The impact of studying on the hippocampal volume in medical students and its correlation with the results of the Final Medical Examination : a single-centre, prospective observational cohort study

Purpose: The hippocampus forms part of the limbic system and is involved in the learning process; it is responsible for transferring information from short-term to long-term memory. The aim of our study was to assess the effect of intensive studying on hippocampal volume and whether this correlates with exam results. Material and methods: The analysis included volunteer final-year medical students who underwent 2 volumetric 3D T1 magnetic resonance imaging scans with an interval of 20 weeks: 19 weeks before and one week after the Final Medical Examination. FreeSurfer software was used to compare the volumes of the whole hippocampus and its subfields between the 2 measurements. We assessed correlations between changes in hippocampal volume and the time students spent studying, between changes in hippocampal volume and the results of the exam, and between time spent studying and exam results. Results: Forty participants (25 women and 15 men; mean age 25 years) were included in the analysis. The right hippocampus presubiculum area increased significantly over the study period (p = 0.029), whereas the volume of the left hippocampus remained unchanged. An increase in the volume of the right hippocampus correlated with longer study time (r = 0.371 in percentage and r = 0.397 in mm3) and better LEK exam results (r = 0.441 in percentage and r = 0.456 in mm3). Conclusions: Our research confirms the role of the hippocampus, particularly the subicular complex, in the process of learning and remembering, and suggest that the plastic abilities of the hippocampus depend on the intensity of learning and translate into better skills

COST Action CA19114, Network for Optimized Astatine labelled Radiopharmaceuticals

Cancer is a major health concerns for European citizens. Thus, the main research aim of this Network for Optimized Astatine labeled Radiopharmaceuticals (NOAR) COST Action is to successfully demonstrate that one of the most promising radionuclides for Targeted Alpha Therapy (TAT), namely astatine-211, can become the European standard for treatment of certain cancerous pathologies. To this end, an efficient networking is essential among all European stakeholders interested in promoting astatine-211 for medical applications. NOAR COST Action brings together European and international excellence labs, astatine-211 production centers, hospitals, industry and patient associations from more than 20 countries, thus covering the whole value chain of innovation: production, chemistry, radiochemistry, biology, preclinical and clinical research and delivery of radiopharmaceuticals to patients. A European web portal will be created containing information for patients, practitioners, researchers, Industry and as a contact point for National and European patient associations. The idea is to gather forces at the European level in order to implement actions to leverage hurdles to the development of this powerful radionuclide and to identify pathologies in which it will be particularly relevant. A special emphasis will be given to train a new generation of young researchers and PhD students, promoting interdisciplinary competencies through international and inter-sectoral mobility. The long-term goal of this project is to make Astatine-211 technology available to all European citizen

Evaluation of an Anti-HER2 Nanobody Labeled with 225Ac for Targeted α‑Particle Therapy of Cancer

Human epidermal growth factor receptor type 2 (HER2) is overexpressed in numerous carcinomas. Nanobodies (Nbs) are the smallest antibody-derived fragments with beneficial characteristics for molecular imaging and radionuclide therapy. Therefore, HER2-targeting nanobodies could offer a valuable platform for radioimmunotherapy, especially when labeled with α-particle emitters, which provide highly lethal and localized radiation to targeted cells with minimal exposure to surrounding healthy tissues. In this study, the anti-HER2 2Rs15d-nanobody was conjugated with 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA) and radiolabeled with an α-emitter 225Ac with a high yield (>90%) and a radiochemical purity above 95%. The 225Ac-DOTA-Nb binding affinity was 4.12 ± 0.47 nM with an immunoreactive fraction above 80%. Binding to low HER2-expressing MDA-MB-231 cells was negligible, whereas HER2-overexpressing SKOV-3 cells could be blocked with an excess of unlabeled nanobody, confirming the specificity of binding. Noncompeting binding to HER2 was observed in the presence of an excess of trastuzumab. The cell-associated fraction of 225Ac-DOTA-Nb was 34.72 ± 16.66% over 24 h. In vitro, the radioconjugate was toxic in an HER2-mediated and dose-dependent manner, resulting in IC50 values of 10.2 and 322.1 kBq/mL for 225Ac-DOTA-Nb and the 225Ac-DOTA control, respectively, on SKOV-3 cells, and 282.2 kBq/mL for 225Ac-DOTA-Nb on MDA-MB-231 cells. Ex vivo biodistribution studies, performed in mice bearing subcutaneous HER2-overexpressing and low HER2-expressing tumors, showed a fast uptake in SKOV-3 tumors compared to MDA-MB-231 (4.01 ± 1.58% ID/g vs 0.49 ± 0.20% ID/g after 2 h), resulting also in high tumor-to-normal tissue ratios. In addition, coinjection of 225Ac-DOTA-Nb with Gelofusine reduced kidney retention by 70%. This study shows that 225Ac-DOTA-Nb is a promising new radioconjugate for targeted α-particle therapy and supports its further development.JRC.G.I.5-Advanced Nuclear Knowledg

Preclinical evaluation of anti-HER2 2Rs15d nanobody labeled with 225Ac

Human Epidermal Growth Factor Receptor type 2 (HER2) is overexpressed in a series of human cancer types such as breast, ovarian, colorectal and urothelial carcinomas and is often associated with a higher recurrence rate and a shorter time to relapse. Intact mAbs are not always ideal vectors for radioimmunotherapy due to their slow pharmacokinetic and normal-tissue clearance. Nanobodies (nbs) are small antibody fragments (~15kDa) with beneficial pharmacokinetic properties, and those targeted to HER2 are very attractive vectors for targeted radionuclide therapy (TRT). The aim of this study was to develop and evaluate a potential molecular-targeted drug based on the anti-HER2-Nb labeled with 225AcJRC.G.I.5-Advanced Nuclear Knowledg

Functionalized TiO2 nanoparticles labelled with 225Ac for targeted alpha radionuclide therapy

The 225Ac radioisotope exhibits very attractive nuclear properties for application in radionuclide therapy. Unfortunately, the major challenge for radioconjugates labelled with 225Ac is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-targeted tissues. In the present work we propose to apply TiO2 nanoparticles (NPs) as carrier for 225Ac and its decay products. The surface of TiO2 nanoparticles with 25 nm diameter was modified with Substance P(5-11), a peptide fragment which targets NK1 receptors on the glioma cells, through the silan-PEG-NHS linker. Nanoparticles functionalized with Substance P(5-11) were synthesized with high yield in a two-step procedure, and the products were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) and thermogravimetric analysis (TGA). The obtained results show that one TiO2-bioconjugate nanoparticle contains in average 80 peptide molecules on its surface. The synthesized TiO2-PEG-SP(5-11) conjugates were labelled with 225Ac by ion-exchange reaction on hydroxyl (OH) functional groups on the TiO2 surface. The labelled bioconjugates almost quantitatively retain 225Ac in phosphate-buffered saline (PBS), physiological salt and cerebrospinal fluid (CSF) for up to 10 days. The leaching of 221Fr, a first decay daughter of 225Ac, in an amount of 30% was observed only in CSF after 10 days. The synthesized 225Ac-TiO2-PEG-SP(5-11) have shown high cytotoxic effect in vitro in T98G glioma cells; therefore, it is a promising new radioconjugate for targeted radionuclide therapy of brain tumours.JRC.G.I.5-Advanced Nuclear Knowledg

The Therapeutic Potential of Anti-HER2 2Rs15d Nanobody Labeled with 225Ac – an In Vitro and In Vivo Evaluation

Human Epidermal Growth Factor Receptor type 2 (HER2) is overexpressed in numerous carcinomas and is often associated with a higher recurrence rate and a shorter time to relapse. Nanobodies (Nbs) are the smallest antibody-derived fragments with beneficial pharmacokinetic properties for molecular imaging and targeted radionuclide therapy (TRT). HER2-targeting nanobodies are very attractive vectors for TRT, especially when labeled with α-particle emitters, which provide highly lethal and localized radiation to targeted cells with minimal exposure to surrounding healthy tissues. The aim of this study was to evaluate the therapeutic potential of the anti-HER2 Nb 2Rs15d labeled with 225Ac.JRC.G.I.5-Advanced Nuclear Knowledg

Evaluation of an Anti-HER2 Nanobody Labeled with ²²⁵Ac for Targeted α‑Particle Therapy of Cancer

Human epidermal growth factor receptor type 2 (HER2) is overexpressed in numerous carcinomas. Nanobodies (Nbs) are the smallest antibody-derived fragments with beneficial characteristics for molecular imaging and radionuclide therapy. Therefore, HER2-targeting nanobodies could offer a valuable platform for radioimmunotherapy, especially when labeled with α-particle emitters, which provide highly lethal and localized radiation to targeted cells with minimal exposure to surrounding healthy tissues. In this study, the anti-HER2 2Rs15d-nanobody was conjugated with 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (<i>p</i>-SCN-Bn-DOTA) and radiolabeled with an α-emitter ²²⁵Ac with a high yield (>90%) and a radiochemical purity above 95%. The ²²⁵Ac-DOTA-Nb binding affinity was 4.12 ± 0.47 nM with an immunoreactive fraction above 80%. Binding to low HER2-expressing MDA-MB-231 cells was negligible, whereas HER2-overexpressing SKOV-3 cells could be blocked with an excess of unlabeled nanobody, confirming the specificity of binding. Noncompeting binding to HER2 was observed in the presence of an excess of trastuzumab. The cell-associated fraction of ²²⁵Ac-DOTA-Nb was 34.72 ± 16.66% over 24 h. <i>In vitro</i>, the radioconjugate was toxic in an HER2-mediated and dose-dependent manner, resulting in IC₅₀ values of 10.2 and 322.1 kBq/mL for ²²⁵Ac-DOTA-Nb and the ²²⁵Ac-DOTA control, respectively, on SKOV-3 cells, and 282.2 kBq/mL for ²²⁵Ac-DOTA-Nb on MDA-MB-231 cells. <i>Ex vivo</i> biodistribution studies, performed in mice bearing subcutaneous HER2-overexpressing and low HER2-expressing tumors, showed a fast uptake in SKOV-3 tumors compared to MDA-MB-231 (4.01 ± 1.58% ID/g vs 0.49 ± 0.20% ID/g after 2 h), resulting also in high tumor-to-normal tissue ratios. In addition, coinjection of ²²⁵Ac-DOTA-Nb with Gelofusine reduced kidney retention by 70%. This study shows that ²²⁵Ac-DOTA-Nb is a promising new radioconjugate for targeted α-particle therapy and supports its further development

Trastuzumab Modified Barium Ferrite Magnetic Nanoparticles Labeled with Radium-223: A New Potential Radiobioconjugate for Alpha Radioimmunotherapy

Barium ferrite nanoparticles (BaFeNPs) were investigated as vehicles for 223Ra radionuclide in targeted alpha-therapy. BaFe nanoparticles were labeled using a hydrothermal Ba2+ cations replacement by 223Ra with yield reaching 61.3 +/- 1.8%. Radiolabeled nanoparticles were functionalized with 3-phosphonopropionic acid (CEPA) linker followed by covalent conjugation to trastuzumab (Herceptin®). Thermogravimetric analysis and radiometric method with the use of [131I]-labeled trastuzumab revealed that on average 19–21 molecules of trastuzumab are attached to the surface of one BaFe–CEPA nanoparticle. The hydrodynamic diameter of BaFe–CEPA–trastuzumab conjugate is 99.9 +/- 3.0 nm in water and increases to 218.3 +/- 3.7 nm in PBS buffer, and the zeta potential varies from +27.2 +/- 0.7 mV in water to -8.8 +/- 0.7 in PBS buffer. The [223Ra]BaFe–CEPA–trastuzumab radiobioconjugate almost quantitatively retained 223Ra (>98%) and about 96% of 211Bi and 94% of 211Pb over 30 days. The obtained radiobioconjugate exhibited high affinity, cell internalization and cytotoxicity towards the human ovarian adenocarcinoma SKOV-3 cells overexpressing HER2 receptor. Confocal studies indicated that [223Ra]BaFe–CEPA–trastuzumab was located in peri-nuclear space. High cytotoxicity of the [223Ra]BaFe–CEPA–trastuzumab bioconjugate was confirmed by radiotoxicity studies on SKOV-3 cell monolayers and 3D-spheroids. In addition, the magnetic properties of the fradiobioconjugate should allow for its use in guide drug delivery driven by magnetic field gradient.JRC.G.I.5-Advanced Nuclear Knowledg