BACKGROUND:New onset diabetes mellitus demonstrates a roughly correlation with pancreatic cancer (PaC), which is unique in PaC and was named as PaC-induced DM, but the inner mechanism remains unclear. Exosomes mediate intercellular communication and bearing microRNAs might be direct constituent of effect in target cells.METHODS AND RESULTS:The isolated exosomes from PaC cells were used to treat pancreatic β cells or the primary mice islets, and the glucose stimulated insulin secretions were measured. We validated the exosomal miR-19a from PaC cells to be an important mediator in the down regulation of insulin secretion by targeting Neurod1, the validated gene involved in insulin secretion, by using the quantitative real-time PCR, western blot, and promoter luciferase activity. The relative insulin, cAMP and Ca2+ expressions were also assayed to verify the inverse correlation between cancerous miR-19a and pancreatic islets Neurod1.CONCLUSIONS:Our study indicated that signal changes between cancer cells and β cells via exosomes might be important in the pathogenesis of PaC-induced DM and supplemented the pathogenesis of PaC-induced DM and provide a possible access of PaC screening strategy.

New-onset diabetes mellitus has a rough correlation with pancreatic cancer (PaC), but the underlying mechanism remains unclear. This study aimed to explore the exosomal microRNAs and their potential role in PaC-induced β-cell dysfunction. The pancreatic β cells were treated with isolated exosomes from PaC cell lines, SW1990 and BxPC-3, before measuring the glucose-stimulated insulin secretion (GSIS), validating that SW1990 and BxPC-3 might disrupt GSIS of both β cell line MIN6 and primary mouse pancreatic islets. The difference in expression profiles between exosomes and exosome-free medium of PaC cell lines was further defined, revealing that miR-19a secreted by PaC cells might be an important signaling molecule in this process. Furthermore, adenylyl cyclase 1 (Adcy1) and exchange protein directly activated by cAMP 2 (Epac2) were verified as the direct targets of exogenous miR-19a, which was involved in insulin secretion. These results indicated that exosomes might be an important mediator in the pathogenesis of PaC-DM, and miR-19a might be the effector molecule. The findings shed light on the pathogenesis of PaC-DM.

Abstract Secreted microRNAs (miRNAs) are novel endocrine factors that play essential pathological and physiological roles. Here, we report that pancreatic β cell‐released exosomal miR‐29 family members (miR‐29s) regulate hepatic insulin sensitivity and control glucose homeostasis. Cultured pancreatic islets were shown to secrete miR‐29s in response to high levels of free fatty acids (FFAs) in vitro. In vivo, high levels of FFAs, promoted by either high‐fat diet (HFD) feeding (physiopathological) or fasting (physiological), increased the secretion of miR‐29s into plasma. Intravenous administration of exosomal miR‐29s attenuated insulin sensitivity. The overexpression of miR‐29s in the β cells of transgenic (TG) mice promoted the secretion of miR‐29s and inhibited the insulin‐mediated suppression of glucose output in the liver. We used selective overexpression of traceable heterogenous mutant miR‐29s in β cells to confirm that islet‐derived exosomal miR‐29s target insulin signalling in the liver and blunt hepatic insulin sensitivity. Moreover, in vivo disruption of miR‐29s expression in β cells reversed HFD‐induced insulin resistance. In vitro experiments demonstrated that isolated exosomes enriched in miR‐29s inhibited insulin signalling in the liver and increased hepatic glucose production. These results unveil a novel β cell‐derived secretory signal—exosomal miR‐29s—and provide insight into the roles of miR‐29s in manipulating glucose homeostasis.

Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H-pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non-cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption. Consequently, intracellular ATP levels plummet, triggering activation of AMP-activated protein kinase (AMPK), and diminishing the mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) signaling. In orthotopic triple-negative breast cancer and subcutaneous lung cancer mouse models, this arylsulfonamide robustly suppresses primary tumor growth, inhibits the formation of distant metastases to the lung, and extends mouse survival while being very well tolerated. These therapeutic effects are further potentiated by co-administration of 2-deoxy-D-glucose (2-DG), a glucose analog and glycolysis inhibitor. Collectively, our findings provide preclinical proof of concept for the further development of this arylsulfonamide in combination with 2-DG towards cancer treatment.

Cancer-associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non-coding RNA involved in the post-transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co-cultured them with pancreatic cancer cell lines, BxPC-3 and SW1990, and observed the conversion from NF to CAF, or at least CAF-like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR-155 was upregulated in PaC-derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR-155 had been taken up. TP53INP1 is a target of miR-155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR-155. Targeting the circulating microRNA might be a potential therapy for malignant tumors.

In the present study, we synthesized a novel cationic copolymer composed of polyethylene glycol 5000 (PEG5K), vitamin E (VE), and diethylenetriamine (DET) at 1:4:20 molar ratio. The resulting PEG5K-VE4-DET20 copolymer formed nanoassemblies when mixed with the neutral PEG5K-VE4 copolymer at 1:8 weight ratio, which were investigated as the nanocarriers for combined delivery of paclitaxel and let-7b mimic. We found that the PEG5K-VE4-DET20 nanoassemblies could entrap paclitaxel for an extended period and burst release the drug in the presence of cathepsin B, demonstrating the biodegradability of the copolymers. At N/P ratio of 12:1, the PEG5K-VE4-DET20 nanoassemblies formed stable polyplexes with let-7b mimic, which were efficiently taken up by tumor cells and underwent endosomal escape. In non-small cell lung cancer A549 cells that harbor mutant KRAS, paclitaxel and let-7b mimic-loaded nanoassemblies (N-PTX/let-7b) markedly potentiated the cytotoxicity of paclitaxel, induced apoptosis, and diminished the invasiveness of tumor cells. In mice bearing subcutaneous A549 xenografts, intravenous administration of N-PTX/let-7b retarded tumor growth more efficaciously than Taxol. Our study demonstrates the promise of the PEG5K-VE4-DET20 nanoassemblies for concurrent delivery of hydrophobic drugs and miRNA mimics.

MicroRNAs (miRNAs) regulate multiple molecular pathways vital for the hallmarks of cancer with a high degree of biochemical specificity and potency. By restoring tumor suppressive miRNAs or ablating oncomiRs, miRNA-based therapies can sensitize cancer cells to conventional cytotoxins and the molecularly targeted drugs by promoting apoptosis and autophagy, reverting epithelial-to-mesenchymal transition, suppressing tumor angiogenesis, and downregulating efflux transporters. The development of miRNA-based therapeutics in combination with small-molecule anticancer drugs provides an unprecedented opportunity to counteract chemoresistance and improve treatment outcome in a broad range of human cancers. This review summarizes the mechanisms and advantages for the combination therapies involving miRNAs and small-molecule drugs, as well as the recent advances in the co-delivery nanocarriers for these agents.

Intestinal inflammation is characterized by epithelial disruption, leading to the loss of barrier function, recruitment of immune cells, and host immune responses to gut microbiota. PepT1, a di/tripeptide transporter that uptakes bacterial products, is up-regulated in inflamed colon tissue, which implies its role in bacterium-associated intestinal inflammation. Although microRNA (miRNA)-mediated gene regulation has been found to be involved in various processes of inflammatory bowel disease (IBD), the biological function of miRNAs in the pathogenesis of IBD remains to be explored. In this study we detected miRNA expression patterns in colon tissues during colitis and investigated the mechanism underlying the regulation of colonic PepT1 by miRNAs. We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR-193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF-κB pathway. Intracolonic delivery of miR-193a-3p significantly ameliorated dextran sodium sulfate-induced colitis, whereas the overexpression of colonic PepT1 via PepT1 3'-untranslated region mutant lentivirus vector abolished the anti-inflammatory effect of miR-193a-3p. Furthermore, antibiotic treatment eliminated the difference in the dextran sodium sulfate-induced inflammation between the presence and absence of miR-193a-3p. These findings suggest that miR-193a-3p regulation of PepT1 mediates the uptake of bacterial products and is a potent mechanism during the colonic inflammation process. Overall, we believe miR-193a-3p may be a potent regulator of colonic PepT1 for maintaining intestinal homeostasis.

BACKGROUND:New-onset diabetes mellitus in pancreatic cancer has been recognized as a paraneoplastic phenomenon caused by the existence of the tumor. Circulating microRNAs (miRNAs) are emerging as non-invasive biomarkers for the detection of various cancers. In the present study, we hypothesized that a specific serum miRNA profile exists in pancreatic cancer-associated new-onset diabetes mellitus (PaC-DM). METHODS:Initial screening of differentially expressed miRNAs in pooled serum samples from 25 PaC-DM patients, 25 non-cancer new-onset type 2 diabetes mellitus (T2DM) patients, and 25 healthy controls was performed by TaqMan low-density arrays (TLDA). A stem-loop quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was conducted to confirm the relative concentrations of candidate miRNAs in 80 PaC-DM, 85 non-cancer new-onset T2DM patients, and 80 healthy controls. RESULTS:The TLDA identified 16 serum miRNAs that were significantly increased in PaC-DM samples. A combination of six serum miRNAs (miR-483-5p, miR-19a, miR-29a, miR-20a, miR-24, miR-25) was selected by qRT-PCR as a biomarker for PaC-DM. The area under the receiver operating characteristic curve (AUC) for the six-miRNA panel training and validation sets was 0.959 (95% confidence interval [CI] 0.890-1.028) and 0.902 (95% CI 0.844-0.955), respectively. The combination of these six miRNAs enabled the discrimination of PaC-DM from non-cancer new-onset T2DM with an AUC of 0.885 (95% CI 0.784-0.986) and 0.887 (95% CI 0.823-0.952) for the training and validation sets, respectively. CONCLUSION:The six-serum miRNA panel may have potential as a biomarker for the accurate diagnosis and discrimination of PaC-DM from healthy controls and non-cancer new-onset T2DM.

KRAS is the most commonly mutated oncogene in human cancers and is associated with poor prognosis and drug resistance. Let-7 is a family of tumor suppressor microRNAs that are frequently suppressed in solid tumors, where KRAS mutations are highly prevalent. In this study, we investigated the potential use of let-7 as a chemosensitizer. We found that let-7b repletion selectively sensitized KRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type KRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEK/ERK and PI3K/AKT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in KRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of β-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of KRAS mutant tumors.

Objective To explore the role of pancreatic cancer-derived microvesicles (MV) and their enclosed microRNAs (miRNA) in the pathogenesis of pancreatic cancer induced diabetes mellitus (DM).Methods The supernatants of three pancreatic cancer cell lines SW1990, BxPC3 and PANC1 were collected, and MV were isolated with gradient centrifugation.The entrance of MV into pancreatic islet cell line MIN6 was proved by Western blot assay and fluorescence-label method.The miRNA-19a levels were measured in MV and MV-free supernatants of three pancreatic cancer cells lines.The three experimental groups were MIN6 cells separately treated by MV derive from SW1990, BxPC3 and PANC1, and untreated MIN6 cells were assigned to the control group.The miRNA-19a levels as well as changes of glucose stimulated insulin secretion (GSIS) were measured.Afterward, pre-miRNA-19a and anti-miRNA-19a were transfected into MIN6 cells by liposome, and the effects of them on GSIS were observed.Results CD63 and AGO2 as the protein markers of MV and the entrance of MV from pancreatic cancer into pancreatic islet cell line MIN6 were detected by Western blotting.The miRNA-19a levels in MV and MV-free supernatants of SW1990, BxPC3 and PANC1 were (132.7±16.0), (32.8±4.3), (78.4±8.9),(22.6±3.3), (63.3±12.0) and (23.3±3.3) pmol/L, respectively, and the differences were statistically significant (t=10.44, 10.12 and 5.56,all P＜0.01).Compared to the MIN6 control group, the miRNA-19a levels of MIN6 treated by MV from SW1990, BxPC3 and PANC1 significantly increased, and the 2-△△Ctvalue was 2.02 ± 0.50, 1.80 ± 0.41 and 2.11 ± 0.59, respectively, and the differences were statistically significant (t=2.97, 2.77, 2.84;all P＜0.05).Stimulated with high glucose, the GSIS of pancreatic islet cells treated by SW1990, BxPC3 and PANC1 in three groups decreased, which were (103.73±16.49), (141.17±11.26), and (138.24±13.97) ng · mg protein-1 · h-1 MV, respectively, and that of control group was (256.24 ± 33.05) ng · mg protein-1 · h-1.The differences were statistically significant (t=4.13, 3.30 and 3.29, all P＜0.05).Compared with control group, GSIS of pre-miRNA-19a treated MIN6 remarkably decreased, which was (126.17± 62.87) ng · mg protein-1 ·h-1 and (316.72±91.87) ng · mg protein-1 · h-1 , and the difference was statistically significant (t=2.97, P＜0.05).GSIS of MIN6 cells transfected with anti-miRNA-19a was higher than that of control group, which was (697.47±77.62) ng · mg protein 1 · h-1 and (355.33 ±84.77) ng · mg protein-1 ·h-1 , and the difference was statistically significant (t=-2.97,P＜0.05).Conclusion The entrance of MV derived from pancreatic cancer into pancreatic islet cell line MIN6 may cause the dysfunction of insulin secretion an important signaling molecules, miRNA-19a.

PURPOSE:The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors.METHODS:A novel copolymer comprised of polyethylene glycol 5000 (PEG114), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG114-VE4-TA4 copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG114-VE4-TA4 micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles were assessed in a human ovarian cancer xenograft murine model.RESULTS:The crosslinked PEG114-VE4-TA4 micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG114-VE4-TA4 micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol®, respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non-crosslinked counterparts and Taxol®.CONCLUSIONS:These results suggest that the crosslinked PEG114-VE4-TA4 nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.

Gemcitabine is a potent anticancer drug approved for the treatment of pancreatic, non-small-cell lung, breast, and ovarian cancers. The major deficiencies of current gemcitabine therapy, however, are its rapid metabolic inactivation and narrow therapeutic window. Herein, we employed polyethylene glycol-b-distearoylphosphatidylethanolamine (PEG-DSPE)/tocopheryl polyethylene glycol 1000 succinate (TPGS) mixed micelles as a delivery system, to improve the pharmacokinetic characteristics of gemcitabine and enhance its antitumor efficacy. By conjugating stearic acid to gemcitabine and subsequently encapsulating stearoyl gemcitabine (GemC18) within PEG-DSPE/TPGS mixed micelles, the deamination of gemcitabine was delayed in vitro and in vivo. Importantly, compared to free gemcitabine, GemC18-loaded micelles pronouncedly prolonged the circulation time of gemcitabine and elevated its concentration in the tumor by 3-fold, resulting in superior antitumor efficacy in mice bearing human pancreatic cancer BxPC-3 xenografts. Our findings demonstrate the promise of PEG-DSPE/TPGS mixed micelles as a nanocarrier system for the delivery of gemcitabine to achieve safer and more efficacious therapeutic outcomes.

背景:已有研究发现部分血清miRNA与胃癌密切相关,但对早期胃癌的研究较少见.目的:探讨血清miR-1、miR-20a、miR-27a、miR-34a、miR-423-5p表达在胃癌尤其是早期胃癌诊断中的价值.方法:采用qRT-PCR法检测180例胃癌患者(包括149例进展期胃癌和31例早期胃癌)、49例癌前变化患者、57名健康对照者的血清miR-1、miR-20a、miR-27a、miR-34a、miR-423-Sp表达.采用ROC曲线判断miRNA的诊断敏感性和特异性.结果:胃癌患者血清miR-1、miR-20a、miR-34a、miR-423-5p表达显著升高(P＜0.05),ROC曲线下面积(AUG)分别为0.894 9、0.814 8、0.6448、0.589 7,四者联合的AUC为0.921 1,敏感性和特异性分别为85.8％和83.3％.早期胃癌中miR-1和miR-20a的表达明显升高(P＜0.05),AUC分别为0.813 8和0.774 2,两者联合的AUC为0.865 3,敏感性和特异性分别为80.5％和83.6％.进展期胃癌中miR-1的表达显著高于早期胃癌(P =0.012 1),且术后表达明显降低(P =0.018 5).结论:miR-1、miR-20a、miR-34a、miR-423-5p可作为肿瘤标记物对胃癌进行诊断,miR-1、miR-20a可作为诊断早期胃癌的标记物.

目的:探讨C型凝集素样受体Dectin-1及相关信号通路在溃疡性结肠炎(ulcerative colitis,UC)肠道黏膜免疫中的作用.方法:选取30例活动期UC患者和20名正常对照者,在内镜下于直肠乙状结肠交界处取4块标本进行研究,UC患者的活检标本取自内镜下可见的炎症活动部位.采用实时PCR、蛋白印迹检法及免疫组织化学法检测标本肠上皮中Deetin-1、IL-23p19和核转录因子-κB (NF-κB)途径相关蛋白激酶磷酸化的表达水平.结果:UC患者结肠黏膜中Dectin-l mRNA及其蛋白的表达水平均明显高于正常对照者(3.75±1.98比1.94±1.37,P＜0.05;2.26±1.49比1.28±0.93,P＜0.01);而UC患者结肠黏膜中IL-23p19 mRNA表达水平明显高于正常对照者(6.01 ±2.48比1.36±1.08,P＜0.01);且IκB和NF-κBp65蛋白磷酸化亦较正常对照者明显增加.UC患者的Dectin-l表达水平与其C反应蛋白的表达量呈正相关.结论:Dectin-1、炎症因子IL-23p19的表达及NF-κB通路活性在UC患者中明显增强,且UC患者的Dectin-1表达水平与其炎症程度呈正相关,提示Dectin-l可能在UC患者肠道黏膜免疫中发挥重要作用.

Recent studies by our group and others show that microRNAs can be actively secreted into the extracellular environment through microvesicles (MVs) and function as secretory signaling molecules that influence the recipient cell phenotypes. Here we investigate the role of monocyte-secreted miR-150 in promoting the capillary tube formation of endothelial cells and in enhancing angiogenesis. In vitro capillary tube formation and in vivo angiogenesis assays showed that monocyte-derived MVs have strong pro-angiogenic activities. By depleting miR-150 from monocytic MVs and increasing miR-150 in MVs derived from cells that normally contain low levels of miR-150, we further demonstrated that the miR-150 content accounted for the pro-angiogenic activity of monocytic MVs in these assays. Using tumor-implanted mice and ob/ob mice as models, we revealed that miR-150 secretion, which is increased for diseases such as cancers and diabetes, significantly promotes angiogenesis. The delivery of anti-miR-150 antisense oligonucleotides into tumor-implanted mice and ob/ob mice via MVs, however, strongly reduced angiogenesis in both types of mice. Our results collectively demonstrate that secretion of miR-150 via MVs can promote angiogenesis in vitro and in vivo, and we also present a novel microRNA-based therapeutic approach for disease treatment.

Objective To analyze the efficacy and safety of Infliximab in treatment of ulcerative colitis(UC).Methods Randomized controlled trials of IFX in patients with UC were searched by electronic retrieve and hand retrieve.Seven studies and seven RCTs were enrolled into the analysis.The information of the trial design,characters of the subjects,results of the studies were analyzed by Revman 4.2 software.Results The long-term and short-term effects in IFX group were significantly different compared with the control group.The long-term and short-term effects in IFX 5 mg/kg group and IFX 10 mg/kg group were significantly different compared with the control group.There was no difference in long-term and short-term effect between IFX group and control group.There was no difference in side effect of medicine between IFX group and control group.Conclusion Infliximab could not only maintain the clinical remission in UC patients,but also decrease the colon resection rate for patients with moderate to severe refractory UC.It could also improve the life qualities.RCT of multiplicity centers is necessary to confirm the conclusion with large samples.

Objectives Cancer stem cells (CSCs) compose a subpopulation of cells within a tumour that can self-renew and proliferate. Growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF) promote cancer stem cell proliferation in many solid tumours. This study assesses whether EGF, bFGF and IGF signalling pathways are essential for colon CSC proliferation and self-renewal. Material and methods Colon CSCs were cultured in serum-free medium (SFM) with one of the following growth factors: EGF, bFGF or IGF. Characteristics of CSC gene expression were evaluated by real time PCR. Tumourigenicity of CSCs was determined using a xenograft model in vivo. Effects of EGF receptor inhibitors, Gefitinib and PD153035, on CSC proliferation, apoptosis and signalling were evaluated using fluorescence-activated cell sorting and western blotting. Results Colon cancer cell HCT116 transformed to CSCs in SFM. Compared to other growth factors, EGF was essential to support proliferation of CSCs that expressed higher levels of progenitor genes (Musashi-1, LGR5) and lower levels of differential genes (CK20). CSCs promoted more rapid tumour growth than regular cancer cells in xenografts. EGFR inhibitors suppressed proliferation and induced apoptosis of CSCs by inhibiting autophosphorylation of EGFR and downstream signalling proteins, such as Akt kinase, extracellular signal-regulated kinase 1/2 (ERK 1/2). Conclusions This study indicates that EGF signalling was essential for formation and maintenance of colon CSCs. Inhibition of the EGF signalling pathway may provide a useful strategy for treatment of colon cancer.

近年来,经肛内镜显微手术(transanal endoscopic microsurgery,TEM)已取得了令人鼓舞的进展,患者可以得到更加个体化的治疗,但狭小的盆腔及周围泌尿生殖器官影鞍响了低位结肠直肠癌手术的彻底清除.