Dynamical properties of water in living cells

With the aim of studying the effect of water dynamics on the properties of biological systems, in this paper, we present a quasi-elastic neutron scattering study on three different types of living cells, differing both in their morphological and tumor properties. The measured scattering signal, which essentially originates from hydrogen atoms present in the investigated systems, has been analyzed using a global fitting strategy using an optimized theoretical model that considers various classes of hydrogen atoms and allows disentangling diffusive and rotational motions. The approach has been carefully validated by checking the reliability of the calculation of parameters and their 99% confidence intervals. We demonstrate that quasi-elastic neutron scattering is a suitable experimental technique to characterize the dynamics of intracellular water in the angstrom/picosecond space/time scale and to investigate the effect of water dynamics on cellular biodiversity

Diversité, structure et endémicité des communautés de vers de terre et de collemboles dans une hêtraie peu aménagée des Pyrénées (France)

We assessed and compared patterns of biodiversity and the composition of two soil invertebrate communities (Collembola and Lumbricidae) in three slightly managed plots in a beech forest of the French Pyrenees. The plots were managed in three different ways: an even-aged (REG), a closed unevenaged stand (NAT ), and an open uneven-aged full-grown stand (IRR ). At each sampling point, earthworms and Collembola from litter, soil, and pitfall traps were collected, and nine edaphic and environmental parameters were measured. The fauna collected was rich in species, and endemic and rare taxa. No clear-cut differences in species richness appeared between plots. Nevertheless, (1) the less disturbed plot, i.e. NAT , hosted a slightly larger number of endemic and rare species than IRR and REG; (2) the structure of both communities in NAT, REG and IRR differed significantly depending on the site elevation and organic nitrogen content (higher in NAT ), soil surface temperature and soil pH level (higher in IRR ), and humus index and soil water content (higher in REG ). Those factors, except elevation, may be explained by the canopy opening partly controlled by management practices; (3) a side aspect of the study was to show that sampling exhaustiveness required more sampling effort for soil than for litter, and more for Lumbricidae than for Collembola. In a broader context, the case documented in this study suggests that management practices with limited clearing of forest cover affect soil biodiversity only slightly, which is in sharp contrast with the collapse in endemic biodiversity induced by reafforestationNous avons évalué et comparé les patrons de biodiversité et la composition de deux communautés d'invertébrés du sol (collemboles et lombrics) dans trois parcelles peu aménagées d'une hêtraie-sapinière dans les Pyrénées françaises. Ces parcelles sont gérées selon trois modalités différentes: une futaie régulière (REG), une futaie irrégulière fermée (NAT) et une futaie irrégulière ouverte (IRR). À chaque point d'échantillonnage les vers de terre et les collemboles ont été collectés dans la litière, le sol et au moyen de pièges Barber, et neuf paramètres édaphiques et environnementaux ont été mesurés. La faune récoltée était riche en espèces ainsi qu'en taxons rares et endémiques. Aucune différence marquée de la richesse spécifique n'est apparue entre les parcelles. Néanmoins (1) le site le moins perturbé, i.e. NAT, hébergeait un nombre légèrement plus élevé d'espèces endémiques et rares que IRR et REG; (2) la structure des deux communautés différait significativement entre NAT, REG et IRR selon l'altitude du site et la teneur en azote organique (plus forte dans NAT), la température à la surface du sol et le pH du sol (plus élevés dans IRR), ainsi que l'indice d'humus et la teneur en eau du sol (plus élevés en REG). Ces facteurs, à l'exception de l'altitude, peuvent s'expliquer par l'ouverture de la canopée partiellement contrôlée par les pratiques de gestion; (3) un à-côté de cette étude est d'avoir montré que l'exhaustivité de l'échantillonnage requiert plus d'efforts pour le sol que pour la litière, et plus pour les lombrics que pour les collemboles. Dans un contexte plus large, le cas traité dans cette étude suggère que des pratiques de gestion avec un éclaircissement limité du couvert forestier n'affectent que légèrement la biodiversité du sol, ce qui contraste fortement avec l'effondrement de la biodiversité endémique qu'induit la reforestation

Drug development in oncology assisted by noninvasive optical imaging.

International audienceEarly and accurate detection of tumors, like the development of targeted treatments, is a major field of research in oncology. The generation of specific vectors, capable of transporting a drug or a contrast agent to the primary tumor site as well as to the remote (micro-) metastasis would be an asset for early diagnosis and cancer therapy. Our goal was to develop new treatments based on the use of tumor-targeted delivery of large biomolecules (DNA, siRNA, peptides, or nanoparticles), able to induce apoptosis while dodging the specific mechanisms developed by tumor cells to resist this programmed cell death. Nonetheless, the insufficient effectiveness of the vectorization systems is still a crucial issue. In this context, we generated new targeting vectors for drug and biomolecules delivery and developed several optical imaging systems for the follow-up and evaluation of these vectorization systems in live mice. Based on our recent work, we present a brief overview of how noninvasive optical imaging in small animals can accelerate the development of targeted therapeutics in oncology

Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers.: CYCLON-induced Rituximab resistance

International audienceImmuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Utilisation des cellules souches mésenchymateuses humaines pour la thérapie cellulaire anti-cancéreuse dans un modèle de glioblastome

La difficulté dans le traitement du cancer, et tout particulièrement dans le cas des gliomes, est liée à la faible quantité de molécules thérapeutiques distribuées au niveau du site tumoral. Les traitements classiques du glioblastome, la tumeur cérébrale maligne la plus courante chez l adulte, conduisent à une médiane de survie de seulement 14 mois. Le pronostic des patients atteints par un gliome malin, tel que le glioblastome multiforme, est très mauvais en dépit des avancées chirurgicales, radio et chimiothérapeutiques. L aptitude des cellules souches mésenchymateuses à migrer vers les sites de lésions dans une variété de conditions pathologiques suggère qu elles peuvent être des vecteurs idéaux pour la délivrance thérapeutique. Dans notre étude, nous avons évalué le pouvoir des Cellules Souches Mésenchymateuses humaines (CSMh) elles-mêmes comme un outil dans la thérapie anti-cancéreuse. En utilisant un modèle de gliome très invasif nous avons suivi in vivo, par imagerie optique de bioluminescence et par imagerie par résonance magnétique (IRM), la migration et l impact des CSMh après injection systémique chez des souris porteuses de tumeurs. Ainsi des souris Nude NMRI ont été greffées avec des cellules de glioblastome humain et des CSMh ont été injectées en systémique. La progression tumorale a été évaluée par IRM ou par imagerie optique de bioluminescence. Notre étude a mis en évidence que les CSMh injectées en systémique ont un tropisme pour les sites tumoraux, migrent à l intérieur de la tumeur où elles restent vivantes. De plus, il s avère que la croissance tumorale a tendance à être ralentie par la seule présence des CSMh et ce, de manière dose-dépendante. Cette étude, réalisée dans les conditions les plus proches de la clinique humaine, ouvre la possibilité d un avenir prometteur quant à la prise en charge du glioblastome.The difficulty in cancer treatment, especially gliomas, is linked to the low level of therapeutic molecules brought to the tumor site. Current treatments for glioblastomas, the most common adult malignant tumor, result in a median survival of only 14 months. The prognosis of patients with malignant gliomas, such as glioblastoma multiforme, is extremely poor, despite their extensive surgical treatment and adjuvant radio and chemo therapy. The ability of bone marrow-derived stem cells to migrate to areas of injury in a range of pathologic conditions suggests that they may be ideal vectors for therapeutic delivery. In our study, we evaluated the power of human Mesenchymal Stem Cells (hMSC) themselves as a diagnostic and a therapeutic tool in cancer therapy. Using highly malignant and invasive human glioma models, we followed, in vivo, by bioluminescence optical imaging and by magnetic resonance imaging (MRI), hMSC migration on tumor bearing mice after systemic injection. Nude mice were engrafted with human glioblastoma cells and hMSC cells were systemically injected. The tumor progression was evaluated using MRI or optical bioluminescence imaging. Our study demonstrated that hMSC injected systemically have a tropism for tumor site, migrate extensively to the tumor and remain alive inside the tumor. Moreover, the tumor growth is slown down only thanks to the presence of hMSC themselves and this phenomenon seems to be dose-dependent. This study, performed in conditions as close as possible from the human clinic, reveals a brilliant future for the glioblastoma treatment.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

The use of ultrasound in transfection and transgene expression.

International audienceThe interaction of ultrasound with tissue leads to radiation pressure, heat generation, and cavitation. These phenomena have been utilised for local gene delivery, transfection and control of expression. Specially designed nanocarriers or adapted ultrasound contrast agents can further enhance local delivery by: (1) increased permeability of cell membranes; (2) local release of genes. Biological carriers may also be used for local gene delivery. Stem cells and immune cells appear especially promising because of their homing capabilities to lesion sites. Imaging methods can be employed for pharmacodistribution and pharmacokinetics. MRI contrast agents can serve as non-invasive reporters on gene distribution when co-delivered with the gene. They can be used to label nanocarriers and cellular transport systems in gene therapy strategies such as those based on stem cells. Finally, ultrasound heating together with the use of a temperature sensitive promoter allows a local, physical, spatio-temporal control of transgene expression, in particular when combined with MRI temperature mapping for monitoring and even controlling ultrasound heating

The role of ultrasound and magnetic resonance in local drug delivery.

International audienceLocal drug delivery has recently attracted much attention since it represents a strategy to increase the drug concentration at the target location and decrease systemic toxicity effects. Ultrasound can be used in different ways to trigger regional drug delivery. It can cause the local drug release from a carrier vehicle and the local increase of cell membrane permeability either by a mechanical action or by a temperature increase. Ultrasound contrast agents may enhance these effects by means of cavitation. Ultrasound can be focused deep inside the body into a small region with dimensions on the order of 1 mm. Several types of drug microcarriers have been proposed, from nano- to micrometer sized particles. The objective of real-time imaging of local drug delivery is to assure that the delivery takes place in the target region, that the drug concentration and the resulting physiological reaction are sufficient, and to intervene if necessary. Ultrasound and nuclear imaging techniques play an important role. MRI is rather insensitive but allows precise targeting of (focused) ultrasound, can provide real-time temperature maps, and gives access to a variety of imaging biomarkers that may be used to assess drug action. Examples from recent articles illustrate the potential of the principles of ultrasound-triggered local drug delivery

Expansion en 2011 de Vespa velutina Lepeletier en Europe (Hym., Vespidae)

Rome Quentin, Muller Franck, Villemant Claire. Expansion en 2011 de Vespa velutina Lepeletier en Europe (Hym., Vespidae). In: Bulletin de la Société entomologique de France, volume 117 (1),2012. p. 114

Gene expression and gene therapy imaging.

International audienceThe fast growing field of molecular imaging has achieved major advances in imaging gene expression, an important element of gene therapy. Gene expression imaging is based on specific probes or contrast agents that allow either direct or indirect spatio-temporal evaluation of gene expression. Direct evaluation is possible with, for example, contrast agents that bind directly to a specific target (e.g., receptor). Indirect evaluation may be achieved by using specific substrate probes for a target enzyme. The use of marker genes, also called reporter genes, is an essential element of MI approaches for gene expression in gene therapy. The marker gene may not have a therapeutic role itself, but by coupling the marker gene to a therapeutic gene, expression of the marker gene reports on the expression of the therapeutic gene. Nuclear medicine and optical approaches are highly sensitive (detection of probes in the picomolar range), whereas MRI and ultrasound imaging are less sensitive and require amplification techniques and/or accumulation of contrast agents in enlarged contrast particles. Recently developed MI techniques are particularly relevant for gene therapy. Amongst these are the possibility to track gene therapy vectors such as stem cells, and the techniques that allow spatiotemporal control of gene expression by non-invasive heating (with MRI guided focused ultrasound) and the use of temperature sensitive promoters