IgM antibodies to P1 cytoadhesin of mycoplasma pneumoniae are part of the natural antibody repertoire expressed early in life

International audienc

Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7β-hydroxycholesterol on glioma cells

International audienceSteroidal maleic anhydrides were prepared in one step: lithocholic, chenodeoxicholic,deoxicholic, ursocholic, and hyodeoxicholic acid derivatives. Their capability to induce celldeath was studied on C6 rat glioma cells, and 7β-hydroxycholesterol was used as positivecytotoxic control. The highest cytotoxicity was observed with lithocholic andchenodeoxicholic acid derivatives (23-(4-methylfuran-2,5-dione)-3α-hydroxy-24-nor-5β-cholane (compound 1a), and 23-(4-methylfuran-2,5-dione)-3α,7α-dihydroxy-24-nor-5β-cholane (compound 1b), respectively), which induce a non-apoptotic mode of cell deathassociated with mitochondrial membrane potential loss and reactive oxygen speciesoverproduction. No cells with condensed and/or fragmented nuclei, no PARP degradation andno cleaved-caspase-3, which are apoptotic criteria, were observed. Similar effects were foundwith 7β-hydroxycholesterol. The cell clonogenic survival assay showed that compound 1bwas more cytotoxic than compound 1a and 7β-hydroxycholesterol. Compound 1b and 7β-hydroxycholesterol also induce cell cycle modifications. In addition, compounds 1a and 1b,and 7β-hydroxycholesterol favour the formation of large acidic vacuoles revealed by stainingwith acridine orange and monodansylcadaverine evocating autophagic vacuoles; they alsoinduce an increased ratio of [LC3-II / LC3-I], and modify the expression of mTOR, Beclin-1,Atg12, and Atg5-Atg12 which is are autophagic criteria. The ratio [LC3-II / LC3-I] is alsostrongly modified by bafilomycin acting on the autophagic flux. Rapamycin, an autophagicinducer, and 3-methyladenine, an autophagic inhibitor, reduce and increase 7β-hydroxycholesterol-induced cell death, respectively, supporting that 7β-hydroxycholesterolinduces survival autophagy. Alpha-tocopherol also strongly attenuates 7β-hydroxycholesterol-induced cell death. However, rapamycin, 3-methyladenine, and α-tocopherol have no effecton compounds 1a and 1b-induced cell death. It is concluded that these compounds trigger anon apoptotic mode of cell death, involving the mitochondria and associated with severalcharacteristics of autophagy

Traitement systémique des métastases cérébrales de mélanome

International audienceMelanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase)