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H Merle-Beral

Publications and source records attributed to H Merle-Beral.

At least 19 recordsLinked to original sources
PubMed2006

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

Aged↗
PubMed2002

High levels of chromosome aberrations correlate with impaired in vitro radiation-induced apoptosis and DNA repair in human B-chronic lymphocytic leukaemia cells.

PURPOSE: To investigate the relationship between the susceptibility of B-chronic lymphoid leukaemia (B-CLL) cells to DNA damage-induced apoptosis, the kinetics of DNA strand-break rejoining, and chromosome damage after exposure to ionizing irradiation. MATERIALS AND METHODS: Lymphocytes from B-CLL patients were gamma-irradiated in vitro with 0.2-5 Gy and stimulated by Staphylococcus aureus cowan I (SAC I) for estimation of chromosomal damage. Induction of apoptosis after irradiation was studied in 50 patients by two methods: morphological characterization of apoptotic cells after fluorescent staining (Hoechst), and specific quantification of mono- and oligonucleosomes in cytoplasmic cell fractions (ELISA assay). Morphological chromosome damage was scored in the first cell generation after irradiation (13 patients). In parallel, the kinetics of DNA single-strand break rejoining were investigated by the alkaline comet assay (12 patients). RESULTS: Ionizing irradiation did not induce apoptosis in lymphocytes from a subset of B-CLL patients. The results suggest that B-CLL cells resistant to radiation-induced apoptosis could repair DNA strand-breaks more rapidly and showed a higher level of chromosome aberrations than radiation-sensitive B-CLL cells. CONCLUSION: Each of three biological effects observed (apoptosis, kinetics of DNA single-strand-break repair, chromosomal damage) might be explained by different modifications occurring in irradiated B-CLL cells. Their convergence strongly suggests that resistance to apoptotic death initiation by DNA damage may be impeded by a rapid engaging of the DNA repair mechanisms. The higher level of chromosome aberrations observed in these cells suggests that the type of DNA repair system involved may generate inaccurate repair.

Apoptosis↗
PubMed2000

Prognostic relevance of a scoring system based on clinical and biological parameters in early chronic lymphocytic leukemia.

INTRODUCTION: Among patients with indolent form of B-cell chronic lymphocytic leukemia, some of them will progress into more advanced stages. To better define this subpopulation of patients, we attempted to define some parameters capable of predicting a pejorative clinical outcome. MATERIALS AND METHODS: Eighty-eight previously untreated patients with B-cell chronic lymphocytic leukemia in Binet stage A were analysed to study the prognostic value of simple serological variables: soluble CD23 (sCD23), beta2 microglobulin (beta2m), lactate-dehydrogenase activities and albumin level. Results were compared to other conventional clinical and biological parameters by univariate and multivariate statistical analysis. RESULTS: Our data show that: (1) among those studied, sCD23 >50 u/ml was the only serological significant parameter clearly correlated with disease progression and (2) stage A" patients (hemoglobin level between 100 and 120 g/l and/or lymphocytosis >30.10(9)/l), axillary lymph nodes and hypogammaglobulinemia were found to be other variables associated with a pejorative outcome. These four variables enabled the establishment of a scoring system, capable of predicting disease progression since 66% of the patients with a score < or =2 are going to evolve into advanced stages vs 12% with a score <2. Furthermore, the time to progression is shortened when the score is increasing. CONCLUSION: Our findings show the prognostic relevance of a scoring system including sCD23 level. This score could be taken into account in the treatment strategy of B-cell chronic lymphocytic leukemia.

Adult↗
PubMed2000

Ocular and central nervous system lymphoma: clinical features and diagnosis.

PURPOSE: To evaluate the clinical, angiographic, and cytopathologic features of ocular and central nervous system (CNS) lymphoma. PATIENTS AND METHODS: Retrospective study of 44 patients over a 10-year period. RESULTS: A total of 36 women and six men, mean age 54 years (range: 36-90 years), were included. The mean time interval between onset of ocular symptoms and diagnosis was 40 months (range: 1-144 months). Ocular involvement was bilateral in 84% of the cases. Laser flare photometry readings averaged 9.6 photons/ms (2.9-78.3 photons/ms). Vitritis was constant. Funduscopy revealed RPE abnormalities in 60.49% of the cases and punctuate retinal infiltrates in 33.5%. The most common findings with fluorescein angiography were window defects and hypofluorescent round lesions. Patients had CNS involvement in 66% of the cases. Cytologic examination of the vitreous samples showed high-grade B lymphoma in 86% of the cases. Interleukin-10 dosage, when performed, showed elevated levels averaging 2352 pg/ml in all vitreous samples. Molecular biology based on PCR confirmed the diagnosis in 12 patients. Treatment included systemic chemotherapy alone or associated with radiotherapy in various regimens. Fourteen patients died during follow-up. Only 12 patients were in complete remission. CONCLUSION: The prognosis of the disease remains poor. However, the new diagnostic tools and therapeutic strategies may improve the diagnostic delay and the survival outcome.

Adult↗
PubMed1999

Theophylline-induced B-CLL apoptosis is partly dependent on cyclic AMP production but independent of CD38 expression and endogenous IL-10 production.

Our recent work has shown that theophylline which inhibits intracellular cyclic adenosine monophosphate (cAMP) degradation is able to kill chronic lymphocytic leukemia (CLL) cells in vitro and synergizes in vitro and in vivo with chlorambucil. In order to test the hypothesis that theophylline works through an indirect increase in cAMP, we have investigated the role of several molecules on B-CLL cells from 20 patients. Direct cAMP inducers such as dibutyryl-cAMP (db-cAMP), prostaglandin-E2 (PGE2) and forskolin induced moderate apoptosis but extremely high levels of intracellular cAMP. By contrast theophylline was highly apoptotic but did not synergize with cAMP inducers. Apoptosis was completely reversed by a cAMP antagonist when induced by PGE2 or forskolin, but was only partially antagonized when induced by theophylline. Since CD38+ CLL cells are more sensitive to apoptosis and since CD38 is enhanced by cAMP inducing agents its expression was investigated. In our hands CD38 was not induced by the above pharmacological compounds. Exogenous IL-10 has been shown to induce CLL cell death; however, apoptosis following treatment with theophylline or cAMP inducers could not be ascribed to endogenous production of IL-10. This ruled out the involvement of cytokines or of an activation or differentiation process in apoptosis. Altogether our data show that an increase in intracellular cAMP mediates apoptosis in vitro but accounts only partly for theophylline-mediated apoptosis.

ADP-ribosyl Cyclase↗
PubMed1998

Simple, fast method of detection apoptosis in lymphoid cells.

To facilitate the analysis of apoptotic cells, the present study proposes a new quantitative method based on the changes of light scatter properties of lymphoid cells undergoing apoptosis measured with a hematology analyzer. Peripheral blood lymphocytes from 40 chronic B-lymphocytic leukemia samples, five acute T-lymphoblastic leukemia samples, three healthy donors and from T-cell lines Jurkat, SUB-T1 and SUP T8) were cultured during 72 hours in medium alone or in the presence of chlorambucil, fludarabine or theophylline, all compounds known to be apoptosis inducers, with or without adjunction of interleukin 4. Samples were run on a Bayer-H1 system and the percentage of apoptotic cells was evaluated by monitoring the lobularity index corresponding to the polymorphonuclear population. Results compared to the dUTP-fluorescein method by flow cytometry and dUTP-peroxidase labeling on slides (TUNEL) showed an excellent correlation (chi-square test: P < 0.01). This method is reliable and simple and allows one to measure routinely the percentage of apoptotic lymphoid cells at short notice in a laboratory of hematology. This is especially valuable, particularly in testing the predictive value of in vitro drug-induced apoptosis before starting a chemotherapy protocol.

Apoptosis↗
PubMed1998

Whipple's syndrome (uveitis, B27-negative spondylarthropathy, meningitis, and lymphadenopathy) associated with Arthrobacter sp. infection.

OBJECTIVE: To report an unusual case of Whipple's disease, including uveitis, seronegative spondylarthropathy, meningitis, and lymphadenopathy, associated with an Arthrobacter sp. infection. DESIGN: Interventional case report. PATIENT AND INTERVENTION: A 60-year-old white man presenting with severe chronic uveitis and systemic inflammatory manifestations was treated efficiently for Whipple's disease after histopathologic analysis of vitreous and inguinal adenopathy biopsy specimens. The authors performed a retrospective, laboratory-based evaluation of stored tissue specimens. MEASUREMENTS: Molecular analysis based on 16S ribosomal RNA gene amplification was applied to pretreatment biopsy specimens of inguinal lymph node to identify a causative bacterial agent. RESULTS: Tropheryma whippelii genome was not detected in these specimens. However, an amplification product was obtained after the first polymerase chain reaction run and subsequently was sequenced. It corresponded to an Arthrobacter sp., a gram-positive agent presenting diagnostic patterns and therapeutic management similar to those of Whipple's disease caused by T. whippelii. CONCLUSION: The absence of T. whippelii identification by molecular amplification during a clinically and histologically oriented Whipple's syndrome should not rule out the diagnosis. Arthrobacter infection may represent a new bacterial etiology of systemic inflammatory disorders involving the eye and associated with periodic acid-Schiff-positive inclusions.

Arthrobacter↗
PubMed1998

Autologous hematopoietic stem cell transplantation as salvage treatment for advanced B cell chronic lymphocytic leukemia.

Given the generally poor outcome of advanced B cell chronic lymphocytic leukemia, experimental approaches are warranted, especially for younger patients in whom classical treatments have failed. We therefore conducted a prospective single-center study, using polychemotherapy (ESHAP) to prepare patients for hematopoietic stem cell collection and autologous stem cell transplantation as consolidation therapy. Twenty patients entered the study. An adequate response to ESHAP was obtained in 13 patients, and sufficient stem cells for grafting were obtained in eight of the 12 patients who underwent the collection procedure. Six of these grafted patients are alive in complete clinical remission a median of 30 months after transplantation. It should be noted that we were only able to graft 40% of the patients enrolled in this study, either because a new remission could not be obtained or because not enough hematopoietic stem cells could be collected. This argues for stem cell collection as soon as a first remission is obtained, even if the autograft is done later in the course of the disease.

Adult↗
PubMed1998

Lack of association between human leukocyte antigens and the anti-Hu syndrome in patients with small-cell lung cancer.

We compared the human leukocyte antigen alleles found in a group of 17 patients with small-cell lung cancer (SCLC), paraneoplastic neurologic syndromes (PNS), and high titers of anti-Hu autoantibodies with those in 30 patients with SCLC but no PNS and no anti-Hu antibodies (control group). There was no difference between the two groups, suggesting that specific haplotypes are not required for the development of the "anti-Hu syndrome."

Alleles↗
PubMed1997

Soluble Fcgamma receptor, Fc gammaRIIa2, is present in two forms in human serum and is increased in patients: with stage C chronic lymphocytic leukemia.

Human Fcgamma receptor type II (FcgammaRII/CD32) can be produced in a soluble form, termed FcgammaRIIa2, which contains the extra- and intracellular regions of the receptor, due to an alternative splicing of the transmembrane domain-encoding exon. We show that human sera contain two forms of FcgammaRIIa2. A full-length secreted protein, which has a 32 kDa backbone, can be detected only in some sera while all sera contain a C-terminal truncated form, lacking part of the intracytoplasmic tail, and exhibiting a 24 kDa protein backbone. The 24 kDa form is significantly increased in sera from stage C patients with B chronic lymphocytic leukemia, compared to healthy donors, stage A and B CLL patients, or CLL patients in complete remission.

Animals↗
PubMed1997

VH gene expression in CD5 positive and CD5 negative B cell chronic lymphoid malignancies.

In this review, we report analyses of VH genes in mature B cell malignancies generally or occasionally bearing CD5 antigen such as B CLL, MCL, SLVL and PLL. In the majority of cases, B CLL and MCL use VH genes in germline configuration. However in some cases a higher rate of random mutations is observed. These differences are not related to CD5 expression but are accounted by Ig phenotype, since less mutations are observed in CLL cases expressing membrane mu delta, when compared to forms exclusively expressing membrane mu. PLL and SLVL cases display mutated V genes independently of CD5 expression. Although there is some evidence that CD5+ B cells constitute a separate lineage, the possibility that CD5 constitutes an activation marker cannot be ruled out. Indeed, CD5- B cells can be induced to differentiate into CD5+ B cells and VH gene analyses showed no significative differences between CD5+ and CD5- B cell lymphoproliferative disorders. In this review we have tried to examine B cell chronic malignancies on the basis of phenotype and VH gene usage. Thus we propose a tentative classification where these disorders are allocated according to these characteristics.

Animals↗
PubMed1996

Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia.

Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.

Adult↗
PubMed1996

Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells.

We tested the effects of theophylline, a phosphodiesterase inhibitor inducing intracellular accumulation of cyclic adenosine monophosphate (cAMP), on malignant B cells from 15 patients with B-chronic lymphocytic leukemia (B-CLL). We observed a large increase in apoptotic cell numbers (mean, 90% v 20% in medium alone) in the presence of theophylline (100 micrograms/mL) or chlorambucil (10 mumol/L) after 72 hours of incubation. Maximal apoptosis (90%) was reached after 36 hours when the two drugs were used together at fourfold lower concentrations, indicating a synergistic effect; no effect was observed with normal B cells, suggesting that the combination might have therapeutic interest. Chlorambucil induced intracellular Ca+2 influx, pointing to the involvement of two signaling pathways that might explain its synergy with theophylline through their effects on oncogenes. The expression of bcl-2 protein, a proto-oncogene inhibiting apoptosis, decreased after incubation with the drugs, while c-myc, recently described as having a potent role in apoptosis, was overexpressed. For p53 we observed an overexpression in the presence of chlorambucil or both theophylline-chlorambucil and a decrease after theophylline incubation. Chlorambucil- and theophylline-induced apoptosis was partially inhibited by interleukin-4 (IL-4), which also abrogated the effects on oncogene expression. These results provide insight into the mechanisms underlying B-CLL apoptosis and suggest that the theophylline-chlorambucil combination may be of therapeutic value in this setting.

Apoptosis↗
PubMed1996

Apoptosis in blood diseases. Review new data.

In this report we reviewed the recent data regarding the involvement of apoptosis or programmed cell death in hematological diseases. We summarized new features of apoptosis including high molecular weight DNA fragmentation and programmed cell death of enucleated cells. We described the recent contributions about the three oncogenes bcl-2, p53 and c-myc. New inducers and inhibitors of apoptosis have been reported, particularly the role of stromal environment, thrombopoietin, erythropoïetin and flt-3 ligand has been mentioned. Apoptosis has been studied in red cell pathology: polycythemia, thalassemia and deficiency in folates, vitamin B12, iron and G6PD. Recently, the involvement of programmed cell death has been documented in bone marrow failure and myelodysplasia. In Acute Leukemia, the therapeutic action of numerous drugs has been proven by their in vitro apoptotic effect. The resistance of malignant cells to apoptosis, in Chronic Myeloïd Leukemia, due to bcr-abl oncogene, has been partially explained by conformational changes in p53 expression and is reversed by retinoic acid. Numerous reports in Chronic Lymphocytic Leukemia have documented the major role of apoptosis in this disease, especially in therapeutic efficacy of Chlorambucil, Fludarabine and Methylxanthine derivatives. At least, in Myeloma, it has been shown that apoptosis is induced by dexamethasone and HMBA, and inhibited by interleukine 6 that prevents activation of SAP Kinases.

Animals↗
PubMed1995

[Uveitis: late complication of undiagnosed Whipple disease].

We report a case of severe chronic bilateral uveitis in a 60-year-old white man without neurological manifestations. Spondylarthritis and isolated malabsorption suggested the diagnosis of Whipple's disease. A normal duodenal biopsy delated the diagnosis, who was secondarily demonstrated an adenopathy biopsy and macrophage study on vitrectomy sample (macrophage distended by periodic acid-Schiff positive material). With 1 year follow-up the uveitis was rapidly and completely cured by an antibiotic association (rifampicin and trimethoprim-sulfamethoxazol). The characteristics of ocular involvement in Whipple's disease and treatment of the disease are discussed.

Anti-Bacterial Agents↗