PubMed Health⌕ Search

Biomedical subjects

L Kopper

Publications and source records attributed to L Kopper.

At least 19 recordsLinked to original sources
PubMed2006

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation.

Chronic lymphocytic leukemia (CLL) is an indolent B-cell non-Hodgkin's lymphoma that may transform into higher-grade lymphoma. The transformation involves an increased number of prolymphocytic cells, termed prolymphocytic transformation (PLT) or the development of diffuse large B-cell lymphoma (DLBL), also referred to as Richter's transformation (RT). To analyze whether activation-induced cytidine deaminase (AID), which is essential for somatic hypermutation (SHM) of normal B-cells, and malfunction of SHM termed aberrant somatic hypermutation (ASHM) are associated with higher-grade transformation of CLL, AID mRNA expression and the mutation pattern of c-MYC, PAX-5 and RhoH genes were analyzed in eight cases of CLL without transformation and in 21 cases that showed RT or PLT. Chronic lymphocytic leukemia cases, which showed no transformation or eventually transformed into higher-grade lymphoma, showed low levels of AID mRNA expression and low frequency of mutations of c-MYC, PAX-5 and RhoH genes. In both RT and PLT, high-levels of AID mRNA expression and high-frequency mutations of c-MYC, PAX-5 and RhoH genes were detected. These results indicate that AID expression and ASHM are associated with higher-grade transformation of CLL and provide further evidences that AID expression and ASHM may be activated during the clonal history of B-cell lymphomas.

Cell Transformation, Neoplastic↗
PubMed2005

Clonal selection in the bone marrow involvement of follicular lymphoma.

To characterize the pathways of bone marrow (BM) involvement of follicular lymphoma (FL), we performed morphological and immunophenotypical analysis of tumor cells from lymph nodes (LNs) and corresponding BMs in 21 patients with FL. In three cases, genealogical trees were constructed based on the immunoglobulin variable region heavy chain (IgV(H)) gene sequences of tumor clones from LNs and BMs. Results showed that FLs within the BMs display identical or lower cytological grades than in the LNs. In the majority of cases, different proportions of tumor cells expressed bcl-2, CD10 and Ki67 in LNs and BMs. Tumor cells in the BM showed ongoing somatic hypermutation of the IgV(H) genes; the distribution of these mutations was highly consistent with antigen selection. The topology of the genealogical trees revealed that different subclones populate the LN and BM and BM infiltration may occur at different points of the clonal evolution of FL. Early descendants of the original tumor clone and derivatives of diversified tumor clones may invade the BM. These results suggest that the BM involvement of FL is associated with intensive clonal selection of tumor cells, and the BM provides a microenvironment similar to the germinal centers of LNs, where tumor cells retain their biological nature.

Bone Marrow↗
PubMed2004

Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter's syndrome.

Patients with chronic lymphocytic leukemia (CLL) may develop diffuse large B-cell lymphoma (DLBL), also known as Richter's syndrome. Mutational status of immunoglobulin (Ig) heavy-chain variable region (VH) genes have prognostic impact in CLL. Patients with mutated VH genes have a stable disease, whereas patients with unmutated VH gene have more aggressive disease. The mutational status of CLLs that transform to DLBL is unknown. To reveal whether Richter's syndrome occurs in CLLs with mutated or unmutated VH genes, we have performed mutational analysis on serial specimens from eight patients. CLL and DLBL tumorclones were identical in five cases and they were different in three cases. Six CLLs expressed unmutated and two cases expressed mutated VH genes. In five of the six unmutated CLLs, the DLBL clones evolved from CLL tumorclones and the VH genes expressed by DLBLs were also unmutated. In one unmutated and two mutated CLLs, the DLBLs expressed mutated VH genes, but in these three cases the DLBL tumorclones developed as independent secondary neoplasm. These results suggest that Richter's syndrome may develop in both mutated or unmutated CLLs, but clonal transformation of CLL to DLBL occur only in the unmutated subgroup of CLL.

Clone Cells↗
PubMed2003

Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma.

Expression of the cell surface receptor Fas is frequently lost or decreased during tumor progression in human colon carcinomas. The methylation status of a 583 bp CpG-rich region within the Fas promoter (-575 to +8) containing 28 CpG sites was determined in human colon carcinoma cell lines. In Caco(2) (no Fas expression), 82-93% of CpG sites were methylated, whereas none were methylated in GC(3)/c1 (high Fas expression). In RKO (intermediate level of Fas), a single CpG site, located at -548, was 100% methylated. The inhibitor of methylation, 5-aza-2'-deoxycytidine (5-azadC), upregulated Fas expression in four of eight cell lines, and sensitized RKO cells to recombinant FasL-induced apoptosis. The p53-binding region in the first intron of the Fas gene was partially methylated in Caco(2), and 5-azadC potentiated Ad-wtp53-induced upregulation of Fas expression. Methylation-specific PCR of the first intron detected partial methylation in four out of 10 colon carcinoma tumor samples in vivo. The data suggest that DNA hypermethylation is one mechanism that contributes to the downregulation of Fas expression and subsequent loss of sensitivity to Fas-induced apoptosis in colon carcinoma cells.

Apoptosis↗
PubMed2001

Molecular pathology of tumor metastasis. I. Predictive pathology.

Millennium reviews of oncology agreed that the last century produced major developments mainly in the management of the primary tumor, but despite all of these results, cancer still remains among the leading causes of death due to the failure of clinical management of disseminated disease. This failure is primarily due to the lack of detailed information on the molecular mechanisms of tumor metastasis. Therefore, one of the hottest fields in experimental oncology is metastasis research, which provides more and more information about the molecular mechanisms. However, this information is fragmented and is not yet exploited in clinical practice. A new field of diagnostic pathology recently emerged, which translates basic research data to diagnostic practice to provide clinically relevant information on the biological potential (in this case metastatic potential) of the malignant tumors. Since tumor cell-extracellular matrix interactions are key features of tumor dissemination, expression of genes responsible for them can define the metastatic potential of malignant tumors. This review summarizes our recent knowledge on the metastatic geno- and phenotype of major human solid tumors: lung, colon, breast, prostate cancers and malignant melanoma.

Female↗
PubMed2001

[The role of syndecans in lymphoid systems]

Syndecans, transmembrane heparan sulfate proteoglycans, play an important role in cell-cell and cell-matrix interactions, as receptors/co-receptors of matrix elements, cytokines, growth factors. These functions are partly non-specific and due to the heparan sulfate chains attached to the ectodomain, and partly specific related to the transmembrane and cytoplasmic domains of the core protein. In hemopoietic cells syndecan-1 is expressed in certain B cells, in pre-B cells and plasma cells. In lymphoproliferative diseases this normal syndecan-1 expression of plasma cells is retained in myelomas/plasmocytomas, other lymphoplasmocytic NHL subtypes and primary effusional lymphomas. Syndecan-1 expression is probably gained in B-CLL, and lost in other NHLs of pre- or post-follicular origin. These results suggest that the expression of syndecan is essential for some NHLs, probably ensuring the required connections to the microenvironment. From a diagnostic point of view, syndecan-1 is a very useful phenotypic marker to identify cells with plasmocytic differentiation. The importance of syndecan expression in CLL and Hodgkin-lymphoma still requires further studies.

Journal Article↗
PubMed2000

IgE-containing cells in gastric mucosa with and without Helicobacter pylori infection.

Gastric mucosa responds with inflammation to Helicobacter pylori (H. pylori) infection. While numerous reports have shown that the immune system produces specific IgG, IgA, and IgM isotype anti H. pylori antibodies, IgE-mediated pathways of H. pylori-associated gastritis are mostly unknown. Our aim was to evaluate whether an increased presence of IgE in the antral gastric mucosa is responsible for the severity of the H. pylori-associated gastritis. The number of IgE-containing cells was estimated in formalin-fixed, paraffin-embedded antral gastric biopsy specimens using immunohistochemistry in three groups of patients: (i) 20 H. pylori-positive cases with moderate inflammation, (ii) 19 H. pylori-negative cases with moderate inflammation, and (iii) 19 H. pylori-negative cases with normal mucosa. In chronic gastritis, the number of IgE-positive cells increased significantly as compared to normal mucosa. In gastritic patients, H. pylori positivity was accompanied by a significant accumulation of IgE-positive cells, mainly plasma cells. These data suggest that IgE-mediated immune response probably plays an important role in the development of H. pylori-associated gastritis.

Adult↗
PubMed2000

Syndecans and the lymphoid system.

Syndecans, transmembrane proteoglycans, play an important role in cell-matrix and cell-cell interactions, as well as modulators in receptor activation. These functions are partly non-specific and related to the heparan sulfate chains attached to the ectodomain, and partly specific due to the transmembrane and cytoplasmic domains of the core protein. In hemopoietic cells syndecan-1 is expressed only in B cells at certain differentiation stages (pre-B and plasma cells). In lymphoproliferative conditions this selective expression is retained in myelomas/plasmacytomas and other lymphoplasmacytic NHL subtypes, and primary effusional lymphomas. It is probably gained in B-CLL, and lost in other NHLs of pre- or post-follicular origin. It is concluded from these empiric results that the expression of syndecan is essential for some NHLs, probably ensuring the required connections to the microenvironment. From a diagnostic point of view, syndecan-1 is a very useful phenotypic marker to indentify cells with plasmacytic differentiation. The importance of syndecan expression in CLL and Hodgkin's lymphoma still requires further studies.

ADAM Proteins↗
PubMed1999

[The effect of trace elements--especially zinc--on metastasizing of Lewis lung tumor].

The effect of a widely used trace element preparation (Béres-Drop Plus, BDP) on the liver metastasis forming potential of 3LL-HH tumor was studied. The daily, oral administration of BDP caused a decrease in the number of liver metastases, irrespective of the presence or absence of the primary spleen tumor. It is suggested, that the zinc component of BDP is responsible, at least partly--for the inhibitory action.

Administration, Oral↗
PubMed1999

Interaction of cytocidal drugs and the inhibition of caspase-3 by 3-nitrosobenzamide.

The effect of 3-nitrosobenzamide (NOBA) on the etoposide, staurosporine and dexamethason induced rapid (4-6 hr), caspase-dependent apoptosis was investigated in thymocytes and lymphoma cells by flow cytometric assay of DNA fragmentation. When NOBA (ED(50) = 4 microM) was added to these cell systems, the rapid onset of apoptosis was prevented. Such apparent protection by NOBA was related to the inactivation of caspase-3, by s-nitrosylation of 1.3 mol -SH per enzyme molecule out of 7 -SH groups. Since NOBA by itself induces DNA fragmentation within 18 hr in lymphoma cells, our results indicate that at least two active cell death pathways exist with apparent dissimilar kinetics and molecular mechanisms.

Animals↗
PubMed1999

[Cell death and tumor formation].

Proliferation and death (apoptosis) are the main cellular functions in the maintenance of the homeostasis of the organism. Disturbances in the regulation of these two basic phenomena may results in the continuous and irreversible accumulation of cells in time and space. This process which could become autonomous without any obvious biological "advantage". Both the overproduction of anti-apoptotic factors (e.g. bcl-2) or the failure of pro-apoptotic signals (e.g. p53) can contribute to tumorigenesis. Authors review the different phases of apoptosis with emphasis on the most important decision making elements in cell death, i.e. caspases and mitochondria, as well as on the interactions of the regulatory pathways. The better understanding of these coordinated and interdependent actions may help to achieve improvements in many fields of oncology.

Apoptosis↗
PubMed1999

Syndecan-1 (CD138) expression in human non-Hodgkin lymphomas.

Syndecan-1, an important transmembrane heparan sulphate proteoglycan is expressed in distinct stages of differentiation of normal lymphoid cells: in pre-B cells and Ig-producing plasma cells; however, its normal function, or presence in lymphoid malignancies, is still largely unknown. The expression of syndecan-1 (CD138) was studied in 57 human non-Hodgkin lymphomas using immunocytochemistry and immunohistochemistry. Positive expression of syndecan-1 was found in the plasma cells in chronic lymphoblastic leukaemia (B-CLL) cases, in different plasmocytoid lymphomas as well as in myeloma. All normal and malignant Tcells, or CD5+ cells other than B-CLL proved to be negative. These results strongly suggest that syndecan-1 expression is a characteristic phenotypic marker for B-CLL and lymphoplasmocytoid lymphomas and could be used for diagnostic purposes.

Biomarkers, Tumor↗
PubMed1998

BCNU is a caspase-mediated inhibitor of drug-induced apoptosis.

BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], a bifunctional (alkylating/carbamoylating) anticancer agent, in noncytotoxic doses (12-50 microM) inhibited drug-induced apoptosis in HT58 human lymphoma cells exposed to etoposide (ETO; 50 microM) as well as in mouse thymocytes exposed to dexamethasone (5 microg/ml) in vitro in 4-h cultures. The cytoplasmic extracts of ETO-treated HT58 cells cleaved both purified poly(ADP-ribose)polymerase and Ac-Asp-Glu-Val-Asp-7-amino-4-methylcoumarin fluorogenic caspase substrate, indicating the presence of active caspases, and these effects were inhibited by BCNU concentration dependently. The carbamoylating decomposite, 2-chloroethyl-isocyanate (6-25 microM), also decreased ETO-induced apoptosis in HT58 cells in vitro and their caspase 3-like activity ex vivo, whereas N-(2-chloroethyl)-N-nitrosocarbamoyl-valinamide, an alkylating and mainly intramolecularly carbamoylating nitrosourea derivative (400 microM), did not influence these phenomena. Furthermore, the activity of recombinant caspase 3 was also strongly inhibited by BCNU and 2-chloroethyl-isocyanate. These results indicate that BCNU, via its carbamoylating capacity, can inactivate cysteine protease(s) essential for ETO-induced apoptosis. This apoptosis-modulating property of BCNU, in turn, may influence the efficacy of chemotherapeutic protocols in the treatment of cancer.

Antineoplastic Agents, Alkylating↗
PubMed1998

Inhibition of DNA topoisomerase I activity by heparan sulfate and modulation by basic fibroblast growth factor.

Eukaryotic DNA topoisomerase I catalyzes changes in the superhelical state of duplex DNA by transiently breaking single strands thereby allowing relaxation of both positively and negatively supercoiled DNA. Topoisomerase I is a nuclear enzyme localized at active sites of transcription, and abnormal levels of the enzyme have been observed in a variety of neoplasms. Because the enzyme binds heparin and, given the presence of heparan sulfate within the nuclei of mammalian cells, we sought to investigate the interaction between topoisomerase I and sulfated glycosaminoglycans isolated from normal and neoplastic human liver. The results demonstrated that low concentrations (approximately 100 nM) of heparan sulfate from normal liver but not from its malignant counterpart effectively blocked relaxation of supercoiled DNA driven by either purified holoenzyme or topoisomerase I activity present in nuclear extracts of three malignant cell lines. Heparin acted at even lower (approximately 10 nM) concentrations. Moreover, we show that basic fibroblast growth factor could interfere with this heparan sulfate/heparin-driven inhibition and that both basic fibroblast growth factor and heparin-binding sites co-localized in the nuclei of U937 leukemic cells. Our results suggest that DNA topoisomerase I activity may be modulated in vivo by specific heparan sulfate moieties present in normal cells but markedly reduced or absent in their transformed counterparts.

Cell Nucleus↗
PubMed1998

Oral administration of a trace element preparation and zinc inhibit liver metastasis of 3LL-HH murine tumor cells.

A trace element preparation (TEP-Beres Drops Plus) was given to liver metastasizing 3LL-HH tumor bearing mice in the presence and after the removal of the primary spleen tumor. In both models when TEP was provided daily and orally in a dose range of 100-5,000 microgram/kg, the number of liver metastasis decreased at an end-point of day 14 and TEP also had inhibitory effect on the primary tumor. The antitumor action proved to be dependent on tumor burden. There was no change in body weight, size distribution of metastases and in the life span of mice. Zn++ could be one of the antimetastatic components among the trace elements. This is the first report on the antimetastatic effect of trace elements in an experimental tumor model.

Administration, Oral↗
PubMed1997

[Androgen-producing adrenocortical adenoma in childhood. Pitfalls of differential diagnosis].

A two-year-old girl presented with clitoromegaly and an abdominal mass. Diagnostic procedures including sonography, computerized tomography, scintigraphy and measurement of catecholamines in urine excluded neuroblastoma, but suspected Wilms-tumor. Before completing the steroid measurements therapy was initiated according to Wilms-tumor (preoperative cytostatic therapy followed by surgical removal of the tumor). Morphology of the tumor, the serum and urinary steroid profile proved a benign adrenocortical adenoma producing mainly delta 5-steroids including the weak androgen, dehydroepiandrosterone.

Adenoma↗