Good practices for 68Ga radiopharmaceutical production

Background: The radiometal gallium-68 (Ga-68) is increasingly used in diagnostic positron emission tomography (PET), with Ga-68-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional Tc-99m agents. In precision medicine, PET applications of Ga-68 are widespread, with Ga-68 radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin. Main body: These Ga-68 radiopharmaceuticals include agents such as [Ga-68]Ga-macroaggregated albumin for myocardial perfusion evaluation, [Ga-68]Ga-PLED for assessing renal function, [Ga-68]Ga-t-butyl-HBED for assessing liver function, and [Ga-68]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (Ge-68) generators and cyclotron production routes strongly positions Ga-68 for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the Ga-68 radiopharmaceutical community, and recommendations for centers interested in establishing Ga-68 radiopharmaceutical production. Conclusion: This review outlines important aspects of Ga-68 radiopharmacy, including Ga-68 production routes using a Ge-68/Ga-68 generator or medical cyclotron, standardized Ga-68 radiolabeling methods, quality control procedures for clinical Ga-68 radiopharmaceuticals, and suggested best practices for centers with established or upcoming Ga-68 radiopharmaceutical production. Finally, an outlook on Ga-68 radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community

Helping behaviour during cooperative learning and learning gains

Is helping behaviour (i.e., solicited help and peer tutoring) during cooperative learning (CL) related to subsequent learning gains? And can teachers influence pupils’ helping behaviour? One hundred one 5th grade pupils from multiethnic schools, 10-12 years old, participated in the study. Forty two pupils (31 immigrant) worked in an experimental condition, characterized by the stimulation of solicited high quality help and 59 (24 immigrant) worked in a control condition. It was found that learning gains were predicted positively by pupils’ unsolicited helping behaviour (i.e., peer tutoring) and negatively by solicited help. Furthermore, teachers were able to affect pupils’ low quality solicited help only. Lastly, immigrant pupils used less helping behaviour than local pupils, irrespective of CL setting

Brain Microvascular Injury and White Matter Disease Provoked by Diabetes-Associated Hyperamylinemia

OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins. METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo. RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome

Mosaic-variegated aneuploidy (MVA) syndrome is a rare childhood disorder characterized by biallelic BUBR1, CEP57, or TRIP13 aberrations; increased chromosome missegregation; and a broad spectrum of clinical features, including various cancers, congenital defects, and progeroid pathologies. To investigate the mechanisms underlying this disorder and its phenotypic heterogeneity, we mimicked the BUBR1(L1012P) mutation in mice (BubR1(L1002P)) and combined it with 2 other MVA variants, BUBR1(X753) and BUBR1(H), generating a truncated protein and low amounts of wild-type protein, respectively. Whereas BubR1(X753/L1002P) and BubR1(H/X753) mice died prematurely, BubR1(H/L1002P) mice were viable and exhibited many MVA features, including cancer predisposition and various progeroid phenotypes, such as short lifespan, dwarfism, lipodystrophy, sarcopenia, and low cardiac stress tolerance. Strikingly, although these mice had a reduction in total BUBR1 and spectrum of MVA phenotypes similar to that of BubR1(H/H) mice, several progeroid pathologies were attenuated in severity, which in skeletal muscle coincided with reduced senescence-associated secretory phenotype complexity. Additionally, mice carrying monoallelic BubR1 mutations were prone to select MVA-related pathologies later in life, with predisposition to sarcopenia correlating with mTORC1 hyperactivity. Together, these data demonstrate that BUBR1 allelic effects beyond protein level and aneuploidy contribute to disease heterogeneity in both MVA patients and heterozygous carriers of MVA mutations

Erratum:BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome (Journal of Clinical Investigation (2020) 130:1 (171-188) DOI: 10.1172/JCI126863)

During the preparation of this manuscript, the same sample was inadvertently included for the +/L1002P and +/– images in Figure 2E. The authors were able to use the original samples to prepare a corrected version. The correct figure is below. The description in Methods for this panel has also been corrected, as below: To assess the mitotic index of spontaneous lymphatic tumors, mitotic cells were visualized by IF labelling of at least 1 paraffin section for pHH3 (EMD Millipore, catalog 06-570), as described (6, 46). The online version of the article has been updated with the corrected information. The authors regret the errors

Golgi Membranes Are Absorbed into and Reemerge from the ER during Mitosis

AbstractQuantitative imaging and photobleaching were used to measure ER/Golgi recycling of GFP-tagged Golgi proteins in interphase cells and to monitor the dissolution and reformation of the Golgi during mitosis. In interphase, recycling occurred every 1.5 hr, and blocking ER egress trapped cycling Golgi enzymes in the ER with loss of Golgi structure. In mitosis, when ER export stops, Golgi proteins redistributed into the ER as shown by quantitative imaging in vivo and immuno-EM. Comparison of the mobilities of Golgi proteins and lipids ruled out the persistence of a separate mitotic Golgi vesicle population and supported the idea that all Golgi components are absorbed into the ER. Moreover, reassembly of the Golgi complex after mitosis failed to occur when ER export was blocked. These results demonstrate that in mitosis the Golgi disperses and reforms through the intermediary of the ER, exploiting constitutive recycling pathways. They thus define a novel paradigm for Golgi genesis and inheritance

Compensating for source directivity in immersive wave experimentation

ISSN:0001-4966ISSN:1520-852

Direct Visualization of Dislocation Dynamics in Grain Boundary Scars

Mesoscale objects with unusual structural features may serve as the analogues of atoms in the design of larger-scale materials with novel optical, electronic or mechanical behaviour. In this paper we investigate the structural features and the equilibrium dynamics of micron-scale spherical crystals formed by polystyrene particles adsorbed on the surface of a spherical water droplet. The ground state of sufficiently large crystals possesses finite-length grain boundaries (scars). We determine the elastic response of the crystal by measuring single-particle diffusion and quantify the fluctuations of individual dislocations about their equilibrium positions within a scar determining the dislocation spring constants. We observe rapid dislocation glide with fluctuations over the barriers separating one local Peierls minimum from the next and rather weak binding of dislocations to their associated scars. The long-distance (renormalised) dislocation diffusion glide constant is extracted directly from the experimental data and is found to be moderately faster than single particle diffusion. We are also able to determine the parameters of the Peierls potential induced by the underlying crystalline lattice.Comment: 11 pages, 4 figures, pdf forma

GATE : a simulation toolkit for PET and SPECT

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols, and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at the address http://www-lphe.epfl.ch/GATE/