Expression of inhibitor of apoptosis protein (IAP) livin/BIRC7 in acute leukemia in adults: correlation with prognostic factors and outcome

The clinical relevance of livin/BIRC7 expression is still controversial in different types of malignancies, therefore this study was designed to evaluate the gene expression of livin in Egyptian adult AML and ALL. Livin expression level was higher in patients with unfavorable prognostic factors at diagnosis in both ALL (p = 0.002) and AML (p = 0.042) and its level was negatively correlated with event free survival (EFS) and overall survival (OS) in both ALL (p < 0.001for both) and AML (p = 0.001 and 0.023 respectively). This study suggests that livin expression is a novel prognostic marker in adult acute leukemia and thus needs to be incorporated into the patient stratification and treatment protocols.     

Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL).

It has been suggested that the expansion of the leukemic cells in chronic lymphocytic leukemia (CLL) is due to dysregulation of pathways of programmed cell death (apoptosis) rather than cell proliferation, although differences may exist in early vs late and treated vs untreated patients. In the present study, we analyzed the expression of 11 proteins in CLL cells that are implicated in the control of apoptosis, proliferation, and differentiation, and correlated this expression profile with survival. Using a quantitative solid-phase radioimmunoassay (RIA), we measured the cellular protein levels of Bcl-2, cyclin D1, PCNA, ATM, Fas, Bax, retinoic acid receptor alpha (RARalpha), retinoic acid receptor beta (RXRbeta), Flt1, VEGF, and cellular beta2-microglobulin in 230 samples of CLL. Univariate analysis using the Cox proportional hazard model showed a correlation with survival of only the following proteins: Bcl-2 (P < 0.001), cyclin D1 (P = 0.027), Fas (P = 0.055), PCNA (P < 0.001), and ATM (P = 0.028). In a multivariate analysis using classification and regression tree analysis (CART), five groups of patients (nodes) could be generated with significant differences of survival expectation (P < 0.0001) based on levels of expression of the above proteins. Based on CART analysis, Bcl-2 levels emerge as the most important protein in predicting survival between all 11 proteins studied. Patients with marked elevation in Bcl-2 levels had the worst outcome while patients with intermediate levels, but with high levels of PCNA and cyclin D1 or abnormal ATM expression had intermediate survival. These data indicate that intracellular levels of proteins such as Bcl-2, ATM, cyclin D1, and PCNA can be used as markers to predict clinical behavior and survival in patients with CLL. The pathways in which these proteins are involved may also represent possible targets for future therapeutic trials in CLL.     

p53凋亡刺激蛋白家族成员在浸润性乳腺癌中的表达及其意义

目的研究p53凋亡刺激蛋白(ASPP)家族成员在浸润性乳腺癌中的表达,并探讨其与p53表达状态、乳腺癌分子分型及预后的关系。 方法收集2005年1月至2010年4月解放军第九八九医院收治的155例浸润性乳腺癌患者组织标本进行回顾性分析。采用免疫组织化学方法检测组织标本中ASPP1、ASPP2、P53凋亡刺激蛋白抑制因子(iASPP)、p53、ER、PR、HER-2和Ki67的表达,并用χ²检验分析ASPP家族成员表达与乳腺癌分子分型和p53状态的关系,采用Kaplan-Meier生存分析方法评价ASPP家族成员表达与患者预后的关系。 结果155例乳腺癌组织中,ASPP1阳性率为13.5%(21/155),ASPP2阳性率为97.4%(151/155),iASPP阳性率为61.3%(95/155)。表达野生型p53者33例,突变型p53者122例,p53的突变率为78.7%(122/155)。ASPP家族成员的表达在野生型p53组与突变型p53组间差异无统计学意义(ASPP1：χ²<0.001,P＝0.987; ASPP2：χ²＝1.110,P＝0.579; iASPP：χ²＝0.244,P＝0.621)。luminal A型44例,luminal B型66例,basal-like型18例,HER-2过表达型27例,ASPP家族成员的表达在不同分子分型乳腺癌组间差异无统计学意义(ASPP1：χ²＝2.325, P＝0.508; ASPP2：χ²＝1.657, P＝0.642; iASPP: χ²＝0.815,P＝0.846)。随访时间2～108个月,中位随访时间66个月,患者3年总生存率为84.5%(131/155),5年OS率为79.4%(123/155)。ASPP1、ASPP2和iASPP表达阳性组与阴性组相比,患者5年OS率的差异均无统计学意义(ASPP1：χ²＝3.790, P＝0.050;ASPP2：χ²＝0.040, P＝0.927;iASPP：χ²＝1.253, P＝0.263)。 结论ASPP家族成员在浸润性乳腺癌中的表达与P53突变、乳腺癌分子分型以及乳腺癌患者预后均无关。     

X连锁凋亡抑制蛋白及其在白血病中的临床意义

X连锁凋亡抑制蛋白(XIAP)是凋亡抑制蛋白家族中最具有抑制活性的一种,通过调节凋亡途径的最后步骤,可以阻断各种刺激引起的凋亡,在白血病的发生及耐药中具有重要作用,而且可能与白血病的预后有关,以XIAP为靶分子有希望为白血病的治疗及耐药逆转提供新的途径.     

MCM2 蛋白在肿瘤中的表达及意义

微小染色体维持蛋白（MCM）是真核生物DNA复制的主要调控因子，在DNA复制的起始和延伸过程中有重要作用，是标志细胞增殖活性的新指标，MCM2是微小染色体维持蛋白家族中的一员，是研究肿瘤细胞生长及评估某些肿瘤预后的较好指标。     

MGMT蛋白的表达与乳腺癌预后关系初探

目的:探讨MGMT蛋白在乳腺癌中的表达及其与乳腺癌预后的关系。方法:应用免疫组化法检测135例乳腺癌患者MGMT蛋白的表达,并探讨其与乳腺癌临床特征及预后的关系。结果:135例乳腺癌中MGMT蛋白总阳性率为84.4 %(114/135),但存在异质性。MGMT蛋白的阳性表达与患者年龄、月经状态、原发肿瘤大小、淋巴结转移情况及肿瘤的临床分期无明显相关性(P>0.05),与生存期无明显相关性(P>0.05),但与ER状况相关(P<0.025)。结论:MGMT蛋白的表达不能作为乳腺癌的一个预后指标。     

Key issues in the treatment of chronic lymphocytic leukaemia (CLL)

The outcome of the treatment of chronic lymphocytic leukaemia (CLL) has improved little over the past 30 years. The recent introduction of purine analogues, particularly fludarabine, may change this situation. These agents are highly effective and generally well tolerated. They raise the possibility of improved disease-free survival and allow appropriate patients to be considered for bone marrow transplantation (BMT). Randomised clinical trials are needed to establish the roles of purine analogues and other novel agents in improving the survival of CLL patients. These trials should use consistent diagnostic and assessment criteria to allow for the clinical heterogeneity of CLL.     

凋亡抑制蛋白FLIP在肝脏组织中的表达和意义

目的:检测凋亡抑制蛋白FLIP在人肝脏不同病变组织中的表达并揭示其在肝癌发生发展中的意义。方法:采用免疫组织化学技术,分析46例肝癌标本,27例肝硬化组织标本,18例肝脏血管瘤标本,12例正常肝组织标本,肝癌Hepg2细胞系10个细胞爬片样本中FLIP蛋白的表达并进行统计学分析比较。结果:凋亡抑制蛋白FLIP在46例肝癌标本中有39例阳性表达(84.73%),在肝癌Hepg2细胞系10个细胞爬片样本中全部阳性表达(100%),27例肝硬化标本中4例阳性表达(14.81%),30例肝血管瘤和正常肝组织中仅2例阳性表达(6.67%),其余均为阴性(P<0.01)。结论:凋亡抑制蛋白FLIP在肝癌组织中阳性表达率明显高于良性肝组织中阳性表达率,这为揭示肝脏恶性肿瘤的发生、发展提供新的理论依据,并为肝癌的有效治疗提供新的思路。     

凋亡抑制蛋白FLIP在喉部病变组织中的表达及意义

目的:检测凋亡抑制蛋白FLIP在人喉部常见病变组织中的表达并揭示其在喉癌等病变发生发展中的意义。方法:采用免疫组织化学EliVision法检测38例喉鳞状细胞癌标本,30例声带息肉组织标本,26例喉乳头状瘤标本,15例正常喉黏膜组织标本,喉癌Hep-2细胞系10个细胞爬片样本中FLIP蛋白的表达并进行统计学分析比较。结果:凋亡抑制蛋白FLIP在38例喉癌标本中有32例阳性表达(84.2%),在喉癌Hep-2细胞系10个细胞爬片样本中全部阳性表达(100%),26例喉乳头状瘤中5例阳性表达(19.2%),30例声带息肉标本中仅2例阳性表达(6.7%),而正常喉黏膜组织中均为阴性。凋亡抑制蛋白FLIP在喉癌组织中表达水平与喉部良性肿瘤和良性病变组织中的表达水平有显著差异(P<0.01)。结论:凋亡抑制蛋白FLIP的表达水平与喉部病变组织的良恶性程度密切相关,提示其可能与喉癌的发生相关。     

凋亡抑制蛋白FLIP在喉部病变组织中的表达及意义

目的：检测凋亡抑制蛋白FLIP在人喉部常见病变组织中的表达并揭示其在喉癌等病变发生发展中的意义。方法：采用免疫组织化学EliVision法检测38例喉鳞状细胞癌标本,30例声带息肉组织标本,26例喉乳头状瘤标本,15例正常喉黏膜组织标本,喉癌Hep-2细胞系10个细胞爬片样本中FLIP蛋白的表达并进行统计学分析比较。结果：凋亡抑制蛋白FLIP在38例喉癌标本中有32例阳性表达（84.2%）,在喉癌Hep-2细胞系10个细胞爬片样本中全部阳性表达（100%）,26例喉乳头状瘤中5例阳性表达（19.2%）,30例声带息肉标本中仅2例阳性表达（6.7%）,而正常喉黏膜组织中均为阴性。凋亡抑制蛋白FLIP在喉癌组织中表达水平与喉部良性肿瘤和良性病变组织中的表达水平有显著差异（P〈0.01）。结论：凋亡抑制蛋白FLIP的表达水平与喉部病变组织的良恶性程度密切相关,提示其可能与喉癌的发生相关。     

Elucidating the role of protein kinase C in chronic lymphocytic leukaemia

While advances have been made in the clinical treatment of chronic lymphocytic leukaemia (CLL) in recent years, it is still an incurable disease and therefore the identification of novel drug therapies is of paramount importance. Understanding the molecular mechanisms that govern the survival of CLL cells is fundamental in achieving this goal. A number of studies indicate that protein kinase C (PKC)- and phosphatidylinositol-3-kinase (PI3K)- mediated signalling pathways are central to CLL cell survival, and as such PKC has gained renewed interest as a potential drug target in CLL. This may be because it represents a closely-related family of ten protein kinases, which due to the redundancy that exists between isoforms offers an opportunity for the design of isoform specific inhibitors drugs that target leukaemic cells whilst showing reduced toxicity for normal cells. Indeed, PKC signalling pathways have already been considered as targets for specific anticancer drugs [1-3]. Therefore, this short review will focus on the effect of modulating PKC activity in CLL cells and explore whether targeting PKCs could represent a valid therapy for this leukaemia.     

Selective inhibition of PED protein expression sensitizes B-cell chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis

B-cell chronic lymphocytic leukaemia (B-CLL) cells fail to undergo apoptosis. The mechanism underlying this resistance to cell death is still largely unknown. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells, and thus represents an attractive tool for the treatment of cancer. Unfortunately, lymphocytes from B-CLL patients are resistant to TRAIL-mediated apoptosis. Thus, we aimed to study the involvement of PED, a DED-family member with a broad antiapoptotic action, in this resistance. We demonstrate that B lymphocytes obtained from patients with B-CLL express high levels of PED. Treatment of B-CLL cells with specific PED antisense oligonucleotides, a protein synthesis inhibitor or HDAC inhibitors, induced a significant downregulation of PED and sensitized these cells to TRAIL-induced cell death. These findings suggest a direct involvement of PED in resistance to TRAIL-induced apoptosis in B-CLL. It also identifies this DED-family member as a potential therapeutic target for this form of leukaemia.     

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.Subject terms: Ovarian cancer, Chemotherapy     

Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia

We wish to validate in a multicentric CLL population a nomogram and a risk score recently developed to predict overall survival (OS). Complete records from 1037 CLL patients were retrospectively collected to estimate OS and time to treatment (TTT). Cox models were used to test the independence of age, β‐2‐microglobulin, absolute lymphocyte count (ALC), sex, Rai stage and number of involved lymph node regions (LNR). Accuracy of prognostic models was tested with the concordance index (c‐index). Median follow‐up was 5.5 years, with 151 deaths and 475 treated patients. Median OS was not reached (65% survival rate at 13.9 years), median TTT was 6 years. We confirmed the ability of the prognostic score to predict OS and TTT in three risk groups, with results comparable with those reported in the original report. However, ALC and Rai stage were not independent predictors, whereas the Binet staging system, which incorporates LNR variable, showed independent predictive power; furthermore, both 5‐ and 10‐year OS estimates from nomogram were lower compared to real data. When separately analysed, the impact of therapy on OS was not selected as independent predictor of OS in our series. According to these results, we proposed a simpler four‐variable model (age, sex, Binet staging, β‐2‐microglobulin) and a new nomogram. This model had a c‐index of 0.78 versus 0.76 of the six‐variable model (p = 0.043), showing better predictive accuracy. External validation and refinement are needed on independent data sets, possibly from cancer registry patients' series. Copyright © 2010 John Wiley & Sons, Ltd.     

凋亡抑制蛋白XIAP在儿童急性白血病中的表达及其临床意义

目的探讨凋亡抑制蛋白XIAP在儿童急性白血病（AL）中的表达及其临床意义。方法54例AL患儿,其中初诊未治26例,治疗后完全缓解（CR）23例,复发5例。应用免疫组织化学方法检测其骨髓细胞XIAP蛋白表达。对照组为10例非恶性血液病且骨髓正常患儿。结果初诊未治AL患儿骨髓中XIAP蛋白表达水平高于缓解期（P〈0．05）和对照组（P〈0．05）,和复发组相比差异无统计学意义（P〉0．05）,且缓解期仍高于对照组（P〈0．05）;初诊未治AL患儿骨髓中XIAP蛋白水平在急性淋巴细胞白血病（ALL）和急性非淋巴细胞白血病（ANLL）组比较差异无统计学意义（P〉0．05）。结论XIAP蛋白在儿童AL患者中高表达,提示XIAP可能通过抑制肿瘤细胞的凋亡参与了儿童AL的发生、发展。     

恶性肿瘤细胞及组织中凋亡抑制蛋白livin的表达及其临床意义

目的：探讨凋亡抑制蛋白livin的两种异构体livinα、和livinβ在多种肿瘤细胞系及肿瘤组织中的表达及其与各类肿瘤临床病理的关系。方法：采用RT-PCR法检测HeLa、SBC-2等12种肿瘤细胞和50例不同肿瘤组织及20例癌旁组织中livinα和livinβ的mRNA的表达水平。结果：12个细胞系中8个细胞系的livin mRNA表达为阳性，分别为HeLa、SPCA-1、SBC-2、PC14、MKN45、LOVO、HHCC、A549，其中A549为弱表达，且livinα的表达强于livinβ；HL-7702、Hep-2、7721、K562四种细胞中livin表达为阴性；50例肿瘤组织中livin mRNA表达阳性率为64．0％，而在癌旁组织中为2％。Livin mRNA的表达与肿瘤患者的肿瘤分化程度、淋巴结转移及TNM分期均无明显相关性。结论：Livin在肿瘤细胞系及肿瘤组织中表达的研究，为进一步研究livin与肿瘤的发生、发展的关系，及其以livin为靶位的肿瘤基因治疗研究提供了有力依据。     

CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia.

Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic leukaemia (B-CLL) cases were analysed for surface expression of CD38. Based on a cut-off value of 20%, CLL patients were categorised into a CD38-positive (> or = 20%, n = 56) and a CD38-negative subgroup (< 20%, n = 77) and separately analysed for clinical and laboratory parameters. Patients in the CD38-positive cohort were characterised by an unfavourable clinical course with a more advanced disease stage, poor responsiveness to chemotherapy, short time to initiation of first treatment and shorter survival. In contrast, the CD38- negative group required minimal or no treatment, remained treatment-free for a longer time period and had prolonged survival (P < 0.05). CD38 expression was a robust marker in the majority of patients in that it was stable over time and not significantly influenced by chemotherapy. In conclusion, our data confirm recent studies suggesting a role of CD38 as a predictor of clinical outcome in patients with B-CLL.