Binding mode of Pyridoclax to myeloid cell leukemia-1 (Mcl-1) revealed by nuclear magnetic resonance spectroscopy, docking and molecular dynamics approaches.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15 µM in combination with anti-Bcl-xL strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1. Communicated by Ramaswamy H. Sarma.

Non-O1, non-O139 Vibrio cholerae bacteraemia in a cirrhotic patient.

Vibrio cholerae serogroups O1 or O139 are the aetiological agents of cholera. The pathogenicity of non-O1, non-O139 V. cholerae is less well known. These worldwide bacteria are responsible for gastrointestinal infections or, more rarely, bacteraemia in patients with an underlying disease, leading to life-threatening complications. We report a case of non-O1, non-O139 V. cholerae bacteraemia due to a haemolytic strain in a cirrhotic patient. Early antibiotherapy allowed a good outcome. The aim of this case report is to underline the virulence of non-choleragenic Vibrio strains, possibly linked to haemolysin production, and the potential danger of consuming undercooked seafood or exposing wounds to sea water in cirrhotic patients.

[Acute hepatic failure as the presenting manifestation of a metastatic lung carcinoma to liver]. / Insuffisance hépatique aiguë révélatrice d'un carcinome pulmonaire avec métastases hépatiques.

Liver failure as a result of neoplasia is a rare event before the terminal stage of the illness. We report a 66-year-old man who presented with clinical features of acute liver failure as the initial manifestation of a small-cell lung carcinoma. Liver was enlarged without ascitis. Abdominal CT-scan revealed a massive hepatomegaly with multiple low-density wedge-shaped lesions. The patient developed stage 3 hepatic encephalopathy and died on day 4. The diagnosis was obtained with post-mortem study. A Medline search of acute liver failure due to small-cell carcinoma identified only 17 cases already published, with a universally poor prognosis.

Peptides corresponding to the N- and C-terminal parts of PEBP are well-structured in solution: new insights into their possible interaction with partners in vivo.

Recently, it has been shown that mammalian PEBPs are implicated in several signalling pathways controlling the cellular cycle. In particular, during brain development, the N-terminal part of mammalian PEBP is specifically cleaved and the resulting 11 amino acid peptide stimulates the growth and activity of acetylcholinergic neurons. The crystallographic structure of bovine and human PEBPs has revealed that their N- and C-terminal parts are accessible and exposed to the solvent suggesting that they may be involved in specific interactions with cellular partners. We have chemically synthetized the two peptides corresponding to these terminal parts and studied their structure in solution by circular dichroism and NMR spectroscopies: both of them are well-structured. The N-terminal peptide is composed of a series of turns, leading to a hook conformation. The C-terminal peptide displays a globally helical conformation similar to that observed in the whole protein; it is characterized by an amphipatic feature with a hydrophobic cluster located on one side. These structural features enlighten previous fluorescence and monolayer experiments and give new insights on the roles of both PEBP termini.