Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution

HelmCoP: An Online Resource for Helminth Functional Genomics and Drug and Vaccine Targets Prioritization

A vast majority of the burden from neglected tropical diseases result from helminth infections (nematodes and platyhelminthes). Parasitic helminthes infect over 2 billion, exerting a high collective burden that rivals high-mortality conditions such as AIDS or malaria, and cause devastation to crops and livestock. The challenges to improve control of parasitic helminth infections are multi-fold and no single category of approaches will meet them all. New information such as helminth genomics, functional genomics and proteomics coupled with innovative bioinformatic approaches provide fundamental molecular information about these parasites, accelerating both basic research as well as development of effective diagnostics, vaccines and new drugs. To facilitate such studies we have developed an online resource, HelmCoP (Helminth Control and Prevention), built by integrating functional, structural and comparative genomic data from plant, animal and human helminthes, to enable researchers to develop strategies for drug, vaccine and pesticide prioritization, while also providing a useful comparative genomics platform. HelmCoP encompasses genomic data from several hosts, including model organisms, along with a comprehensive suite of structural and functional annotations, to assist in comparative analyses and to study host-parasite interactions. The HelmCoP interface, with a sophisticated query engine as a backbone, allows users to search for multi-factorial combinations of properties and serves readily accessible information that will assist in the identification of various genes of interest. HelmCoP is publicly available at: http://www.nematode.net/helmcop.html

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Gold nanoparticles prepared by laser ablation in aqueous biocompatible solutions: assessment of safety and biological identity for nanomedicine applications

Florian Correard,1,2 Ksenia Maximova,3 Marie-Anne Estève,1,2 Claude Villard,1 Myriam Roy,4 Ahmed Al-Kattan,3 Marc Sentis,3 Marc Gingras,4 Andrei V Kabashin,3 Diane Braguer1,2 1Aix Marseille Université, INSERM, CR02 UMR_S911, Marseille, France; 2APHM, Hôpital Timone, Marseille, France; 3Aix Marseille Université, CNRS, LP3 UMR 7341, Marseille, France; 4Aix Marseille Université, CNRS, CINAM, UMR 7325 Marseille, France Abstract: Due to excellent biocompatibility, chemical stability, and promising optical properties, gold nanoparticles (Au-NPs) are the focus of research and applications in nanomedicine. Au-NPs prepared by laser ablation in aqueous biocompatible solutions present an essentially novel object that is unique in avoiding any residual toxic contaminant. This paper is conceived as the next step in development of laser-ablated Au-NPs for future in vivo applications. The aim of the study was to assess the safety, uptake, and biological behavior of laser-synthesized Au-NPs prepared in water or polymer solutions in human cell lines. Our results showed that laser ablation allows the obtaining of stable and monodisperse Au-NPs in water, polyethylene glycol, and dextran solutions. The three types of Au-NPs were internalized in human cell lines, as shown by transmission electron microscopy. Biocompatibility and safety of Au-NPs were demonstrated by analyzing cell survival and cell morphology. Furthermore, incubation of the three Au-NPs in serum-containing culture medium modified their physicochemical characteristics, such as the size and the charge. The composition of the protein corona adsorbed on Au-NPs was investigated by mass spectrometry. Regarding composition of complement C3 proteins and apolipoproteins, Au-NPs prepared in dextran solution appeared as a promising drug carrier. Altogether, our results revealed the safety of laser-ablated Au-NPs in human cell lines and support their use for theranostic applications. Keywords: protein corona, nanocarrier, cytotoxicity, green chemistry, neuroblastoma, glioblastom

Evaluation of IVOCT imaging of coronary artery metallic stents with neointimal coverage

Accuracy of IVOCT for measurement of neointimal thickness and effect of neointima in the appearance of metallic struts in IVOCT images was investigated. Phantom vessels were constructed and coronary stents were deployed and covered with thick (250–400 μm) and thin (30–70 μm) phantom neointima. High resolution Micro-CT images of the stent struts were recorded as a gold standard. IVOCT images of the phantom vessels were acquired with various luminal blood scattering strengths and measured neointimal thicknesses from IVOCT and Micro-CT images were compared. In transparent lumen, comparison of IVOCT and Micro-CT neointima thickness measurements found no significant difference (p > 0.05) in the thick neointima phantom but a significant difference (p < 0.05) in the thin neointima phantom. For both thick and thin neointima, IVOCT neointimal thickness measurements varied from Micro-CT values by as much as ±35 %. Increased luminal scattering due to presence of blood at concentrations <5 % did not interfere with measurement of thin neointimas and was validated by ANOVA analysis (p = 0.95). IV-OCT measurement of strut feature size with an overlying thin neointima match true values determined with Micro-CT (p = 0.82). Presence of a thick neointima resulted in lateral elongation or merry-go-rounding of stent strut features in IVOCT images. Phantom IVOCT images suggest that thick neointimal layers can result in more than 40 % lateral elongation of stent strut features. Simulated IVOCT images of metallic stent struts with varying neointimal thickness suggest that neointimal light scattering can introduce the merry-go-round effect