Localization by chromosome microdissection of a recurrent breakpoint region on chromosome 6 in human B-cell lymphoma

Deletion of the long arm of chromosome 6 (6q) is one of the most common chromosomal alterations in human B-cell lymphomas. Conventional cytogenetic banding analysis and loss-of-heterozygosity (LOH) studies have detected several common regions of deletion ranging across the entire long arm (6q), with no defined recurrent breakpoint yet identified. We describe here a strategy combining chromosome microdissection and fluorescence in situ hybridization (Micro-FISH) to determine a minimal region of deletion along chromosome 6. Seven clinical cases and one cell line of follicular lymphoma containing a t(14;18) and one case of diffuse lymphoma, also with a t(14;18), were used for this study. All nine cases had previously defined abnormalities of chromosome 6 determined by cytogenetic analysis. The results of chromosome dissection were unexpected and in contrast to the suggestion of disparate breakpoints by conventional chromosome banding. Specifically, Micro-FISH analysis provided evidence for a common breakpoint at 6q11 in seven of nine cases. After Micro-FISH analysis, all of the presumed simple deletions of chromosome 6 were carefully reanalyzed and shown to actually represent either nonreciprocal translocations (three cases), interstitial deletions (five cases), or isochromosome (one case). The recurrent proximal breakpoint (6q11) was detected in seven of nine cases, with the minimal region of deletion encompassing 6q11 to 6q21. By analogy to other tumor systems, the identification of recurring breakpoints within 6q11 may suggest that a gene(s) important to the genesis or progression of follicular lymphoma can be localized to this band region.     

Signaling in the motility responses of the human neutrophil

The neutrophil has developed into one of the most efficient vertebrate motile cells. It migrates through tissues, where it encounters multiple chemoattractant signals with complex spatial and temporal characteristics. The directional movement of the neutrophil is signaled by the binding of chemoattractants and chemokines to G-protein-coupled receptors expressed on the plasma membrane. The signals from the ligand-bound receptors are transmitted along signaling pathways and initiate various cell responses, such as motility, superoxide production, and secretion. The signaling of the motility responses finds its climax in the polymerization of F-actin, which results in lamella formation and overall rearrangement of the cellular cytoskeleton and cell crawling. Also, during motility, adhesion receptors attach to and detach from their ligands and provide the necessary traction for crawling. These events are highly synchronized and allow the cell to orient in shallow chemoattractant gradients even when more than one chemoattractants are present. Due to the complexity of the motility responses, the signaling of their regulation is still not well understood. Recent advances in the understanding of the mechanism of F-actin polymerization have shown that the small GTPasess Cdc42, Rac2, and RhoA, play a critical role in motility. The bound integrin receptors may also contribute to the signaling of motility via tyrosine kinase phosphorylation of guanine nucleotide exchange factors and other regulatory proteins. In this review, we discuss the signaling of neutrophil motility in relation to the response of the cell to chemoattractant activation. © 2002 Biomedical Engineering Society. PAC2002: 8717Jj, 0130Rr     

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine)

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.2 microM in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs.     

雷公藤单─有效成分T＿4对类风湿关节炎患者滑膜细胞产生前列腺素E＿2的影响

雷公藤单─有效成分Ｔ＿４对类风湿关节炎患者滑膜细胞产生前列腺素Ｅ＿２的影响要庆平，张乃峥（北京协和医院北京１００７３０）雷公藤（ＴｒｉｐｔｅｒｙｇｉｕｍｗｉｌｆｏｒｄｉｉＨｏｏｋ）的半纯品多甙（Ｔ２）目前较多地用于类风湿关节炎（ＲＡ）。近年来从Ｔ２中...     

防治成人呼吸窘迫综合征的人工重组肺泡表面活性剂研制II.生物发光法筛选制剂处方

在前期用表面化学方法进行防治成人呼吸窘迫综合征的药物制剂处方筛选基础上,通过建立尘肺动物模型,用生物发光技术从清除自由基能力角度对制剂进行处方筛选,获到了有良好表面性能和一定自由基清除能力的人工重组肺泡表面活性剂制剂处方。该制剂有待经模型动物防治试验评价。     

Intermembrane transfer and antioxidative action of α-tocopherol in liposomes

Institute of Physiology, Bulgarian Academy of Sciences, Sofia 1113. I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad 194223. University of California, Berkeley 94720. (Presented by Academician of the Academy of Medical Sciences of the USSR S. E. Severin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 109, No. 1, pp. 37–39, January, 1990.     

Sensitivity of alpha-amanitin to oxidation by a lactoperoxidase-hydrogen peroxide system.

Oxidation of alpha-amanitin - a potent hepatotoxin found in the mushroom Amanita phalloides - by a lactoperoxidase-hydrogen peroxide system was investigated by different techniques. (i). UV spectroscopy of the mixture after 24 h incubation reveals a significant decrease in the absorbance range characteristic of the putative reactive moiety of the toxin, the tryptathionine group. (ii). Formation of a new product was detected by Thin Layer Chromatography. (iii). In vivo experiments with non-inbred male albino mice showed a lowered toxicity of the modified toxin in comparison with that of the native one. Taking into account the latter results concerning the sensitivity of the toxin towards an oxidising system, the formation and reactivity of an alpha-amanitin derivative is discussed in the course of A. phalloides poisoning (inhibition of RNA polymerase type II and development of damaging radical species).     

p53 overexpression as a marker of poor prognosis in mantle cell lymphomas with t(11;14)(q13;q32)

The t(11;14)(q13;q32) translocation, which juxtaposes the BCL1 oncogene with the Ig heavy chain locus, has been associated with an uncommon subtype of non-Hodgkin's lymphoma (NHL) termed mantle cell lymphoma (MCL). To date, no molecular marker that serves as an indicator of tumor progression or clinical prognosis has been described for NHLs with this translocation. We examined a panel of NHLs with t(11;14) for overexpression of p53 and correlated the results with single-strand conformation polymorphism (SSCP) analysis, karyotypic features, and clinical course. NHLs with t(11;14) were identified from 30 patients. The diagnosis was MCL for 23 of 30, small lymphocytic lymphoma for 4 of 30, and diffuse large-cell lymphoma for 3 of 30 cases. The results of immunohistochemistry analysis using a monoclonal anti-p53 antibody on paraffin-embedded specimens were compared with the SSCP data, the tumor karyotypes, and clinical course of each patient. DNA sequencing of exons was performed on cases that showed conformational changes by SSCP analysis. NHLs from 5 of 23 patients with MCL were positive for p53 overexpression. Deletions of chromosome 17p were identified in 2 of 30 cases, both of which were MCLs showing p53 overexpression. Two of the five MCLs with p53 overexpression showed evidence for TP53 mutations. None of the 18 MCLs negative for p53 overexpression showed conformational changes by SSCP. For these 18 patients with MCLs that did not overexpress p53, the median survival was 63 months, compared with 12 months for the 5 patients with MCLs positive for p53 overexpression (P < .001). These results suggest that p53 overexpression in MCL with t(11;14)(q13;q32) may serve as a marker of poor prognosis.