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Biomedical subjects

B Klein

Publications and source records attributed to B Klein.

At least 19 recordsLinked to original sources
PubMed1992

C-reactive protein and beta-2 microglobulin produce a simple and powerful myeloma staging system.

Multiple myeloma (MM) staging procedures are still inadequate for detection of the optimal therapeutic procedure for an individual patient. The Durie & Salmon staging system and serum beta 2-microglobulin (beta 2M) are used worldwide because of their easy clinical application. Other prognostic parameters, such as myeloma cell proliferative activity, are of exceeding importance, but are not as simple as standard methods. Recently, interleukin-6 (IL-6) has been shown to be a major growth factor for MM. IL-6 is a pleiotropic cytokine acting on several cell lineages, and, at the hepatocyte level, stimulates the synthesis of acute phase proteins, such as the well known C-Reactive Protein (CRP). Serum CRP concentration actually reflects the IL-6 activity. A survival analysis carried out in 162 MM patients at diagnosis showed that serum CRP level is a highly significant prognostic factor. Moreover, serum CRP was independent of serum beta 2M. This feature allowed stratification of MM patients into 3 groups according to CRP and beta 2M serum levels: (1) low risk group, CRP and beta 2M less than 6 mg/L (50% of patients); (2) intermediate risk group, CRP or beta 2M greater than or equal to 6 mg/L (35% of patients); (3) high risk group, CRP and beta 2M greater than or equal to 6 mg/L (15% of patients). Survival was 54, 27, and 6 months, respectively (P less than .0001). We thus propose a new and powerful myeloma staging system based on simple and reliable laboratory evaluations.

C-Reactive Protein↗
PubMed1992

Up-regulation of interleukin (IL)-6 receptor gene expression in vitro and in vivo in IL-6 deprived myeloma cells.

Myeloma cells absolutely require interleukin-6 (IL-6) for growing in vivo in patients with multiple myeloma and exogenous IL-6-dependent myeloma cell lines have been reproducibly obtained. In this study we show a dramatic up-regulation of the IL-6 receptor (gp80 chain) gene expression in myeloma cell lines following the removal of exogenous IL-6. Such a regulation was also known to occur in IL-6-deprived myeloma cells in vivo in three patients who were treated with optimal doses of anti-IL-6 monoclonal antibodies. The direct effect of IL-6 on IL-6 receptor gene expression in myeloma cells was further confirmed by adding IL-6 to an autonomously growing myeloma cell line.

Blotting, Northern↗
PubMed1992

Interleukin-6 dependence of advanced malignant plasma cell dyscrasias.

The authors, and others, clearly have established that interleukin-6 (IL-6) is the major growth factor for human myeloma cells in vitro. It is a critical conceptual point whether or not IL-6 remains involved in the final phases of disease progression in malignant plasma cell dyscrasias. To answer this question, the authors evaluated the in vitro IL-6 dependence of the proliferation of myeloma cells from the bone marrow of 13 patients with advanced multiple myeloma (MM) and from the peripheral blood of 13 patients with plasma cell leukemia (seven primary and six secondary cases). Their results show that myeloma cell growth was totally dependent on IL-6 in 25 of 26 patients. Myeloma cells of only one patient did not respond to IL-6 in vitro. Actually, the cells from this patient were not proliferating in vivo. Identical patterns of IL-6 dependence of myeloma cells were found in the peripheral blood and bone marrow from four patients with PCL. The authors conclude that, in the terminal phase of malignant plasma cell dyscrasias, tumoral growth is totally dependent on IL-6 in vitro. This observation is critical in considering the investigation of anti-IL-6 therapy in patients with advanced MM.

Aged↗
PubMed1992

CD5 B lymphocyte antigen in monoclonal gammopathy.

Because B lymphocytes bearing the CD5 antigen have been involved in many B-cell malignancies, we have investigated the presence of the CD5 B-cell antigen on B and plasma cells in monoclonal gammopathy. Quantification of CD5 B cells was made in the peripheral blood of seven individuals with monoclonal gammopathy of undetermined significance (MGUS) and in that of 21 patients with multiple myeloma (MM). The bone marrow of ten patients with MM was also studied. Patients with progressive MM presented a significant reduction in both B and CD5 B lymphocytes (i.e., percentages and absolute numbers), when compared with individuals with MGUS and patients with stable MM. These latter individuals and patients did not differ from healthy donors. No CD5 B cells were found in the bone marrow of patients with MM. Moreover, no CD5 antigen could be detected on eight freshly established human myeloma cells lines including six totally dependent on interleukin-6. However, it was weakly expressed on two standard myeloma cell lines not requiring exogenous interleukin-6 (i.e., RPMI 8226 and U 266). In conclusion, our data show mainly an overall reduction of the polyclonal CD5 B lymphocytes similar to what is observed for the other polyclonal B lymphocytes in patients with active MM. Finally, the expression of the CD5 antigen human myeloma cell lines is not constant.

Antigens, CD↗
PubMed1992

High amounts of circulating interleukin (IL)-6 in the form of monomeric immune complexes during anti-IL-6 therapy. Towards a new methodology for measuring overall cytokine production in human in vivo.

A patient with plasma cell leukemia was treated with anti-interleukin (IL)-6 monoclonal antibodies (mAb) for 2 months. Using chromatography on protein A-Sepharose, anti-murine-IgG-Sepharose, anti-IL-6-mAb-Sepharose and gel filtration at pH 2.3, we have demonstrated that the anti-IL-6 mAb, by preventing the binding of IL-6 to its cell membrane receptor and its renal elimination, has induced huge amounts of IL-6 to circulate in the form of monomeric immune complexes. By using this observation, we have developed a mathematical modelling that allows the determination of the overall daily production of IL-6 in this patient, which was in the range of 15 micrograms per day. Overall in vivo production of cytokines has never been evaluated in animals or in humans before.

Antibodies, Monoclonal↗
PubMed1992

Isolation and characterization of a cDNA from Cuphea lanceolata encoding a beta-ketoacyl-ACP reductase.

A cDNA encoding beta-ketoacyl-ACP reductase (EC 1.1.1.100), an integral part of the fatty acid synthase type II, was cloned from Cuphea lanceolata. This cDNA of 1276 bp codes for a polypeptide of 320 amino acids with 63 N-terminal residues presumably representing a transit peptide and 257 residues corresponding to the mature protein of 27 kDa. The encoded protein shows strong homology with the amino-terminal sequence and two tryptic peptides from avocado mesocarp beta-ketoacyl-ACP reductase, and its total amino acid composition is highly similar to those of the beta-ketoacyl-ACP reductases of avocado and spinach. Amino acid sequence homologies to polyketide synthase, beta-ketoreductases and short-chain alcohol dehydrogenases are discussed. An engineered fusion protein lacking most of the transit peptide, which was produced in Escherichia coli, was isolated and proved to possess beta-ketoacyl-ACP reductase activity. Hybridization studies revealed that in C. lanceolata beta-ketoacyl-ACP reductase is encoded by a small family of at least two genes and that members of this family are expressed in roots, leaves, flowers and seeds.

3-Oxoacyl-(Acyl-Carrier-Protein) Reductase↗
PubMed1992

Prognostic factors in node-positive operable breast cancer patients receiving adjuvant chemotherapy.

A retrospective analysis of prognostic factors in 214 consecutive node-positive (N+) operable breast cancer patients, receiving Melphalan + 5-fluorouracil adjuvant chemotherapy between 1980 and 1984 was performed. Median follow-up was 95 months. Actuarial disease-free interval (DFI) and survival (S) were determined according to age, menopausal status, histology, size of primary tumor (T), multifocality, tumor location, hormonal receptor status, number of N+, size of N+, tumor spread in axillary fat, and interval between surgery and onset of adjuvant chemotherapy. On univariate analysis two factors were prognostic for DFI and S: number of N+ and T size. A comparison between traditionally classified T1 and T2 patients revealed no significant difference, but when the cut-off point was shifted from 2 cm to 3 cm, T size represented a highly significant prognostic factor. In patients with T less than or equal to 3 cm 5-year DFI was 54% and 5-year S was 76%, while in patients with T greater than 3 cm the respective values were 23% (p less than 0.001) and 41% (p less than 0.001). These significant DFI and S differences persisted after adjustment for number of N+ by bivariate analysis. Multivariate analysis supported the importance of T greater than 3 cm as a strong adverse predictor. Four adverse variables, T greater than 3 cm, number of N+ greater than or equal to 4, multifocality, and tumor spread in axillary fat were used to divide our patients into three subsets with significantly different DFI: Group I, with none of the above factors; Group II, with only one factor present; and Group III, with more than one factor present (5 years DFI 66%, 45%, and 21%, respectively; p less than 0.001).

Breast Neoplasms↗
PubMed1992

The critical role of interleukin-6, interleukin-1B and macrophage colony-stimulating factor in the pathogenesis of bone lesions in multiple myeloma.

Lytic bone lesions and hypercalcemia are common features of multiple myeloma. In contrast, they are exceptional in other B-cell malignancies. Myeloma bone involvement is related to an uncoupling process associating increased osteoclastic resorption with decreased bone formation. Several osteoclast-activating factors, such as interleukin-1, macrophage colony-stimulating factor, and interleukin-6, are involved in this process. However, interleukin-6, the major myeloma cell growth factor, plays a critical role in myeloma-induced bone resorption.

Bone Resorption↗
PubMed1992

Conserved natural humoral immunity to thyroglobulin in patients with multiple myeloma.

We studied humoral immunity to human thyroglobulin (hTg) during the course of multiple myeloma (MM). In this report, we describe the anti-hTg antibody activity in the sera of patients with MM. Among 63 sera tested, 28 (44%) had IgG anti-hTg autoantibodies (aAb), 16 (25%) exhibited IgM aAb, and six (9%) had IgA anti-hTg aAb. For the majority of sera the anti-hTg autoantibody activity was associated with more than one immunoglobulin class. IgG anti-hTg antibodies were observed in 9/11 patients with IgA MM and in 19/40 patients with IgG MM. The IgM anti-hTG antibody activity was found in the sera of 11 patients with IgG MM. These results show that the anti-hTg activity in these patients is associated with residual polyclonal immunoglobulins. However, in the serum of one patient presenting a double monoclonal gammopathy (IgG and IgA lambda MM), the anti-hTg activity was carried by both the IgG lambda and the IgA lambda molecules, suggesting that in this case the activity was due to the monoclonal immunoglobulin itself. We also studied the epitopic specificity pattern of all these anti-hTg aAb. Only three sera recognized one antigenic region on hTg, suggesting that the majority of the anti-hTg aAb in MM patients were directed against antigenic regions other than those recognized by our panel of murine mAb. In conclusion, our results demonstrated that humoral immunity to hTg is maintained in MM patients. These data contrast with the well-documented suppression of immunity to foreign, especially bacterial, antigens described in MM.

Adult↗
PubMed1992

The fate of altered hepatocytic foci as a result of treatment with oxodipine, a calcium channel blocker.

The dietary administration of the calcium channel blocker oxodipine to Fischer (F344) rats for 12 and 30 months resulted in increased incidence of altered hepatocytic foci (AHF). As the Environmental Protection Agency (EPA) regards AHF as potentially precancerous it is important to accumulate experimental evidence which may negate this theory. In the case of oxodipine we proved that with dosages close to maximum tolerated dose (MTD) for prolonged periods no hepatic neoplasms were produced. The possible nature of such AHF is discussed.

Alkaline Phosphatase↗
PubMed1992

p53 shares an antigenic determinant with proteins of 92 and 150 kilodaltons that may be involved in senescence of human cells.

A panel of primary human cells and virus-transformed derivatives were tested for events that coincide with immortalization. In all primary and precrisis cells, two proteins of 92 and 150 kDa that shared an epitope with p53 were found; in most of their immortalized derivatives, however, they were absent. Expression of these proteins may be involved in senescence.

Antigens, Polyomavirus Transforming↗
PubMed1992

Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist cetrorelix (SB-75) in normal men.

In rats and nonhuman primates the new GnRH antagonist cetrorelix (SB-75; [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6,D-Ala10]GnR H) has been shown to suppress testosterone secretion effectively and persistently. A clinical phase I study was performed to assess the hormonal effects of this highly potent antagonist in normal men. After 2 control examinations 30 young male volunteers were randomly assigned to 6 treatment groups (n = 5/group), and single doses of 0 (placebo), 0.25, 0.5, 1.0, 2.0, and 5.0 mg cetrorelix were administered sc. Blood samples were obtained over the course of 7 days postinjection. After maximal cetrorelix serum levels were achieved 1 h postinjection, the GnRH antagonist serum levels decreased with a terminal t1/2 of 29.8 +/- 4.2 h (mean +/- SE). LH secretion was suppressed dose- and time-dependently; maximal suppression occurred 4-6 h postinjection. Suppression of FSH did not reach statistical significance. Doses of 1.0, 2.0, and 5.0 mg cetrorelix significantly suppressed testosterone secretion compared to that in the placebo group. After the administration of 1.0 mg cetrorelix, maximal suppression was seen 8 h after injection, with testosterone levels of 7.5 +/- 1.1 nmol/L compared to 15.8 +/- 2.2 nmol/L in the placebo group. Maximal testosterone suppression by 2.0 and 5.0 mg cetrorelix occurred 12 h after injection, with testosterone concentrations of 4.9 +/- 0.5 and 2.2 +/- 0.4 nmol/L, respectively, compared to 16.5 +/- 1.7 nmol/L in the placebo group. Twenty-four hours after the injection of 1.0 and 2.0 mg cetrorelix, testosterone values were no longer significantly different from those in the placebo group, whereas in the 5.0-mg dose group testosterone concentrations increased slightly and reached serum concentrations in the lower normal range after 48 h. The only side-effect observed after the administration of cetrorelix was a transient local erythema at the injection site that disappeared within 30 min. No local induration or pruritus, or any adverse systemic side-effect occurred in any volunteer. In conclusion, the new GnRH antagonist cetrorelix effectively decreases serum LH and testosterone concentrations in a dose- and time-dependent manner and, therefore, has potential for treatment of sex hormone-dependent diseases and male contraception.

Follicle Stimulating Hormone↗