Mechanisms of TRAIL-induced apoptosis in leukemic plasmacytoid dendritic cells.

International audienceOBJECTIVE: Dendritic cells play a central role in regulating the innate and adaptive immune responses. Plasmacytoid dendritic cells (PDC) represent a newly identified kind of DC with specialized functions aimed at fighting against viral infections. Recently, we have shown that CD4+CD56+ malignancies were leukemia arising from PDC, with a particularly aggressive clinical course. Hence, we asked whether these malignant PDC could be killed via TRAIL, a death-inducing ligand that belongs to a new class of anticancer drugs currently under development. MATERIALS AND METHODS: In this study we used a PDC line (GEN2.2) we recently developed from leukemic PDC as a model. RESULTS: We show that GEN2.2 PDC are sensitive to TRAIL-induced apoptosis and can be killed in vitro by TRAIL-expressing NK cells. Our results suggest that TRAIL binds to Death Receptor 5 (DR5) expressed by GEN2.2 and induces apoptosis mainly via caspases 10, 8, and 3. Interestingly, during infection with influenza, DR5 decreases on GEN2.2 cell surface, which consequently become resistant to TRAIL-induced apoptosis. Moreover, we confirmed the expression of DR5 or DR4 on half of LPDC tested, suggesting the possibility to kill these cells via TRAIL. Hopefully, normal PDC expressed neither DR4 nor DR5. CONCLUSION: These results suggest that TRAIL agonists represent a therapeutic alternative for the treatment of LPDC

Activated Clotting Time Monitoring during Atrial Fibrillation Catheter Ablation: Does the Anticoagulant Matter?

Atrial fibrillation (AF) catheter ablation is performed in patients receiving direct oral anticoagulants (DOACs) with intra-procedural unfractionated heparin (UFH) administration to achieve activated clotting time (ACT) at 300 s, as for vitamin K antagonist (VKA). We determined whether ACT monitoring might be transposed from VKA to DOAC-treated patients. Blood was taken from 124 patients receiving uninterrupted dabigatran, rivaroxaban, apixaban, or VKA or being untreated. DOAC concentration or INR (VKA) were measured. ACT was determined at baseline, and after spiking with UFH doses equivalent to 1000, 2500, 5000 and 10000 IU in vivo. At baseline, anticoagulants prolonged ACT differently, ACT was longer with dabigatran and shorter with apixaban despite similar concentrations. ACT strongly correlated with INR and dabigatran concentration, but not with apixaban or rivaroxaban concentrations. Moreover, UFH effects on ACT prolongation depended on the anticoagulant: dose-response curves in samples with VKA and dabigatran were parallel whereas ACT prolongation in response to UFH was significantly smaller with rivaroxaban and especially apixaban. Therefore, UFH to achieve ACT at 300 s might be transposed from VKA to uninterrupted dabigatran-treated patients but not to patients receiving FXa-inhibitors, especially apixaban. Targeting 300 s might expose to UFH overdosing and bleeding, questioning the current anticoagulation strategy

Ebola Virus RNA Stability in Human Blood and Urine in West Africa’s Environmental Conditions

We evaluated RNA stability of Ebola virus in EDTA blood and urine samples collected from infected patients and stored in West Africa’s environmental conditions. In blood, RNA was stable for at least 18 days when initial cycle threshold values were <30, but in urine, RNA degradation occurred more quickly

Severe Ebola Virus Infection With Encephalopathy: Evidence for Direct Virus Involvement

International audienceno abstrac

Performances, feasibility and acceptability of nasopharyngeal swab, saliva and oral-self sampling swab for the detection of severe acute respiratory syndrome coronavirus 2

International audienc

Occupational Exposures to Ebola Virus in Ebola Treatment Center, Conakry, Guinea

We report 77 cases of occupational exposures for 57 healthcare workers at the Ebola Treatment Center in Conakry, Guinea, during the Ebola virus disease outbreak in 2014−2015. Despite the high incidence of 3.5 occupational exposures/healthcare worker/year, only 18% of workers were at high risk for transmission, and no infections occurred

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.</jats:p