Ⅰ：谷氨酰半胱氨酸连接酶在肾透明细胞癌中表达的研究；Ⅱ：原位球形回肠膀胱术的尿动力学研究
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摘要
背景
肾细胞癌(Renal cell carcinoma, RCC)通常又被称为肾癌,是一组来源于肾小管上皮细胞的恶性肿瘤,属于泌尿系统中最常见的一种的恶性肿瘤,近年来,肾细胞癌的发病率和死亡率均有逐年增高的趋势,其发病机理还不完全明了。近年来,已有充分研究证据表明,在肿瘤的发生发展过程中,细胞氧化还原系统的动态平衡发生了非常重要的变化,氧化应激可能在肿瘤的发生发展过程起着重要的作用,这与氧化应激导致细胞的DNA损伤密切相关[1]。活性氧产物的增加与肿瘤病人病情的进展密切相关,甚至,在癌前病变中就已经发现活性氧产物有所增加[2-4]。在恶性肿瘤细胞中,抗氧化物的水平降低伴随着活性氧产物的增多。在肾透明细胞癌中,细胞氧化还原系统的平衡状态同样发生了巨大的变化[5]。在RCC中,一些氧化相关的脂质、蛋白及DNA发生相应的改变[6]。Mougiakakos等研究发现活性氧成分在黑色素瘤的发生发展过程中扮演着重要的角色,抗氧化治疗能够有效的抑制肿瘤的进展和转移[1]。谷胱甘肽在机体的生化的防御系统中起着相当重要的作用,其主要的生理作用之一就是能够清除掉机体内在代谢过程中产生的自由基,做为机体的一种非常重要的抗氧化剂,保护体内各种蛋白质和各种酶等大分子的巯基。谷氨酰半胱氨酸连接酶(GCL)作为谷胱甘肽代谢过程中的关键酶,其催化亚基更高水平的表达能够使肿瘤细胞内活性氧产物水平显著降低并且减低肿瘤细胞增殖的程度[1]。
目的
目前,谷胱甘肽代谢过程中的关键酶谷氨酰半胱氨酸连接酶在肾细胞癌中尚无系统性的研究,我们的研究目的是通过对GCL在基因水平、蛋白水平和活性水平的研究,探讨其在肾透明细胞癌中变化,为肾细胞癌的治疗和预后的判断提供一定的实验室依据。
方法
对肾透明细胞癌和正常查体人群的临床血液学、生物化学及血凝指标等实验室参数进行了统计分析；采用实时荧光定量PCR (quantitative realtime-PCR)方法对46例肾透明细胞癌组织和39例对照癌旁肾组织中的GCL的催化亚基(GCLC)和调节亚基(GCLM) mRNA的表达情况进行分析检测；运用蛋白印迹(Western blotting)方法对肾透明细胞癌组织和对照癌旁肾组织中的GCL的催化亚基(GCLC)和调节亚基(GCLM)蛋白的表达情况进行分析检测；运用酶活性分析检测肾透明细胞癌组织和对照癌旁肾组织中的GCL活性的变化。实验中所获得的数据采用统计学软件SPSS13.0进行分析处理,采用Student's two-tailed t-tests进行差异性分析,p<0.05认为差异具有显著性,所有数据均使用均数±标准误(SEM)来表示。
结果
通过荧光定量PCR的分析结果显示,与对照组相比较,在肾透明细胞癌组织中GCLc基因和GCLm基因的表达呈现出明显下降的趋势,其差别具有统计学意义(GCLc基因：CCRCC组1±0.028,对照组3.74±0.545；p<0.01)(GCLm基因：CCRCC组1±0.05,对照组3.07±0.571；p<0.01)。通过蛋白印迹的分析结果显示,与对照组相比较,在。肾透明细胞癌组织中GCLC和GCLM的蛋白含量呈现出明显下降的趋势,其差别具有统计学意义(GCLc基因：CCRCC组0.983±0.022,对照组1.248±0.076；p<0.05)(GCLm基因：CCRCC组1.103±0.014,对照组1.306±0.033；p<0.05)。通过酶活性分析显示,与对照组相比较,GCL酶活性在。肾透明细胞癌组织中的活性显著增高(p<0.01)。肾透明细胞癌中GCL的平均酶活为342±85mmol/min/mg protein,而对照组织中的GCL平均酶活为98±21mmol/min/mg protein。
结论
在肾透明细胞癌中,谷氨酰半胱氨酸连接酶的催化亚基和调节亚基的基因表达和蛋白含量明显降低,提示在肾细胞癌中可能通过谷氨酰半胱氨酸连接酶基因表达和蛋白含量的变化进而调节谷胱甘肽在肿瘤细胞中的表达,从而对肿瘤细胞的氧化状态造成影响,进而影响肿瘤细胞的增殖和分化；肾透明细胞癌中GCL酶活性显著升高,提示在肿瘤细胞中,可能因为酶含量的变化需要更高的酶活性来调节细胞的氧化平衡状态。本研究结果显示谷胱甘肽代谢过程中的限速酶谷氨酰半胱氨酸连接酶可能作为治疗肾细胞癌及判断肾细胞癌患者预后的一个有效的靶点。
背景
膀胱肿瘤在世界范围内恶性肿瘤发病率的排名中位列第九位,随着生活环境的改变以及人类自然寿命的不断延长,它的发病率目前呈逐渐上升。在我国的泌尿系肿瘤中膀胱肿瘤是泌尿外科临床上最常见的恶性肿瘤,无论是其发病率还是死亡率都位居第一位,是一种对患者生命安全造成直接威胁的恶性泌尿系统疾病。膀胱癌的发病年龄没有特定性,可见于任何年龄的人群甚至是婴幼儿,但其主要发病年龄还是在30岁以后的中老年人,并且其发病率和死亡率随着年龄的增长呈现递增的趋势。
膀胱癌的发生是多因素、多步骤、长期的病理过程,外在环境因素和内在遗传因素都可能是膀胱肿瘤发生的原因,二者互为影响。目前吸烟和接触化工产品是公认的两大致癌原因。膀胱正常细胞的恶变始于细胞内DNA的改变,目前大多数病因学的研究主要集中在膀胱正常细胞的改变,癌基因是原癌基因的突变方式,后者编码人体正常细胞生长所必需的生长因子和受体蛋白。原癌基因发生突变后成为癌基因,癌基因可使正常细胞发生无节制的分裂生长,从而导致膀胱癌复发和进展。
对于浸润性膀胱癌,根治性膀胱切除加分盆腔淋巴结清扫术是提高浸润性膀胱癌患者生存率、减少局部复发和远处转移最有效的方法。其中原位新膀胱术是首选的膀胱替代方法,目前原位新膀胱术可应用于男性和女性患者,已经逐渐成为膀胱全切术后尿流改道主要的手术方式。原位膀胱术以其术后长期出色的生活质量、新膀胱功能和排尿方式证实了其作为首选的膀胱重建术式。而部分患者术后尿失禁、输尿管狭窄及长期的保留导尿则降低了原位膀胱重建术后患者的生活质量。尿流动力学是利用电生理学、流体力学的原理及传感器技术对尿路贮尿、排尿及病理生理进行研究的一门科学,它可以直接利用图像和数据来量化地反映尿路的功能。国内有关胱全切加原位球形回肠膀胱术的研究未见报道,其临床效果也尚待进一步验证。因此自2009年8月以来,我们对行根治性膀胱全切加原位球形回肠膀胱术的46例男性患者,应用尿流动力仪对利用末段回肠制作的球形储尿囊进行了系统的检测,对其进行充盈性膀胱测压、压力／流率、尿道压力等测定,同时分析我院近几年的该类手术病例的随访数据如围手术期并发症、生活质量评分、排尿和控尿的调查,评价新膀胱的功能,从尿动力学角度阐明其尿动力学特点,进一步减少和预防术后新膀胱输尿管尿液返流、残余尿、尿失禁、夜间遗尿等并发症,提出了我们的观点,使该术式能够更好地应用于临床。
本研究将全面深入地分析原位球形回肠膀胱术的并发症、尿动力学特点以及生活质量调查,为该项手术的改进和临床应用提供科学依据。
目的
膀胱全切为肌层浸润膀胱癌的标准术式,而回肠新膀胱为原位膀胱替代最常用的选择。我们对行根治性膀胱全切加原位球形回肠膀胱术的46例男性患者术后并发症、尿动力学数据和生活质量随访的临床资料进行回顾性分析,研究患者术后12个月内新膀胱功能的特点,深入地分析原位球形回肠膀胱术的并发症、尿动力学特点以及生活质量调查,探讨新膀胱的尿动力特征和临床效果,为该项手术的改进提供临床依据。
患者和方法
这项研究包括2009年8月～2011年8月期间行根治性膀胱全切加原位球形回肠膀胱术的46例男性膀胱癌患者,术后并发症以及生活质量的调查于术后12个月完成。于术后第3、6、9、12个月分别对患者进行回肠新膀胱进行尿动力学测定,观察新膀胱的容量、充盈期压力和排尿期新膀胱压力-流率、尿道压、自由尿流率和残余尿量的变化。我们记录患者的排尿方式、白天和夜间的排尿次数以及控尿情况,并对患者的尿动力学资料进行比较。我们采用一种有效的调研方法(SF-36,以邮递的方式进行)对根治性膀胱全切加原位球形回肠代膀胱术的46例男性膀胱癌患者的生活质量展开调查。对所有患者生活质量的调查被分生理生活质量和心理生活质量两部分,将结果然后与公布的以年龄为基础的基准作比较。
结果
46例患者有28例术后有早期并发症,包括切口感染、肠梗阻、酸中毒,但是只有3例(6.5%)需要外科手术干预,12例有晚期并发症如输尿管吻合口狭窄、后尿道狭窄。46例患者均能自行排尿,研究证实患者功能性膀胱容量于术后3到12个月从386毫升增加到了455毫升(范围为366毫升到784毫升),控尿情况也随之好转。手术建立的回肠新膀胱在充盈期具有良好的顺应性,术后几个月时大多数新膀胱容量不超过400毫升时其基本压力不大于15厘米水柱,膀胱完全充盈其压力平均为18.5厘米水柱。术后最大尿流率和残余尿量分别为19.6毫升每秒和32毫升。术后12个月时46例患者中有44例(95.6%)白天可控和27例(58.6%)夜间可控。12个月时我们通过对术后不同时期尿动力学检查结果的比较,发现新膀胱功能于术后平均6个月达到了以较短的肠管获得低压、可控、较大容量的目标,并处于稳定。通过CT、彩超和血肌酐测定发现只有4例输尿管狭窄但没有肾功能破坏及上尿路肿瘤复发,影像学检查发现在膀胱没有过度充盈的情况下没有发生膀胱输尿管反流。患者通过增加腹压和开放尿道可以获得排尿,尿动力学检查发现排尿期回肠新膀胱没有发生像正常膀胱逼尿肌一样的收缩。生活质量调查显示与相同年龄的正常人相比较,根治性膀胱全切加原位球形回肠代膀胱术的患者术后并没有降低患者的生活质量。有关病因和危险因素分类方面的知识揭示了通过新膀胱的正确设计、精细的外科技巧可以有效预防新膀胱机能失败的发生,另外对患者的选择也是非常重要的因素。
结论
我们的研究发现利用原位球形回肠膀胱术建立新膀胱贮尿和排尿功能与正常的膀胱类似,它所需的回肠较其它术式较短,尿动力学检查以及生活质量调查结果提示新膀胱容量较大、压力低、可控性良好、生活质量佳,是一种原位膀胱重建的良好术式。
创新和意义
本研究在国内首次全面深入地对根治性膀胱全切加原位球形回肠膀胱术的46例男性膀胱癌患者进行了术后并发症、尿动力学检查以及生活质量的调查,对该项手术的改进提供了科学依据。本研究还在国内率先探讨尿失禁与肠管蠕动的关系,为今后该项手术提供了有效的参考数据和循证医学支持。此外,本研究还对白天尿失禁和夜间尿失禁进行了比较,有关这方面的研究国内文献尚未见报道。
Background
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, and its incidence is increasing in recent years. But its pathogenesis has not been yet fully elucidated. Oxidative stress has been implicated in the carcinogenic process, which is mainly due to oncogenic DNA damages. In addition, enhanced production of reactive oxygen species (ROS) has been linked to disease progression by promoting survivability, proliferation, and even horizontal cell growth. Noticeable, elevated ROS production can already be observed in premalignant lesions. Endogenous antioxidants are found at reduced levels from tumor patients, which is in line with observations of increased ROS levels in tumor cells of more aggressive phenotypes. There is growing evidence suggesting that during tumor growth important changes appear in the cellular redox homeostasis. It is believed that renal cell carcinoma (RCC) of the clear cell type also belongs to tumors in which signifiant changes occur in cellular redox balance. Thus, in RCC marked oxidative alterations of lipids, proteins and DNA have been found. Higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Glutamate-L-cysteine ligase (GCL) catalyzes the rate-limiting step of glutathione [L-g-glutamyl-cysteinyl-glycine(GSH)] synthesis, the key cellular antioxidant. Higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation.
Objective
In this study, we detect the gene and protein expression of GCLc and GCLm in renal tissues through quantitative real-time PCR and western blotting, and analyze the GCL activity between clear cell renal cell carcinoma and control groups. Through experiments in vitro, we aim to do the preliminary investigations on the biological functions of GCL in the pathogenic mechanism of RCC.
Methods
The hematologic indexes of the blood, the biochemical parameters and coagulation markers were analyzed in clear cell renal cell carcinoma and healthy control groups. Semi-quantative real time-PCR (qRT-PCR) was used to assay the mRNA expression of GCLc and GCLm subunit in clear cell renal cell carcinoma and control para-carcinoma tissue groups. Protein contents of GCLc and GCLm subunit in clear cell renal cell carcinoma and control para-carcinoma tissue groups were determined by Western blotting. GCL activity was determined by a fluorescence assay.Data was analyzed through SPSS13.0Software. Difference analysis was done using Student's two-tailed t-tests. p<0.05indicate the differences. Data are expressed as mean±S.E.
Results
The results indicated that the mRNA expression of GCLc and GCLm subunit in clear cell renal cell carcinoma has a significant decrease compared with control para-carcinoma tissue groups through Semi-quantative real time-PCR (GCLc: CCRCC group1±0.028, Control groups3.74±0.545; p<0.01)(GCLm:CCRCC group1±0.05, Control groups3.07±0.571;p<0.01). Through Western blotting, the results indicated that the protein contents of GCLC and GCLM subunit in clear cell renal cell carcinoma has a significant decline compared with control para-carcinoma tissue groups (GCLc:CCRCC group0.983±0.022, Control groups1.248±0.076; p <0.05)(GCLm:CCRCC group1.103±0.014, Control groups1.306±0.033; p<0.05). The analysis of GCL activity indicated that GCL activity in clear cell renal cell carcinoma was improved compared with control groups (CCRCC group:342±85mmol/min/mg protein; Control groups:98±21mmol/min/mg protein;p <0.01)
Conclusions
The mRNA expression and protein content of GCLC and GCLM in clear cell renal cell carcinoma was decreased. Perhaps, expression of GSH in tumor cells of renal cell carcinoma was regulated by gene expression of glutamine cysteine ligase and the change of protein content, thus affect the oxidation state, the proliferation and differentiation of tumor cells. The GCL enzyme activity in cells of renal clear cell carcinoma increased significantly. The result may be implied that change of enzyme content in tumor cells need higher enzyme activity to regulate the equilibrium of cell oxidation state. The results show that glutamine cysteine ligase may be as an indicator for treatment and judging the prognosis of patients with renal cell carcinoma.
Background
Bladder transitional cell carcinoma (BTCC) is the ninth most common urologic tumor in worldwide. The morbidity rate is increasing with the change of circumstance and the prolonged life. In China, BTCC is the most common urologic tumor for its highest morbidity and mortality. Though BTCC have not specific incident age, even can appear in infants, it really show a tendency of onset after age of30's. furthermore, the morbidity and mortality show directly correlation with age.
The carcinogenesis of bladder cancer is a long process covered multi-factor and multi-step. During the carcinogenesis, genetic factors and environmental factors exist comprehensive cross-talk. Currently, most people accept smoking and chemical materials can lead to carcinogenesis.The initial change during carcinogenesis is from DNA, the most common manner is DNA mutation. Proto-oncogene change to oncogene by mutation, then the cellular division become endless and cause carcinogenesis at last.
Currently radical cystectomy with bilateral pelvic Lymphadenectomy followed with urinary diversion is the primary treatment modality in individuals with muscle-invasive bladder cancer. Among the different techniques of urinary diversion, Neobladder become the most popular technique these years. The superiority of neobladder mainly reflected by excellent life quality after operation and satisfied urinary control. Though with these superiorities, few patients would followed incontinence and ureterostenosis as well as long time catherization, these factors do decrease the life quality of these patients. Urodynamics is one kind of science that reflect the functional urethra by picture and data based on electrophysiology, fluid mechanics, sensor technology. There are very few reports about the urinary control after the procedure of neobladder, thus the clinical effectiveness still need further research in China. From Aug.2009, we perform urodynamic researchs on46patients that received neobladder. Our research covered filling cystometry, pressure-flow study, urethral pressure, etc. meanwhile, aimed to decrease the incidence of vesicoureteral reflux, residual urine, incontinence, enuresis, we further analyzed the perioperative complications, life quality score, urinary control and some others factors focused on the neobladder.
Current research will offer further evidences for the improvemwnt of orthotopic continent ileal N-bladder reconstruction by comprehensively analyze the complications, urodynamic features and life quality.
Objective
Radical cystectomy is the method of choice in management of muscle invasive, organ-confined tumors of the bladder (T2-T4, NO-Nx). The most frequent continent orthotopic urinary diversion after radical cystectomy is the ileal neobladder. To retrospectively review our clinical experience with a single series of46patients who underwent orthotopic continent ileal N-bladder replacement after radical cystectomy during a12-month period. Data are concerning the changes in complications,urodynamic characteristics functional outcomes and quality of life. The object of this study is to evaluate the urodynamic and functional characteristics of46patients and to provide proof for this technique's improvement.
Methods
The study included46consecutive Chinese patients with orthotopic continent ileal N-bladder replacement after radical cystectomy created using the modified technique described previously. We examined the complications.urodynamic characteristics functional outcomes and quality of life.Complications, functional outcomes and health-related quality of life (HRQL, using the Short-Form36instrument)were evaluated in46patients with a mean follow-up of12months. Urodynamics were obtained a mean of11months (range3to24) after construction of the neobladder and it was performed in all patients to determine neobladder capacity, filling and voiding pressures,urethral pressure profile,peak and mean urinary flow and postvoid residual urine. All perioperative and longterm complications were recorded. The voiding pattern, frequency of micturition and continence were assessed, and a complete urodynamic profile recorded. A total of46patients completed by mail the SF-36, a validated quality-of-life survey. Completed surveys were then analyzed into physical (PCS) and mental (MCS) component quality-of-life scores per published protocols. Results were then compared with published age-based norms.
Results
There were23early complications in46patients, including wound infection, ileus, and pyelonephritis etc, although open surgical intervention was required in only nine (6.5%). with9late complications including uretero-intestinal stricture in four and entero-urethral stricture in five. All patients could void spontaneously, the mean maximum cystometric pouch capacity was546ml(range from366ml to784ml). The neobladders demonstrated good compliance for the storage of urine, with a mean basal pressure of less than15cm. water at volumes of less than400cc and of22.4cm. water (range1to72) at100%capacity.The mean maximum flow rate, voided volume and postvoid residualwere19.6mL/s and42mL.The mean maximum flow rate, voided volume and postvoid residualwere18.6mL/s,345.3mL and24.5mL respectively. Daytime and nighttime continence were achieved in95.6%and58.6%respectively. Upper tract surveillance with computed tomography,renal ultrasound and serum creatinine estimation has shown4right ureteral strictures but no significant upper tract deterioration or ureteral recurrence.significant reflux was not observed during video urodynamics unless the reservoir was overfilled. During voiding.by outlet relaxation and straining if necessary. Ulike a normal bladder, no isolated intravesical pressure increase occurred. Through interviews and questionnaires we can find the neobladder'function attain stable at6months after its reconstruction. The HRQL survey after surgery showed no significant differences scores between the46patients with a ileal neobladder and an age-matched control population in chinese. Knowledge of the pathogenesis and identification of risk factors implies that prevention through proper design of the neobladder, meticulous surgical technique, and patient selection is paramount.
Conclusions
In this study, we found that orthotopic global neobladder reconstruction offers similar storage and voiding functions to normal bladder. We conclude that an orthotopic continent ileal N-bladder constructed shorter ileum than other similar operations. The urodynamics results and quality of life outcome proves that it has an adequate capacity at low pressures with a satisfactory continence rate. Our data suggest that although it is not a complication-free procedure, we advocate its use when possible.
肾细胞癌(Renal cell carcinoma, RCC)通常又被称为肾癌,是一组来源于肾小管上皮细胞的恶性肿瘤,属于泌尿系统中最常见的一种的恶性肿瘤,近年来,肾细胞癌的发病率和死亡率均有逐年增高的趋势,其发病机理还不完全明了。近年来,已有充分研究证据表明,在肿瘤的发生发展过程中,细胞氧化还原系统的动态平衡发生了非常重要的变化,氧化应激可能在肿瘤的发生发展过程起着重要的作用,这与氧化应激导致细胞的DNA损伤密切相关[1]。活性氧产物的增加与肿瘤病人病情的进展密切相关,甚至,在癌前病变中就已经发现活性氧产物有所增加[2-4]。在恶性肿瘤细胞中,抗氧化物的水平降低伴随着活性氧产物的增多。在肾透明细胞癌中,细胞氧化还原系统的平衡状态同样发生了巨大的变化[5]。在RCC中,一些氧化相关的脂质、蛋白及DNA发生相应的改变[6]。Mougiakakos等研究发现活性氧成分在黑色素瘤的发生发展过程中扮演着重要的角色,抗氧化治疗能够有效的抑制肿瘤的进展和转移[1]。谷胱甘肽在机体的生化的防御系统中起着相当重要的作用,其主要的生理作用之一就是能够清除掉机体内在代谢过程中产生的自由基,做为机体的一种非常重要的抗氧化剂,保护体内各种蛋白质和各种酶等大分子的巯基。谷氨酰半胱氨酸连接酶(GCL)作为谷胱甘肽代谢过程中的关键酶,其催化亚基更高水平的表达能够使肿瘤细胞内活性氧产物水平显著降低并且减低肿瘤细胞增殖的程度[1]。
目的
目前,谷胱甘肽代谢过程中的关键酶谷氨酰半胱氨酸连接酶在肾细胞癌中尚无系统性的研究,我们的研究目的是通过对GCL在基因水平、蛋白水平和活性水平的研究,探讨其在肾透明细胞癌中变化,为肾细胞癌的治疗和预后的判断提供一定的实验室依据。
方法
对肾透明细胞癌和正常查体人群的临床血液学、生物化学及血凝指标等实验室参数进行了统计分析；采用实时荧光定量PCR (quantitative realtime-PCR)方法对46例肾透明细胞癌组织和39例对照癌旁肾组织中的GCL的催化亚基(GCLC)和调节亚基(GCLM) mRNA的表达情况进行分析检测；运用蛋白印迹(Western blotting)方法对肾透明细胞癌组织和对照癌旁肾组织中的GCL的催化亚基(GCLC)和调节亚基(GCLM)蛋白的表达情况进行分析检测；运用酶活性分析检测肾透明细胞癌组织和对照癌旁肾组织中的GCL活性的变化。实验中所获得的数据采用统计学软件SPSS13.0进行分析处理,采用Student's two-tailed t-tests进行差异性分析,p<0.05认为差异具有显著性,所有数据均使用均数±标准误(SEM)来表示。
结果
通过荧光定量PCR的分析结果显示,与对照组相比较,在肾透明细胞癌组织中GCLc基因和GCLm基因的表达呈现出明显下降的趋势,其差别具有统计学意义(GCLc基因：CCRCC组1±0.028,对照组3.74±0.545；p<0.01)(GCLm基因：CCRCC组1±0.05,对照组3.07±0.571；p<0.01)。通过蛋白印迹的分析结果显示,与对照组相比较,在。肾透明细胞癌组织中GCLC和GCLM的蛋白含量呈现出明显下降的趋势,其差别具有统计学意义(GCLc基因：CCRCC组0.983±0.022,对照组1.248±0.076；p<0.05)(GCLm基因：CCRCC组1.103±0.014,对照组1.306±0.033；p<0.05)。通过酶活性分析显示,与对照组相比较,GCL酶活性在。肾透明细胞癌组织中的活性显著增高(p<0.01)。肾透明细胞癌中GCL的平均酶活为342±85mmol/min/mg protein,而对照组织中的GCL平均酶活为98±21mmol/min/mg protein。
结论
在肾透明细胞癌中,谷氨酰半胱氨酸连接酶的催化亚基和调节亚基的基因表达和蛋白含量明显降低,提示在肾细胞癌中可能通过谷氨酰半胱氨酸连接酶基因表达和蛋白含量的变化进而调节谷胱甘肽在肿瘤细胞中的表达,从而对肿瘤细胞的氧化状态造成影响,进而影响肿瘤细胞的增殖和分化；肾透明细胞癌中GCL酶活性显著升高,提示在肿瘤细胞中,可能因为酶含量的变化需要更高的酶活性来调节细胞的氧化平衡状态。本研究结果显示谷胱甘肽代谢过程中的限速酶谷氨酰半胱氨酸连接酶可能作为治疗肾细胞癌及判断肾细胞癌患者预后的一个有效的靶点。
背景
膀胱肿瘤在世界范围内恶性肿瘤发病率的排名中位列第九位,随着生活环境的改变以及人类自然寿命的不断延长,它的发病率目前呈逐渐上升。在我国的泌尿系肿瘤中膀胱肿瘤是泌尿外科临床上最常见的恶性肿瘤,无论是其发病率还是死亡率都位居第一位,是一种对患者生命安全造成直接威胁的恶性泌尿系统疾病。膀胱癌的发病年龄没有特定性,可见于任何年龄的人群甚至是婴幼儿,但其主要发病年龄还是在30岁以后的中老年人,并且其发病率和死亡率随着年龄的增长呈现递增的趋势。
膀胱癌的发生是多因素、多步骤、长期的病理过程,外在环境因素和内在遗传因素都可能是膀胱肿瘤发生的原因,二者互为影响。目前吸烟和接触化工产品是公认的两大致癌原因。膀胱正常细胞的恶变始于细胞内DNA的改变,目前大多数病因学的研究主要集中在膀胱正常细胞的改变,癌基因是原癌基因的突变方式,后者编码人体正常细胞生长所必需的生长因子和受体蛋白。原癌基因发生突变后成为癌基因,癌基因可使正常细胞发生无节制的分裂生长,从而导致膀胱癌复发和进展。
对于浸润性膀胱癌,根治性膀胱切除加分盆腔淋巴结清扫术是提高浸润性膀胱癌患者生存率、减少局部复发和远处转移最有效的方法。其中原位新膀胱术是首选的膀胱替代方法,目前原位新膀胱术可应用于男性和女性患者,已经逐渐成为膀胱全切术后尿流改道主要的手术方式。原位膀胱术以其术后长期出色的生活质量、新膀胱功能和排尿方式证实了其作为首选的膀胱重建术式。而部分患者术后尿失禁、输尿管狭窄及长期的保留导尿则降低了原位膀胱重建术后患者的生活质量。尿流动力学是利用电生理学、流体力学的原理及传感器技术对尿路贮尿、排尿及病理生理进行研究的一门科学,它可以直接利用图像和数据来量化地反映尿路的功能。国内有关胱全切加原位球形回肠膀胱术的研究未见报道,其临床效果也尚待进一步验证。因此自2009年8月以来,我们对行根治性膀胱全切加原位球形回肠膀胱术的46例男性患者,应用尿流动力仪对利用末段回肠制作的球形储尿囊进行了系统的检测,对其进行充盈性膀胱测压、压力／流率、尿道压力等测定,同时分析我院近几年的该类手术病例的随访数据如围手术期并发症、生活质量评分、排尿和控尿的调查,评价新膀胱的功能,从尿动力学角度阐明其尿动力学特点,进一步减少和预防术后新膀胱输尿管尿液返流、残余尿、尿失禁、夜间遗尿等并发症,提出了我们的观点,使该术式能够更好地应用于临床。
本研究将全面深入地分析原位球形回肠膀胱术的并发症、尿动力学特点以及生活质量调查,为该项手术的改进和临床应用提供科学依据。
目的
膀胱全切为肌层浸润膀胱癌的标准术式,而回肠新膀胱为原位膀胱替代最常用的选择。我们对行根治性膀胱全切加原位球形回肠膀胱术的46例男性患者术后并发症、尿动力学数据和生活质量随访的临床资料进行回顾性分析,研究患者术后12个月内新膀胱功能的特点,深入地分析原位球形回肠膀胱术的并发症、尿动力学特点以及生活质量调查,探讨新膀胱的尿动力特征和临床效果,为该项手术的改进提供临床依据。
患者和方法
这项研究包括2009年8月～2011年8月期间行根治性膀胱全切加原位球形回肠膀胱术的46例男性膀胱癌患者,术后并发症以及生活质量的调查于术后12个月完成。于术后第3、6、9、12个月分别对患者进行回肠新膀胱进行尿动力学测定,观察新膀胱的容量、充盈期压力和排尿期新膀胱压力-流率、尿道压、自由尿流率和残余尿量的变化。我们记录患者的排尿方式、白天和夜间的排尿次数以及控尿情况,并对患者的尿动力学资料进行比较。我们采用一种有效的调研方法(SF-36,以邮递的方式进行)对根治性膀胱全切加原位球形回肠代膀胱术的46例男性膀胱癌患者的生活质量展开调查。对所有患者生活质量的调查被分生理生活质量和心理生活质量两部分,将结果然后与公布的以年龄为基础的基准作比较。
结果
46例患者有28例术后有早期并发症,包括切口感染、肠梗阻、酸中毒,但是只有3例(6.5%)需要外科手术干预,12例有晚期并发症如输尿管吻合口狭窄、后尿道狭窄。46例患者均能自行排尿,研究证实患者功能性膀胱容量于术后3到12个月从386毫升增加到了455毫升(范围为366毫升到784毫升),控尿情况也随之好转。手术建立的回肠新膀胱在充盈期具有良好的顺应性,术后几个月时大多数新膀胱容量不超过400毫升时其基本压力不大于15厘米水柱,膀胱完全充盈其压力平均为18.5厘米水柱。术后最大尿流率和残余尿量分别为19.6毫升每秒和32毫升。术后12个月时46例患者中有44例(95.6%)白天可控和27例(58.6%)夜间可控。12个月时我们通过对术后不同时期尿动力学检查结果的比较,发现新膀胱功能于术后平均6个月达到了以较短的肠管获得低压、可控、较大容量的目标,并处于稳定。通过CT、彩超和血肌酐测定发现只有4例输尿管狭窄但没有肾功能破坏及上尿路肿瘤复发,影像学检查发现在膀胱没有过度充盈的情况下没有发生膀胱输尿管反流。患者通过增加腹压和开放尿道可以获得排尿,尿动力学检查发现排尿期回肠新膀胱没有发生像正常膀胱逼尿肌一样的收缩。生活质量调查显示与相同年龄的正常人相比较,根治性膀胱全切加原位球形回肠代膀胱术的患者术后并没有降低患者的生活质量。有关病因和危险因素分类方面的知识揭示了通过新膀胱的正确设计、精细的外科技巧可以有效预防新膀胱机能失败的发生,另外对患者的选择也是非常重要的因素。
结论
我们的研究发现利用原位球形回肠膀胱术建立新膀胱贮尿和排尿功能与正常的膀胱类似,它所需的回肠较其它术式较短,尿动力学检查以及生活质量调查结果提示新膀胱容量较大、压力低、可控性良好、生活质量佳,是一种原位膀胱重建的良好术式。
创新和意义
本研究在国内首次全面深入地对根治性膀胱全切加原位球形回肠膀胱术的46例男性膀胱癌患者进行了术后并发症、尿动力学检查以及生活质量的调查,对该项手术的改进提供了科学依据。本研究还在国内率先探讨尿失禁与肠管蠕动的关系,为今后该项手术提供了有效的参考数据和循证医学支持。此外,本研究还对白天尿失禁和夜间尿失禁进行了比较,有关这方面的研究国内文献尚未见报道。
Background
Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, and its incidence is increasing in recent years. But its pathogenesis has not been yet fully elucidated. Oxidative stress has been implicated in the carcinogenic process, which is mainly due to oncogenic DNA damages. In addition, enhanced production of reactive oxygen species (ROS) has been linked to disease progression by promoting survivability, proliferation, and even horizontal cell growth. Noticeable, elevated ROS production can already be observed in premalignant lesions. Endogenous antioxidants are found at reduced levels from tumor patients, which is in line with observations of increased ROS levels in tumor cells of more aggressive phenotypes. There is growing evidence suggesting that during tumor growth important changes appear in the cellular redox homeostasis. It is believed that renal cell carcinoma (RCC) of the clear cell type also belongs to tumors in which signifiant changes occur in cellular redox balance. Thus, in RCC marked oxidative alterations of lipids, proteins and DNA have been found. Higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation. Glutamate-L-cysteine ligase (GCL) catalyzes the rate-limiting step of glutathione [L-g-glutamyl-cysteinyl-glycine(GSH)] synthesis, the key cellular antioxidant. Higher GCLC levels were associated with lower presence of intracellular ROS and interestingly also lower rates of cell proliferation.
Objective
In this study, we detect the gene and protein expression of GCLc and GCLm in renal tissues through quantitative real-time PCR and western blotting, and analyze the GCL activity between clear cell renal cell carcinoma and control groups. Through experiments in vitro, we aim to do the preliminary investigations on the biological functions of GCL in the pathogenic mechanism of RCC.
Methods
The hematologic indexes of the blood, the biochemical parameters and coagulation markers were analyzed in clear cell renal cell carcinoma and healthy control groups. Semi-quantative real time-PCR (qRT-PCR) was used to assay the mRNA expression of GCLc and GCLm subunit in clear cell renal cell carcinoma and control para-carcinoma tissue groups. Protein contents of GCLc and GCLm subunit in clear cell renal cell carcinoma and control para-carcinoma tissue groups were determined by Western blotting. GCL activity was determined by a fluorescence assay.Data was analyzed through SPSS13.0Software. Difference analysis was done using Student's two-tailed t-tests. p<0.05indicate the differences. Data are expressed as mean±S.E.
Results
The results indicated that the mRNA expression of GCLc and GCLm subunit in clear cell renal cell carcinoma has a significant decrease compared with control para-carcinoma tissue groups through Semi-quantative real time-PCR (GCLc: CCRCC group1±0.028, Control groups3.74±0.545; p<0.01)(GCLm:CCRCC group1±0.05, Control groups3.07±0.571;p<0.01). Through Western blotting, the results indicated that the protein contents of GCLC and GCLM subunit in clear cell renal cell carcinoma has a significant decline compared with control para-carcinoma tissue groups (GCLc:CCRCC group0.983±0.022, Control groups1.248±0.076; p <0.05)(GCLm:CCRCC group1.103±0.014, Control groups1.306±0.033; p<0.05). The analysis of GCL activity indicated that GCL activity in clear cell renal cell carcinoma was improved compared with control groups (CCRCC group:342±85mmol/min/mg protein; Control groups:98±21mmol/min/mg protein;p <0.01)
Conclusions
The mRNA expression and protein content of GCLC and GCLM in clear cell renal cell carcinoma was decreased. Perhaps, expression of GSH in tumor cells of renal cell carcinoma was regulated by gene expression of glutamine cysteine ligase and the change of protein content, thus affect the oxidation state, the proliferation and differentiation of tumor cells. The GCL enzyme activity in cells of renal clear cell carcinoma increased significantly. The result may be implied that change of enzyme content in tumor cells need higher enzyme activity to regulate the equilibrium of cell oxidation state. The results show that glutamine cysteine ligase may be as an indicator for treatment and judging the prognosis of patients with renal cell carcinoma.
Background
Bladder transitional cell carcinoma (BTCC) is the ninth most common urologic tumor in worldwide. The morbidity rate is increasing with the change of circumstance and the prolonged life. In China, BTCC is the most common urologic tumor for its highest morbidity and mortality. Though BTCC have not specific incident age, even can appear in infants, it really show a tendency of onset after age of30's. furthermore, the morbidity and mortality show directly correlation with age.
The carcinogenesis of bladder cancer is a long process covered multi-factor and multi-step. During the carcinogenesis, genetic factors and environmental factors exist comprehensive cross-talk. Currently, most people accept smoking and chemical materials can lead to carcinogenesis.The initial change during carcinogenesis is from DNA, the most common manner is DNA mutation. Proto-oncogene change to oncogene by mutation, then the cellular division become endless and cause carcinogenesis at last.
Currently radical cystectomy with bilateral pelvic Lymphadenectomy followed with urinary diversion is the primary treatment modality in individuals with muscle-invasive bladder cancer. Among the different techniques of urinary diversion, Neobladder become the most popular technique these years. The superiority of neobladder mainly reflected by excellent life quality after operation and satisfied urinary control. Though with these superiorities, few patients would followed incontinence and ureterostenosis as well as long time catherization, these factors do decrease the life quality of these patients. Urodynamics is one kind of science that reflect the functional urethra by picture and data based on electrophysiology, fluid mechanics, sensor technology. There are very few reports about the urinary control after the procedure of neobladder, thus the clinical effectiveness still need further research in China. From Aug.2009, we perform urodynamic researchs on46patients that received neobladder. Our research covered filling cystometry, pressure-flow study, urethral pressure, etc. meanwhile, aimed to decrease the incidence of vesicoureteral reflux, residual urine, incontinence, enuresis, we further analyzed the perioperative complications, life quality score, urinary control and some others factors focused on the neobladder.
Current research will offer further evidences for the improvemwnt of orthotopic continent ileal N-bladder reconstruction by comprehensively analyze the complications, urodynamic features and life quality.
Objective
Radical cystectomy is the method of choice in management of muscle invasive, organ-confined tumors of the bladder (T2-T4, NO-Nx). The most frequent continent orthotopic urinary diversion after radical cystectomy is the ileal neobladder. To retrospectively review our clinical experience with a single series of46patients who underwent orthotopic continent ileal N-bladder replacement after radical cystectomy during a12-month period. Data are concerning the changes in complications,urodynamic characteristics functional outcomes and quality of life. The object of this study is to evaluate the urodynamic and functional characteristics of46patients and to provide proof for this technique's improvement.
Methods
The study included46consecutive Chinese patients with orthotopic continent ileal N-bladder replacement after radical cystectomy created using the modified technique described previously. We examined the complications.urodynamic characteristics functional outcomes and quality of life.Complications, functional outcomes and health-related quality of life (HRQL, using the Short-Form36instrument)were evaluated in46patients with a mean follow-up of12months. Urodynamics were obtained a mean of11months (range3to24) after construction of the neobladder and it was performed in all patients to determine neobladder capacity, filling and voiding pressures,urethral pressure profile,peak and mean urinary flow and postvoid residual urine. All perioperative and longterm complications were recorded. The voiding pattern, frequency of micturition and continence were assessed, and a complete urodynamic profile recorded. A total of46patients completed by mail the SF-36, a validated quality-of-life survey. Completed surveys were then analyzed into physical (PCS) and mental (MCS) component quality-of-life scores per published protocols. Results were then compared with published age-based norms.
Results
There were23early complications in46patients, including wound infection, ileus, and pyelonephritis etc, although open surgical intervention was required in only nine (6.5%). with9late complications including uretero-intestinal stricture in four and entero-urethral stricture in five. All patients could void spontaneously, the mean maximum cystometric pouch capacity was546ml(range from366ml to784ml). The neobladders demonstrated good compliance for the storage of urine, with a mean basal pressure of less than15cm. water at volumes of less than400cc and of22.4cm. water (range1to72) at100%capacity.The mean maximum flow rate, voided volume and postvoid residualwere19.6mL/s and42mL.The mean maximum flow rate, voided volume and postvoid residualwere18.6mL/s,345.3mL and24.5mL respectively. Daytime and nighttime continence were achieved in95.6%and58.6%respectively. Upper tract surveillance with computed tomography,renal ultrasound and serum creatinine estimation has shown4right ureteral strictures but no significant upper tract deterioration or ureteral recurrence.significant reflux was not observed during video urodynamics unless the reservoir was overfilled. During voiding.by outlet relaxation and straining if necessary. Ulike a normal bladder, no isolated intravesical pressure increase occurred. Through interviews and questionnaires we can find the neobladder'function attain stable at6months after its reconstruction. The HRQL survey after surgery showed no significant differences scores between the46patients with a ileal neobladder and an age-matched control population in chinese. Knowledge of the pathogenesis and identification of risk factors implies that prevention through proper design of the neobladder, meticulous surgical technique, and patient selection is paramount.
Conclusions
In this study, we found that orthotopic global neobladder reconstruction offers similar storage and voiding functions to normal bladder. We conclude that an orthotopic continent ileal N-bladder constructed shorter ileum than other similar operations. The urodynamics results and quality of life outcome proves that it has an adequate capacity at low pressures with a satisfactory continence rate. Our data suggest that although it is not a complication-free procedure, we advocate its use when possible.
引文
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45. Valverde M, Rojas E, Kala SV, Kala G, Lieberman MW:Survival and cell death in cells constitutively unable to synthesize glutathione. Mutat Res 2006, 594(1-2):172-180.
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48. Loft S, Poulsen HE:Cancer risk and oxidative DNA damage in man. J Mol Med(Berl) 1996.74(6):297-312.
49. Qin XJ, Hudson LG, Liu W, Ding W, Cooper KL. Liu KJ:Dual actions involved in arsenite-induced oxidative DNA damage. Chem Res Toxicol 2008, 21(9):1806-1813.
50. Ames BN, Shigenaga MK, Gold LS:DNA lesions, inducible DNA repair, and cell division:three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 1993,101 Suppl 5:35-44.
51. Moller P, Wallin H:Adduct formation, mutagenesis and nucleotide excision repair of DNA damage produced by reactive oxygen species and lipid peroxidation product. Mutat Res 1998,410(3):271-290.
52. Clerkin JS, Naughton R, Quiney C, Cotter TG:Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 2008, 266(1):30-36.
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