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Aging is associated with detrimental bone loss leading to fragility fractures in both men and women. Notably, a majority of bone loss with aging is cortical, as well as a large number of fractures are non-vertebral and at the non-hip sites. Nacre is a product of mollusks composed of calcium carbonate embedded in organic components. As our previous study demonstrated the protective effect of nacre supplementation on trabecular bone loss in ovariectomized rats, we sought to evaluate the effect of dietary nacre on bone loss related to aging in female mice which do not suffer true menopause as observed in women. The current study compared the effect of a 90-day long nacre-supplemented diet to that of Standard or CaCO 3 diets on both bone mass and strength in 16-month-old C57BL/6 female mice. Multiple approaches were performed to assess the microarchitecture and mechanical properties of long bones, analyze trabecular histomorphometry, and measure bone cell-related gene expressions, and bone turnover markers. In the cortex, dietary nacre improved cortical bone strength in line with lower expression levels of genes reflecting osteoclasts activity compared to Standard or CaCO 3 diets (p < 0.05). In the trabeculae, nacre-fed mice were characterized by a bone remodeling process more active than the other groups as shown by greater histomorphometric parameters and osteoblast-related gene expressions (p < 0.05). But these differences were not exhibited at the level of the trabecular microarchitecture at this age. Collectively, these data suggest that dietary nacre should be a potential candidate for reducing aging-associated cortical bone loss in the elderly., Competing Interests: Declaration of competing interest MR provides scientific consultation for Megabiopharma. TT reports receiving lecture fees from Amgen, Arrow, Biogen, BMS, Chugai, Galapagos, Grunenthal, Jansen, LCA, Lilly, MSD, Nordic, Novartis, Pfizer, Sanofi, Thuasne, Theramex, UCB and research grants or investigator's fees from Bone Therapeutics, UC. HM reports fees from Amgen, Arrow, Biogen, BMS, CellTrion, Chugai, Galapagos, Fresenius Kabi, Jansen, Lilly, MSD, Nodic, Novartis, Pfizer, Sanofi, and UCB. All other authors state that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Resorbable hydrogels are widely used as scaffolds for tissue engineering. These hydrogels can be modified by grafting dendrimer-linked functionalized molecules (dendrigrafts). Our aim was to develop a tunable poly(L-lysine) dendrigrafts (DGL)/PEG-based hydrogel with an inverse porosity and to investigate its osteogenic potential. DGL/PEG hydrogels were emulsified in a surfactant-containing oil solution to form microspheres. The toxicity was evaluated on Human Vascular Endothelial Cells (HUVECs) and Bone Marrow Mesenchymal Stem Cells (hMSCs) with Live/Dead and MTT assays. The effects on HUVECs were investigated through C5 Complement expression by RT-PCR and C5a/TGF-β1 secretion by ELISA. Recruitment of hMSCs was investigated using Boyden chambers and their osteogenic differentiation was studied by measuring Alkaline Phosphatase activity (ALP) and BMP-2 secretion by ELISA. Adjusting the stirring speed during the emulsification allowed to obtain spherical microspheres with tunable diameters (10-1600 µm). The cell viability rate with the hydrogel was 95 and 100% with HUVECs and hMSCs, respectively. Incubating HUVECs with the biomaterial induced a 5-fold increase in TGF-β1 and a 3-fold increase in Complement C5a release. Furthermore, HUVEC supernatants obtained after incubation with the hydrogel induced a 2.5-fold increase in hMSC recruitment. The hydrogel induced a 3-fold increase both in hMSC ALP activity and BMP-2 secretion. Overall, the functionalized hydrogel enhanced the osteogenic potential by interacting with endothelial cells and hMSCs and represents a promising tool for bone tissue engineering.

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on the metal element gadolinium, AGuIX nanoparticles have been shown to increase the radiosensitivity of cancers. Although it is a rare nanomaterial that has entered preclinical trials, the unclear biological mechanism hinders its further clinical application. In this study, we demonstrated the effectiveness of AGuIX nanoparticles in the radiosensitization of triple-negative breast cancer. We found that AGuIX nanoparticles increased the level of DNA damage by compromising the homologous recombination repair pathway instead of the non-homologous end joining pathway. Moreover, the results showed that AGuIX nanoparticles induced apoptosis, but the degree of apoptosis ability was very low, which cannot fully explain their strong radiosensitizing effect. Ferroptosis, the other mode of cell death, was also discovered to play a significant role in radiation sensitization, and AGuIX nanoparticles may regulate the anti-ferroptosis system by inhibiting the NRF2-GSH-GPX4 signaling pathway., (© 2022. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background and Purpose: Brain metastasis impacts greatly on patients' quality of life and survival. The phase I NANO-RAD trial assessed the safety and maximum tolerated dose of systemic administration of a novel gadolinium-based nanoparticle, AGuIX, in combination with whole brain radiotherapy in patients with multiple brain metastases not suitable for stereotactic radiotherapy., Materials and Methods: Patients with measurable brain metastases received escalating doses of AGuIX nanoparticles (15, 30, 50, 75, or 100 mg/kg intravenously) on the day of initiation of WBRT (30 Gy in 10 fractions) in 5 cohorts of 3 patients each. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events v4.03., Results: Fifteen patients with 354 metastases were included. No dose-limiting toxic effects were observed up to AGuIX 100 mg/kg. Plasma elimination half-life of AGuIX was similar for all groups (mean 1.3 h; range 0.8-3 h). Efficient targeting of metastases (T 1 MRI enhancement, tumor selectivity) and persistence of AGuIX contrast enhancement were observed in metastases from patients with primary melanoma, lung, breast, and colon cancers. The concentration of AGuIX in metastases after administration was proportional to the injected dose. Thirteen of 14 evaluable patients had a clinical benefit, with either stabilization or reduction of tumor volume. MRI analysis showed significant correlation between contrast enhancement and tumor response, thus supporting a radiosensitizing effect., Conclusion: Combining AGuIX with radiotherapy for patients with brain metastases is safe and feasible. AGuIX specifically targets brain metastases and is retained within tumors for up to 1 week; ongoing phase II studies will more definitively assess efficacy., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium's collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com , we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form., Competing Interests: CH was employed by Signals GmbH & Co. KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Altincekic, Korn, Qureshi, Dujardin, Ninot-Pedrosa, Abele, Abi Saad, Alfano, Almeida, Alshamleh, de Amorim, Anderson, Anobom, Anorma, Bains, Bax, Blackledge, Blechar, Böckmann, Brigandat, Bula, Bütikofer, Camacho-Zarco, Carlomagno, Caruso, Ceylan, Chaikuad, Chu, Cole, Crosby, de Jesus, Dhamotharan, Felli, Ferner, Fleischmann, Fogeron, Fourkiotis, Fuks, Fürtig, Gallo, Gande, Gerez, Ghosh, Gomes-Neto, Gorbatyuk, Guseva, Hacker, Häfner, Hao, Hargittay, Henzler-Wildman, Hoch, Hohmann, Hutchison, Jaudzems, Jović, Kaderli, Kalniņš, Kaņepe, Kirchdoerfer, Kirkpatrick, Knapp, Krishnathas, Kutz, zur Lage, Lambertz, Lang, Laurents, Lecoq, Linhard, Löhr, Malki, Bessa, Martin, Matzel, Maurin, McNutt, Mebus-Antunes, Meier, Meiser, Mompeán, Monaca, Montserret, Mariño Perez, Moser, Muhle-Goll, Neves-Martins, Ni, Norton-Baker, Pierattelli, Pontoriero, Pustovalova, Ohlenschläger, Orts, Da Poian, Pyper, Richter, Riek, Rienstra, Robertson, Pinheiro, Sabbatella, Salvi, Saxena, Schulte, Schiavina, Schwalbe, Silber, Almeida, Sprague-Piercy, Spyroulias, Sreeramulu, Tants, Tārs, Torres, Töws, Treviño, Trucks, Tsika, Varga, Wang, Weber, Weigand, Wiedemann, Wirmer-Bartoschek, Wirtz Martin, Zehnder, Hengesbach and Schlundt.)

A tool can function as a body part yet not feel like one: Putting down a fork after dinner does not feel like losing a hand. However, studies show fake body-parts are embodied and experienced as parts of oneself. Typically, embodiment illusions have only been reported when the fake body-part visually resembles the real one. Here we reveal that participants can experience an illusion that a mechanical grabber, which looks scarcely like a hand, is part of their body. We found changes in three signatures of embodiment: the real hand's perceived location, the feeling that the grabber belonged to the body, and autonomic responses to visible threats to the grabber. These findings show that artificial objects can become embodied even though they bear little visual resemblance to the hand.

Radiotherapy is the main treatment for cancer patients. A major concern in radiotherapy is the radiation resistance of some tumors, such as human nonsmall cell lung cancer. However, the radiation dose delivered to the tumors is often limited by the possibility of collateral damage to surrounding healthy tissues. A new and efficient gadolinium-based nanoparticle, AGuIX, has recently been developed for magnetic resonance imaging-guided radiotherapy and has been proven to act as an efficient radiosensitizer. The amplified radiation effects of AGuIX nanoparticles appear to be due to the emission of low-energy photoelectrons and Auger electron interactions. We demonstrated that AGuIX nanoparticles exacerbated radiation-induced DNA double-strand break damage and reduced DNA repair in the H1299 nonsmall cell lung cancer cell line. Furthermore, we observed a significant improvement in tumor cell damage and growth suppression, under radiation therapy, with the AGuIX nanoparticles in a H1299 mouse xenograft model. This study paves the way for research into the radiosensitization mechanism of AGuIX nanoparticles and provides a scientific basis for the use of AGuIX nanoparticles as radiosensitizing drugs.

Objectives: Off-label drug prescribing is a public health and economic issue. The aim of this study was to describe off-label prescription in general practice in France, in terms of frequency and nature, and to identify its main determining factors., Design: Multicentre cross-sectional study SETTING: Twenty-three training general practice offices PARTICIPANTS: All the voluntary patients coming for a medical consultation or visited at home over a cumulative period of 5 days per office between November 2015 and January 2016., Methods: Eleven interns, acting as observers, collected data. Two reviewers analysed the drugs prescribed by the trainers, in order to identify those prescribed off-label in terms of their indication or the age of the patient. We used a univariate, then a multivariate model, based on hierarchical mixed-effects logistic regression., Results: Among the 4932 drug prescriptions registered, 911 (18.5%[95% CI17.4% to 19.6%]) were off-label, of which 865 (17.6%) due to the indication of the drug and 58 (1.2%) due to the age of the patient. The prescription never mentioned the off-label use, neither was the patient informed of it, as required by the French law. With the multivariate analysis, variables contributing to off-label prescription were the number of drugs (OR=1.05 for each additional drug), the initiation of new drug therapy (OR=1.26) and the non-specific goal of the prescription (OR=1.43); the age of the patient ≤14 years (OR=1.42); the rural location of the physician's practice (OR=1.38) and the low frequency of the visits of national health insurance representatives (OR=0.93)., Conclusion: Almost one out of five drugs prescribed in French general practice was off-label. It seems necessary to better train physicians in clinical pharmacology, to provide them with more effective drug prescription software, to reinforce postmarketing surveillance and to clearly define off-label use by consensus., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Occurrence of multiple brain metastases is a critical evolution of many cancers with significant neurological and overall survival consequences, despite new targeted therapy and standard whole brain radiotherapy (WBRT). A gadolinium-based nanoparticle, AGuIX, has recently demonstrated its effectiveness as theranostic and radiosensitiser agent in preclinical studies. The favourable toxicity profile in animals and its administration as a simple intravenous injection has motivated its use in patients with this first in human study., Methods and Analysis: The NANO-RAD study is a phase I, first in human injection, monocentric, open-label, dose-escalation study to investigate the safety, the tolerability and the spectrum of side effects of AGuIX in combination with WBRT (30 Gy, 10 fractions of 3 Gy) for patients with multiple brain metastases. Five dose escalation cohorts are planned: 15, 30, 50, 75 and 100 mg/kg. A total of 15-18 patients will be recruited into this trial. The primary objective is to determine the maximum-tolerated dose of AGuIX nanoparticles combined with WBRT for the treatment of multiple brain metastases. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.4.03. Secondary objectives are pharmacokinetic profile, distribution of AGuIX in metastases and surrounding healthy tissue visualised by MRI, intracranial progression-free survival and overall survival. Intracranial response will be determined according to Response Evaluation Criteria in Solid Tumour Criteria V.1.1 comparing MRI performed prior to treatment and at each follow-up visits., Ethics and Dissemination: Approval was obtained from the ethics committee Sud Est V, France (Reference number 15-CHUG-48). The study was approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (Reference number 151519A-12). The results will be published in peer-reviewed journals or disseminated through national and international conferences., Trial Registration Number: NCT02820454; Pre-results., Competing Interests: Competing interests: FL and OT have to disclose the patent WO2011/135101. GLD and OT have to disclose the patent WO2009/053644. These patents protect the AGuIX® nanoparticles described in this publication. SD and GLD are employees from NH TherAguix that is developing the AGuIX® nanoparticles. The trial medication (AGuIX®) and a financial grant for study organization are supplied by NH TherAguix, Villeurbanne, France., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Wilson's disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene ATP7B affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the ATP7B gene in patients with abnormal biological copper profile., Methods: All psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the ATP7B gene was performed., Results: A total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one ATP7B mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either ATP7B allele was detected., Conclusion: Results of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. Trial registration CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010.

Aim: This study reports the use of gadolinium-based AGuIX nanoparticles (NPs) as a theranostic tool for both image-guided radiation therapy and radiosensitization of brain tumors., Materials & Methods: Pharmacokinetics and regulatory toxicology investigations were performed on rodents. The AGuIX NPs' tumor accumulation was studied by MRI before 6-MV irradiation., Results: AGuIX NPs exhibited a great safety profile. A single intravenous administration enabled the tumor delineation by MRI with a T1 tumor contrast enhancement up to 24 h, and the tumor volume reduction when combined with a clinical 6-MV radiotherapy., Conclusion: This study demonstrates the efficacy and the potential of AGuIX NPs for image-guided radiation therapy, promising properties that will be assessed in the upcoming Phase I clinical trial.