Dissecting the role of the CXCL12/CXCR4 axis in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build‐up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse‐free and overall survival. The CXCR4 ligand, CXCL12 (SDF‐1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a ‘multi‐hit’ therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre‐clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a ‘multi‐hit’ therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM

Identification of circulating microRNAs as diagnostic biomarkers for use in multiple myeloma

BACKGROUND: Multiple myeloma is a plasma cell disorder that is characterised by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal paraprotein in the blood or urine and associated organ dysfunction. It accounts for approximately 1% of cancers and 13% of haematological cancers. Myeloma arises from an asymptomatic proliferation of monoclonal plasma cells termed monoclonal gammopathy of undetermined significance (MGUS). METHODS: MicroRNA expression profiling of serum samples was performed on three patient groups as well as normal controls. Validation of the nine microRNAs detected as promising biomarkers was carried out using TaqMan quantitative RT-PCR. MicroRNA levels in serum were normalised using standard curves to determine the numbers of microRNAs per μl of serum. RESULTS: Three serum microRNAs, miR-720, miR-1308 and miRNA-1246, were found to have potential as diagnostic biomarkers in myeloma. Use of miR-720 and miR-1308 together provides a powerful diagnostic tool for distinguishing normal healthy controls, as well as patients with unrelated illnesses, from precancerous myeloma and myeloma patients. In addition, the combination of miR-1246 and miR-1308 can distinguish MGUS from myeloma patients. CONCLUSION: We have developed a biomarker signature using microRNAs extracted from serum which has potential as a diagnostic and prognostic tool for multiple myeloma

DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers

DIS3 is the catalytic subunit of the exosome, a protein complex involved in the 3’ to 5’ degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two proteincoding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is missing a segment with conserved amino-acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 as well as the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared to isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared to isoform 2 whereas Acute Myeloid Leukemia (AML) and chronic myelomonocytic leukaemia (CMML) patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers

Rubrique de mycologie méditerranéenne (1)

International audienc

On the Writing of Books on Moral Theology: An Ignorant Man's Complaint

n/

Rubrique de mycologie méditerranéenne (2). Les meilleurs et plus toxiques champignons des Cévennes (Espinousse, Aigoual,...) et d'un peu toutes les montagnes méditerranéennes

International audienc

An Integrated Solution for Secure Group Communication in Wide-Area Networks

Many distributed applications require a secure reliable group communication system to provide coordination among the application components. This paper describes a secure group layer (SGL) which bundles a reliable group communication system, a group authorization and access control mechanism, and a group key agreement protocol to provide a comprehensive and practical secure group communication platform. SGL also encapsulates the standard message security services (i.e, confidentiality, authenticity and integrity). A number of challenging issues encountered in the design of SGL are brought to light and experimental results obtained with a prototype implementation are discussed. Keywords: security, group communication, group authorization and access control, group key agreement. 1

Rubrique de mycologie méditerranéenne (4). Les meilleurs et plus toxiques champignons des Cévennes (Espinousse, Aigoual,...) et d'un peu toutes les montagnes méditerranéennes

International audienc

Etude et développement de tôles plaquées en acier inoxydable spécial austéno-ferritique pour les lessiveurs discontinus de pâte à papier

Les lessiveurs plaqués d’acier inoxydable utilisés dans le procédé Kraft sont depuis quelques années très sérieusement endommagés. Les phénomènes de projection des liqueurs et de caléfaction au niveau des parois semblent être responsables de cette corrosion comme le montrent des examens réalisés sur des autoclaves usagés.Des essais de laboratoire réalisés dans des solutions industrielles montrent que l’agressivité de ces dernières n’est pas seule responsable des corrosions observées. Des effets de parois chaudes provoqués par un flux thermique sont nécessaires pour retrouver en laboratoire des vitesses de corrosion similaires à celles observées sur les placages en acier austénitique AISI 316 Ti. Par ailleurs, la mise en évidence de risque de corrosion sous contrainte sur les nuances classiques et les bons résultats obtenus sur une nuance austéno-ferritique permettent de préconiser un nouveau placage inoxydable à structure biphasée.Un lessiveur neuf réalisé suivant ce principe se révèle beaucoup plus résistant à la corrosion que les anciens lessiveurs plaqués d’acier inoxydable austénitique. Des examens systématiques réalisés sur ce dernier, montrent bien que ces phénomènes de caléfaction sont particulièrement intenses sur des défauts géométriques. La bonne tenue d’une zone polie laisse espérer que ce nouveau placage avec un bon état de surface améliore sensiblement le comportement des lessiveurs utilisés actuellement