Tracing back ancient oral microbiomes and oral pathogens using dental pulps from ancient teeth

Ancient dental pulps are highly precious samples because they conserve DNA from humans and blood-borne pathogens for ages. However, little is known about the microbial communities present in dental pulps. Here, we analyzed ancient and modern dental pulp samples from different time periods and geographic regions and found that they are colonized by distinct microbial communities, which can be differentiated from other oral cavity samples. We found that despite the presence of environmental bacteria, ancient dental pulps conserve a clear and well-conserved record of oral microbes. We were able to detect several different oral pathogens in ancient and modern dental pulps, which are commonly associated with periodontal diseases. We thus showed that ancient dental pulps are not only valuable sources of DNA from humans and systemic infections, but also an open window for the study of ancient oral microbiomes

EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands

The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA.</p

Approche microdosimétrique de la radioimmunothérapie alpha

La radioimmunothérapie-alpha (RIT-alpha) est une modalité thérapeutique prometteuse contre les cancers diffus et les maladies résiduelles. Le court parcours des particules alpha permet une irradiation spécifique des cellules tumorales. Ce traitement est également efficace en raison de la forte cytotoxicité de ces particules. En revanche, la dose de rayonnements délivrée aux cellules d'une tumeur est distribuée de façon non-uniforme et peut avoir une grande influence sur le succès de cette thérapie. Un modèle microdosimétrique de calcul des dépôts d énergie au sein de différentes cibles subcellulaires a été développé. Il permet le calcul rapide des distributions d énergie spécifique dans les cibles considérées et la modélisation de la survie cellulaire après une irradiation alpha. L apport de la méthode microdosimétrique sur la modélisation de la survie cellulaire a été comparé à une méthode macrodosimétrique. La microdosimétrie s avère être un outil de modélisation beaucoup plus précis dans de nombreuses configurations rencontrées in vitro. La prise en compte de la distribution non-uniforme de l activité lors du traitement de cellules isolées ou de groupes de cellules va modifier la forme des courbes de survie cellulaire et ne peut être négligée. L application de ce modèle à des données in vitro a permis de vérifier la grande toxicité des particules alpha par rapport aux particules ß. Un autre résultat important est la mise en évidence d une réponse cellulaire à une irradiation alpha. Le modèle développé a permis de déterminer les paramètres clé du succès d'un traitement de RIT-alpha. Les indications quantitatives fournies par cette étude peuvent indiquer des voies d'optimisation de la RIT-alpha.Alpha-radioimmunotherapy (alpha-RIT) is a promising therapeutic method against disseminated cancers and minimal residual diseases. The short range of -particles allows for a specific irradiation of the tumor cells. The efficacy of this treatment is also high due to the observed cytotoxicity of these particles. On the other hand, the radiation dose delivered to the tumor cells can be distributed non-uniformly and this can have a great impact on the success of this therapeutic method. A microdosimetric model that calculates energy depositions within numerous cellular or subcellular targets has been developed. It allows for the fast calculations of the distributions of specific energy within considered targets and the evaluation of the cell survival after an alpha-irradiation. The impact of the microdosimetric method on cell survival prediction has been evaluated and compared with a macrodosimetric method. Microdosimetry reveals to be a more precise tool for numerous configurations encountered in vitro. Taking into account the non uniform distribution of activity at the cell level modified the shape of survival curves and this phenomenon was identified as an important parameter for treatment outcomes. The application of this model to in vitro data has confirmed the high cytotoxicity of alpha-particles in comparison with ß-particles. The second important result is the demonstration of a cellular response to alpha-irradiation. The developed tool was also used to determine the key parameters of alpha-RIT success. Quantitative values calculated in this study could provide indications on the way of optimizing alpha-RIT.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept

International audienceScandium radionuclides have been identified in the late 1990s as promising for nuclear medicine applications, but have been set aside for about 20 years. Among the different isotopes of scandium, 43Sc and 44Sc are interesting for positron emission tomography imaging, whereas 47Sc is interesting for therapy. The 44Sc/47Sc or 43Sc/47Sc pairs could be thus envisaged as true theranostic pairs. Another interesting aspect of scandium is that its chemistry is governed by the trivalent ion, Sc3+. When combined with its hardness and its size, it gives this element a lanthanide-like behavior. It is then also possible to use it in a theranostic approach in combination with 177Lu or other lanthanides. This article aims to review the progresses that have been made over the last decade on scandium isotope production and coordination chemistry. It also reviews the radiolabeling aspects and the first (pre) clinical studies performed

A Compartmental Model of Mouse Thrombopoiesis and Erythropoiesis to Predict Bone Marrow Toxicity After Internal Irradiation.

In targeted radionuclide radiotherapy, the relationship between bone marrow (BM) toxicity and absorbed dose seems to be elusive. A compartmental model of mouse thrombopoiesis and erythropoiesis was set up to predict the depletion of hematopoietic cells as a function of the irradiation dose delivered to BM by injected radiopharmaceuticals. All simulated kinetics were compared with experimental toxicity for several stages of differentiation of the 2 hematopoietic lineages

DNA damage-centered signaling pathways are effectively activated during low dose-rate Auger radioimmunotherapy.: Signaling pathways induced by 125I-RIT

International audienceINTRODUCTION: Low dose-rate radioimmunotherapy (RIT) using (125)I-labelled monoclonal antibodies ((125)I-mAbs) is associated with unexpected high cytotoxicity per Gy. METHODS: We investigated whether this hypersensitivity was due to lack of detection of DNA damage by the targeted cells. DNA damage was measured with the alkaline comet assay, gamma-H2AX foci and the micronucleus test in p53(-/-) and p53(+/+) HCT116 cells exposed to increasing activities of internalizing anti-HER1 (125)I-mAbs or non-internalizing anti-CEA (125)I-mAbs. The expression of proteins involved in radiation response and progression of cells through the cycle were determined. RESULTS: Cell hypersensitivity to low absorbed doses of anti-CEA (125)I-mAbs was not due to defect in DNA damage detection, since ATM (ataxia telangiectasia mutated gene), gamma-H2AX, p53 and p21 were activated in RIT-treated HCT116 cells and G2/M cell cycle arrest was observed. Moreover, the alkaline comet assay showed that DNA breaks accumulated when cells were placed at 4°C during exposure but were repaired under standard RIT conditions (37°C), suggesting that lesions detected under alkaline conditions (mostly DNA single strand breaks and alkali-labile sites) are efficiently repaired in treated cells. The level of gamma-H2AX protein corroborated by the level of foci measured in nuclei of treated cells was shown to accumulate with time thereby suggesting the continuous presence of DNA double strand breaks. This was accompanied by the formation of micronuclei. CONCLUSION: Hypersensitivity to non-internalizing (125)I-mAbs is not due to lack of detection of DNA damage after low absorbed dose-rates. However, DNA double strand breaks accumulate in cells exposed both to internalizing and non-internalizing (125)I-mAbs and lead to micronuclei formation. These results suggest impairment in DNA double strand breaks repair after low absorbed doses of (125)I-mAbs

Re : Tumor Targeting and Three-Dimensional Voxel-Based Dosimetry to Predict Tumor Response, Toxicity, and Survival after Yttrium-90 Resin Microsphere Radioembolization in Hepatocellular Carcinoma

Editor: We read with great interest the paper of Allimant et al (1) recently published in the Journal of Vascular and Interventional Radiology. Beside the clinical predictions of the paper, which look valuable, we are disappointed by the feeling that, motivated by the development of simple tools, mathematics becomes more and more overlooked in clinical dosimetry, resulting in hollow formalism. [...

Nanovectorized radiotherapy by convection-enhanced delivery (CED), a promising strategy that demonstrates high efficacy in a murine model of human endometrial adenocarcinoma

International audienceAim: To evaluate the biodistribution, the toxicity, the dosimetry and the antitumor efficacy of intra-tumoral injection of rhenium-188 loaded nanoparticles (LNC-188Re-SSS) by CED. Materials and methods: Ishikawa endometrial carcinoma cell lines were implanted subcutaneously in nude mice (n=70). For biodistribution and efficacy studies CED procedure was realized at D28 after tumour implantation. CED was performed using an osmotic pump (0.5μL/min for 20 minutes) after immobilisation of anaesthetized mice on a stereotactic frame. For biodistribution studies, animals (n=30) were injected by CED either with 3MBq of 188ReO4- (n=15) or LNC-188Re-SSS (n=15) and sacrificed at 1h (n=10), 24h (n=10) or 72h (n=10). For efficacy studies, control group mice were injected by CED with saline (n=8) or blank LNC (n=8) and treated group mice were injected with escalating dose of LNC-188Re-SSS: 3MBq (n=8), 6 MBq (n=8) or 12 MBq (n=8). Efficacy on tumour growth was assessed by clinical palpation and μMRI. The time for the tumour volume doubling was chosen as endpoint, leading to the euthanasia of the animal. The physical dose deposited in the tumour for each treated animal was estimated by Monte Carlo simulation (Geant4) using measured biodistribution and μMRI tumour volumes,. Haematological toxicity in mice was evaluated using blood sampling of 50μL (retro-orbital sinus) at D2, D7, D14 and D21 after treatment with saline (n=4) and after treatment with LNC-188Re-SSS, 3MBq (n=4), 6 MBq (n=4) or 12 MBq (n=4). Results: Nanovectorization of 188Re combined with CED allowed the confinement of more than 30 % of ID in the tumour limiting therefore urinary excretion of 188Re since 0,1% versus 81,9% of ID were excreted in urine 24h after CED of LNC-188Re-SSS and 188ReO4- respectively (p=0.016). Nanovectorized radiotherapy has drastically increased the median survival time compared with control group. Animals whose tumor received a dose higher than 69 Gy (69-340 Gy) showed an ISTmedian of + 933%, whereas animals whose tumor received a dose lower than 69 Gy (21-67Gy) showed an ISTmedian of + 391%. Complete response with eradication of the tumor was observed in 4/12 (33.3%) animals of the former group. Depletion of platelets was observed following LNC-188Re-SSS injection with a time to nadir between D14-D21 whereas transient lymphocyte depletion was only observed at D7 for the highest administered activities (12MBq).Conclusion: CED of LNC-188Re-SSS demonstrates interesting biodistribution properties and high efficacy in a model of human endometrial carcinoma.</p

Apoptosis and p53 are not involved in the anti-tumor efficacy of (125)I-labeled monoclonal antibodies targeting the cell membrane.: Running title: 125I-RIT-induced cell death mechanisms

International audienceINTRODUCTION: (125)I-labeled monoclonal antibodies ((125)I-mAbs) can efficiently treat small solid tumors. Here, we investigated the role of apoptosis, autophagy and mitotic catastrophe in (125)I-mAb toxicity in p53(-/-) and p53(+/+) cancer cells. METHODS: We exposed p53(-/-) and p53(+/+) HCT116 cells to increasing activities of internalizing (cytoplasmic location) anti-HER1 (125)I-mAbs, or non-internalizing (cell surface location) anti-CEA (125)I-mAbs. For each targeting model we established the relationship between survival and mean nucleus absorbed dose using the MIRD formalism. RESULTS: In both p53(-/-) and p53(+/+) HCT116 cells, anti-CEA (125)I-mAbs were more cytotoxic per Gy than anti-HER1 (125)I-mAbs. Sensitivity to anti-CEA (125)I-mAbs was p53-independent, while sensitivity to anti-HER1 (125)I-mAbs was higher in p53(-/-) HCT 116 cells, suggesting that they act through different signaling pathways. Apoptosis was only induced in p53(+/+) HCT116 cells and could not explain cell membrane radiation sensitivity. Inhibition of autophagy did not modify the cell response to (125)I-mAbs. By contrast, mitotic death was similarly induced in both p53(-/-) and p53(+/+) HCT116 cells by the two types of (125)I-mAbs. We also showed using medium transfer experiments that γ-H2AX foci were produced in bystander cells. CONCLUSION: Cell membrane sensitivity to (125)I-mAbs is not mediated by apoptosis and is p53-independent. Bystander effects-mediated mitotic death could be involved in the efficacy of (125)I-mAbs binding cell surface receptors