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National space agencies and private corporations aim at an extended presence of humans in space in the medium to long term. Together with currently suboptimal technology, microgravity and cosmic rays raise health concerns about deep-space exploration missions. Both of these physical factors affect the cardiovascular system, whose gravity-dependence is pronounced. Heart and vascular function are, therefore, susceptible to substantial changes in weightlessness. The altered cardiovascular function in space causes physiological problems in the postflight period. A compromised cardiovascular system can be excessively vulnerable to space radiation, synergistically resulting in increased damage. The space radiation dose is significantly lower than in patients undergoing radiotherapy, in whom cardiac damage is well-documented following cancer therapy in the thoracic region. Nevertheless, epidemiological findings suggest an increased risk of late cardiovascular disease even with low doses of radiation. Moreover, the peculiar biological effectiveness of heavy ions in cosmic rays might increase this risk substantially. However, whether radiation-induced cardiovascular effects have a threshold at low doses is still unclear. The main countermeasures to mitigate the effect of the space environment on cardiac function are physical exercise, antioxidants, nutraceuticals, and radiation shielding.

The number of patients treated with charged-particle radiotherapy as well as the number of treatment centers is increasing worldwide, particularly regarding protons. However, high-linear energy transfer (LET) particles, mainly carbon ions, are of special interest for application in radiotherapy, as their special physical features result in high precision and hence lower toxicity, and at the same time in increased efficiency in cell inactivation in the target region, i.e., the tumor. The radiobiology of high-LET particles differs with respect to DNA damage repair, cytogenetic damage, and cell death type, and their increased LET can tackle cells’ resistance to hypoxia. Recent developments and perspectives, e.g., the return of high-LET particle therapy to the US with a center planned at Mayo clinics, the application of carbon ion radiotherapy using cost-reducing cyclotrons and the application of helium is foreseen to increase the interest in this type of radiotherapy. However, further preclinical research is needed to better understand the differential radiobiological mechanisms as opposed to photon radiotherapy, which will help to guide future clinical studies for optimal exploitation of high-LET particle therapy, in particular related to new concepts and innovative approaches. Herein, we summarize the basics and recent progress in high-LET particle radiobiology with a focus on carbon ions and discuss the implications of current knowledge for charged-particle radiotherapy. We emphasize the potential of high-LET particles with respect to immunogenicity and especially their combination with immunotherapy.

Cancer treatment, today, consists of surgery, chemotherapy, radiation, and most recently immunotherapy. Combination immunotherapy-radiotherapy (CIR) has experienced a surge in public attention due to numerous clinical publications outlining the reduction or elimination of metastatic disease, following treatment with specifically ipilimumab and radiotherapy. The mechanism behind CIR, however, remains unclear, though it is hypothesized that radiation transforms the tumor into an vaccine which immunotherapy modulates into a larger immune response. To date, the majority of attention has focused on rotating out immunotherapeutics with conventional radiation; however, the unique biological and physical benefits of particle irradiation may prove superior in generation of systemic effect. Here, we review recent advances in CIR, with a particular focus on the usage of charged particles to induce or enhance response to cancerous disease.

Background The rapidly increasing clinical demand for 68 Ga-labelled radiopharmaceuticals continues to challenge current production capacities, particularly in high-throughput nuclear medicine departments. Although dual-generator concepts have previously been explored, all reported approaches to date have required either pre-purification, fractionated elution, or additional cartridge-based concentration steps, which add complexity and limit routine clinical implementation. In the present study, we report for the first time a fully automated, GMP-compliant synthesis protocol using two iThemba 68 Ge/ 68 Ga generators connected in series on a standard EasyOne module applicable to three clinically relevant tracers. We successfully established robust GMP production of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-FAPI-46, and [ 68 Ga]Ga-PentixaFor without any pre-purification or fractional elution. A key mechanistic finding of this work is the critical role of direct ascorbic acid addition to the reaction medium, which effectively suppresses radiolysis and metal-ion interference under high-activity conditions. Results We established a Good Manufacturing Practice (GMP)-compliant, fully automated synthesis of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-Pentixafor, and [ 68 Ga]Ga-FAPI-46 using two 68 Ge/ 68 Ga iThemba generators connected in series, of which the older generator is replaced with a new one every 6 months. This configuration enabled elution of maximum activity of 3750 MBq and minimum activity of 2345 MBq, exceeding the elution activity achieved with a single generator by 2300 and 901 MBq respectively. The corrected yield of the labelled products was 91 ± 5% (72 ± 5% non-decay corrected). The additional activity of the labeled products obtained through the two generator configuration enables the examination of 2–4 additional patients per batch and thus resulting in significant cost savings. The direct addition of ascorbic acid to the reaction medium was essential, as it suppressed radiolysis and minimized the impact of metallic impurities. This innovation enabled reproducible labeling without pre-purification, which has not previously been demonstrated with SnO 2 -based generators. Conclusions Dual-generator elution on the EasyOne module without modification of Trasis single-use cassettes provides a robust and scalable approach for high-yield production of 68 Ga radiopharmaceuticals. The integration of series-connected iThemba generators with in-situ radiolysis control by ascorbic acid ensures consistent GMP-compliant synthesis of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-Pentixafor, and [ 68 Ga]Ga-FAPI-46. This method improves production efficiency, reduces costs, and expands clinical accessibility.

Background [ 18 F]Fallypride PET has been used to study D2/3 receptor occupancy and density in neuropsychiatric disorders including Huntington’s disease (HD) and aging in humans. Nevertheless, the various synthetic methods including those provided by commercial synthesizers for [ 18 F]fallypride exhibit a disadvantage concerning the necessity of using a HPLC purification step, which causes difficulties in the automation, leads to long synthesis times and moderate yields. Therefore utilizing the purification step by SPE cartridges is considered highly desirable for future commercialization of radiopharmaceutical cassettes. In our lab we have developed a simplified reliable automatic Radiosynthesis of [ 18 F]fallypride by using SPE cartridges for the purification step without the need of HPLC. Results A simplified Radiosynthesis of [ 18 F]fallypride has been developed without the use of HPLC for both a commercial cassette based synthesis system (AllinOne (AiO) system, Trasis, Belgium) and a research synthesis module with fixed tubing (RNplus, Synthra, Germany). The cleaning step involves a serial combination of several SPE cartridges. The synthesis time was shortened by 44% compared to synthesis using HPLC. At the same time the not decay corrected yield increases from 44 to 59% by using TBAHCO 3 as phase transfer catalysts and from 17 to 31% for the synthesis with K 2 CO 3 /Kryptofix-[2.2.2] compared to synthesis using HPLC. The Radiochemical purity was always > 98% and all quality control parameters (e.g. sterility, endotoxin, stability and Radiochemical purity) conformed with requirements of the European Pharmacopoeia. Conclusions A GMP compliant automatic synthesis of [ 18 F]fallypride including purification using simple solid phase extraction cartridges instead of HPLC was developed and evaluated. The implementation of the simplified synthesis in both used commercial modules allows efficient and reproducible Radiosynthesis of [ 18 F]fallypride and leads to short synthesis times and high radiochemical yields with high radiochemical purity.

Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as “synthetic torpor” in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animal in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an effective strategy to protect humans during long term space exploration of the solar system.

BackgroundThe recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [68Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [68Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge.Our aim was to simplify the synthesis and shorten the automated synthesis of [68Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community.ResultsWe developed and evaluated the GMP compliant automatic synthesis of [68Ga]Ga-FAPI-46 using two different 68Ge/68Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [68Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing.ConclusionsIndependent of the synthesis modules or the generators employed we were able to complete the synthesis of [68Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia.

Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy.

Robotic process automation is a disruptive technology to automate already digital yet manual tasks and subprocesses as well as whole business processes rapidly. In contrast to other process automation technologies, robotic process automation is lightweight and only accesses the presentation layer of IT systems to mimic human behavior. Due to the novelty of robotic process automation and the varying approaches when implementing the technology, there are reports that up to 50% of robotic process automation projects fail. To tackle this issue, we use a design science research approach to develop a framework for the implementation of robotic process automation projects. We analyzed 35 reports on real-life projects to derive a preliminary sequential model. Then, we performed multiple expert interviews and workshops to validate and refine our model. The result is a framework with variable stages that offers guidelines with enough flexibility to be applicable in complex and heterogeneous corporate environments as well as for small and medium-sized companies. It is structured by the three phases of initialization, implementation, and scaling. They comprise eleven stages relevant during a project and as a continuous cycle spanning individual projects. Together they structure how to manage knowledge and support processes for the execution of robotic process automation implementation projects.