B淋巴增殖性疾病的SOX11、cyclin D1、cyclin D2和cyclin D3的表达研究

目的 探讨各B淋巴增殖性疾病(B-LPD)中SOX11、cyclin D1、cyclin D2和cyclin D3表达的差异和相关性,以及与慢性淋巴细胞白血病(CLL)患者临床特征的关系.方法 采用实时定量逆转录PCR(qRT-PCR)技术检测154例B-LPD患者与12例健康对照SOX11、cyclin D1、cyc...     

Ileocolonic lymphomas: a series of 16 cases

BACKGROUND: Colonoscopic and clinical differences between primary ileocolonic mucosa-associated lymphoid tissue (MALT) lymphoma and mantle cell lymphoma (MCL) have not been defined. METHODS: We reviewed colonoscopic and clinical features in eight patients with primary MALT lymphoma and eight patients with MCL in the terminal ileum and/or colorectum. All cases were examined for CD5 and/or cyclin D1 expression. RESULTS: Endoscopic features of MALT lymphoma were characterized as protrusions that were covered with normal-appearing mucosa with or without ulceration. The gross appearances of MALT lymphomas were categorized as solitary (4 patients), multiple (3 patients), and multiple lymphomatous polyposis (MLP) (1 patient). The gross features of MCL at endoscopy were categorized as multiple protrusions (2 patients), and MLP (6 patients). The clinical stages of patients with MCL were more advanced than in patients with MALT lymphoma. CONCLUSIONS: Solitary or multiple protrusions at an early clinical stage is the most common presentation pattern of patients with MALT lymphoma, but an MLP appearance at an early stage is also possible. On the other hand, MLP appearance with an advanced clinical stage is the main presentation pattern in patients with MCL, although multiple protrusions with an early clinical stage is also possible. Histological and immunohistochemical investigation including that of cyclin D1 and CD5 expression is essential to make the final diagnosis.     

CD20-targeted measles virus shows high oncolytic specificity in clinical samples from lymphoma patients independent of prior rituximab therapy

New therapeutic modalities for B-cell non-Hodgkin's lymphomas (B-NHL) are needed, especially for relapsing and aggressive subtypes. Toward this end, we previously generated a fully CD20-targeted and armed measles virus, and tested its efficacy in a xenograft model of mantle cell lymphoma (MCL). Here, we quantify its spread in peripheral blood mononuclear cells and/or tissue of patients with different histological subtypes of B-NHL, including splenic marginal zone lymphoma (SMZL). CD20-targeted MV efficiently infects lymphoma cells from SMZL and MCL while sparing most cells in the CD20-negative population, in contrast to the parental vaccine-lineage MV, which infects CD20-positive and CD20-negative cells equally. Rituximab therapy (4-8 months before relapse) did not interfere with the infectivity and specificity of MV(green)H(blind)antiCD20 in patient lymphoma samples. Thus, CD20-targeted oncolytic virotherapy is likely to be effective after previous antiCD20 therapy.     

骨肉瘤中D类周期素的mRNA表达

目的 探讨骨肉瘤中D类三种周期素——D1、D2及D3 mRNA的表达。方法运用逆转录聚合酶链反应(RT-PCR)及半定量RT-PCR方法检测正常软组织和骨肉瘤中3种周期素D mRNA表达。结果正常软组织中检测不到周期素D1 mRNA的表达，而骨肉瘤组织中均可检测到，但多数表达较弱；正常软组织及骨肉瘤组织中均存在周期素D2、周期素D3 mRNA的表达，骨肉瘤中周期素D2、周期素D3的mRNA表达均明显高于软组织中的表达。结论周期素D2、D3可能在骨肉瘤失控的增生中起主要作用。     

肝癌中cyclin D1和cyclin E的表达及其意义

目的 :研究cyclinD1和cyclinE蛋白在肝癌中的表达和意义。方法 :用免疫组化方法检测肝癌组织 5 0例 ,癌旁组织 2 2例 ,正常肝组织 9例中cyclinD1和cyclinE蛋白的表达。结果 :cyclinD1和cyclinE只在肝癌中有过度表达 ,其过度表达与肿瘤分化程度和有无肝内转移相关。结论 :本试验表明 :cyclinD1和cyclinE过度表达可反应肝癌的侵袭力 ,它们与肝癌的发生发展密切相关。     

套细胞淋巴瘤中P53基因的研究进展

套细胞淋巴瘤(mantle cell lymphoma,MCL)是2001年WHO淋巴造血组织肿瘤新分类中的一种独立的B细胞非霍奇金淋巴瘤,几乎所有的MCL都有t(11;14)(q13;q32)易位,此易位使11q13上的BCL-1癌基因(cyclin D1)与14q32上的IgH基因重排,导致cyclin D1过度表达,促进细胞由G1期进入S期而使G1期缩短。MCL临床病程和转归呈异质性,许多临床和实验室特征可影响其预后,其中P53基因的异常与MCL的病程及转归密切相关。本文就P53基因的缺失、突变与MCL的关系,P53异常患者的治疗作一综述。     

肺癌组织中细胞周期蛋白D1的检测及其意义

检测细胞周期蛋白Ｄ１（ＣｙｃｌｉｎＤ１）在肺癌及癌前病变和正常肺组织的表达,探讨它在肺癌诊断中的作用及其与生物学行为的关系。方法收集肺癌及癌前病变和正常肺组织,采用免疫组化ＳＰ法检测ＣｙｃｈｎＤ１的表达。结果正常肺组织和鳞状化生的支气管上皮未见ＣｙｃｌｉｎＤ１表达,在轻－中－重度不典型增生、原位癌、浸润癌,ＣｙｃｌｉｎＤ１表达的阳性率逐渐升高,阳性细胞数也增多,肺癌组织中ＣｙｃｌｉｎＤ１表达的总阳性率为５６．４％。低分化癌的阳性率高于中高分化癌（Ｐ＜０．０５）：无论鳞癌还是腺癌,ＣｙｃｌｉｎＤ１阳性组的增殖活性高于阴性组（Ｐ＜０．０５）。肺鳞癌有淋巴结转移组ＣｙｃｌｉｎＤ１的阳性率高于无转移组（Ｐ＜０．０５）。结论ＣｙｃｌｉｎＤ１表达与肺癌的发生和增殖有关,而且ＣｙｃｌｉｎＤ１表达是支气管粘膜上皮癌变的早期事件,提示ＣｙＣｌｉｎＤ１可作为判断肿瘤发生可能性的标记物,在肺癌的早期诊断中可能具有重要意义。ＣｙＣｌｉｎＤ１表达与肺鳞癌分化不良及淋巴结转移有关,可能是预后不良的标志。     

Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum.

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Recent studies have demonstrated that elevated cyclin D1 levels correlate with decreased survival in human pancreatic cancer. In this study we expressed in a stable manner a cyclin D1 antisense cDNA construct in PANC-1 human pancreatic cancer cells. Expression of the antisense construct caused a decrease in cyclin D1 mRNA and protein levels and in cyclin D1-associated kinase activity. Antisense expressing clones displayed significantly increased doubling times, decreased anchorage-dependent and -independent basal growth, and complete loss of tumorigenicity in nude mice. EGF, FGF-2, and IGF-I enhanced mitogen-activated protein kinase activity in antisense expressing clones, but failed to stimulate their proliferation. In contrast, all three growth factors were mitogenic in parental cells. Furthermore, the inhibitory effect of cisplatinum on cell proliferation was enhanced markedly in the antisense expressing clones. These findings indicate that cyclin D1 overexpression contributes to abnormal growth and tumorigenicity in human pancreatic cancer and to the resistance of pancreatic cancer to chemotherapeutic agents.     

Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice.

D-type cyclin/cyclin-dependent kinase (CDK) complexes regulate transit through the restriction point of the cell cycle, and thus are required for the initiation of DNA synthesis. Transgenic mice which overexpress cyclin D1 in the heart were produced to determine if D-type cyclin deregulation would alter myocardial development. Cyclin D1 overexpression resulted in a concomitant increase in CDK4 levels in the adult myocardium, as well as modest increases in proliferating cell nuclear antigen and CDK2 levels. Flow cytometric and morphologic analyses of dispersed cell preparations indicated that the adult transgenic cardiomyocytes had abnormal patterns of multinucleation. Histochemical analyses confirmed a marked increase in number of cardiomyocyte nuclei in sections prepared from the transgenic mice as compared with those from control animals. Tritiated thymidine incorporation analyses revealed sustained cardiomyocyte DNA synthesis in adult transgenic hearts.     

霍奇金淋巴瘤的免疫表型与鉴别诊断

目的　研究霍奇金淋巴瘤 (HL)的免疫表型和鉴别诊断。方法　采用SP免疫组化法检测 5 6例HL患者瘤细胞及背景细胞的免疫表型 ,根据WHO 2 0 0 0淋巴瘤新分类重新评价。结果　HL患者 47例 ,其中结节性淋巴细胞为主型HL(NLPHL) 2例 ,经典型HL(CHL) 4 3例 ,未分类 2例 ;富于T细胞的B细胞淋巴瘤 (TCRBCL) 6例 ,间变性大细胞淋巴瘤 (ALCL) 2例以及转移性肿瘤 1例。NLPHL中L&H细胞呈CD2 0 (+) ,CD1 5(- ) ,CD3 0 (- ) ;背景细胞中TIA 1阳性细胞稀少 ,CD57阳性细胞多见。CHL中诊断性R S细胞及变异型R S细胞呈CD1 5(+) (81% ) ,CD3 0 (+) (10 0 % ) ,其中 3例共同表达CD2 0 呈弱阳性 ;背景细胞中TIA 1阳性细胞多见 ,而CD57阳性细胞稀少。TCRBCL中瘤细胞呈CD2 0(+) ,CD1 5(- ) ,CD3 0 (- ) ;背景细胞中TIA 1阳性细胞增多 ,CD57阳性细胞少见。ALCL中瘤细胞呈CD3(+) ,CD3 0 (+) ,ALK 1(+) ,CD1 5(- ) ,CD2 0 (- ) ,背景细胞中TIA 1阳性细胞多见 ,CD57阳性细胞少见。结论　石蜡免疫组化检测瘤细胞CD2 0 、CD3 、CD1 5、CD3 0 以及背景细胞TIA 1、CD57、CD2 0 和CD45RO 的表达 ,有助于HL的诊断和鉴别诊断     

Disappearance of cyclin A correlates with permanent withdrawal of cardiomyocytes from the cell cycle in human and rat hearts.

The regulated expression of cyclins controls the cell cycle. Because cardiomyocytes in adult mammals withdraw permanently from the cell cycle and thus cannot regenerate after injury, we examined cyclin expression during development by comparing cyclin A-E mRNA levels in fetal and adult human hearts. Cyclin B mRNA was detectable in adult hearts, although at a level markedly lower than that in fetal hearts. Levels of cyclin C, D1, D2, D3, and E mRNA were essentially identical in the two groups. In contrast, cyclin A mRNA was undetectable in adult hearts whereas cyclin A mRNA and protein were readily detectable in fetal hearts and cardiomyocytes, respectively. We then measured cyclin A mRNA and protein levels in rat hearts at four stages of development (fetal and 2, 14, and 28 d). Cyclin A mRNA and protein levels decreased quickly after birth (to 37% at day 2) and became undetectable within 14 d, an observation consistent with reports that cardiomyocytes stop replicating in rats by the second to third postnatal week. This disappearance of cyclin A gene expression in human and rat hearts at the time cardiomyocytes become terminally differentiated suggests that cyclin A downregulation is important in the permanent withdrawal of cardiomyocytes from the cell cycle.     

周期蛋白D3在小儿急性白血病细胞中的表达及期作用研究

目的　检测周期蛋白D1、D2 、D3 在小儿急性白血病细胞中的表达 ,并研究周期蛋白D3 在小儿急性白血病发病机制中的作用。方法　采用免疫组织化学法检测 43例急性白血病患者白血病细胞和 3种白血病细胞系中周期蛋白D的表达 ;用反义技术和流式细胞术研究周期蛋白D3在白血病细胞增殖中的作用。结果　小儿急性淋巴细胞白血病与急性非淋巴细胞白血病细胞中周期蛋白D3 阳性表达率分别为 47%和 38% ,急性白血病患者中周期蛋白D1阳性表达率约为5 % ,周期蛋白D2 表达均为阴性 ,正常对照组骨髓细胞周期蛋白D1、D2 、D3 表达均为阴性。周期蛋白D3 在白血病细胞系CEM细胞中表达阳性 ,用周期蛋白D3 反义脱氧寡核苷酸与CEM细胞共培养后 ,细胞增殖受到抑制。结论　周期蛋白D3 在小儿急性白血病细胞中呈现过度表达 ,并对白血病细胞增殖产生重要影响。     

The rGel/BLyS fusion toxin specifically targets malignant B cells expressing the BLyS receptors BAFF-R, TACI, and BCMA

B lymphocyte stimulator (BLyS) is crucial for B-cell survival, and the biological effects of BLyS are mediated by three cell surface receptors designated B cell-activating factor receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antibody (BCMA). Increased expression of BLyS and its receptors has been identified in numerous B-cell malignancies. We generated a fusion toxin designated rGel/BLyS for receptor-mediated delivery of the recombinant gelonin (rGel) toxin to neoplastic B cells, and we characterized its activity against various B-cell tumor lines. Three mantle cell lymphoma (MCL) cell lines (JeKo-1, Mino, and SP53) and two diffuse large B-cell lymphoma (DLBCL) cell lines (SUDHL-6 and OCI-Ly3) expressing all three distinct BLyS receptors were found to be the most sensitive to the fusion toxin (IC(50) = 2-5 pmol/L and 0.001-5 nmol/L for MCL and DLBCL, respectively). The rGel/BLyS fusion toxin showed specific binding to cells expressing BLyS receptors and rapid internalization of the rGel component into target cells. The cytotoxic effects of rGel/BLyS were inhibited by pretreatment with free BLyS or with soluble BAFF-R, TACI, and BCMA decoy receptors. This suggests that the cytotoxic effects of the fusion toxin are mediated through BLyS receptors. The rGel/BLyS fusion toxin inhibited MCL cell growth through induction of apoptosis associated with caspase-3 activation and poly (ADP-ribose) polymerase cleavage. Our results suggest that BLyS has the potential to serve as an excellent targeting ligand for the specific delivery of cytotoxic molecules to neoplastic B cells expressing the BLyS receptors, and that the rGel/BLyS fusion toxin may be an excellent candidate for the treatment of B-cell malignancies especially MCL and DLBCL.     

Role of DMP1 and its future in lung cancer diagnostics

Lung cancer is the most lethal carcinoma worldwide. Mutations of p53, inactivation of p16(INK4a), and overexpression of cyclins E, A and B are independently associated with poor prognoses of patients, while the prognostic value of cyclin D1 or RB expression is inconclusive. Cyclin D binding myb-like protein 1 (Dmp1) encodes a DNA binding protein that receives signals from oncogenic Ras and functions as a tumor suppressor by activating the Arf-p53 [corrected] pathway. Dmp1 has been shown to be haplo-insufficient for tumor suppression in mouse models including K-ras-mediated lung carcinogenesis. The human DMP1 gene is located on chromosome 7q21, and our recent results revealed that the hDMP1 gene is deleted, but not mutated or silenced, in approximately 40 % of human non-small-cell lung carcinomas. These cases typically retained wild-type ARF and p53 and expressed very low levels of the hDMP1 protein. Thus, hDMP1 loss could be a novel diagnostic marker for non-small-cell lung carcinomas.