Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A

Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germ-line missense mutations in the RET proto-oncogene. Only a minor fraction of human disorders are simple monogenic diseases, and the identification of polymorphisms that increase susceptibility, including variations in pathological phenotypes, to human diseases is one of the key problems in medical genetics. To explore this idea, we analyzed the polymorphisms G691S (exon 11) and S904S (TCC-TCG, exon 15) of RET in 198 individuals corresponding to 35 unrelated Spanish MEN 2A families (104 patients with oncogenic MEN 2A mutation and 94 healthy relatives). We found strong cosegregation between both polymorphisms (100% Fisher's exact test, P < 0.001) using a control population containing 653 healthy individuals (362 females and 291 males). Interestingly, we found that the homozygous for these polymorphisms were, on average, 10 years younger at diagnosis compared with heterozygous and wild-type homozygous (P = 0.037). Taken together, all these findings could indicate that the G691S and S904S variants of RET have a modifier effect on the age at onset of MEN 2A. Moreover, compared with the control population, the homozygote status was significantly more prevalent in a series of 110 sporadic thyroid carcinoma (odds ratio = 2.36), suggesting that these polymorphisms may play a role as a low penetrance risk factor.     

胰腺癌患者血清中S100A8与S100A9水平及其临床意义

目的检测胰腺癌患者血清S100A8与S100A9的水平及探讨其临床意义。方法收集胰腺癌患者90例,同期纳入体检健康者50例为对照组。检测两组研究者血清中S100A8和S100A9的水平。分析胰腺癌患者血清S100A8和S100A9水平与其临床病理特征的相关性。对所有患者疗后随访6个月,比较死亡组与存活组患者血清中S100A8和S100A9水平。结果胰腺癌患者血清中S100A8和S100A9水平显著高于对照组(P<0.01)。胰腺癌患者血清中S100A8和S100A9水平与患者年龄、性别、肿瘤部位无显著相关(P>0.05),与其分化程度、临床分期呈明显相关(P<0.01)。6个月随访结果:27例死亡,18例存活,其中死亡组患者入院时血清S100A8和S100A9水平明显高于存活组,比较有显著性差异(P<0.01)。结论胰腺癌患者血清中S100A8和S100A9水平明显提高,且与其恶性程度密切相关,可能对临床评估胰腺癌预后有一定参考价值。     

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

Increased levels of the homodimeric calcium-binding protein, S100A4, have been shown to cause a metastatic phenotype in at least three independent model systems of breast cancer and its presence in carcinoma cells has been shown to be associated with a reduction in the survival of patients suffering from a range of different cancers. S100A4 has been shown to interact in vitro with another member of the S100 family of proteins, S100A1. The purpose of the present study was to find out whether S100A1 could affect S100A4 function. Fluorescence resonance energy transfer was used to show the interaction of S100A4 and S100A1 in living cells and the binding affinities between S100A4 and S100A1 were determined using a biosensor. S100A1 reduced the S100A4 inhibition of nonmuscle myosin A self-association and phosphorylation in vitro. S100A1 reduced S100A4 induced motility and growth in soft agar and metastasis in vivo. The results show for the first time that interactions between different S100 proteins can affect cancer-related activity, and that the presence of S100A1 protein in carcinoma cells might modulate the effect of S100A4 on their metastatic abilities.     

血清S100A8和S100A9对原发性肝癌的临床诊断价值

目的 探讨原发性肝癌患者血清S100A8和S100A9的表达水平及其与临床病理特征的相关性.方法 收集原发性肝癌患者共90例,同期选择在我院进行体检健康者50例作为对照组;检测2组血清S100A8和S100A9的水平;分析肝癌患者血清S100A8和S100A9水平与临床病理特征的相关性;比较随访期间死亡组与存活组患者血清S100A8和S100A9表达.结果 与对照组比较,肝癌组患者血清S100A8和S100A9均显著升高(P＜0.01).肝癌患者血清S100A8和S100A9的高表达与患者的年龄、性别、大小、病理分型无关(P＞0.05),而与TNM分期、分化程度、淋巴结转移以及血行转移有关(P＜0.01).所有患者6个月定期随访,31例死亡,59例存活;死亡组患者入院时血清S100A8和S100A9表达均显著高于存活组,差异有统计学意义(P＜0.01).结论 原发性肝癌患者血清S100A8和S100A9水平均显著升高,与肝癌的恶性程度关系密切,有望成为原发性肝癌预后的重要评判指标.     

Differential expression of S100A2 and S100A4 during progression of human prostate adenocarcinoma.

PURPOSE: To establish the clinical significance of calcium binding proteins S100A2 and S100A4 during progression of human prostate adenocarcinoma. PATIENTS AND METHODS: Expression pattern of S100A2 and S100A4 was determined in normal human prostate epithelial cells (NHPE); virally transformed prostate epithelial cells (PZ-HPV-7); several human prostate carcinoma cells (22Rv1, DU145, LNCaP, and PC3); tissue samples obtained during transuretheral prostatic resection from patients with benign prostate hyperplasia (BPH), prostatitis, and adenocarcinoma; and paraffin-embedded sections from pair-matched benign and cancer specimens of different tumor grade. RESULTS: High constitutive protein expression of S100A2 was observed in NHPE and PZ-HPV-7 cells, whereas its complete absence was observed in 22Rv1, DU145, LNCaP, and PC3 cells. Tissue samples of BPH and prostatitis exhibited higher mRNA and protein levels of S100A2 than low-grade cancer (Gleason score 6). Immunohistochemical analysis further confirmed high levels of S100A2 in benign tissues and a progressive loss with increasing tumor grade. The protein level of S100A4 was significantly higher in all carcinoma cells compared with NHPE and PZ-HPV-7 cells. The mRNA and protein level of S100A4 was significantly higher in high-grade cancer specimens compared with BPH, prostatitis, and low-grade cancer. The high levels of S100A4 observed in cancer tissue correlated with increasing tumor grade. CONCLUSION: Loss of S100A2 and increased expression of S100A4 may be an important event during progression of prostate cancer in humans.     

Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer.

PURPOSE: S100 proteins comprise a family of calcium-modulated proteins that have recently been associated with epithelial tumors. We examined the expression of two members of this family, S100A8 and S100A9, together with the S100 receptor RAGE (receptor for advanced glycation end products) in human prostate adenocarcinomas and in prostatic intraepithelial neoplasia. EXPERIMENTAL DESIGN: Tissue specimens of 75 patients with organ-confined prostate cancer of different grades were analyzed by immunohistochemistry for expression of S100A8, S100A9, and RAGE. In addition, in situ hybridization of S100A8 and S100A9 was done for 20 cases. An ELISA was applied to determine serum concentrations of S100A9 in cancer patients compared with healthy controls or to patients with benign prostatic hyperplasia (BPH). RESULTS: S100A8, S100A9, and RAGE were up-regulated in prostatic intraepithelial neoplasia and preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed weak expression of the proteins. There was a high degree of overlap of S100A8 and S100A9 expression patterns and of S100A8 or S100A9 and RAGE, respectively. Frequently, a gradient within the tumor tissue with an increased expression toward the invaded stroma of the prostate was observed. S100A9 serum levels were significantly elevated in cancer patients compared with BPH patients or healthy individuals. CONCLUSION: Our data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas. Furthermore, S100A9 in serum may serve as useful marker to discriminate between prostate cancer and BPH.     

Gastric cancers overexpress S100A calcium-binding proteins

Serial analysis of gene expression provides quantitative and comprehensive expression profiling in a given cell population. In our efforts to define the genes overexpressed in carcinoma of the stomach, we performed serial analysis of gene expression analyses on dissected neoplastic and normal gastric epithelia. We identified 91,334 expressed tags, including 26,633 that were unique. The 20 most up-regulated genes (P < 0.01) in gastric cancer (GC) compared with normal gastric epithelia included several keratins that are specific for epithelial cells such as keratin 6A, 13, and 17. Interestingly, five calcium-binding proteins (S100A2, S100A7, S100A8, S100A9, and S100A10) were overexpressed. Quantitative real-time PCR on primary GC samples demonstrated overexpression of S100A2 in 18 of 20 tumors (90%). The other calcium-binding proteins were overexpressed in 25-45% of the GC samples that we studied. Our results indicate that S100A proteins may be important for gastric tumorigenesis. Additional investigations are required to elucidate the biological role of calcium-binding proteins in cancer.     

A Clinico-pathological study of Reinke’S oedema

An analysis of 92 eases of Reinke’s oedema was done in this study. It wen most often seen in middle-aged persons. A Male predilection (57%) was found. In 68 (74%) cases, the lesions were unilateral and in 24 (26%) teses, the lesions were bilateral. Smoking (83%), vocal alms or misuse (80%) and chromnic respiratory tract infection (43%) were the main aetiological factors. No significant relationship of reinke’s oedema with hypotkyroidsm was found. There were no dysplastic changes in the epithelium The treatment of reinke’s oedema is a combination of surgery and vocal rehabilitation. Conventional microlaryngeal surgery is ideal for the treatment of Reinke’s oedema. Acquired laryngeal web involving the anterior part of the vocal cords may develop if stripping of the both vocal cords is performed carelessly. Operating measures do not prevent recurrences of Reinke’s oedema. Voice therapy and cessation of smoking in the postoperative period play important roles in the long term treatment results of Reinke’s oedema.     

Small fenestra Stapedectomy (S.F.S.) or Stapedotomy—A. review

Stapedectomy opration has withstood the test of time and is now a standard operation for the last 3 decedes Different methods of Stapedectomy performed are : (1) Total Stapedectomy (L.F.S.); (2) Partial Stapedectomy : and (3) Small fenestra Stapedectomy (S.F.S.) or Stapedotomy. The immediate success rate is practically same in all the above techniques, but it has been observed that incidence, of inner ear hazards are less in S. F. S. compared to L.F.S. in delayed and long term post-operative period. Incidence of perilymph fistula is practically nil in case of S.F.S. compared to 4% in L. F. S. In overall long term result the success rate of Stapedectomy appears to be better (94%) in S. F. S. compared with 86% in L. F. S.     

S100A8和S100A9在子宫颈鳞癌组织中的表达

目的:探讨S100A8、S100A9在子宫颈鳞癌及正常宫颈组织中的表达及其意义。方法:采用半定量的RT-PCR技术和免疫组织化学的方法,从mRNA及蛋白水平检测32例子宫颈鳞癌和15例正常宫颈组织中S100A8、S100A9的表达,及与不同临床病理参数的关系。结果:子宫颈鳞癌组织中,S100A8、S100A9在mRNA及蛋白水平上均低表达(P<0.05),其中,低分化肿瘤的表达明显低于高、中分化肿瘤(P<0.05)。结论:S100A8、S100A9在子宫颈鳞癌组织中低表达,且可能与鳞状细胞的分化程度相关。提示S100A8、S100A9低表达可能与子宫颈鳞癌的发生发展有关系。     

S100A7和S100A4在外阴鳞癌与外阴硬化性苔藓中的表达及意义

目的:检测外阴鳞癌（vulvar squamous cell carcinoma,VSCC）及外阴硬化性苔藓（vulvar lichen sclerosus,VLS）中S100A7和S100A4蛋白的表达,探讨其与疾病的发生发展关系。方法:采用免疫组化方法测定S100A7及S100A4蛋白在25例VSCC、20例VLS及15例外阴正常皮肤组织中的表达,并结合临床病理资料进行分析。结果:S100A7蛋白在VLS和VSCC中的表达明显高于正常皮肤（P＜0.05）,且早期VLS中的表达高于进展期（P＜0.05）;Ⅲ期VSCC中的表达高于Ⅰ-Ⅱ期（P＜0.05）,高分化VSCC中的表达高于中低分化（P＜0.05）。S100A4蛋白在VLS中的表达与正常皮肤无明显差异（P＞0.05）,但早期VLS中的表达高于进展期（P＜0.05）;S100A4在VSCC的癌巢中几乎不表达,但在间质细胞中的表达高于正常皮肤（P＜0.05）,中低分化VSCC中的表达高于高分化（P＜0.05）。S100A4表达与临床分期无关。结论:S100A7和S100A4蛋白高表达与VSCC的发生、发展有关,与VLS的进展呈负相关。     

钙结合蛋白S100A4与肿瘤

钙结合蛋白家族成员其结构相似,都具有与钙离子结合的区域,但功能不尽相同,特别是与肿瘤的关系的研究显示出不同的功能作用。S100A4是一个与细胞分化及肿瘤的发生、转移、预后密切相关的蛋白。文章将对钙结合蛋白S100A4基因的定位、结构特点、组织分布及其与肿瘤的关系等加以回顾。     

S100A7蛋白功能与肿瘤的关系

S100A7蛋白功能多样,涉及细胞的增殖、分化、凋亡、信号转导、脂质代谢、黏附、迁移等多种基本生命活动,其表达主要见于炎症性疾病和肿瘤,与某些肿瘤及其转移密切相关.