Dose-dependent Research Articles

Total ionising dose multilayer shielding optimisation for nanosatellites on geostationary transfer orbit

The rising number of proposed nanosatellite missions with Commercial Off-The-Shelf electronics to higher orbits necessitates innovative, compact, and lightweight radiation shielding. In this study, several thousand multilayer radiation shielding configurations were simulated against trapped particle spectra predicted for a geostationary transfer orbit to demonstrate how material combinations and layer structures can be selected to minimise the total ionising dose inside nanosatellites with constrained mass budgets. The Geant4 Radiation Analysis for Space (GRAS) application was used to calculate ionising dose deposition behind multilayer shielding. Thousands of planar shielding stacks were procedurally generated and simulated on top of silicon plates representing sensitive semiconductor devices. To allow for comparison between configurations, all shielding stacks had a total mass of 1.5 g/cm2, and shielding performance was evaluated based on the total ionising dose absorbed by the silicon plates. The simulations consistently show that configurations with low-atomic-number (low-Z) materials on top of high-Z materials yield the lowest doses. The two- and three-layer mass allocation optimisations demonstrate the non-linear dependence of ionising dose on mass allocation between materials. Optimised polyethylene-lead shields achieved up to 30% lower ionising doses compared to an equal mass of either of the two materials or up to 50% lower than the same mass of aluminium. Contrary to previous claims about Z-graded shielding, no significant improvements were observed for using more than two different materials, and optimisation of multilayer shields tends to reduce them to two-layer structures. Optimal multilayer radiation shielding depends on various factors and must be tailored to specific radiation environments and mission requirements. The primary contributions of this article are the methods presented for achieving this tailoring using open-source software and parallel computing. The multilayer simulations performed for this work resulted in an extensive dataset for multilayer shielding performance that enabled novel visualisations of the ionising dose dependence on shielding composition based on quantitative results.

Modeling the Risk of Hearing Loss From Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review

The Pediatric Normal Tissue Effects in the Clinic (PENTEC) hearing loss (HL) task force reviewed investigations on cochlear radiation dose-response relationships and risk factors for developing HL. Evidence-based dose-response data are quantified to guide treatment planning. A systematic review of the literature was performed to correlate HL with cochlear dosimetry. HL was considered present if a threshold exceeded 20 dB at any frequency. Radiation dose, ototoxic chemotherapy exposure, hearing profile including frequency spectra, interval to HL, and age at radiation therapy (RT) were analyzed. Literature was systematically reviewed from 1970 to 2021. This resulted in 739 abstracts; 19 met inclusion for meta-analysis, and 4 included data amenable to statistical modeling. These 4 studies included 457 cochleas at risk in patients treated with RT without chemotherapy, and 398 cochlea treated with chemotherapy. The incidence and severity of cochlear HL from RT exposure alone is related to dose and age. Risk of HL was <5% in cochlea receiving a mean dose ≤35 Gy but increased to 30% at 50 Gy. HL risk ranged from 25% to 40% in children under the age of 5 years at diagnosis, declining to 10% in older children for any radiation dose. Probability of similar severe HL occurred at doses 18.3 Gy higher for children <3 versus >3 years of age. High-frequency HL was most common, with average onset occurring 3.6 years (range, 0.4-13.2 years) after RT. Exposure to platinum-based chemotherapies added to the rates of HL at a given cochlear dose level, with 300 mg/m2 shifting the dose response by 7 Gy. In children treated with RT alone, risk of HL was low for cochlear dose <35 Gy and rose when dose exceeded 35 Gy without clear RT dose dependence. High-frequency HL was most prevalent, but all frequencies were affected. Children younger than 5 years were at highest risk of developing HL, although independent effects of dose and age were not fully elucidated. Future reports with more granular data are needed to better delineate time to onset of HL and the effects of chemoradiotherapy.

Safety and efficacy of peficitinib in Asian patients with rheumatoid arthritis who had an inadequate response or intolerance to methotrexate: results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study

The efficacy and safety of the oral Janus kinase inhibitor peficitinib were investigated in Asian patients with rheumatoid arthritis (RA). In this double-blind, phase 3 study, patients from mainland China, Korea, and Taiwan with RA and an inadequate response/intolerance to methotrexate were randomized (1:1:1) to once-daily placebo (N=128), peficitinib 100mg(N=129), or 150mg(N=128) in combination with non-biologic DMARDs. At Week 24, patients receiving placebo switched to peficitinib 100mg or 150mg. American College of Rheumatology (ACR) 20 response at Week 24/early termination (ET) was the primary endpoint. Adverse events (AEs) were assessed. The study was registered at ClinicalTrials (NCT03660059). 385 patients were included in the analysis. ACR20 responses were statistically significantly higher in both peficitinib 100mg (56.6%) and 150mg (56.3%) groups versus placebo (24.2%); Odds Ratio (95% confidence interval, CI) 4.14 (2.42, 7.08) and 4.07 (2.38, 6.96), respectively (both P<0.001) at Week 24/ET. The incidence rate of herpes zoster related disease (herpes zoster and varicella) was higher in patients who received peficitinib versus placebo, but no dose dependency was observed (incidence rate/100 patient-years (95% CI): peficitinib 6.7 (4.32, 10.37); placebo 3.7 (0.93, 14.88). In Asian patients with RA and an inadequate response/intolerance to methotrexate, peficitinib 100mg and 150mg demonstrated superiority to placebo in the reduction of RA symptoms and was well tolerated. No additional benefit was observed with use of the higher peficitinib dose in this study population of predominantly Chinese patients. Astellas Pharma.

Prospective, Multicenter Phase II Trial of Non-Pegylated Liposomal Doxorubicin Combined with Ifosfamide in First-Line Treatment of Advanced/Metastatic Soft Tissue Sarcomas.

Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m2) on day 1 along with ifosfamide (3000 mg/m2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity.

Multivalent, asymmetric IL-2-Fc fusions show enhanced selectivity for regulatory T cells.

The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (Treg) cells. IL-2 receptors consist of combinations of α, β, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively Treg-selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor. However, we found that refining the designs to focus on targeting the high-affinity receptor through avidity effects is key to optimizing Treg selectivity. We profiled the dynamics and dose dependency of signaling responses in primary human immune cells induced by engineered fusions composed of either wild-type IL-2 or mutant forms with altered affinity, valency, and fusion to the antibody Fc region for stability. Treg selectivity and signaling response variations were explained by a model of multivalent binding and dimer-enhanced avidity-a combined measure of the strength, number, and conformation of interaction sites-from which we designed tetravalent IL-2-Fc fusions that had greater Treg selectivity in culture than do current designs. Biasing avidity toward IL2Rα with an asymmetrical multivalent design consisting of one α/β chain-binding and one α chain-binding mutant further enhanced Treg selectivity. Comparative analysis revealed that IL2Rα was the optimal cell surface target for Treg selectivity, indicating that avidity for IL2Rα may be the optimal route to producing IL-2 variants that selectively target Tregs.

Dose and dose rate dependence of precipitation in a series of surveillance RPV steels under ion and neutron irradiation

Life extension of light water reactors requires robust models to predict the embrittlement of reactor pressure vessel (RPV) steels under long-term neutron irradiation. Embrittlement is due to nanoscale precipitation hardening by phases containing Cu, Mn, Ni, and Si, resulting in increases of the ductile to brittle transition temperature. Embrittlement data for low flux, high fluence extended life conditions, up to 80 years or more, are largely not available. Thus, higher flux, accelerated test reactor irradiations have been used to help develop models to predict low flux embrittlement at high fluence. Here flux, or dose rate, is expressed in units of displacements per atom per second (dpa/s). The dose rate can significantly influence precipitate evolution in a way that depends on fluence (dpa), temperature, and alloy composition, as well as flux itself. Here, we explore precipitation in surveillance steels with varying compositions at high fluxes (10−5–10−6 dpa/s) produced using 70 MeV Fe2+ ion irradiations. Atom probe tomography was used to characterize the dose dependence of precipitation at very high ion irradiation dose rates, and to evaluate corresponding similarities or differences compared to neutron irradiated steels at a much lower dose rate of ≈ 5 × 10−9 dpa/s. The data show that, on average, the ion irradiation precipitate volume fractions increase by factors of ∼ 1.5 to 2 between 0.3 dpa and 1.2 dpa. Limited data show that the major effect of neutron versus ion irradiation is the former has lower precipitate number densities and larger sizes. Otherwise, the precipitates are remarkably similar in composition and volume fraction.

Some reflections on immunosuppressants and their delivery to the lungs by aerosol in the treatment of COVID-19

Disorders of immune homeostasis represent the key pathogenetic link of COVID-19, which often manifests as a hyperimmune response to the pathogen, leading to severe uncontrolled inflammation in lungs, followed by complications and death. Accordingly, a certain therapeutic potential is provided by different pharmacological drugs with distinct mechanisms of action, This class of drugs should, however, act in common direction by suppressing the immune response, thus being often classified as immunosuppressants (IS). Of them, the most promising are immunobiological preparations, which include monoclonal antibodies, as well as purinergic regulatory agents. There are several attempts to use the “classical” IS by a certain way, e.g., cytostatics and calcineurin inhibitors which found clinical application in transplantology and oncology. However, their usage for treatment of uncontrolled inflammation of respiratory tract was abandoned by the end of XX century. Meanwhile, the aerosol route of drug administration optimizes treatment, both in terms of their effectiveness, and the reduction of side effects thus promoting usage of IS for treatment of uncontrolled airway inflammation. Previously, the analysis of therapeutic opportunities for some IS delivered as aerosols to the lungs in COVID-19 therapy was not carried out, thus bein the purpose of our work. Methodological analysis was carried out using various databases of biomedical scientific information, including Index Medicus, PubMed, Embase, Cohrane Clinical Trials gov registry and patent databases.The efficiency of the impact of various IS subgroups in COVID-19, including their administration by inhalations into the respiratory ways, was assessed. The role of regulatory T cells considered the central regulator of immune response, in pathogenesis of COVID-19 was considered, and their therapeutic potential was characterized, dependent on phase and severity of the disease as well as drug dose dependence. Methods and approaches to the use of IP, advantages and disadvantages are discussed. The expediency and future prospects of their application are considered.One may conclude that the effectiveness of cytostatics and calcineurin inhibitors in the treatment of airway inflammation in COVID-19 remains unconfirmed and seems to be unpromising. Meanwhile, biological preparations, including monoclonal antibodies and purinergic regulatory agents, offer great promise in this respect.

Transdiagnostic analysis of adverse childhood experiences and their association with psychopathology–A TRANS-D conform study

Transdiagnostic approaches challenge traditional psychiatric classification systems. Adverse childhood experiences (ACE) represent a transdiagnostic risk factor for psychopathology with dose dependency. As different qualities of ACE typically co-occur, we identified ACE patterns to assess their power for predicting psychopathology compared to traditional diagnoses. Following TRANS-D guidelines, we categorized participants (N=360) with persistent depressive disorder (PDD), borderline personality disorder (BPD), or healthy control status (HC) into subcategories defined by ACE pattern, using the Childhood Trauma Questionnaire (CTQ). Improvement of the transdiagnostic vs. diagnostic approach in predicting psychopathology was evaluated in a cross-validated predictive modeling framework focusing on the clinical sample of PDD and BPD patients. Results were externally validated in another transdiagnostic sample (N=138). Seven pattern-based subcategories with distinct ACE profiles were identified in the primary sample and replicated in the validation sample. Patterns cut across diagnostic groups. Predictive modeling showed that diagnoses could not predict depressive symptoms and loneliness. Transdiagnostic constructs systematically predicted all measures. This study showcases ACE as a promising construct for transdiagnostic research. Our data-driven framework identified robust ACE subcategories mapping onto general and interpersonal psychopathology. Patterns of CTQ-based information may provide an approach to integrating information on co-occurring ACE to inform diagnostics and treatment.

SPECTRAL-LUMINESCENT AND ELECTROPHYSICAL STUDY OF RADIATION OXIDATION OF BERYLLIUM IN WATER

The radiation oxidation of Be in water at room temperature in the absorbed dose range Dγ = 0.5…180 kGy was studied by radiothermoluminescence (RTL), infrared reflection-adsorption spectroscopy (IRRAS), and electrical conductivity. The participation and role of surface relaxing intermediate-active particles in the dynamics of changes in the oxidation process are considered. Using the RTL method, the role of surface oxygen hole centers generated by γ-irradiation and chemisorbed oxygen in the formation of nanooxide films was experimentally established. The formation of nanooxide films on the surface of Be in water was traced in the IR reflection spectra. The kinetics of radiation oxidation of beryllium has been studied and its radiation passivation has been established. According to the logarithmic dose dependence of the surface resistivity Be, two stages of the oxidation process were revealed. It is shown that the formation of nano oxide films leads to a decrease in the surface electrical conductivity of beryllium by 2 orders of magnitude and an increase in the thickness of oxide films by 1.6 times.

Single-cell DNA sequencing-a potential dosimetric tool.

We hypothesised that single-cell whole-genome sequencing has the potential to detect mutational differences in the genomes of the cells that are irradiated with different doses of radiation and we set out to test our hypothesis using in silico and in vitro experiments. In this manuscript, we present our findings from a Monte Carlo single-cell irradiation simulation performed in TOPAS-nBio using a custom-built geometric nuclear deoxyribonucleic acid (DNA) model, which predicts a significant dose dependence of the number of cluster damages per cell as a function of radiation dose. We also present preliminary experimental results, obtained from single-cell whole-genome DNA sequencing analysis performed on cells irradiated with different doses of radiation, showing promising agreement with the simulation results.

Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (β = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Influence of Dose Distribution in the Target on the Values of Integral Radiobiological Criteria Based on Synthetic Dose-Volume Histograms

Purpose: To investigate the influence of absorbed dose distribution in the tumor volume on the values of&#x0D; integral radiobiological criteria, such as the probability of local tumor control (Tumor Control Probability, TCP) and normal tissue complication probability (NTCP), based on synthetic dose-volume histograms (DVH), which enables to assess the treatment effectiveness and probability of complications&#x0D; from healthy organs and tissues.&#x0D; Material and methods: Synthetic dose-volume histograms were considered theoretically possible to analyze the dependence of equivalent uniform dose (EUD) on values of Nimirko model parameters and absorbed dose distribution for both tumor and critical organs. The calculation was carried out in Wolfram&#x0D; Mathematica program based on the algorithm, where an array of absorbed dose values per fraction of&#x0D; irradiation volume with step by absorbed dose was calculated for the given values of absorbed dose and&#x0D; the parameter determining the width of distribution. The resulting array was differentiated to obtain&#x0D; the differential DVH. The EUD values were obtained from the normalized differential DVHs.&#x0D; Results: During analysis of EUD value dependence on parameter a values determining degree of nonlinearity of absorbed dose summation in sub-volumes of irradiation and on absorbed dose distribution&#x0D; the following was revealed: for critical organs at high values of parameter a the essential role belongs to&#x0D; high and average values of absorbed dose, and for tumors at low values of parameter a the main role belongs to the minimum value of absorbed dose. Thus, the value of parameter a should be negative for a&#x0D; tumor, and positive for critical organs, and should be specifically defined for specific structures.&#x0D; Conclusion: To improve the predictive value (prediction) of the effect of radiotherapy using the&#x0D; TCP/NTCP Nimirko model, an adequate definition of the parameter a, the value of which can only be determined from absorbed dose distributions over the volume of anatomical structures within clinical trials, is necessary.

Anticancer Potential of Dendritic Poly(aryl ether)-Substituted Polypyridyl Ligand-Based Ruthenium(II) Coordination Entities.

This paper studies the anticancer potency of dendritic poly(aryl ether)-substituted polypyridyl ligand-based ruthenium(II) coordination entities. The dendritic coordination entities were successfully designed, synthesized, and characterized by different spectral methods such as Fourier transform infrared (FTIR), 1H and 13C- NMR, and mass spectrometry. Further, to understand the structure and solvation behavior of the coordination entities, we performed all-atom molecular dynamics (MD) simulations. The behavior, configuration, and size of the coordination entities in DMSO and water were studied by calculating the radius of gyration (Rg) and solvent-accessible surface area (SASA). The MTT assay was used to assess the in vitro cytotoxicity of all of the coordination entities against cancerous A549 (lung cancer cells), MDA MB 231 (breast cancer cells), and HepG2 (liver cancer cells) and was found to be good with comparable IC50 values with respect to the standard drug cisplatin. The coordination entities exhibited dose dependence, and the highest activity was shown against HepG2 cell lines in comparison to the other cancer cell lines. In addition, fluorescence staining studies, such as AO/EB, DAPI, and cell death analysis by PI staining, were performed on the coordination entities to understand the apoptosis mechanism. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) assays confirmed apoptosis in cancer cells via the mitochondrial pathway. The DNA fragmentation assay was done followed by molecular docking analysis with DNA executed to strengthen and support the experimental observations.

Antioxidant and hypercholesterolemia effects of Lagerstroemia speciosa ethanolic green and red leaf extracts against Lauric acid and ketogenic diets in female albino rats

The study investigates the therapeutic value of Lagerstroemia speciosa ethanolic green and red leaf extracts against Lauric acid (LA) and a Ketogenic diet (KGD) in Albino rats. Lauric acid is an important constituent in breast milk, forming nutritional factors and having various medicinal values. It is present in 6.2% of human breast milk, 3.1% of goat milk, and 2.9% in cow milk. It is also found in plant sources like coconut, cohune, and palm kernel oil. The Ketogenic diet uses fat, protein, and low carbohydrate for energy. The experimental groups were fed a Ketogenic diet for 21 days, with the treated groups showing a significant increase in blood cell count and Hg levels. The phytochemical profile reveals abundant phytoconstituents, including corosolic acid, lagerstroemin, and anthocyanin, at high levels. The study compared experimental groups fed with LELE Low Dose and High Dose (250 and 500 mg/kg body weight) and standard groups treated with KGD and Lauric acid. The treated groups showed significant elevations in biochemical parameters and increased blood cells and Hg levels. LELE's anti-hypercholesterolemia activity in KGD significantly reduced body weight, total lipid profile, and blood glucose in a dose-dependent manner. The study found that LELE is safe and non-toxic, with the treated group demonstrating dose dependence and decreased obesity.

An Anterior Second Heart Field Enhancer Regulates the Gene Regulatory Network of the Cardiac Outflow Tract.

Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5 (NK2 homeobox 5), GATA6 (GATA binding protein 6), and TBX1 (T-box transcription factor 1) have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT. We generated mice harboring a 226-nucleotide deletion of a highly conserved cardiac enhancer containing 2 GATA-binding sites located ≈9.4 kb upstream of the transcription start site of Nkx2-5 (Nkx2-5∆enh) using CRISPR-Cas9 gene editing and assessed phenotypes. Cardiac defects in Nkx2-5∆enh/∆enh mice were structurally characterized using histology and scanning electron microscopy, and physiologically assessed using electrocardiography, echocardiography, and optical mapping. Transcriptome analyses were performed using RNA sequencing and single-cell RNA sequencing data sets. Endogenous GATA6 interaction with and activity on the NKX2-5 enhancer was studied using chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing in human induced pluripotent stem cell-derived cardiomyocytes. Nkx2-5∆enh/∆enh mice recapitulated cyanotic conotruncal defects seen in patients with NKX2-5, GATA6, and TBX1 mutations. Nkx2-5∆enh/∆enh mice also exhibited defects in right Purkinje fiber network formation, resulting in right bundle-branch block. Enhancer deletion reduced embryonic Nkx2-5 expression selectively in the right ventricle and OFT of mutant hearts, indicating that enhancer activity is localized to the anterior second heart field. Transcriptional profiling of the mutant OFT revealed downregulation of important genes involved in OFT rotation and septation, such as Tbx1, Pitx2, and Sema3c. Endogenous GATA6 interacted with the highly conserved enhancer in human induced pluripotent stem cell-derived cardiomyocytes and in wild-type mouse hearts. We found critical dose dependency of cardiac enhancer accessibility on GATA6 gene dosage in human induced pluripotent stem cell-derived cardiomyocytes. Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5-dependent rotation and septation gene programs.

Cerium Oxide Nanoparticles Protect Cortical Astrocytes from Oxygen-Glucose Deprivation through Activation of the Ca2+ Signaling System.

Most of the works aimed at studying the cytoprotective properties of nanocerium are usually focused on the mechanisms of regulation of the redox status in cells while the complex effects of nanocerium on calcium homeostasis, the expression of pro-apoptotic and protective proteins are generally overlooked. There is a problem of a strong dependence of the effects of cerium oxide nanoparticles on their size, method of preparation and origin, which significantly limits their use in medicine. In this study, using the methods of molecular biology, immunocytochemistry, fluorescence microscopy and inhibitory analysis, the cytoprotective effect of cerium oxide nanoparticles obtained by laser ablation on cultured astrocytes of the cerebral cortex under oxygen-glucose deprivation (OGD) and reoxygenation (ischemia-like conditions) are shown. The concentration effects of cerium oxide nanoparticles on ROS production by astrocytes in an acute experiment and the effects of cell pre-incubation with nanocerium on ROS production under OGD conditions were studied. The dose dependence for nanocerium protection of cortical astrocytes from a global increase in calcium ions during oxygen-glucose deprivation and cell death were demonstrated. The concentration range of cerium oxide nanoparticles at which they have a pro-oxidant effect on cells has been identified. The effect of nanocerium concentrations on astrocyte preconditioning, accompanied by increased expression of protective proteins and limited ROS production induced by oxygen-glucose deprivation, has been investigated. In particular, a correlation was found between an increase in the concentration of cytosolic calcium under the action of nanocerium and the suppression of cell death. As a result, the positive and negative effects of nanocerium under oxygen-glucose deprivation and reoxygenation in astrocytes were revealed at the molecular level. Nanocerium was found to act as a "double-edged sword" and to have a strictly defined concentration therapeutic "window".

Strontium chloride improves bone mass by affecting the gut microbiota in young male rats.

Bone mass accumulated in early adulthood is an important determinant of bone mass throughout the lifespan, and inadequate bone deposition may lead to associated skeletal diseases. Recent studies suggest that gut bacteria may be potential factors in boosting bone mass. Strontium (Sr) as a key bioactive element has been shown to improve bone quality, but the precise way that maintains the equilibrium of the gut microbiome and bone health is still not well understood. We explored the capacity of SrCl2 solutions of varying concentrations (0, 100, 200 and 400 mg/kg BW) on bone quality in 7-week-old male Wistar rats and attempted to elucidate the mechanism through gut microbes. The results showed that in a Wistar rat model under normal growth conditions, serum Ca levels increased after Sr-treatment and showed a dose-dependent increase with Sr concentration. Three-point mechanics and Micro-CT results showed that Sr exposure enhanced bone biomechanical properties and improved bone microarchitecture. In addition, the osteoblast gene markers BMP, BGP, RUNX2, OPG and ALP mRNA levels were significantly increased to varying degrees after Sr treatment, and the osteoclast markers RANKL and TRAP were accompanied by varying degrees of reduction. These experimental results show that Sr improves bones from multiple angles. Further investigation of the microbial population revealed that the composition of the gut microbiome was changed due to Sr, with the abundance of 6 of the bacteria showing a different dose dependence with Sr concentration than the control group. To investigate whether alterations in bacterial flora were responsible for the effects of Sr on bone remodeling, a further pearson correlation analysis was done, 4 types of bacteria (Ruminococcaceae_UCG-014, Lachnospiraceae_NK4A136_group, Alistipes and Weissella) were deduced to be the primary contributors to Sr-relieved bone loss. Of these, we focused our analysis on the most firmly associated Ruminococcaceae_UCG-014. To summarize, our current research explores changes in bone mass following Sr intervention in young individuals, and the connection between Sr-altered intestinal flora and potentially beneficial bacteria in the attenuation of bone loss. These discoveries underscore the importance of the "gut-bone" axis, contributing to an understanding of how Sr affects bone quality, and providing a fresh idea for bone mass accumulation in young individuals and thereby preventing disease due to acquired bone mass deficiency.

A retrospective survey to establish institutional diagnostic reference levels for CT urography examinations based on clinical indications: preliminary results.

Objective. To establish institutional diagnostic reference levels (IDRLs) based on clinical indications (CIs) for three- and four-phase computed tomography urography (CTU).Methods. Volumetric computed tomography dose index (CTDIvol), dose-length product (DLP), patients' demographics, selected CIs like lithiasis, cancer, and other diseases, and protocols' parameters were retrospectively recorded for 198 CTUs conducted on a Toshiba Aquilion Prime 80 scanner. Patients were categorised based on CIs and number of phases. These groups' 75th percentiles of CTDIvoland DLP were proposed as IDRLs. The mean, median and IDRLs were compared with previously published values.Results. For the three-phase protocol, the CTDIvol(mGy) and DLP (mGy.cm) were 22.7/992 for the whole group, 23.4/992 for lithiasis, 22.8/1037 for cancer, and 21.2/981 for other diseases. The corresponding CTDIvol(mGy) and DLP (mGy.cm) values for the four-phase protocol were 28.6/1172, 30.6/1203, 27.3/1077, and 28.7/1252, respectively. A significant difference was found in CTDIvoland DLP between the two protocols, among the phases of three-phase (except cancer) and four-phase protocols (except DLP for other diseases), and in DLP between the second and third phases (except for cancer group). The results are comparable or lower than most studies published in the last decade.Conclusions. The CT technologist must be aware of the critical dose dependence on the scan length and the applied exposure parameters for each phase, according to the patient's clinical background and the corresponding imaging anatomy, which must have been properly targeted by the competent radiologist. When clinically feasible, restricting the number of phases to three instead of four could remarkably reduce the patient's radiation dose. CI-based IDRLs will serve as a baseline for comparison with CTU practice in other hospitals and could contribute to national DRL establishment. The awareness and knowledge of dose levels during CTU will prompt optimisation strategies in CT facilities.

Estimation of relative biological effectiveness of 225Ac compared to 177Lu during [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy using TOPAS/TOPAS-nBio/MEDRAS

AimOver recent years, [225Ac]Ac-PSMA and [177Lu]Lu-PSMA radiopharmaceutical therapy have evolved as a promising treatment option for advanced prostate cancer. Especially for alpha particle emitter treatments, there is still a need for improving dosimetry, which requires accurate values of relative biological effectiveness (RBE). To achieve that, consideration of DNA damages in the cell nucleus and knowledge of the energy deposition in the location of the DNA at the nanometer scale are required. Monte Carlo particle track structure simulations provide access to interactions at this level. The aim of this study was to estimate the RBE of 225Ac compared to 177Lu. The initial damage distribution after radionuclide decay and the residual damage after DNA repair were considered.MethodsThis study employed the TOol for PArtcile Simulation (TOPAS) based on the Geant4 simulation toolkit. Simulation of the nuclear DNA and damage scoring were performed using the TOPAS-nBio extension of TOPAS. DNA repair was modeled utilizing the Python-based program MEDRAS (Mechanistic DNA Repair and Survival). Five different cell geometries of equal volume and two radionuclide internalization assumptions as well as two cell arrangement scenarios were investigated. The radionuclide activity (number of source points) was adopted based on SPECT images of patients undergoing the above-mentioned therapies.ResultsBased on the simulated dose–effect curves, the RBE of 225Ac compared to 177Lu was determined in a wide range of absorbed doses to the nucleus. In the case of spherical geometry, 3D cell arrangement and full radionuclide internalization, the RBE based on the initial damage had a constant value of approximately 2.14. Accounting for damage repair resulted in RBE values ranging between 9.38 and 1.46 for 225Ac absorbed doses to the nucleus between 0 and 50 Gy, respectively.ConclusionIn this work, the consideration of DNA repair of the damage from [225Ac]Ac-PSMA and [177Lu]Lu-PSMA revealed a dose dependency of the RBE. Hence, this work suggested that DNA repair is an important aspect to understand response to different radiation qualities.

Rapid SERS Detection of Botulinum Neurotoxin Type A.

Surface-enhanced Raman scattering (SERS) is a powerful technique for decoding of 2-5-component mixes of analytes. Low concentrations of analytes and complex biological media are usually non-decodable with SERS. Recognition molecules, such as antibodies and aptamers, provide an opportunity for a specific binding of ultra-low contents of analyte dissolved in complex biological media. Different approaches have been proposed to provide changes in SERS intensity of an external label upon binding of ultra-low contents of the analytes. In this paper, we propose a SERS-based sensor for the rapid and sensitive detection of botulinum toxin type A. The silver nanoisland SERS substrate was functionalized using an aptamer conjugated with a Raman label. The binding of the target affects the orientation of the label, providing changes in an analytical signal. This trick allowed detecting botulinum toxin type A in a one-stage manner without additional staining with a monotonous dose dependence and a limit of detection of 2.4 ng/mL. The proposed sensor architecture is consistent with the multiarray detection systems for multiplex analyses.