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International journal of environmental research and public health 20(9), 5670 (2023). doi:10.3390/ijerph20095670, Published by MDPI AG, Basel

Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to confirm their structures. The benzoylbenzofuran and isoflavone analogues were evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and benzoylbenzofuran derivatives exhibited potent antiproliferative effects against the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated SIRT1 activity to below 50%. The most active compounds were the isoflavone quinones 38, 39, and 40, at IC

The radiosensitivity of haematopoietic stem and progenitor cells (HSPCs) to neutron radiation remains largely underexplored, notwithstanding their potential role as target cells for radiation-induced leukemogenesis. New insights are required for radiation protection purposes, particularly for aviation, space missions, nuclear accidents and even particle therapy. In this study, HSPCs (CD34+CD38+ cells) were isolated from umbilical cord blood and irradiated with 60Co γ-rays (photons) and high energy p(66)/Be(40) neutrons. At 2 h post-irradiation, a significantly higher number of 1.28 ± 0.12 γ-H2AX foci/cell was observed after 0.5 Gy neutrons compared to 0.84 ± 0.14 foci/cell for photons, but this decreased to similar levels for both radiation qualities after 18 h. However, a significant difference in late apoptosis was observed with Annexin-V+/PI+ assay between photon and neutron irradiation at 18 h, 43.17 ± 6.10% versus 55.55 ± 4.87%, respectively. A significant increase in MN frequency was observed after both 0.5 and 1 Gy neutron irradiation compared to photons illustrating higher levels of neutron-induced cytogenetic damage, while there was no difference in the nuclear division index between both radiation qualities. The results point towards a higher induction of DNA damage after neutron irradiation in HSPCs followed by error-prone DNA repair, which contributes to genomic instability and a higher risk of leukemogenesis.

Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activityviaubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given.

The number of proton therapy facilities and the clinical usage of high energy proton beams for cancer treatment has substantially increased over the last decade. This is mainly due to the superior dose distribution of proton beams resulting in a reduction of side effects and a lower integral dose compared to conventional X-ray radiotherapy. More recently, the usage of metallic nanoparticles as radiosensitizers to enhance radiotherapy is receiving growing attention. While this strategy was originally intended for X-ray radiotherapy, there is currently a small number of experimental studies indicating promising results for proton therapy. However, most of these studies used low proton energies, which are less applicable to clinical practice; and very small gold nanoparticles (AuNPs). Therefore, this proof of principle study evaluates the radiosensitization effect of larger AuNPs in combination with a 200 MeV proton beam. CHO-K1 cells were exposed to a concentration of 10 μg/ml of 50 nm AuNPs for 4 hours before irradiation with a clinical proton beam at NRF iThemba LABS. AuNP internalization was confirmed by inductively coupled mass spectrometry and transmission electron microscopy, showing a random distribution of AuNPs throughout the cytoplasm of the cells and even some close localization to the nuclear membrane. The combined exposure to AuNPs and protons resulted in an increase in cell killing, which was 27.1% at 2 Gy and 43.8% at 6 Gy, compared to proton irradiation alone, illustrating the radiosensitizing potential of AuNPs. Additionally, cells were irradiated at different positions along the proton depth-dose curve to investigate the LET-dependence of AuNP radiosensitization. An increase in cytogenetic damage was observed at all depths for the combined treatment compared to protons alone, but no incremental increase with LET could be determined. In conclusion, this study confirms the potential of 50 nm AuNPs to increase the therapeutic efficacy of proton therapy.

A better understanding of the combined impact of different space stressors on human health is urgently warranted, considering the upcoming long-duration missions beyond lower Earth orbit. Therefore, a growing number of particle accelerator facilities implement ground-based set-ups to study the effect of simulated space radiation with simulated psychological or physical stressors. The immune system is highly sensitive to these types of stressors and limited information is currently available on the impact of the complex space radiation environment on the astronauts’ immune function. This pilot study presents a first step in the implementation of a ground-based set-up with neutron irradiation, which is considered to be an important secondary component in space radiation fields. The effect of dose rate on immune alterations was studied using the in vitro cytokine release assay. Whole blood samples (n=8) were exposed to 0.125 or 1Gy of neutron irradiation (fluence-weighted average energy: 29.8 MeV) at a lower dose rate (LDR) of 0.015Gy/min and a higher dose rate (HDR) of 0.400Gy/min. Immediately post-irradiation, blood samples were stimulated with lipopolysaccharide (LPS), heat-killed Listeria monocytogenes (HKLM) or lectin pokeweed mitogen (PWM), and incubated for 24 hours. Cell-mediated immunity was examined by analysing interleukin­-2 (IL­-2), interferon-gamma (IFN­-γ), tumour necrosis factor-alpha (TNF­-α), and interleukin­-10 (IL­-10) plasma levels. Stimulants significantly increased all cytokine levels except IL­-2, where only PWM induced a significant increase. In general, no statically significant changes were observed in IL­-2, IFN­-γ and TNF­-α concentrations at different neutron doses and dose rates when compared to their stimulated, sham-irradiated controls. After PWM-stimulation, IL­-10 levels were significantly increased at 0.125Gy HDR and 1Gy LDR. In a pooled analysis, the HDR significantly increased IL­-2 titres (under PWM-stimulation) and IFN­-γ titres (with all stimulants), but significantly decreased TNF­-α secretion in unstimulated cultures. Due to the limited sample number, no strong conclusions could be made in this pilot study on the effect of neutron radiation as a single stressor on cytokine secretion in response to different stimuli. However, some interesting trends and dose rate effects were observed, which pave the way for future investigations on the synergistic effects of multiple space stressors on immune cell function.

Despite numerous clinical trials and pre-clinical developments, the treatment of glioblastoma (GB) remains a challenge. The current survival rate of GB averages one year, even with an optimal standard of care. However, the future promises efficient patient-tailored treatments, including targeted radionuclide therapy (TRT). Advances in radiopharmaceutical development have unlocked the possibility to assess disease at the molecular level allowing individual diagnosis. This leads to the possibility of choosing a tailored, targeted approach for therapeutic modalities. Therapeutic modalities based on radiopharmaceuticals are an exciting development with great potential to promote a personalised approach to medicine. However, an effective targeted radionuclide therapy (TRT) for the treatment of GB entails caveats and requisites. This review provides an overview of existing nuclear imaging and TRT strategies for GB. A critical discussion of the optimal characteristics for new GB targeting therapeutic radiopharmaceuticals and clinical indications are provided. Considerations for target selection are discussed, i.e. specific presence of the target, expression level and pharmacological access to the target, with particular attention to blood-brain barrier crossing. An overview of the most promising radionuclides is given along with a validation of the relevant radiopharmaceuticals and theranostic agents (based on small molecules, peptides and monoclonal antibodies). Moreover, toxicity issues and safety pharmacology aspects will be presented, both in general and for the brain in particular.

Simple Summary The current routine treatment for glioblastoma (GB), the most lethal high-grade brain tumor in adults, aims to induce DNA damage in the tumor. However, the tumor cells might be able to repair that damage, which leads to therapy resistance. Fortunately, DNA repair defects are common in GB cells, and their survival is often based on a sole backup repair pathway. Hence, targeted drugs inhibiting essential proteins of the DNA damage response have gained momentum and are being introduced in the clinic. This review gives a perspective on the use of radiopharmaceuticals targeting DDR kinases for imaging in order to determine the DNA repair phenotype of GB, as well as for effective radionuclide therapy. Finally, four new promising radiopharmaceuticals are suggested with the potential to lead to a more personalized GB therapy. Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

Auger electron emitters are considered to be a promising strategy for targeted radionuclide therapy of metastatic diseases, given their high linear energy transfer (LET) and short range in tissue which could potentially limit normal tissue toxicity. Particularly Auger electron emitters that can be targeted into the DNA of tumor cells have been considered as an attractive cancer therapy in the past decade. In this study, the efficiency of the Auger electron emitter 123I (half-life 13.2 h) to induce chromosomal damage was investigated by using the cytokinesis-block micronucleus assay. A stannylated deoxyuridine was synthesized and radiolabeled with 123I, resulting in 123IUdR that carried the Auger electron emitter across the nuclear membrane and allowed its incorporation into newly synthesized DNA. The DNA damage caused by the 123I Auger cascade was estimated by evaluating the induced micronuclei frequencies in human peripheral blood lymphocytes obtained from three different donors. The isolated lymphocytes were stimulated with phytohemagglutinin (1 mg/ml) for 48 h before pulse labeling with 123IUdR and the S-phase fraction was determined using flow cytometry. Geant4 Monte Carlo calculations were performed to determine the absorbed dose in cells by the Auger emitter. The relative biological effectiveness (RBE) was calculated by comparing the dose response curves for 123IUdR with the reference dose response curves, obtained with 60Co γ-ray irradiation in this study, for lymphocytes of the same donors. This resulted in a range of individual RBE values from 3 up to 10, depending on the donor and the radiation dose. In addition, dose limiting RBE values (RBEMax) were calculated for each donor and ranged from 5 to 11, dependent on the inherent radiosensitivity of the donors. This study provides valuable information on the RBE of Auger electron emitter 123I, which is identified as a promising theranostic radionuclide for future targeted radionuclide therapy.

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

The lack of information on how biological systems respond to low-dose and low dose-rate exposures makes it difficult to accurately assess the carcinogenic risks. This is of critical importance to space radiation, which remains a serious concern for long-term manned space exploration. In this study, the &gamma, H2AX foci assay was used to follow DNA double-strand break (DSB) induction and repair following exposure to neutron irradiation, which is produced as secondary radiation in the space environment. Human lymphocytes were exposed to high dose-rate (HDR: 0.400 Gy/min) and low dose-rate (LDR: 0.015 Gy/min) p(66)/Be(40) neutrons. DNA DSB induction was investigated 30 min post exposure to neutron doses ranging from 0.125 to 2 Gy. Repair kinetics was studied at different time points after a 1 Gy neutron dose. Our results indicated that &gamma, H2AX foci formation was 40% higher at HDR exposure compared to LDR exposure. The maximum &gamma, H2AX foci levels decreased gradually to 1.65 &plusmn, 0.64 foci/cell (LDR) and 1.29 &plusmn, 0.45 (HDR) at 24 h postirradiation, remaining significantly higher than background levels. This illustrates a significant effect of dose rate on neutron-induced DNA damage. While no significant difference was observed in residual DNA damage after 24 h, the DSB repair half-life of LDR exposure was slower than that of HDR exposure. The results give a first indication that the dose rate should be taken into account for cancer risk estimations related to neutrons.

Due to the advantages of charged particles compared to conventional radiotherapy, a vast increase is noted in the use of particle therapy in the clinic. These advantages include an improved dose deposition and increased biological effectiveness. Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Recent studies have demonstrated that activation of the Hh pathway, in response to X-rays, can lead to radioresistance and increased migratory, and invasive capabilities of cancer cells. Here, we investigated the effect of X-rays, protons, and carbon ions on cell survival, migration, and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines. In addition, the potential modulation of cell survival and migration by the Hh pathway inhibitor GANT61 was investigated. We found that in both cell lines, carbon ions were more effective in decreasing cell survival and migration as well as inducing more significant alterations in the Hh pathway genes compared to X-rays or protons. In addition, we show here for the first time that the Hh inhibitor GANT61 is able to sensitize DAOY medulloblastoma cells to particle radiation (proton and carbon ion) but not to conventional X-rays. This important finding demonstrates that the results of combination treatment strategies with X-ray radiotherapy cannot be automatically extrapolated to particle therapy and should be investigated separately. In conclusion, combining GANT61 with particle radiation could offer a benefit for specific cancer types with regard to cancer cell survival. KK is a recipient of a SCK.CEN-KUL PhD grant. KK, NB, MV, and BB received a Horizon2020 travel grant (No. 654002) for experiments at GANIL. KK received an EU CONCERT travel grant and Belgian Hadron therapy Consortium (BHTC) travel grant, whereas MM received an FWO travel grant to perform experiments at iThemba LABS in South-Africa. KH is a clinical research fellow of the Research Foundation Flanders, Belgium.

Measurements of the dose equivalent at different distances from the isocenter of the proton therapy center at iThemba LABS were previously performed with a tissue-equivalent proportional counter (TEPC). These measurements showed that the scattered radiation levels were one or two orders of magnitude higher in comparison to other passive scattering delivery systems. In order to reduce these radiation levels, additional shielding was installed shortly after the measurements were done. Therefore, the aim of this work is to quantify and assess the reduction of the secondary doses delivered in the proton therapy room at iThemba LABS after the installation of the additional shielding. This has been performed by measuring microdosimetric spectra with a TEPC at 11 locations around the isocenter when a clinical modulated beam of 200 MeV proton was impinging onto a water phantom placed at the isocenter.

Intensity modulated radiotherapy (IMRT) is one of the modern conformal radiotherapies that is widely used within the context of cancer patient treatment. It uses multiple radiation beams targeted to the tumor, however, large volumes of the body receive low doses of irradiation. Using γ-H2AX and global genome expression analysis, we studied the biological responses induced by low doses of ionizing radiation in prostate cancer patients following IMRT. By means of different bioinformatics analyses, we report that IMRT induced an inflammatory response via the induction of viral, adaptive, and innate immune signaling. In response to growth factors and immune-stimulatory signaling, positive regulation in the progression of cell cycle and DNA replication were induced. This denotes pro-inflammatory and pro-survival responses. Furthermore, double strand DNA breaks were induced in every patient 30 min after the treatment and remaining DNA repair and damage signaling continued after 18-24 h. Nine genes belonging to inflammatory responses (TLR3, SH2D1A and IL18), cell cycle progression (ORC4, SMC2 and CCDC99) and DNA damage and repair (RAD17, SMC6 and MRE11A) were confirmed by quantitative RT-PCR. This study emphasizes that the risk assessment of health effects from the out-of-field low doses during IMRT should be of concern, as these may increase the risk of secondary cancers and/or systemic inflammation.

Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.

International audience; In this note, the authors describe the MULTIBIODOSE software, which has been created as part of the MULTIBIODOSE project. The software enables doses estimated by networks of laboratories, using up to five retrospective (biological and physical) assays, to be combined to give a single estimate of triage category for each individual potentially exposed to ionizing radiation in a large scale radiation accident or incident. The MULTIBIODOSE software has been created in Java. The usage of the software is based on the MULTIBIODOSE Guidance the program creates a link to a single SQLite database for each incident, and the database is administered by the lead laboratory. The software has been tested with Java runtime environment 6 and 7 on a number of different Windows, Mac, and Linux systems, using data from a recent intercomparison exercise. The Java program MULTIBIODOSE-1.0.jar is freely available to download from http//www.multibiodose.eu/software or by contacting the software administrator MULTIBIODOSE-software@gmx.com. © 2014 Health Physics Society.

Purpose The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE.NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals. Methods A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting. Results Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago. Conclusion It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained. Electronic supplementary material The online version of this article (doi:10.1007/s00259-011-1904-z) contains supplementary material, which is available to authorized users.

Objectives Investigation of DNA damage induced by CT x-rays in paediatric patients versus patient dose in a multicentre setting. Methods From 51 paediatric patients (median age, 3.8 years) who underwent an abdomen or chest CT examination in one of the five participating radiology departments, blood samples were taken before and shortly after the examination. DNA damage was estimated by scoring γ-H2AX foci in peripheral blood T lymphocytes. Patient-specific organ and tissue doses were calculated with a validated Monte Carlo program. Individual lifetime attributable risks (LAR) for cancer incidence and mortality were estimated according to the BEIR VII risk models. Results Despite the low CT doses, a median increase of 0.13 γ-H2AX foci/cell was observed. Plotting the induced γ-H2AX foci versus blood dose indicated a low-dose hypersensitivity, supported also by an in vitro dose–response study. Differences in dose levels between radiology centres were reflected in differences in DNA damage. LAR of cancer mortality for the paediatric chest CT and abdomen CT cohort was 0.08 and 0.13 ‰ respectively. Conclusion CT x-rays induce DNA damage in paediatric patients even at low doses and the level of DNA damage is reduced by application of more effective CT dose reduction techniques and paediatric protocols. Key Points • CT induces a small, significant number of double-strand DNA breaks in children. • More effective CT dose reduction results in less DNA damage. • Risk estimates based on the LNT hypothesis may represent underestimates.