Sofie Biosciences (United States)

International audience

Astrophysical observations provide compelling evidence for gravitationally interacting dark matter in the universe that cannot be explained by the standard model of particle physics. The extraordinary amount of data from the CERN LHC presents a unique opportunity to shed light on the nature of dark matter at unprecedented collision energies. This Report comprehensively reviews the most recent searches with the CMS experiment for particles and interactions belonging to a dark sector and for dark-sector mediators. Models with invisible massive particles are probed by searches for signatures of missing transverse momentum recoiling against visible standard model particles. Searches for mediators are also conducted via fully visible final states. The results of these searches are compared with those obtained from direct-detection experiments. Searches for alternative scenarios predicting more complex dark sectors with multiple new particles and new forces are also presented. Many of these models include long-lived particles, which could manifest themselves with striking unconventional signatures with relatively small amounts of background. Searches for such particles are discussed and their impact on dark-sector scenarios is evaluated. Many results and interpretations have been newly obtained for this Report.

The development of new positron-emission tomography (PET) tracers is enabling researchers and clinicians to image an increasingly wide array of biological targets and processes. However, the increasing number of different tracers creates challenges for their production at radiopharmacies. While historically it has been practical to dedicate a custom-configured radiosynthesizer and hot cell for the repeated production of each individual tracer, it is becoming necessary to change this workflow. Recent commercial radiosynthesizers based on disposable cassettes/kits for each tracer simplify the production of multiple tracers with one set of equipment by eliminating the need for custom tracer-specific modifications. Furthermore, some of these radiosynthesizers enable the operator to develop and optimize their own synthesis protocols in addition to purchasing commercially-available kits. In this protocol, we describe the general procedure for how the manual synthesis of a new PET tracer can be automated on one of these radiosynthesizers and validated for the production of clinical-grade tracers. As an example, we use the ELIXYS radiosynthesizer, a flexible cassette-based radiochemistry tool that can support both PET tracer development efforts, as well as routine clinical probe manufacturing on the same system, to produce [18F]Clofarabine ([18F]CFA), a PET tracer to measure in vivo deoxycytidine kinase (dCK) enzyme activity. Translating a manual synthesis involves breaking down the synthetic protocol into basic radiochemistry processes that are then translated into intuitive chemistry "unit operations" supported by the synthesizer software. These operations can then rapidly be converted into an automated synthesis program by assembling them using the drag-and-drop interface. After basic testing, the synthesis and purification procedure may require optimization to achieve the desired yield and purity. Once the desired performance is achieved, a validation of the synthesis is carried out to determine its suitability for the production of the radiotracer for clinical use.

New radiolabeled probes for positron-emission tomography (PET) are providing an ever-increasing ability to answer diverse research and clinical questions and to facilitate the discovery, development, and clinical use of drugs in patient care. Despite the high equipment and facility costs to produce PET probes, many radiopharmacies and radiochemistry laboratories use a dedicated radiosynthesizer to produce each probe, even if the equipment is idle much of the time, to avoid the challenges of reconfiguring the system fluidics to switch from one probe to another. To meet growing demand, more cost-efficient approaches are being developed, such as radiosynthesizers based on disposable "cassettes," that do not require reconfiguration to switch among probes. However, most cassette-based systems make sacrifices in synthesis complexity or tolerated reaction conditions, and some do not support custom programming, thereby limiting their generality. In contrast, the design of the ELIXYS FLEX/CHEM cassette-based synthesizer supports higher temperatures and pressures than other systems while also facilitating flexible synthesis development. In this paper, the syntheses of 24 known PET probes are adapted to this system to explore the possibility of using a single radiosynthesizer and hot cell for production of a diverse array of compounds with wide-ranging synthesis requirements, alongside synthesis development efforts. Most probes were produced with yields and synthesis times comparable to literature reports, and because hardware modification was unnecessary, it was convenient to frequently switch among probes based on demand. Although our facility supplies probes for preclinical imaging, the same workflow would be applicable in a clinical setting.

In recent decades there have been two significant legislative amendments to shared parenting in Belgium. In 1995, joint exercise of parental responsibilities was introduced as the default legal position. In 2006, the legislation required that in all cases of joint parenthood in which parents could not agree on children's living arrangements, equally divided alternating residence must first be considered by the judge. In this article, we summarize recent research findings from Belgium about alternating residence for children. There has been a fourfold increase in alternating residence, and families in these arrangements became increasingly diverse. Compared to children living exclusively with their mothers, children in alternating residences report a better relationship with their father, while mothers report a more active personal social life. For children, alternating residence is found to be more challenging under certain conditions (e.g. no communication between parents).

Economou, James S. MD, PhD; Slamon, Dennis J. MD, PhD; Ribas, Antoni MD, PhD; Phelps, Michael E. PhD Author Information

Fully automated radiosynthesizers are continuing to be developed to meet the growing need for the reliable production of PET tracers made under current good manufacturing practice guidelines. There is a current trend toward supporting kitlike disposable cassettes that come preconfigured for particular tracers, thus eliminating the need for cleaning protocols between syntheses and enabling quick transitions to synthesizing other tracers. Though ideal for production, these systems are often limited for the development of novel tracers because of pressure, temperature, and chemical compatibility considerations. This study demonstrated the versatile use of the ELIXYS fully automated radiosynthesizer to adapt and produce 8 different (18)F-labeled PET tracers of varying complexity. Three-reactor syntheses of 2-deoxy-2-(18)F-fluoro-β-d-arabinofuranosylcytosine (d-(18)F-FAC), 2-deoxy-2-(18)F-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-(18)F-FMAU), and 2-deoxy-2-(18)F-fluoro-5-ethyl-β-d-arabinofuranosyluracil (d-(18)F-FEAU) along with the 1-reactor syntheses of d-(18)F-FEAU, (18)F-FDG, 3-deoxy-3-(18)F-fluoro-l-thymidine ((18)F-FLT), (18)F-fallypride, 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)-guanine ((18)F-FHBG), and N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB), were all produced using ELIXYS without the need for any hardware modifications or reconfiguration. Synthesis protocols were adapted and slightly modified from those in the literature but were not fully optimized. Furthermore, (18)F-FLT, (18)F-FDG, and (18)F-fallypride were produced sequentially on the same day and used for preclinical imaging of A431 tumor-bearing severe combined immunodeficient mice and wild-type BALB/c mice. To assess future translation to the clinical setting, several batches of tracers were subjected to a full set of quality control tests. All tracers were produced with radiochemical yields comparable to those in the literature. (18)F-FLT, (18)F-FDG, and (18)F-fallypride were successfully used to image the mice, with results consistent with those reported in the literature. All tracers that were subjected to clinical quality control tests passed. The ELIXYS radiosynthesizer facilitates rapid tracer development and is capable of producing multiple (18)F-labeled PET tracers suitable for clinical applications using the same hardware setup.