磷酸酶SHP-1与消化系统肿瘤关系的研究现状

含有SH2结构域的蛋白酪氨酸磷酸酶SHP-1,属于非受体型蛋白酪氨酸磷酸酶家族,主要在造血细胞和上皮细胞中表达,是多种信号转导通路如JAK/STAT、PI3K-AKT等的负向调节因子.SHP-1在抑制淋巴瘤、白血病等肿瘤的发生及发展中起到重要作用.随着生物技术的进步及SHP-1基因突变小鼠模型被广泛应用,SHP-1在消化系统肿瘤(特别是肝癌)的发生、发展方面所起的作用也逐渐被发现.     

抗IgA Fc受体抗体的作用机制

体外实验和动物实验证实,抗IgA Fc受体I(FcαRI)单抗具有抑制炎症信号通路,治疗感染性疾病、改善免疫及非免疫相关肾脏疾病肾组织病变等作用.虽然早有研究证实抗FcαRI单抗的疗效与FcαRI中抑制性免疫受体酪氨酸激活基序(immunoreceptor tyrosine-based activation motifs,ITAM)介导的抑制性信号(ITAMi)有关,但直到近期ITAMi的分子机制才被阐明,即低亲和性配体或单克隆抗体与FcαRI结合后可促使FcαRI移位及含Src同源结构域2(Src homology 2,SH2)的酪氨酸磷酸酶1(SHP-1)在细胞膜脂质结构中募集,激活性受体与FcαRI等受体及SHP-1在细胞脂筏上的共区域化促进了大分子抑制体的形成,在SHP-1的作用下激活信号被抑制.这一机制的明确为IgA FcαRI单抗治疗肾脏疾病提供了新的理论依据.     

SHP-1基因在骨髓增生异常综合征中表达的研究

目的探讨骨髓增生异常综合征（MDS）患者蛋白质酪氨酸磷脂酶1（SHP-1）基因的表达情况。方法应用半定量逆转录—聚合酶链反应（RT-PCR）检测80例MDS患者及30名正常对照者白细胞的SHP-1 mRNA的表达。结果 SHP-1在对照组及MDS低危组、中危-1组、中危-2组、高危组间比较有统计学差异（P〈0.01）,低危组/中危-1组中表达水平高于中危-2组/高危组（P〈0.01）。结论 SHP-1作为一个潜在的抑癌基因可能在MDS的发病中发挥着重要作用,SHP-1基因的表达可作为判断MDS病情的指标。     

老年尖锐湿疣患者人乳头瘤病毒基因型及复发危险因素

目的探讨老年尖锐湿疣(CA)患者人乳头瘤病毒(HPV)的基因型及其复发危险因素。方法采用核酸分子快速导流杂交基因芯片技术,对153例老年CA患者皮损组织进行HPV感染分型检测,结合流行病学资料,采用Logistic回归分析,评价影响老年CA复发的相关危险因素。结果 153例皮损组织中检测出150例HPV阳性,检出率为98.04%;共检测出HPV基因型15种,未发现HPV 18、35、39、42、43、56等型别。各型别检出率由高到低分别为HPV 6(46.41%)、11(25.49%)、33(10.46%)、52(10.46%)、58(10.46%)、16(9.15%)、59(6.54%)、31(5.23%)、68(5.23%)、45(4.58%)、51(4.58%)、53(4.58%)、66(4.58%)、CP8304(3.27%)、44(1.96%)。153例老年CA患者经过CO2激光治疗后随访6个月,有96例复发,57例未复发,复发率62.75%。多因素Logistic回归分析结果显示嗜酒(OR=2.058,95%CI:1.52~4.18)、皮损发生特殊部位(OR=3.286,95%CI:1.42~8.82)、皮损处感染为HPV 16(OR=3.152,95%CI:1.58~6.97)以及HPV多重感染(OR=3.558,95%CI:2.18~9.53)是老年CA患者复发的危险因素。结论老年CA患者以低危型HPV 6、11为主,高危感染率高并以混合感染形式存在,老年CA患者嗜酒、皮损部位、感染HPV型别及多重感染是CA复发的危险因素。     

SHP-1基因在多发性骨髓瘤中的表达及意义

目的探讨SHP-1基因在多发性骨髓瘤中的表达及意义。方法用RT-PCR的方法对初治的69例多发性骨髓瘤患者和21例正常对照的骨髓进行SHP-1水平的监测。结果①SHP-1 mRNA在正常对照组中呈阳性表达,初治、无治疗反应组多发性骨髓瘤患者中SHP-1表达的阳性率与表达水平明显低于正常对照组(p<0.01)。缓解后SHP-1 mRNA的表达升高,但低于正常对照组(P<0.01)。②Ⅰ期、Ⅱ期、Ⅲ期多发性骨髓瘤之间SHP-1 mRNA的表达水平比较无统计学意义。③SHP-1表达阳性组缓解率(86.2%)明显高于表达阴性组(42.5%)(P<0.01)。结论 SHP-1基因可能参与了多发性骨髓瘤的发病,但发病机制不清楚,其发挥了负调节作用,它表达降低或缺失影响着多发性骨髓瘤的发生发展。SHP-1与多发性骨髓瘤的疗效预后有关,可能用来作为判断疗效预后的指标。     

携带HPV11型基因组细胞三维培养模型的建立及其衣壳蛋白L1的表达

目的用携带人乳头瘤病毒11型(HPV11)基因组的角质形成细胞(HPV11.HaCaT细胞),在体外建立皮肤类似培养物三维模型,观察HPV11衣壳蛋白L1是否表达,为进一步建立体外病毒复制系统和药效筛选模型奠定基础。方法用人成纤维细胞和I型鼠尾胶原制备真皮类似物凝胶,接种HPV11.HaCaT细胞进行三维培养。同时以正常HaCaT细胞作对照。15天时取皮肤类似物进行冰冻切片,HE染色进行组织结构检查,免疫组化法检查角蛋白10、泛角蛋白以及HPV11L1蛋白表达。结果HE染色显示,HPV11.HaCaT细胞和正常HaCaT细胞的层数明显增多。免疫组化显示,两种细胞的皮肤类似物角蛋白10、泛角蛋白表达全部阳性。HPV11.HaCaT细胞表达L1蛋白阳性,而正常HaCaT表达L1蛋白阴性。结论三维培养方式可诱导HPV11.HaCaT细胞分化,皮肤类似培养物出现细胞分化标志,并且表达HPV11型衣壳蛋白L1。     

男性尖锐湿疣患者的固定性伴宫颈HPV检测及光动力治疗效果

目的探讨男性尖锐湿疣(CA)现症患者的固定异性性伴侣宫颈人乳头瘤病毒(HPV)的感染情况,以及使用光动力疗法治疗HPV亚临床感染及潜伏感染的疗效。方法检测男性CA现症患者的固定未发病异性性伴侣(观察组)的宫颈HPV感染情况,与健康体检妇女人群(健康体检组)对照。将观察组中发现的HPV阳性的病例随机分为治疗组和对照组,治疗组给予光动力治疗,观察CA的发病率和HPV的转阴率;对照组定期随访。结果入选观察组病例共120例,子宫颈HPV感染发生率为58.33%,与健康体检组(4.55%)比较差异有统计学意义(χ2=75.558,P0.05)。治疗组通过光动力治疗,CA发病率为5.71%,较对照组(34.29%)低,差异有统计学意义(χ2=8.929,P0.05);治疗组HPV转阴率为85.71%,对照组为5.71%,差异均有统计学意义(χ2=54.914,P0.05)。结论对男性CA患者的固定性伴侣进行早期监测和干预,能有效预防CA的发生,对控制性传播疾病的蔓延及宫颈癌的发生具有重要意义。     

Wnt-1信号转导分子在艾滋病并发尖锐湿疣组织中的表达研究

目的 研究Wnt-1信号转导分子在AIDS并发CA组织中的表达,探讨Wnt信号通路在AIDS并发CA过度增殖中所起的作用。方法 对经HPV分型DNA芯片技术检测试剂盒检测AIDS并发HPV16/18型阳性的AIDS/CA组和AIDS/CA癌变组、CA组、健康对照组(H组),应用免疫组化方法检测Wnt-1蛋白的表达强度和表达位置。结果AIDS/CA组和AIDS/CA癌变组Wnt-1表达强度均显著高于H组(Z=5.658,P=0.011;Z=5.888,P=0.000),且AIDS/CA癌变组Wnt-1表达强度高于CA组(Z=12.342,P=0.038)。与AIDS/CA组相比,AIDS/CA癌变组和CA组Wnt-1表达强度差异均无统计学意义(Z=10.480,P=0.266;Z=3.240,P=1.000)。各组表达位置差异有统计学意义(χ²=14.121,P=0.008)。与AIDS/CA癌变组的表达位置相比,AIDS/CA组和CA组表达位置差异均有统计学意义(χ²=10.480,P=0.003;χ²=8.933,P=...     

HPV分型及梅毒与尖锐湿疣复发的关系

目的探讨人类乳头瘤病毒(HPV)的基因分型及梅毒与尖锐湿疣(CA)患者皮损复发的关系。方法采用荧光定量聚合酶链反应(PCR)体外扩增和脱氧核糖核酸(DNA)反向点杂交相结合的DNA芯片技术,对杭州师范大学附属医院2010年10月至2013年9月皮肤性病科门诊诊断为CA的患者的皮损组织进行HPV检测及分型,并随访A组(同时合并梅毒感染的CA患者,低危型A1组,高危型A2组)、B组(单纯的CA患者,低危型B1组,高危型B2组),经微波治疗后尖锐湿疣的复发率。结果满足调查条件的198例患者中,A组48例(A1组33例,A2组15例),B组150例(B1组98例,B2组52例)。A组共34例复发,其中A1组占60.6%(20/33),A2组占93.3%(14/15)。B组共79例复发,其中B1组占40.8%(40/98),B2组占75.0%(39/52)。A组与B组比较,差异有统计学意义(χ2=4.898,P0.05),A1与A2、B1与B2及A1与B1三组之间复发率比较差异均有统计学意义(χ2分别为3.880、15.924、3.894,P均0.05),但A2与B2之间复发率比较差异无统计学意义(χ2=1.388,P0.05)。结论合并梅毒可能提高尖锐湿疣的复发率,尤其在HPV低危型中更为显著,不论是否合并梅毒,HPV高危型较低危型尖锐湿疣患者皮损更易复发。     

高危型人乳头瘤状病毒感染和p16INK4A在食管鳞癌患者中的预后价值

目的明确食管鳞癌中高危型人乳头瘤病毒(HPV)感染与p16蛋白表达的关系和预后价值。方法 105例行食管鳞癌根治术患者纳入研究,所有病例应用DNA-DNA原位杂交技术分别检测HPV16型和18型,应用免疫组化检测p16蛋白表达,采用Kappa检验检测HPV感染与p16蛋白的异常表达是否存在一致性。统计患者5年生存期(OS)和5年无进展生存期(PFS),应用Cox比例风险模型进行单因素和多因素分析。结果 105例患者中p16蛋白表达阳性为39例(37. 1%),29例被检测到HPV阳性,全部为16型,其中25例(86. 2%)患者肿瘤组织中检测到p16蛋白的阳性表达; 76例HPV阴性患者中14例(18. 4%)检测到p16蛋白表达阳性,两组差异有统计学意义(P<0. 001)。p16阳性组患者的5年OS和5年PFS分别为64. 1%和58. 7%,而p16阴性组患者的5年OS和5年PFS分别为45. 5%和37. 9%,p16阳性组的5年OS及5年PFS均明显好于p16阴性组(P=0. 02、P=0. 007)。结论食管鳞癌患者HPV感染后p16蛋白过度表达,HPV感染的分子检测标志物可以用p16蛋白免疫组化染色来替代。肿瘤组织中HPV感染或者p16蛋白过度表达的患者具有较好的预后。     

Correlation between deoxyribonucleic acid loads of human papillomavirus and recurrence of condylomata acuminata

To determine the correlation between deoxyribonucleic acid (DNA) loads of human papillomavirus (HPV) and recurrence of condylomata acuminata (CA), 31 cases of primary CA and 32 cases of recurrent CA were assayed for the HPV6/11 and HPV16/18 DNA loads by real-time fluorogenic quantitative PCR. The results showed 62 of the 63 cases were HPV6/11 DNA positive (98.4%). The ranges of HPV6/11 DNA contained in primary and recurrent CA were 1.4 x 10(3)-6.7 x 10(7) and 1.2 x 10(4)-3.6 x 10(8) copies/mL, respectively. Of the 62 cases which were HPV6/11 DNA positive, seven cases were also HPV16/18 DNA positive (11.3%). The ranges of HPV16/18 DNA levels in primary and recurrent CA were 1.9 x 10(3)-1.6 x 10(4) and 1.4 x 10(5)-1.7 x 10(7) copies/mL, respectively . The HPV6/11 and HPV16/18 DNA loads in recurrent CA were statistically higher than that found in primary CA (P = 0.041 and 0.023, respectively). The DNA loads of HPV6/11 were correlated with the duration, extent of the disease and frequency of recurrence. There is a significant correlation between loads of HPV DNA and recurrence of CA. These findings have important implications for the treatment of CA.     

caspase-10在甲状腺分化癌中的表达及临床意义

目的 探讨caspase-10表达在甲状腺分化癌(DTC)发生、发展及预后中的作用.方法 37例DTC来自于2006年1月至2007年12月行甲状腺切除术患者.取DTC患者病理标本,链霉菌抗生物素蛋白-过氧化物酶连结法(S-P)染色,光镜下检测DTC患者caspase-10表达,分析caspase-10在DTC中的表达与临床病理特征之间的关系.取同期46例结节性甲状腺肿组织标本作为对照.结果 结节性甲状腺肿细胞质或细胞膜,可见到较多的棕色或黄色caspase-10表达颗粒,但在DTC中棕色或黄色表达颗粒不明显.caspase-10表达阳性率在DTC患者中为29.73%(11/37),在结节性甲状腺肿患者中为71.74%(33/46),二者比较差异有统计学意义(χ2=14528,P<0.01);在DTC有淋巴结转移患者中,caspase-10阳性表达率(11.11%,2/18)明显低于无淋巴结转移患者(47.37%,9/19),二者比较差异有统计学意义(χ2=4.210,P<0.01);caspase-10表达与性别、年龄、国际肿瘤(TNM)分期以及病理分型无关(P>0.05).结论 caspase-10表达下调在甲状腺分化癌的发生和侵袭中发挥重要作用.     

Human papillomavirus type-distribution in condylomata acuminata of mainland China: a meta-analysis

The aim of this work was to study the human papillomavirus (HPV) type-distribution in condylomata acuminata (CA) of mainland China and to estimate the potential role of HPV prophylactic vaccines for CA in mainland China. Forty-three studies using polymerase chain reaction to detect HPV were included in this meta-analysis, and totally 5247 CA cases and 436 controls were included. The overall and type-specific prevalence of HPV 6, 11, 40, 42, 43, 44 were estimated using non-conditional logistic regression model. Overall HPV prevalence was 84.2% and 4.6% for CA and controls, respectively. Estimated HPV types 6, 11, 40, 42 positive fractions in CA were 54.9%, 41.1%, 2.7% and 2.0%, respectively, and exactly 0% for HPV types 43 and 44. HPV 6 and/or 11-positive fractions were 83.0% in mainland China. Thus, prophylactic HPV vaccine has the potential to protect up to 83% of CA cases in mainland China.     

尖锐湿疣患者HPV型别及DNA载量与复发的关系

目的研究天津地区尖锐湿疣（CA）患者人乳头瘤病毒（HPV）6/11、16/18型及DNA载量与复发的关系。方法采用实时荧光定量聚合酶链反应（FQ-PCR）检测CA患者皮损中HPV型别及DNA载量,并随访至少3个月观察有无复发。结果83例CA标本中,HPV阳性80例（96.4%）,其中单纯HPV6/11型63例,单纯HPV16/18型4例,HPV6/11型和HPV16/18型混合感染13例,不同型别复发率比较无统计学差异（P〉0.05）。HPV6/11阳性标本中,复发组与未复发组DNA载量比较有统计学差异（P〈0.05）。结论CA患者的HPV感染以HPV6/11型为主,患者疣体中HPV DNA载量与复发有关。     

PCR检测在尖锐湿疣诊断中的综合评价

对７０例外阴病变的病例进行严格质控的ＰＣＲ检测，并结合病史、组织病理改变及ＨＰＶ核壳抗原免疫组化检测进行综合分析。结果表明，４０例具有ＣＡ组织病理特征的病例中，３７例ＨＰＶ６／１１ＤＮＡＰＣＲ检测阳性，３０例原病理诊断为鳞状上皮乳头状增生或假性湿疣的病例中，有７例检出ＨＰＶＤＮＡ。综合分析的结果提示，对于有典型ＣＡ组织学特征者，结合临床，即使不做ＰＣＲ检则也可做出正确诊断。ＰＣＲ检测的意义在于为无典型ＣＡ组织学特征的病例增加一有价值的诊断依据，而不能仅根据ＰＣＲ结果武断地做出结论。     

Increased expression of tyrosine phosphatase SHP-2 in Helicobacter pylori-infected gastric cancer

AIM:To explore the alteration of tyrosine phosphatase SHP-2 protein expression in gastric cancer and to assess its prognostic values.METHODS:Three hundred and five consecutive cases of gastric cancer were enrolled into this study.SHP-2 expression was carried out in 305 gastric cancer specimens,of which 83 were paired adjacent normal gastric mucus samples,using a tissue microarray immunohistochemical method.Correlations were analyzed between expression levels of SHP-2 protein and tumor parameters or clinical outcomes.Serum anti-Helicobacter pylori(H.pylori) immunoglobulin G was detected with enzyme-linked immunosorbent assay.Cox proportional hazards model was used to evaluate prognostic values by compassion of the expression levels of SHP-2 and disease-specific survivals in patients.RESULTS:SHP-2 staining was found diffuse mainly in the cytoplasm and the weak staining was also observed in the nucleus in gastric mucosa cells.Thirty-two point five percent of normal epithelial specimen and 62.6% of gastric cancer specimen were identified to stain with SHP-2 antibody positively(P < 0.001).Though SHP-2 staining intensities were stronger in the H.pylori(+) group than in the H.pylori(-) group,no statistically significant difference was found in the expression levels of SHP-2 between H.pylori(+) and H.pylori(-) gastric cancer(P = 0.40).The SHP-2 expression in gastric cancer was not significantly associated with cancer stages,lymph node metastases,and distant metastasis of the tumors(P = 0.34,P = 0.17,P = 0.52).Multivariate analysis demonstrated no correlation between SHP-2 expression and disease-free survival(P = 0.86).CONCLUSION:Increased expression of SHP-2 protein in gastric cancer specimen suggesting the aberrant upregulation of SHP-2 protein might play an important role in the gastric carcinogenesis.     

宫颈脱落细胞中人乳头瘤病毒52型感染及整合状态分析

目的 探讨人乳头瘤病毒(Human papillomavirus,HPV)感染及其整合状况在宫颈病变中的意义.方法 应用HPV L1 通用引物MY09/11 和HPV52 E6 型特异性引物进行多聚酶链反应(Polymerase chain reaction,PCR)检测宫颈脱落细胞标本中HPV 总感染及HPV52 感...     

Human papillomavirus infection and filaggrin expression in paraffin-embedded biopsy specimens of extragenital Bowen's disease and genital bowenoid papulosis

Summary Cutaneous Bowen's disease (BD) and genital bowenoid papulosis (BP) are considered as precancerous or cancerous lesions that are sometimes infected with human papillomavirus (HPV). We studied retrospectively paraffin-embedded sections of 11 samples of cutaneous BD and 6 samples of genital BP from the general population for HPV infection and filaggrin expression. Using in situ hybridization with biotinylated probes of HPV types 1, 2, 5, 6, 11, 16, and 18, under stringent and/or non-stringent conditions and a streptavidin-alkalinephosphatase complex for hybrid detection, HPV DNA was detected in 6/17 cases (5 BD and 1 BP). Positive nuclei were located in intermediate or upper epithelial cell layers. HPV 16 was found in 2 cases of BD but associated either with HPV 2 or 18. Three additional lesions reacted only under non-stringent conditions; HPV could not be typed with the probes used. The positive case of BP reacted with the four probe types 1, 2, 16, 18 and was negative with HPV 6 or 11. Viral antigen was not detected by indirect immunofluorescence with a rabbit antiserum directed to group-specific viral capsid antigen. Differentiation disorders were observed in the intermediate and upper cell layers of these specimens, as shown by a reduced expression of filaggrin/profilaggrin, a marker of terminal differentiation, in extragenital BD (7/11 cases), and an increased expression in genital BP (4/5 cases) although viral DNA was not always detectable. This study shows that in situ hybridization is a valuable technique for HPV DNA detection and its typing in BD and BP lesions on deparaffinized sections. The positive nuclei were located in the cell layers that exhibited abnormal expression of differentiation. There is no relation between the HPV infecting type and the filaggrin expression.Abbreviations BD cutaneous Bowen's disease - BP genital bowenoid papulosis - HPV human papilloma virus - EV Epidermodysplasia Verruciformis     

109例尖锐湿疣患者的HPV型别特点分析

目的了解尖锐湿疣患者人乳头瘤病毒(human papilloma virus,HPV)感染的型别特点,为疾病的治疗和预后的判断提供理论依据。方法采用流式荧光-液态芯片技术对109例尖锐湿疣患者(男76例,女33例)进行HPV基因型别检测,分析男女患者感染HPV基因型及感染类型特点。结果尖锐湿疣患者的HPV DNA阳性检出率为87.16%,阳性检出率前6位的基因型分别为HPV6、HPV11、HPV16、HPV39、HPV18、HPV51。男女患者之间HPV DNA阳性检出率差异无统计学意义;在HPV感染类型方面,女性多重感染率为78.57%,男性为53.73%,女性明显高于男性(P0.05);在感染型别方面,女性高危型感染率为49.21%,男性为25.20%,女性明显高于男性(P0.05)。结论尖锐湿疣患者感染的HPV以低危亚型、多重感染为主,亦有一定比例的高危型感染。不同性别的尖锐湿疣患者感染HPV的特点有差异,男性患者以低危型别和单一类型感染为主,而女性以高危型别和混合的多重类型感染为主。HPV感染对女性影响要大于男性,要重视对成年女性的HPV的筛查,做到及早发现及早治疗,改善女性的生活质量。     

C-erbB-2蛋白和缝隙连接蛋白43在胃癌组织中的表达及意义

目的探讨C-erbB-2癌蛋白和缝隙连接蛋白43（connexin,Cx43）在腺型胃癌中的表达并分析其临床意义。方法应用免疫组织化学SP法分别检测C-erbB-2癌蛋白、Cx43在48例腺型胃癌和26例胃炎组织中的表达,并分析其与临床病理参数的关系。结果C-erbB-2癌蛋白、Cx43阳性呈棕黄色颗粒定位于细胞膜或细胞质;C-erbB-2癌蛋白在胃癌中的阳性表达率（50.0%）显著高于胃炎黏膜组织的阳性率（2χ=6.70,P〈0.05）;Cx43在胃癌中阳性率（43.8%）显著低于胃炎黏膜组织的阳性率（χ2=23.03,P〈0.05）;C-erbB-2癌蛋白的表达与胃癌的大小、分化程度及淋巴结转移呈显著相关（2χ=6.00、9.41、5.49,P值均〈0.05）;Cx43蛋白表达降低或缺失同样与胃癌的分化程度及淋巴结转移呈显著相关（χ2=7.49、6.86,P值均〈0.05）;C-erbB-2癌蛋白和Cx43蛋白呈负相关（χ2=0.01,r=-0.378,P〈0.05）。结论C-erbB-2癌蛋白的高表达、Cx43表达降低或缺失与胃癌分化程度、浸润转移密切相关,联合检测C-erbB-2和Cx43有助于判断胃癌的生物学行为。