Soluble epoxide hydrolase inhibitor promotes immunomodulation to inhibit bone resorption.

BACKGROUND AND OBJECTIVE: Soluble epoxide hydrolase (sEH) is an enzyme in the arachidonate cascade which converts epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 enzymes, to dihydroxy-eicosatrienoic acids. In the last 20 years with the development of inhibitors to sEH it has been possible to increase the levels of EETs and other EpFAs in in vivo models. Recently, studies have shown that EETs play a key role in blocking inflammation in a bone resorption process, but the mechanism is not clear. In the current study we used the sEH inhibitor (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea [TPPU]) to investigate the immunomodulatory effects in a mouse periodontitis model. MATERIAL AND METHODS: Mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 6) that were treated orally, daily for 15 days, with 1 mg/kg of TPPU. Then, the mice were killed and their jaws were analyzed for bone resorption using morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by microarray PCR or western blotting. RESULTS: Infected mice treated with TPPU showed lower bone resorption than infected mice without treatment. Interestingly, infected mice showed increased expression of sEH; however, mice treated with TPPU had a reduction in expression of sEH. Besides, several proinflammatory cytokines and molecular markers were downregulated in the gingival tissue in the group treated with 1 mg/kg of TPPU. CONCLUSION: The sEH inhibitor, TPPU, showed immunomodulatory effects, decreasing bone resorption and inflammatory responses in a bone resorption mouse model.

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells.

Anticancer drugs can induce tumor cell death by caspase-dependent apoptosis. The observation that procaspase-10 expression decreased in leukemic cells from acute myeloblastic leukemia patients at first relapse led us to explore the role of caspase-10 in cytotoxic drug-induced apoptosis. We show that caspase-10 is activated in etoposide-treated cells in a dose- and time-dependent manner. A caspase-10 peptide inhibitor, a caspase-10 dominant-negative mutant or a small interfering RNA (siRNA)-mediated downregulation of the enzyme negatively interfere with drug-induced cell death and caspase-2, -3, -8 and -9 activation. The extrinsic pathway to apoptosis is not involved in drug-induced caspase-10 activation that occurs downstream of Bax redistribution to mitochondria and cytochrome c release from this organelle. siRNA-mediated downregulation of Apaf-1 prevents etoposide-mediated activation of caspase-10. In a cell-free assay, cytochrome c and dATP treatment of cell extracts after immunodepletion of either caspase-3 or caspase-9 indicates that caspase-10 is activated downstream of caspase-9. Then, caspase-10 is involved in a feedback amplification loop that amplifies caspase-9 and -3 activities. Altogether, these data indicate an active role for caspase-10 in cytotoxic drug-induced tumor cell death, downstream of the mitochondria.

The protein kinase C activators phorbol esters and phosphatidylserine inhibit neutral sphingomyelinase activation, ceramide generation, and apoptosis triggered by daunorubicin.

To address the role of protein kinase C (PKC) in the regulation of ceramide production, we evaluated the impact of the PKC activators 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine on the apoptotic signaling pathway triggered by the chemotherapeutic drug daunorubicin. Treatment of U937 and HL-60 cells with 0.5-1 microM daunorubicin induced a greater than 30% activation of neutral sphingomyelinase activity within 4-10 min with concomitant sphingomyelin hydrolysis and ceramide generation. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate and phosphatidylserine inhibited daunorubicin-induced neutral sphingomyelinase activation, sphingomyelin hydrolysis, ceramide generation, and apoptosis. The apoptotic response could be restored by the addition of 25 microM cell-permeant C6-ceramide. In conclusion, PKC emerges as a potentially critical negative regulator of the anthracycline-activated sphingomyelin-ceramide apoptotic pathway.

Regulation of i- and I-antigen expression in the K562 cell line.

Expression of i- and I-antigen in K562 cultured under different conditions of culture was investigated. Under standard conditions of culture, i-antigen expression was very high (100% of i-labeled cells) in contrast to I-antigen expression of which was very low (2 to 5% of I-labeled cells). The addition of hemin to K562 cells did not modify the mean antigenic density or the proportion of i- and I-labeled cells. In contrast, sodium butyrate elicited an important increase in the proportion of cells exhibiting I-antigen associated to a decrease of i-antigenic density. The effect of butyrate was reversible and dependent upon de novo protein and messenger RNA synthesis since it was abolished in the presence of cycloheximide or actinomycin D. The stimulation of i-antigen conversion to I-antigen elicited by butyrate cannot be directly related to an induction of differentiation since evidence in this sense is lacking; in fact, butyrate did not increase the hemoglobin content of K562 cells. The passage from exponential to stationary phase of growth (cell density inhibition) was associated with an increase in I-antigen expression and a slight decrease in i-antigen density on the surface of K562 cells.

Early expression of glycophorin C during normal and leukemic human erythroid differentiation.

Glycophorins C and D (GPC and GPD) are two erythrocyte glycoproteins which originate from the same gene but differ in their NH2-terminal residues. The cell surface expression of these glycoproteins during normal and erythroid differentiation has been investigated with monoclonal and polyclonal antibodies and has been compared to the expression of glycophorin A (GPA), the major sialoglycoprotein of human red cells. Using glycosylation-independent antibodies (monoclonal or polyclonal), GPC or GPD was detected in erythroid and nonerythroid cell lineages. However, a glycosylation-dependent monoclonal antibody (MR4-130) detected an epitope on GPC which appears to be erythroid specific, suggesting that lineage specificity of this glycoprotein is related to some carbohydrate structures. During normal erythroid differentiation, GPC was expressed early at the level of erythroid progenitors (part of erythroid burst-forming unit and erythroid colony-forming unit) as detected with a glycosylation-independent monoclonal antibody (APO 3), whereas GPA is only present during terminal erythroid differentiation. The MR4-130 epitope was not coordinately expressed on the cell surface with the GPC molecule in the erythroid differentiation, since it was detected at the level of the more mature erythroid colony-forming unit slightly later than the GPC polypeptide. In four erythroleukemic patients, blast cells blocked at discrete stages of the erythroid differentiation were also investigated with antibodies and complementary DNA probes for GPA and GPC. GPA was immunologically detected in three of four cases, and its cell surface expression was correlated with the amount of specific mRNA in the cells, as seen by Northern blot analysis. GPC was immunologically detected on the blast cells of all four patients. However, in two cases including one with positive expression of GPA, the MR4-130 epitope was absent from the GPC molecule. By Northern blot analysis, we found that the GPC/GPD mRNA was present at a high level in all four patient samples. Western blot analysis of GPC and GPD in two of these patients revealed that these mRNAs were mostly translated into the GPD molecule, suggesting that these glycoproteins might be differently processed in certain cases of erythroleukemia.

Influence of Bcl-2 overexpression on the ceramide pathway in daunorubicin-induced apoptosis of leukemic cells.

We have previously demonstrated that daunorubicin (DNR) induces apoptosis in some leukemic myeloid cell lines. We investigated a potential protective role for Bcl-2 in apoptosis induced by DNR in two leukemic cell lines, one myeloid and one lymphoid, overexpressing the anti-apoptotic gene Bcl-2. Parental cells treated with DNR exhibited classical features of apoptosis 6 h after drug exposure, all the cells being dead after 30-48 h. In contrast, overexpression of Bcl-2 significantly delayed, but did not prevent the occurrence of DNR-induced apoptosis, with no surviving cells 96 h after drug exposure. To elucidate the mechanism of the protection mediated by Bcl-2, we explored the signaling pathway which initiates DNR-induced apoptosis. In this report, we show that, in both the myeloid and lymphoid parental cell lines, DNR triggered a sphingomyelin (SM) hydrolysis after 10-15 min with a concomitant ceramide generation. Moreover, exogenous ceramide induced DNA fragmentation in these cells, with levels similar to those observed with DNR treatment. In contrast, Bcl-2 overexpression protected the cells against apoptosis induced by ceramide treatment, without preventing the early SM hydrolysis nor the ceramide generation in these cells. Our results strongly suggest that Bcl-2-mediated protection of DNR-induced apoptosis is effected downstream of the SM-ceramide signaling pathway.

Selective inhibition of apoptosis by TPA-induced differentiation of U937 leukemic cells.

U937 leukemic cells treated for 24 h with 16 nM 12-O-tetradecanoylphorbol 13-acetate (TPA), that induces their macrophagic terminal differentiation, become resistant to etoposide-induced apoptosis. Exposure of undifferentiated U937 cells to 50 microM etoposide for 6 h, that triggers apoptosis in 80% cells, activates procaspase-2L, -3 and -8, induces the mitochondrial release of cytochrome c and decreases Mcl-1 expression without modifying Bcl-2, Bcl-xL and Bax protein levels. All these events are inhibited in TPA-differentiated U937 cells that are also resistant to vinblastine-induced and Fas-mediated cell death. Interestingly, these cells are not inherently resistant to apoptosis induction. Exposure of TPA-differentiated U937 cells to 0.8 microg/ml cycloheximide for 24 h, that triggers apoptosis in 50% cells, activates procaspase-2L, -3 and -8, induces the mitochondrial release of cytochrome c and decreases Bcl-xL expression without modifying Bcl-2, Mcl-1 and Bax protein levels. All these events are not observed in undifferentiated cells treated in similar conditions. These results indicate that the apoptotic pathway that involves the release of cytochrome c from mitochondria and the cleavage of procaspases remains functional in TPA-differentiated cells.

Ceramide generation occurring during 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis is caspase independent and is not required to trigger cell death.

Biological activities of oxysterols seem tightly regulated. Therefore, the ability to induce cell death of structurally related oxysterols, such as those oxidized at C7(7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol), was investigated on U937 cells at different times of treatment in a concentration range of 5-80 microg/ml. Whereas all oxysterols accumulate inside the cells, strong inhibition of cell growth and increased permeability to propidium iodide were observed only with 7beta-hydroxycholesterol and 7-ketocholesterol, which trigger an apoptotic process characterized by the occurrence of cells with fragmented and/or condensed nuclei, and by various cellular dysfunctions: loss of mitochondrial transmembrane potential, cytosolic release of cytochrome c, activation of caspase-9 and -3 with subsequent enhanced activity of caspase-3, degradation of poly(ADP-ribose) polymerase, and increased accumulation of cellular C16 : 0 and C24 : 1 ceramide species. This ceramide generation is not attributed to caspase activation since inhibition of 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis by Z-VAD-fmk (100 microM), a broad spectrum caspase inhibitor, did not reduce C16 : 0 and C24 : 1 ceramide species accumulation. Conversely, when U937 cells were treated with 7beta-hydroxycholesterol and 7-ketocholesterol in the presence of fumonisin B1 (100 microM), a specific inhibitor of ceramide synthase, C16 : 0 and C24 : 1 ceramide species production was completely abrogated whereas apoptosis was not prevented. Noteworthy, 7alpha-hydroxycholesterol induced only a slight inhibition of cell growth. Collectively, these results are consistent with the notion that the alpha or beta hydroxyl radical position of oxysterols oxidized at C7 plays a key role in the induction of the apoptotic process. In addition, our findings demonstrate that 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis involve the mitochondrial signal transduction pathway and they suggest that C16 : 0 and C24 : 1 ceramide species generated through ceramide synthase play a minor role in the commitment of 7beta-hydroxycholesterol- and 7-ketocholesterol-induced cell death.

Lack of ceramide generation in TF-1 human myeloid leukemic cells resistant to ionizing radiation.

The mechanism(s) by which ionizing radiation (IR) induces cell death is of fundamental importance in understanding cell sensitivity and resistance. Here we evaluated the response to IR of two subclones of the autonomous human erythromyeloblastic cell line TF-1: TF-1-34 (which expresses CD34) and TF-1-33 (which lacks CD34). In clonogenic assays, TF-1-34 cells were found to be relatively less sensitive to IR compared to TF-1-33 cells based on the D0 determination (3.01 vs 1.56 Gy). Furthermore, after IR at 12 Gy, TF-1-33 cell viability decreased by approximately 50% within 24 h, whereas TF-1-34 cell growth was unaffected during this time. Gradual loss of TF-1-34 cell viability was observed only after 48 h. Morphological and molecular analysis revealed that TF-1-33 cells died of apoptosis, and TF-1-34 cells of delayed reproductive cell death. While IR produced comparable amounts of DNA double strand breaks (DSB) in both cell lines, TF-1-34 retained DSB much longer than TF-1-33 suggesting that radioresistance and the defective apoptotic response of TF-1-34 cells was not related to a higher DNA repair capacity. However, the lack of an apoptotic response in TF-1-34 was correlated to the absence of a sphingomyelin (SM)-ceramide (CER) signaling pathway. Indeed, IR triggered in TF-1-33 cells but not in TF-1-34, SM hydrolysis (25% at 12 Gy) and CER generation (>50%) through the activation of neutral but not acid sphingomyelinase. Synthetic cell permeate CER induced apoptosis in both TF-1-33 and TF-1-34 cells. This study indicates that alterations of the SM-CER signaling pathway can significantly influence the cell death process as well as the survival of acute myeloid leukemia cells after IR exposure.

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies.

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti- and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NFkappaB transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.

Natural resistance of acute myeloid leukemia cell lines to mitoxantrone is associated with lack of apoptosis.

The purpose of this study was to characterize mitoxantrone-induced cytotoxicity in KG1a and TF-1, two P-glycoprotein expressing AML cell lines which display early differentiation phenotypes, compared to more mature HL-60 and U937 cells. KG1a and TF-1 cells were found to be 30-40-fold more resistant to mitoxantrone than HL-60 and U937 cells. Uptake and efflux of mitoxantrone were similar for all cell lines. Moreover, a potent P-glycoprotein blocker (PSC833) had no impact on either accumulation or efflux. No differences were found in the appearance and removal of mitoxantrone-induced DNA-protein complexes. These results suggest that resistance of KG1a and TF-1 cells is not related to a decreased interaction between mitoxantrone and topoisomerase II. Further studies showed that the mechanisms of cell death were different for sensitive and resistant cell lines. Thus, mitoxantrone induced rapid apoptotic cell death in sensitive cells as indicated by characteristic morphological changes and both high molecular weight and internucleosomal DNA fragmentation. In contrast, mitoxantrone induced a G2-M block in resistant cells followed by a progressive loss of viability with necrotic features. Neither oligonucleosomal nor large DNA fragments were detected in these cells during a post-treatment period of up to 96 h. Finally, drug-induced activation of the AP-1 transcription factor was higher in resistant cell lines than in sensitive ones whereas activation of NF-kappaB was comparable. Therefore, our study provides evidence that certain AML cells display natural resistance to mitoxantrone which is independent of drug transport and drug-target interactions but appears to be associated with the inability of the drug to induce apoptosis in these cells.

Early increase in DcR2 expression and late activation of caspases in the platelet storage lesion.

Platelet transfusion is widely used to prevent bleeding in patients with severe thrombocytopenia. The maximal storage duration of platelet concentrates is usually 5 days, due to the platelet storage lesion that impairs their functions when stored for longer times. Some of the morphological and biochemical changes that characterize this storage lesion are reminiscent of cell death by apoptosis. The present study analyzed whether proteins involved in nucleated cell apoptosis could play a role in the platelet storage lesion. Storage of leukocyte-depleted platelets obtained by apheresis is associated with a late and limited activation of caspases, mainly caspase-3. This event correlates with an increased expression of the pro-apoptotic BH3-only protein Bim in the particulate fraction and a slight and late release of the pro-apoptotic mitochondrial protein Diablo/Smac in the cytosol. Platelets do not express the death receptors Fas, DR4 and DR5 on their plasma membrane, while the expression of the decoy receptor DcR2 increases progressively during platelet storage. Addition of low concentrations of the cryoprotector dimethylsulfoxide accelerates platelet caspase activation during storage, an effect that is partially prevented by the caspase inhibitor z-VAD-fmk. Altogether, DcR2 expression on the plasma membrane is an early event while caspase activation is a late event during platelet storage. These observations suggest that caspases are unlikely to account for the platelet storage lesion. As a consequence, addition of caspase inhibitors may not improve the quality of platelet concentrates stored in standard conditions.

Pregnancy in women with immune thrombocytopenic purpura.

Thirty-six women with immune thrombocytopenic purpura were studied during 37 pregnancies, and maternal characteristics with predictive value for the fetal platelet count were determined. Nine neonates were thrombocytopenic, with a platelet count of less than 50 x 10(9)/L in eight. Four of these nine neonates delivered to a subgroup of 31 mothers were studied prospectively; the frequency of thrombocytopenia in neonates of women with immune thrombocytopenic purpura was thus 13%. Only two of these nine neonates presented with hemorrhagic syndromes (two, petechial purpura; one, intracranial bleeding). The frequency of neonatal thrombocytopenia was higher in mothers with deep thrombocytopenia and in those who had not responded to corticosteroid treatment following diagnosis. No prognostic value could be assigned to the other maternal characteristics studied, such as a history of splenectomy, maternal treatment at the time of delivery, or the presence of platelet autoantibodies evaluated either with the platelet immunofluorescence test or the platelet Western blot immunoassay.

The phosphoinositide 3-kinase/Akt pathway is activated by daunorubicin in human acute myeloid leukemia cell lines.

Daunorubicin induces apoptosis in myeloid leukemia cells by activation of neutral sphingomyelinase and ceramide generation occurring 4-10 min after daunorubicin addition. We show here that daunorubicin is able to increase the phosphoinositide 3-kinase activity and enhance intracellular phosphoinositide 3-kinase lipid products prior to ceramide generation. Daunorubicin activates Akt, a downstream phosphoinositide 3-kinase effector. Interestingly, the phosphoinositide 3-kinase inhibitors wortmannin and LY294002 accelerate daunorubicin-induced apoptosis in U937 cells. The phosphoinositide 3-kinase/Akt pathway has been involved in cell survival following serum deprivation, tumor necrosis factor alpha, anti-Fas and UV radiations. Our results suggest that anti-tumor agents such as daunorubicin may also activate anti-apoptotic signals that could contribute to drug resistance.

Involvement of de novo ceramide biosynthesis in lymphotoxin-induced oligodendrocyte death.

Both experimental and clinical studies suggest that lymphotoxin (LT) plays an important role in multiple sclerosis (MS) by inducing oligodendrocyte (OL) depletion. However, the mechanism of LT cytotoxicity is unknown. Because of the role of ceramide as a cell death mediator for a large variety of cytotoxic molecules, we have investigated the possible role of this second messenger in LT-induced cytotoxicity on SV40 immortalized new-born mice OL. Human recombinant LT exposure (50 ng/ml) resulted in intracellular ceramide accumulation which peaked at 48 h (approximately 170% increase) and paralleled LT-induced cytotoxicity. Moreover, fumonisin B1, a potent and specific ceramide synthase inhibitor, not only inhibited ceramide accumulation but also protected OL from LT cytotoxicity. These results suggest that LT-induced ceramide synthase stimulation and subsequent increased intracellular ceramide concentration are implicated in oligodendrocyte death.

Antitumor agent-induced apoptosis in myeloid leukemia cells: a controlled suicide.

Traditional antitumor research has generally believed that the cytotoxicity of antitumor agents was directly correlated with the amount of drug-induced cellular lesions. Accordingly, oncologists have tried to improve anticancer agent/target interactions by increasing the intracellular dose of active effectors. However, a growing body of evidence stemming from both clinical and experimental observations, strongly suggests that similar anticancer-induced lesions may result in different cellular responses, greatly influencing cytotoxicity. For example, it has been shown that in some but not all cellular models, antitumor agents trigger apoptosis, an irreversible process which leads to a rapid and complete elimination of tumor cells. Several of these studies also demonstrated that apoptosis induced by antitumor agents is highly regulated by multiple signaling pathways which are themselves influenced by oncogenes, protein kinase activities, external stimuli and the oxidative balance. Therefore, it appears that cell death commitment is controlled by both external and internal factors which interfere downstream of drug- or ionizing radiation-target interaction. The characterization of these mediators may provide novel strategies for modulating intracellular signaling pathways in order to promote apoptosis in drug-resistant tumor cells.

Methyltransferase inhibitor S-adenosyl-L-homocysteine sensitizes human breast carcinoma MCF7 cells and related TNF-resistant derivatives to TNF-mediated cytotoxicity via the ceramide-independent pathway.

In this study we investigated the signalling requirements for TNF-induced cytotoxicity modulated by the methyltransferase inhibitor S-adenosyl-L-homocysteine (AdoHcy) using the TNF-sensitive human breast carcinoma MCF7 cells and its established TNF-resistant clones (R-A1 and clone 1001). Our data indicate that inhibition of methylation reactions by adenosine plus homocysteine, which are known to condense within cells to AdoHcy, markedly potentiated TNF-induced cytotoxicity in MCF7 cells and rendered related TNF-resistant variants, TNF-sensitive by a mechanism independent from the ceramide pathway. We demonstrated that the dominant-negative derivative of FADD (FADD-DN) blocked methylation inhibition/TNF-induced cell death. Moreover, TNF-mediated cytotoxicity modulated by AdoHcy was blocked by the ICE-inhibiting peptide z-VAD-fmk, suggesting that an ICE-like protease is required for the methylation inhibition/TNF-inducible death pathway. In conclusion, these results suggest that the methyltransferase inhibitor AdoHcy potentiates TNF-induced cytotoxicity in MCF7 cells and renders TNF-resistant MCF7 clones, TNF-sensitive via the ceramide independent pathway and that FADD and the ICE-like protease are likely necessary components in transducing methylation inhibition/TNF signals for cell death.

[Post-transfusion purpura. An unknown cause of acute immune thrombocytopenia. 4 new cases]. / Le purpura post-transfusionnel. Une cause méconnue de thrombopénie aiguë immunologique. Quatre nouveaux cas.

Post-transfusion purpura is characterized by the occurrence of acute immune thrombocytopenia 5 to 10 days after transfusion of platelet-containing blood products in subjects who had been alloimmunized to specific platelet antigens. Four cases are reported here. Three of these 4 patients, who had a rare PLA1 platelet phenotype, had developed, during a previous sensitization (pregnancy n = 2, transfusion n = 1), an allo antibody directed against PLA1 antigen. The fourth patient presented a specific anti-PLA2 antibody. Thrombocytopenia (platelet count between 4 and 40 x 10(9)/1) appeared 1 to 12 days after the responsible transfusion and showed as haematomas (n = 3) or haemoptysis (n = 1). One patient was asymptomatic and remained untreated. The remaining 3 patients received corticosteroids orally associated, in one case, with infusions of human immunoglobulin concentrates. Thrombocytopenia was corrected within 5 to 13 days. In such cases, whenever another blood transfusion is necessary, a preventive treatment with perfectly platelet-free blood products is mandatory. Platelet depletion by freezing-thawing of red cell concentrates is probably not always sufficient, since recurrence was observed with such a product in one of our patients. The exact cause of immune destruction of autologous platelet remains a mystery.

[Chemodectoma of the orbit. Apropos of a case and review of the literature]. / Chémodectome de l'orbite. A propos d'un cas et revue de la littérature.

The clinical, follow up and diagnostic features of a case of chemodectoma (paraganglioma) of the orbit are reviewed. 30 cases are reported in the literature. Chemodectoma may arise in any area of the body where non chromaffin paraganglion structures are situated. These are localized in the orbit of the chimpanzee but not in the orbit of man. Malignant behavior of chemodectoma has been a controversial subject, with most authors considering them to be benign tumors. Some authors have diagnosed locally recurrent and infiltrative tumors as malignant. The authors report one case of chemodectoma of the orbit. A 5 year old child has had right exophthalmos. She was treated by tumorectomy. The follow-up is marked by recurrence of the tumor and infiltration of the right hemi-face.

[Derivative of bleomycin generates less of ROS? Less of fibrosis? Alternative in the development of an efficacy anticancer therapy but less toxic]. / Dérivé de la bléomycine générant moins de ROS? Moins de fibrose? Une alternative dans le développement d'une thérapie anticancéreuse efficace mais moins toxique.

Deglycobleomycin (DBLM), the aglycon of the glycopeptide antitumor drug bleomycin (BLM), was first used since 1980 during comparative studies between BLM and DBLM in order to elucidate the role of the sugar component in the mechanism of action of BLM. In fact, the deglycosylation of BLM reduce the toxicity of this molecule and fails to produce reactive oxygen species, responsible for pulmonary fibrosis, and for anti-neoplastic activity of BLM. This causes toxic DNA lesions and ultimately leads to cell death. The therapeutic use of BLM is limited by a dose-dependent lung toxicity that eventually leads to fibrosis. Testing BLM-derivative molecules and defining their molecular mechanisms involved in tumor cell death may help to design new therapeutic approach with limited toxicity profile while maintaining anti-tumoral properties. The present review was undertaken to determine the effect of carbohydrate moiety in the mechanism of BLM induced cytotoxicity behind a comparative studies between BLM and DBLM.