胰腺癌細(xì)胞內(nèi)VNN1高表達(dá)可以通過(guò)旁分泌cysteamine的方式加劇癌旁胰島的氧化應(yīng)激反應(yīng),進(jìn)而抑制胰島的活性及功能。VNN1的下游產(chǎn)物cysteamine在胰腺癌相關(guān)性新發(fā)糖尿病患者血清內(nèi)呈特異性高表達(dá),檢測(cè)血清內(nèi)cysteamine的濃度可以用于胰腺癌相關(guān)性新發(fā)糖尿病和單純新發(fā)糖尿病之間的鑒別,進(jìn)而可能用于胰腺癌的早期篩查。此外,我們制備的MRI造影劑USPIO-VNN1可以對(duì)VNN1高表達(dá)的胰腺癌細(xì)胞進(jìn)行活體靶向示蹤,結(jié)合我們前期的研究說(shuō)明USPIO-VNN1可能對(duì)繼發(fā)有新發(fā)糖尿病的早期胰腺癌組織進(jìn)行特異性成像,進(jìn)而有可能提高胰腺癌的早期診斷率。
[Abstract]:Background: pancreatic cancer has a high malignancy and a poor prognosis. Early diagnosis of pancreatic cancer is difficult due to the lack of early symptoms and predicted markers. Surgical treatment is the only radical cure for pancreatic cancer. However, the disease is usually advanced at the time of diagnosis, resulting in less than 20%. of patients who have been operated on. Therefore, early diagnosis has been made. Many studies have shown that new onset diabetes can be an early complication of pancreatic cancer. This type of diabetes is also known as a new type of diabetes associated with pancreatic cancer. Therefore, new onset diabetes can be used for early screening of pancreatic cancer. However, the incidence of new onset diabetes in China The rate is far higher than that of pancreatic cancer. How to screen a small number of pancreatic cancer related new diabetic patients from a large number of common new diabetic patients is still a difficult problem. In our previous study, we found that recombinant human vascular non inflammatory factor 1 (Vanin-1, VNN1) is in the cancer tissue and outside of the new diabetic patients with pancreatic adenocarcinoma. There is a specific high expression in the peripheral blood cells, which can be used to differentiate between new diabetes and pancreatic cancer related new onset diabetes, and can be used for early screening of pancreatic cancer. However, the specific mechanism of VNN1 induced pancreatic cancer related new onset diabetes is still not clear. In this study, we explored pancreatic cancer cells. The effect of high expression of internal VNN1 on the paracancerous islets of the pancreas and its molecular mechanism. We also used clinical specimens to detect whether the downstream products of VNN1 can also be used for the early diagnosis of pancreatic cancer. In addition, we have synthesized the VNN1 functionalized superparamagnetic iron oxide nanoparticles (USPIO-VNN1) on the basis of our previous study. Magnetic resonance imaging (MRI) was used to observe the target tracer effect of USPIO-VNN1 on VNN1 high expression of pancreatic cancer cell lines, and further explore whether USPIO-VNN1 could be specific imaging of early pancreatic cancer. Method: transfection of VNN1 gene overexpression vector to two pancreatic cancer cell lines of PANC-1 and CFPAC-1, and to establish the stability of high expression of VNN1. The pancreatic cancer cell lines PANC-VNN1 and CFPAC-VNN1. isolated the original islets from the pancreas of C57BL/6J (B6) mice. The co culture system of pancreatic cancer cells and the primary islets of mice was constructed by using the special Transwell chamber of 6 orifice plates (0.4 micron m). The primary pancreatic islets and pancreatic cancer cells were cultured for 24 hours, and trypan blue staining was used to detect the original generation. The activity of islets, the activity of the original islets and the content of reactiveoxygenspecies (ROS), the function of the primary islet cells using insulin release, and the original islet of the 200 or 400 islet equivalent (isletequivalent, IEQ) to B6rag1-/- (immunodeficiency) type 1 diabetic mice The content of insulin (insulin) in the original islet and the content of VNN1 in the tissue specimens of pancreatic cancer were detected by immunohistochemistry staining method, and the content of GSH in the primary islet cells was detected by glutathione (glutathione, GSH), and West was used. Ern blot method was used to detect the content of cleaved Caspase-3, cleaved caspase-9 and antioxidant protein peroxisome proliferator activated receptor gamma (peroxisome proliferator-activated receptor Ganma, PPARy) in the original islet. The content of cysteamine (cysteamine) in the serum samples of pancreatic cancer patients in the condition of pancreatic cancer cell condition. We use three acetyl acetone iron as the precursor to prepare the iron core of super small superparamagnetic iron oxide nanoparticles (USPIO), and then use the high molecular polymer polyethylene glycol (polyethylene glycol, PEG). USPIO was used to synthesize PEG-USPIO with good water solubility, and the physical and chemical properties of PEG-USPIO were detected by transmission electron microscope, nano laser particle size analyzer, low temperature magnetic field test and sample preparation system, Fourier transform infrared spectrometer and so on. N- hydroxy butyl two imide (N-hydroxysuccinimide, NHS) and two ethyl two ethyl propyl ester were used. (ethyldiethylaminopropylcarbodiimide, EDC) combined PEG-USPIO and VNN1 monoclonal antibodies to synthesize USPIO-VNN1. to incubate PANC-VNN1 and control cells with PEG-USPIO (iron concentration 40 ug/ml) or USPIO-VNN1 (iron concentration 40 ug/ml) for incubating 24h, using Prussian blue staining and 3 T clinical magnetic resonance imaging system The labeling efficiency of PEG-USPIO, USPIO-VNN1 for pancreatic cancer cells was detected. PANC-VNN1 and control cells were used to establish nude mice model of subcutaneous tumor, and PEG-USPIO solution was injected through the tail vein (iron concentration was 20 mg/kg) or USPIO-VNN1 solution (iron concentration was 20 mg/kg) for 24 hours, and the high expression of USPIO-VNN1 to VNN1 high expression pancreas was detected by magnetic resonance scanning. Results: trypan blue staining and flow analysis showed that the primary islets (PANC-VNN1 and CFPAC-VNN1 cells) were cultured for 24 hours after PANC-VNN1 and CFPAC-VNN1 cells, compared with the untreated group (the islets not co cultured with pancreatic cancer cells) and the control cell group (the islets co cultured with the control cells). The survival rate of.Western blot showed a significant increase in the contents of cleaved caspase-3 and cleaved caspase-9 in the primary islets of PANC-VNN1 and CFPAC-VNN1 cells. Immunohistochemistry showed that the integrity of the original islet structure of the group was also obviously broken. The insulin base release of the primary islets of the NC-VNN1 and CFPAC-VNN1 cells decreased significantly. The original islets of the untreated group, the control cell group and the PANC-VNN1 cell group were transplanted under the renal capsule of the B6 rag1-/- (immunodeficiency) type 1 diabetic mice. After the transplantation of the 200 or 400 IEQ original islets, the co culture group and the non pancreatic cancer cell co culture group and the other group were compared. Compared with the diabetic mice of the cell co culture group, the diabetic mice in the PANC-VNN1 cell co culture group were more late to reach the normal blood glucose level by.HPLC assay. After 24 hours of complete culture medium, PANC-VNN1 and CFPAC-VNN1 cells secreted to the quantity of cysteamine (downstream products of VNN1) in the extracellular conditioned culture. Compared with the control group, the concentration of Cysteamine and ROS in the islet cells of PANC-VNN1 and CFPAC-VNN1 cells increased significantly compared with those in the untreated and control groups, and the expression of GSH and PPAR gamma decreased significantly. The pre incubation of the antioxidant GSH and 1O micron M of the PPAR gamma agonist, thiazolidane two ketones, respectively, was preincubated. The original islets were cultured for 2 hours, and then the original islets and pancreatic cancer cells were co cultured for 24 hours. The results showed that the content of ROS in the original islet of PANC-VNN1 cell group decreased obviously. In addition, the survival rate and insulin release ability of the original islets of the group were significantly increased. The VNN1 protein in the cancerous tissues of the patients with urine is highly specific. In addition, we also use HPLC to detect the content of cysteamine in the serum of the patients and healthy people. The results showed that the pancreatic cancer patients with non new diabetes mellitus, new type 2 diabetes and healthy people, were associated with new diabetic patients with pancreatic cancer. The concentration of cysteamine in serum increased significantly. After the analysis of the ROC curve (receiver operating characteristic curve), we found that the concentration of cysteamine in the serum was detected in the new onset type 2 diabetic patients with the area under the curve (Area Under Curve, AUC) of 0.828 + 0.039 (P0.05). The microscope scan showed that the core diameter of the iron oxide core of USPIO was about 3-7nm, and the distributed uniform.USPIO was synthesized by the high molecular polymer PEG package. The results of the nano laser particle size analyzer showed that the average particle size of PEG-USPIO in the aqueous solution was about 20nm., and the saturated magnetic force of PEG-USPIO at room temperature was found at room temperature. After connecting PEG-USPIO and VNN1 monoclonal antibodies to 35 emu/g. to synthesize USPIO-VNN1., PANC-VNN1 and control cells were incubated with PEG-USPIO and USPIO-VNN1 respectively with iron concentration of 40 ug/ml, respectively, and Prussian blue staining showed that USPIO-VNN1 co cultured PANC-VNN1 cells appeared to be fine. Small blue iron particles, and other 3 groups (PEG-USPIO + control cell group, PEG-USPIO + PANC-VNN1 cell group, USPIO-VNN1 + control cell group) no obvious blue iron particles.MRI scan showed that the USPIO-VNN1+PANC-VNN1 cell group showed T2 signal (transverse relaxation time weighted signal) decreased, but the other 3 groups did not have obvious signal change. The PEG-USPIO solution (iron concentration 20 mg/kg) or USPIO-VNN1 solution (iron concentration 20 mg/kg) was injected into the tail vein for 24 hours in PANC-VNN1 or the control cells of the tumor mice respectively. The MRI scan showed that the PANC-VNN1 cells in the PANC-VNN1 cell of the tail vein injected with USPIO-VNN1 solution were reduced in the tumor block, while the other 3 groups of tumor bearing mice were not in the tumor block. Visible signal change was seen. After staining the tissue section of the tumor block with Prussian blue, the scattered iron particles were found in the USPIO-VNN1 + PANC-VNN1 cell group, while the other 3 groups did not see this phenomenon. In addition, we also found that USPIO-VNN1 had good biocompatibility in mice and no obvious cytotoxicity. Conclusion: pancreas The high expression of VNN1 in adenocarcinoma cells can increase the oxidative stress response of the islets paracancerous by paracrine cysteamine, and then inhibit the activity of the islet and the downstream product cysteamine of the functional.VNN1 in the serum of the new diabetic patients with pancreatic cancer. The concentration of cysteamine in the serum can be detected in the pancreas. The identification of cancer related new onset diabetes and simple new onset diabetes may be used for early screening of pancreatic cancer. In addition, our MRI contrast agent USPIO-VNN1 can target VNN1 highly expressed pancreatic cancer cells in vivo. Combined with our previous study, we suggest that USPIO-VNN1 may be secondary to new onset diabetes. Specific imaging of early pancreatic cancer tissue may improve the early diagnosis rate of pancreatic cancer.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R735.9

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 王平;黃鎮(zhèn);崔彥;;胰腺癌的早期診斷[J];腫瘤學(xué)雜志;2015年10期

2 Quan-Jun Lin;Feng Yang;Chen Jin;De-Liang Fu;;Current status and progress of pancreatic cancer in China[J];World Journal of Gastroenterology;2015年26期

3 祝鵬;王偉軍;;胰腺癌癌前病變基因研究進(jìn)展[J];腫瘤防治研究;2014年10期

4 Marco Del Chiaro;Ralf Segersvrd;Matthias Lohr;Caroline Verbeke;;Early detection and prevention of pancreatic cancer:Is it really possible today?[J];World Journal of Gastroenterology;2014年34期

5 Keiichi Okanoi;Yasuyuki Suzuki;;Strategies for early detection of resectable pancreatic cancer[J];World Journal of Gastroenterology;2014年32期

6 何相宜;袁耀宗;;胰腺癌與糖尿病關(guān)系的研究進(jìn)展[J];臨床肝膽病雜志;2014年08期

7 鄧倩曦;姜政;;糖尿病與胰腺癌關(guān)系的研究進(jìn)展[J];安徽醫(yī)藥;2014年05期

8 Jin He;Andrew J Page;Matthew Weiss;Christopher L Wolfgang;Joseph M Herman;Timothy M Pawlik;;Management of borderline and locally advanced pancreatic cancer:Where do we stand?[J];World Journal of Gastroenterology;2014年09期

9 Raffaele Pezzilli;Nico Pagano;;Is diabetes mellitus a risk factor for pancreatic cancer?[J];World Journal of Gastroenterology;2013年30期

10 Keiichi Okano;Keitaro Kakinoki;Shintaro Akamoto;Masanobu Hagiike;Hisashi Usuki;Yuka Yamamoto;Yoshihiro Nishiyama;Yasuyuki Suzuki;;~(18)F-fluorodeoxyglucose positron emission tomography in the diagnosis of small pancreatic cancer[J];World Journal of Gastroenterology;2011年02期

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