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International audience; Millimeter waves (MMW) are broadband frequencies that have recently been used in several applications in wireless communications, medical devices and nonlethal weapons [i.e., the nonlethal weapon, Active Denial Systems, (ADS) operating at 94-95 GHz, CW]. However, little information is available on their potential effects on humans. These radio-frequencies are absorbed and stopped by the first layer of the skin. In this study, we evaluated the effects of 94 GHz on the gene expression of skin cells. Two rat populations consisting of 17 young animals and 14 adults were subjected to chronic long-term 94 GHz MMW exposure. Each group of animals was divided into exposed and sham subgroups. The two independent exposure experiments were conducted for 5 months with rats exposed 3 h per day for 3 days per week to an incident power density of 10 mW/cm, which corresponded to twice the ICNIRP limit of occupational exposure for humans. At the end of the experiment, skin explants were collected and RNA was extracted. Then, the modifications to the whole gene expression profile were analyzed with a gene expression microarray. Without modification of the animal's temperature, long-term chronic 94 GHz-MMW exposure did not significantly modify the gene expression of the skin on either the young or adult rats.

Purpose Glioblastoma is one of the most aggressive primary brain cancers. The precise grading of tumors is important to adopt the best follow-up treatment but complementary methods to histopathological diagnosis still lack in achieving an unbiased and reliable classification. Experimental design To progress in the field, a rapid Matrix Assisted Laser Desorption Ionization - Time of Flight Mass spectrometry (MALDI-TOF MS) protocole, devised for the identification and taxonomic classification of microorganisms and based on the analysis of whole cell extracts, was applied to glioma cell lines. Results The analysis of different human glioblastoma cell lines permitted to identify distinct proteomic profiles thus demonstrating the ability of MALDI-TOF to distinguish different malignant cell types. Conclusions and clinical relevance In the study, the authors showed the ability of MALDI-TOF profiling to discriminate glioblastoma cell lines, demonstrating that this technique could be used in complement to histological tumor classification. The proposed procedure is rapid and inexpensive and could be used to improve brain tumors classification and help propose a personalized and more efficient treatment.

International audience; Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, 31P and 2H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.

The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood–brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). The PANK2 catalyzes the first step of coenzyme A (CoA) biosynthesis, a pathway producing an essential cofactor that plays a key role in energy and lipid metabolism. The majority of PANK2 mutations reduces or abolishes the activity of the enzyme. In around 10% of cases with PKAN, the presence of deformed red blood cells with thorny protrusions in the circulation has been detected. Changes in membrane protein expression and assembly during erythropoiesis were previously explored in patients with PKAN. However, data on red blood cell membrane phospholipid organization are still missing in this disease. In this study, we performed lipidomic analysis on red blood cells from Italian patients affected by PKAN with a particular interest in membrane physico-chemical properties. We showed an increased number of small red blood cells together with membrane phospholipid alteration, particularly a significant increase in sphingomyelin (SM)/phosphatidylcholine (PC) and SM/phosphatidylethanolamine (PE) ratios, in subjects with PKAN. The membrane structural abnormalities were associated with membrane fluidity perturbation. These morphological and functional characteristics of red blood cells in patients with PKAN offer new possible tools in order to shed light on the pathogenesis of the disease and to possibly identify further biomarkers for clinical studies.

International audience

Tumors invade space through cancer cell proliferation and tumor mass expansion. Tumor growth is maintained over time using the cancer stem cell pool, which is the cell population with self-renewal potential. The work by Conley et al. (1) provided evidence that antiangiogenic agents increase cancer stem cells through the generation of tumor hypoxia. These findings are in accordance with the findings showing that hypoxia induces stem cell markers expression in cancer cells (2, 3) and that antiangiogenic therapy elicits malignant progression of tumors (4). Thus, there is now sufficient evidence to reconsider the role of tumor angiogenesis in cancer progression. Tissues need nutrients and oxygen for growth, and tumors behave as other tissues. This view is the classical view, in which, according to the work by Folkman (5), the role of tumor angiogenesis fulfills the function of normal vessels that is to deliver oxygen and metabolites and remove waste products. However, tumor vessels are abnormal and fail to fulfill these functions. Therefore, tumors have naturally chronic and cyclic hypoxic regions. This paradoxical consequence of tumor angiogenesis is that, because of its deficiencies, it also generates hypoxia. In pathology such as cancer, a defect in a physiological process does not necessarily suppress the function of the process but can generate a novel function required for disease development. Here, the other function of tumor angiogenesis is to maintain tumor growth over time through cancer stem cell increase. This dual nature of tumor angiogenesis ensures a balance between growth over space (by providing oxygen and nutrients; i.e., physiological function) and growth over time (by generating hypoxic regions that increase the cancer stem cell pool; i.e., pathophysiological function). Hence, tumors require both the physiological and pathophysiological functions of tumor angiogenesis. Therefore, the significance of tumor angiogenesis is the generation of a tumor space–time continuum.

International audience; Gliomas are extremely aggressive and lethal forms of brain cancer. Unlike many other cancer types, glioma cells rarely metastasize. They spread throughout the brain and invasiveness of glioma cells is a major cause of therapeutic failure. In plant ecosystem, biodiversity acts locally as a barrier to ecological invasion. By analogy, we hypothesize that the low cell diversity of differentiated tissues, a counterpart of their functional specificity, opens the way to local cancer cell invasion. Seeding the brain tumor microenvironment with heterogeneous cell populations could be a mean to limit cancer cell invasion by enhancing cell biodiversity.