Dose-response Research Articles

Secondary cancer risk in six anatomical sites when using PAT, IMPT, and VMAT/IMRT radiotherapy

Background and purposeCompared to intensity modulated proton therapy (IMPT), proton arc therapy (PAT) is expected to improve dose conformality, delivery efficiency, and provide a more favorable LET distribution. Alternatively, the low-dose bath is potentially spread over larger volumes, which could impact the likelihood of developing a radiation-induced, secondary cancer (SC). The goal of this study was to evaluate this risk in several anatomical sites using newly developed commercial tools. Materials and methodsTreatment plans encompassing six anatomical sites, five patients per site, and three techniques per patient were created using RayStation. Techniques included PAT and IMPT for protons, and either volumetrically modulated radiotherapy (VMAT) or intensity modulated radiotherapy (IMRT) for photons. Risk estimates were based on the organ-equivalent dose (OED) concept using both Schneider’s mechanistic dose–response model for carcinoma induction and a linear dose–response model. ResultsWith few exceptions, mean and integral dose were lowest with PAT. For protons, the factor OEDIMPT/OEDPAT ranged from 0.7 to 1.8 with both the mechanistic and linear model, while for photons OEDphoton/OEDPAT ranged from 1.5 to 10 using the mechanistic model and 1.3 to using the linear model. A strong correlation was found between mean dose and OED for organs with significant repopulation/repair (high R value) and less cell death from single hit interactions (low α value). ConclusionBased on results from both mechanistic and linear risk models, the transition from IMPT to PAT should not substantially affect SC risk in patients treated with proton therapy. Additionally, when using Schneider’s model, the shapes of the dose–response curves can be used as a good predictor of how SC risk will respond to shifts from intermediate dose to low dose as anticipated when moving from IMPT to PAT.

Metabolomics highlights biochemical perturbations occurring in the kidney and liver of mice administered a human dose of colistin.

Introduction: Colistin (CMS) is used for the curation of infections caused by multidrug-resistant bacteria. CMS is constrained by toxicity, particularly in kidney and neuronal cells. The recommended human doses are 2.5-5mg/kg/day, and the toxicity is linked to higher doses. So far, the in vivo toxicity studies have used doses even 10-fold higher than human doses. It is essential to investigate the impact of metabolic response of doses, that are comparable to human doses, to identify biomarkers of latent toxicity. The innovation of the current study is the in vivo stimulation of CMS's impact using a range of CMS doses that have never been investigated before, i.e., 1 and 1.5mg/kg. The 1 and 1.5mg/kg, administered in mice, correspond to the therapeutic and toxic human doses, based on previous expertise of our team, regarding the human exposure. The study mainly focused on the biochemical impact of CMS on the metabolome, and on the alterations provoked by 50%-fold of dose increase. The main objectives were i) the comprehension of the biochemical changes resulting after CMS administration and ii) from its dose increase; and iii) the determination of dose-related metabolites that could be considered as toxicity monitoring biomarkers. Methods: The in vivo experiment employed two doses of CMS versus a control group treated with normal saline, and samples of plasma, kidney, and liver were analysed with a UPLC-MS-based metabolomics protocol. Both univariate and multivariate statistical approaches (PCA, OPLS-DA, PLS regression, ROC) and pathway analysis were combined for the data interpretation. Results: The results pointed out six dose-responding metabolites (PAA, DA4S, 2,8-DHA, etc.), dysregulation of renal dopamine, and extended perturbations in renal purine metabolism. Also, the study determined altered levels of liver suberylglycine, a metabolite linked to hepatic steatosis. One of the most intriguing findings was the detection of elevated levels of renal xanthine and uric acid, that act as AChE activators, leading to the rapid degradation of acetylcholine. This evidence provides a naïve hypothesis, for the potential association between the CMS induced nephrotoxicity and CMS induced 39 neurotoxicity, that should be further investigated.

Impact of sample preparation temperature on Li and Ce co-doped MgB4O7 dosimetry performance: A plausible scenario for controlling defect clustering

MgB4O7 co-doped with Ce and Li has been recognized as a promising dosimetric material for spatially-resolved optically stimulated luminescence (OSL) measurements. Nevertheless, conflicting information exists in the literature regarding its dosimetric characteristics. These include discrepancies in fading, the proportion of shallow traps, the range of linear dose response, and a notable absence of direct sensitivity comparisons. These discrepancies are likely attributed to variations in the synthesis methods utilized to produce this material. As part of our research initiative aiming at elucidating the influence of synthesis on the luminescence properties, we are examining in this contribution a single parameter – specifically, the sample preparation temperature – and assessing its impact on the luminescence properties. For the first time, we identified a correlation between the width of the thermoluminescence (TL) glow curves, the TL, optically stimulated luminescence (OSL), and radioluminescence (RL) intensities, as well as the fading characteristics over time and annealing temperature. We show that annealing at higher temperature leads to narrowing of the main TL peak (c.a. 240 °C at 5 °C/s heating rate) compared with samples prepared at lower temperatures, which in turn leads to a decrease in the integrated TL intensity of that peak. Despite exhibiting lower intensity, samples prepared at temperatures above 800 °C show less than 10 % TL/OSL fading over 60 days. Our measurements suggest an involvement of clustered defects for the samples prepared at 600 °C, with a shift towards a scenario of delocalized transitions in samples prepared at higher temperatures.

Impact of microwave power on equivalent dose (De) evaluation in ESR dating

ESR (electron spin resonance) spectra of quartz samples irradiated with varying gamma (γ) dose were measured at different microwave power levels (0–200 mW). The microwave power saturation characteristics of Al and E′ centers were systematically investigated, and the mechanisms by which the power saturation characteristics affected equivalent dose (De) fitting results in ESR dating were revealed. The experimental results demonstrated that irradiation reduces the spin-lattice relaxation time, resulting in the inability to intrinsically characterize the number of spins in a series of aliquots when the ESR intensity exhibits significant saturation. The simulation results indicated that changes in spin-lattice relaxation characteristics can cause distortion in the dose response curve (DRC) at high power levels, leading to deviations in De values. A method that uses the slope of the approximate linear regime of the power saturation curve (PSC) as an intrinsic metric of ESR intensity is proposed; this method has been preliminarily validated in both experiments and simulations.

Salmonella Prevalence in Raw Cocoa Beans and a Microbiological Risk Assessment to Evaluate the Impact of Cocoa Liquor Processing on the Reduction of Salmonella

Salmonella in raw cocoa beans (n = 870) from main sourcing areas over nine months was analyzed. It was detected in 71 (ca. 8.2%) samples, with a contamination level of 0.3–46 MPN/g except for one sample (4.1 × 104 CFU/g). Using prevalence and concentration data as input, the impact of thermal treatment in cocoa processing on the risk estimate of acquiring salmonellosis by a random Belgian chocolate consumer was calculated by a quantitative microbiological risk assessment (QMRA) approach. A modular process risk model from raw cocoa beans to cocoa liquor up to a hypothetical final product (70–90% dark chocolate tablet) was set up to understand changes in Salmonella concentrations following the production process. Different thermal treatments during bean or nib steam, nib roasting, or liquor sterilization (achieving a 0–6 log reduction of Salmonella) were simulated. Based on the generic FAO/WHO Salmonella dose–response model and the chocolate consumption data in Belgium, salmonellosis risk per serving and cases per year at population level were estimated. When a 5 log reduction of Salmonella was achieved, the estimated mean risk per serving was 3.35 × 10−8 (95% CI: 3.27 × 10−10–1.59 × 10−7), and estimated salmonellosis cases per year (11.7 million population) was 88 (95% CI: <1–418). The estimated mean risk per serving was 3.35 × 10−9 (95% CI: 3.27 × 10−11–1.59 × 10−8), and the estimated salmonellosis cases per year was 9 (95% CI: <1–42), for a 6 log reduction. The current QMRA model solely considered Salmonella reduction in a single-step thermal treatment in the cocoa process. Inactivation obtained during other process steps (e.g. grinding) might occur but was not considered. As the purpose was to use QMRA as a tool to evaluate the log reduction in the cocoa processing, no postcontamination from the processing environment and ingredients was included. A minimum of 5 log reduction of Salmonella in the single-step thermal treatment of cocoa process was considered to be adequate.

Unraveling the difference of sensitivity to ozone between non-hybrid native poplar and hybrid poplar clones: A flux-based dose-response analysis

Poplars are economically important tree crops and biologically important model plants, which are known to be sensitive to ozone (O3). Although surface O3 is considered as a significant global environmental issue because of its phytotoxicity and greenhouse effect, the knowledge of the dose-response (DR) relationships in poplars for the assessment of O3 risk is still limited. Hence, this study aimed at collecting data of studies with manipulative O3 exposures of poplars within FACE (Free Air Concentration Enhancement) and OTC (Open-Top Chamber) facilities. The datasets contain studies on hybrid poplar clones and a non-hybrid native poplar (Populus nigra L.) reporting both AOT40 (Accumulated exposure Over a Threshold of 40 ppb) and POD1 (Phytotoxic Ozone Dose above a threshold of 1 nmol m−2 Projected Leaf Area [PLA] s−1) to compare exposure- and flux-based indices. As a result, linear regression analysis showed that the flux-based POD1 was better than the exposure-based AOT40 to explain the biomass response of poplars to O3. From the DR relationships, a critical level (CL) of 5.7 mmol m−2 POD1 has been derived corresponding to 4% biomass growth reduction for hybrid poplar clones, which can be considered very sensitive to O3, while the non-hybrid native poplar was less sensitive to O3 (CL: 10.3 mmol m−2 POD1), although the potential risk of O3 for this taxon is still high due to very high stomatal conductance. Moreover, the different experimental settings (OTC vs. FACE) have affected the AOT40-based DR relationships but not the POD1-based DR relationships, suggesting that poplar responses to O3 were principally explained by stomatal O3 uptake regardless of the different experimental settings and exposure patterns. These results highlight the importance of the flux-based approach, especially when scaling up from experimental datasets to the O3 risk assessment for poplars at the regional or global scale.

Hypereosinophilic syndrome response to mepolizumab in the setting of a compassionate use program.

Mepolizumab, an anti-interleukin-5 antibody, has been proven a safe and effective glucocorticoid-sparing drug for many patients with non-clonal hypereosinophilic syndrome (HES) and is now approved in many countries. It remains unclear however which patients are most likely to benefit from therapy and whether the currently approved dosing regimen is appropriate for all. This observational retrospective study included all HES patients who were enrolled in the MHE104317 compassionate use program (CUP) in our center. Patient and disease characteristics, mepolizumab dosing, and both clinical and hematological responses to treatment were collected from medical files. Treatment responses and mepolizumab dosing requirements were analyzed according to disease characteristics. Eighteen HES patients were enrolled in the CUP, of which 9 are still on treatment. The median duration of exposure to mepolizumab was 45 months (maximum 18 years). A lower number of affected organs, requirement for glucocorticoid dosing ≤10 mg prednisone-equivalent, and single-organ HES were associated with a higher likelihood of complete response. Lymphocytic variant (L-) HES was less treatment-responsive, leading to withdrawal and/or requiring higher mepolizumab dosing to achieve some degree of disease control. In contrast, all patients with single-organ disease had a complete response that could often be maintained despite increasing between-dose intervals. Few potentially treatment-related adverse events were observed despite prolonged exposure. This study confirms the efficacy and safety of mepolizumab in HES, although patients with L-HES rarely experience a complete response. In contrast, patients with single-organ disease affecting the lungs are often super-responders, and decreasing mepolizumab dosing may be attempted.

Thermoluminescence characteristics of gamma-irradiated Gd:Mg doped silica glass

This study explores the characteristics of thermoluminescence (TL) yield of silica glass doped with Gd2O3 and MgO for dosimetry via sol-gel route, with varying concentrations of rare earth metal oxides, ranging from 0.1 to 0.8 mol%. Gamma irradiation was delivered using 1.25 MeV 60Co, with entrance doses of 2–10 Gy. The characterization of Gd:Mg-doped SiO2 included assessing TL dose response, sensitivity, linearity index, glow curve, and fading. It has been found that 0.2 mol% Gd:Mg-doped SiO2 shows promising TL dosimetric properties due to its high linearity, high sensitivity, and low thermal fading. In addition, it demonstrated exceptional dosimetric response across the entire dose range studied, with a coefficient of determination R2 exceeding 91%. A computerized glow curve deconvolution method was conducted to determine the kinetic parameters by using Glowfit software. The glow curves include five peaks associated with activation energies and frequency factors with values 0.88–2.42 eV and 5.58 × 106–7.22 × 1026 s−1, respectively. The 0.2 mol% Gd:Mg-doped SiO2 demonstrates minimal fading effects, retaining a significant portion of the TL signal with ∼33% of the initial signal lost over 28 days post-irradiation. The results indicate that the Gd:Mg-doped SiO2 offers a promising performance as a low-cost passive radiation dosimeters.

AGING MANAGEMENT WITH THE USE OF EXOSOMES, PRP/PRF WITH ALBUMIN GEL (PLASMA GEL) AND ASSOCIATED TECHNIQUES IN OROFACIAL HARMONIZATION TREATMENT

Aging, it is a physiological process that involves a progressive decline in the function of the organs, with loss of homeostasis and increased likelihood of disease disease and death. This account focuses on the classic perspectives on the biogenesis of exosomes, and age-related associated changes. Due to its ability to transmit biological information between cells, this work also discusses the interaction of mesenchymal cell exosomes, as a potent adjuvant in the treatment of association of orofacial harmonization techniques. The demand for aesthetic and rejuvenating treatments is increasing in society, thus, each day, the demand for orofacial harmonization increases exponentially in order to slow aging. Orofacial harmonization is a set of procedures performed by the dentist, which aims at the aesthetic and functional balance of the face. Exosomes are membranous extracellular vesicles ranging from 30 to 200 nm in diameter. Exosomes has been found to be secreted by most cell types, including immune cells (B cells, T cells, mastocytes, dendritic cells), neuronal cells, epithelial cells, endothelial cells, embryonic cells, cancer cells and cells mesenchymal trunk (mscs). The search for youth and perfect skin is a natural desire for the human being. And in this way, collagen biostimulation stands out as a safe and effective option to rejuvenate the skin, fighting the signs of aging and promoting a firmer, toned and radiant appearance. Research in exosomes therapies continues to prosper. Subsequent data on indications, dose response, safety, effectiveness and ability to combine therapy with exosomes as a “skin primer” for biostimulation techniques, such as calcium hydroxylapatite (CAHA), platelet rich plaketers (PRP) and fibrin matrix Platelet plasma, (PRFM) is growing rapidly.

Addition of GM-CSF during in vitro oocyte maturation improves embryo development and implantation and birth rate in mice.

The present study determined whether adding granulocyte macrophage colony stimulating factor (GM-CSF) during in vitro oocyte maturation (IVM) could improve oocyte developmental competence by examining embryo development and implantation and birth rates following embryo transfer in mice. In an initial dose response experiment, we demonstrated that the addition of 2 and 10 ng/mL of GM-CSF during IVM increased cumulus expansion (P<0.05) but did not affect fertilisation rate compared with the control group. The addition of 10 ng/mL increased blastocyst rate (17.0%; P<0.05) and tended to increase the number of good quality blastocysts present at 96 h of culture (+19.4%; P=0.06) and increased blastocyst inner cell mass (+25.2%; P<0.001), trophectoderm (+29.9%; P<0.01), and total cell numbers (+28.6%; P<0.05). GM-CSF also reduced the incidence of DNA damage in blastocysts in the 10 ng/mL group (-16.2%) compared with the control group. These improvements translated into increases in implantation rate (+21.0%; P<0.05) and birth rate (+17.0%; P<0.05) following the transfer of vitrified blastocysts.GM-CSF treatment did not alter any fetal and placental parameters. Together these results suggest that the addition of GM-CSF during IVM may improve livestock in vitro embryo production and human IVM.

Investigating luminescence signals of pharmaceuticals and dietary supplements for emergency dosimetry

This study investigates the potential use of dietary supplements and pharmaceuticals containing magnesium, calcium or potassium for emergency dosimetry applications using the phenomenon of optically stimulated luminescence (OSL). Signal measurements were carried out using different stimulation wavelengths, and blue light stimulation was found to be the most efficient. More than half of the samples exhibited a measurable OSL signal and relatively high radiation sensitivity compared to other previously measured emergency detectors. Moreover, samples generally demonstrated a linear dose response. Possible causes of their high zero-dose signal were investigated: mechanical processing and UV light excitation. As variability in sensitivity was observed, the test-dose protocol was used during measurements. Furthermore, the study showed a significant loss of OSL signal intensity within 24 h after irradiation, which suggests the necessity for a fading correction. Finally, a dose recovery test was performed to evaluate the materials and the test-dose protocol under realistic conditions. The findings indicate the potential for using pharmaceuticals and dietary supplements in the event of a radiation emergency due to their dosimetric properties and ease of obtaining.

Impact on pregnancy outcomes of intermittent preventive treatment with sulfadoxine-pyrimethamine in urban and peri-urban Papua New Guinea: a retrospective cohort study

BackgroundIntermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) reduces malaria-attributable adverse pregnancy outcomes and may also prevent low birth weight (< 2,500 g) through mechanisms independent of malaria. Malaria transmission in Papua New Guinea (PNG) is highly heterogeneous. The impact of IPTp-SP on adverse birth outcomes in settings with little or no malaria transmission, such as PNG’s capital city Port Moresby, is unknown.MethodsA retrospective cohort study was conducted amongst HIV-negative women with a singleton pregnancy who delivered at Port Moresby General Hospital between 18 July and 21 August 2022. The impact of IPTp-SP doses on adverse birth outcomes and anaemia was assessed using logistic and linear regression models, as appropriate.ResultsOf 1,140 eligible women amongst 1,228 consecutive births, 1,110 had a live birth with a documented birth weight. A total of 156 women (13.7%) did not receive any IPTp-SP, 347 women (30.4%) received one, 333 (29.2%) received two, and 304 (26.7%) received the recommended ≥ 3 doses of IPTp-SP. A total of 65 of 1,110 liveborn babies (5.9%) had low birth weight and there were 34 perinatal deaths (3.0%). Anaemia (haemoglobin < 100 g/L) was observed in 30.6% (243/793) of women, and 14 (1.2%) had clinical malaria in pregnancy.Compared to women receiving 0–1 dose of IPTp-SP, women receiving ≥ 2 doses had lower odds of LBW (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.26, 0.96), preterm birth (aOR 0.58; 95% CI 0.32, 1.04), perinatal death (aOR 0.49; 95% CI 0.18, 1.38), LBW/perinatal death (aOR 0.55; 95% CI 0.27, 1.12), and anaemia (OR 0.50; 95% CI 0.36, 0.69). Women who received 2 doses versus 0–1 had 45% lower odds of LBW (aOR 0.55, 95% CI 0.27, 1.10), and a 16% further (total 61%) reduction with ≥ 3 doses (aOR 0.39, 95% CI 0.14, 1.05). Birth weights for women who received 2 or ≥ 3 doses versus 0–1 were 81 g (95% CI −3, 166) higher, and 151 g (58, 246) higher, respectively.ConclusionsProvision of IPTp-SP in a low malaria-transmission setting in PNG appears to translate into substantial health benefits, in a dose–response manner, supporting the strengthening IPTp-SP uptake across all transmission settings in PNG.

The Impact of Non-Pain Factors on Pain Interference Among U.S. Service Members and Veterans with Symptoms of Mild Traumatic Brain Injury.

U.S. Service members and Veterans (SM/V) experience elevated rates of traumatic brain injury (TBI), chronic pain, and other non-pain symptoms. However, the role of non-pain factors on pain interference levels remains unclear among SM/Vs, particularly those with a history of TBI. The primary objective of this study was to identify factors that differentiate high/low pain interference, given equivalent pain intensity among U.S. SM/V participating in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) national multi-center prospective longitudinal observational study. An explainable machine learning was used to identify key predictors of pain interference conditioned on equivalent pain intensity. The final sample consisted of n = 1,577 SM/Vs who were predominantly male (87%), and 83.6% had a history of mild TBI(s) (mTBI), while 16.4% were TBI negative controls. The sample was categorized according to pain interference level (Low: 19.9%, Moderate: 52.5%, and High: 27.6%). Both pain intensity scores and pain interference scores increased with the number of mTBIs (p < 0.001), and there was evidence of a dose response between the number of injuries and pain scores. Machine learning models identified fatigue and anxiety as the most important predictors of pain interference, whereas emotional control was protective. Partial dependence plots identified that marginal effects of fatigue and anxiety were associated with pain interference (p < 0.001), but the marginal effect of mTBI was not significant in models considering all variables (p > 0.05). Non-pain factors are associated with functional limitations and disability experience among SM/V with an mTBI history. The functional effects of pain may be mediated through multiple other factors. Pain is a multi-dimensional experience that may benefit most from holistic treatment approaches that target comorbidities and build supports that promote recovery.

Trinexapac-Ethyl Dose–Response Curve for Eucalyptus Growth and Hormonal Crosstalk Between Leaf and Shoot Apical Bud

Trinexapac-Ethyl Dose–Response Curve for Eucalyptus Growth and Hormonal Crosstalk Between Leaf and Shoot Apical Bud

Understanding the physiological and biological response to ambient heat exposure in pregnancy: protocol for a systematic review and meta-analysis

IntroductionClimate change increases not only the frequency, intensity and duration of extreme heat events but also annual temperatures globally, resulting in many negative health effects, including harmful effects on pregnancy...

Associations of sugary beverage consumption with chronic obstructive pulmonary disease, asthma, and asthma–chronic obstructive pulmonary disease overlap syndrome: a prospective cohort study

BackgroundThe associations between specific types of sugary beverages and major chronic respiratory diseases remain relatively unexplored. ObjectivesThis study aimed to investigate the associations of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and natural juices (NJs) with chronic obstructive pulmonary disease (COPD), asthma, and asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS). MethodsThis prospective cohort study included 210,339 participants from the UK Biobank. Sugary beverage intake was measured in units (glasses/cans/cartons/250 mL) through 24-h dietary questionnaires. Logistic regression and Cox proportional hazards models were used to analyze the prevalence and incidence, respectively. Quantile G-computation was used to estimate the joint associations and relative contributions of the 3 types of sugary beverages. ResultsOver a median follow-up of 11.6 y, 3491 participants developed COPD, 4645 asthma, and 523 ACOS. In prevalence analysis, certain categories of SSB and NJ consumption were associated with increased asthma prevalence, while high ASB consumption (>2 units/d) was linked to higher risks of all 3 outcomes. In incidence analysis, high SSB consumption (>2 units/d) was associated with incident COPD (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.19, 1.98) and asthma (HR: 1.22; 95% CI: 0.98, 1.52). Dose‒response relationships were observed for ASB consumption with all 3 outcomes (continuous HR: 1.98; 95% CI: 1.36, 2.87, for COPD; continuous HR: 1.65; 95% CI: 1.24, 2.20, for asthma; and continuous HR: 2.84; 95% CI: 1.20, 6.72, for ACOS). Moderate NJ consumption (>0–1 unit/d) was inversely associated with COPD (HR: 0.89; 95% CI: 0.82, 0.97), particularly grapefruit and orange juice. Joint exposure to these beverages (per unit increase) was associated with COPD (HR: 1.15; 95% CI: 1.02, 1.29) and asthma (HR: 1.16; 95% CI: 1.06, 1.27), with ASBs having greater positive weights than SSBs. ConclusionsConsumption of SSBs and ASBs was associated with increased risks of COPD, asthma, and potentially ACOS, whereas moderate NJ consumption was associated with reduced risk of COPD, depending on the juice type.

A method to improve sensitivity of Ferrous ammonium sulfate - Benzoic acid - Xylenol orange (FBX) aqueous radiation dosimeter

Ferrous ammonium sulfate - Benzoic acid - Xylenol orange (FBX) solution is known for its dosimetry properties in the dose range applicable in radiation oncology. Several attempts at improving its dose sensitivity have been reported in literature. The current work explores a novel method to improve the dose response of the system in the range 0–10 Gy with the original standard composition of the solution. Value of the sensitivity of the dosimeter was found to be 7.471/Gy with excellent linearity using the developed method. This is 115 times higher than the sensitivity obtained using the conventional methods.

Radiation Therapy Dose Response in Bulky Relapsed/Refractory Large B-Cell Lymphoma

PurposeTo assess whether a radiotherapy (RT) dose affects response in bulky tumors in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). MethodsData from r/r DLBCL patients treated with salvage- or palliative-intent RT (2008-2020) at a single institution were examined. Index lesion size ≥7.5 cm was defined as bulky. Equivalent doses in 2 Gray (Gy) fractions (EQD2) were calculated to compare doses between conventional and hypofractionated (HF, ≥2.5 Gy/fraction) schemes. Objective response rates (ORR) were compared using non-parametric Mann-Whitney U test or Kruskal-Wallis tests with Dunn's multiple comparison corrections. Freedom from local progression (FFLP) was assessed using Kaplan-Meier and Cox proportional hazard regression analyzes. Results183 courses of 151 unique patients were included (salvage: 37%, palliative: 63%). Non-bulky and bulky tumors were irradiated in 109 (60%) and 74 (40%) courses, respectively. Median EQD2 was 33 Gy (IQR=23-39 Gy) with HF in 84 (46%) cases. Of those with post-RT imaging (80%), the ORR was 59% with a trend towards worsened ORR in bulky tumors (50% vs. 65%, p=0.077). For bulky tumors, RT regimens with EQD2s >30 Gy were associated with better ORR (≤30 Gy vs. >30 Gy: 27% vs. 64%, p=0.0073), whereas a lower EQD2 cut-off was sufficient for non-bulky tumors (≤20 Gy vs. >20 Gy: 38% vs. 75%, p=0.0011). On multivariable regression, bulky tumor size was associated with worsened FFLP (HR=2.07, 95% CI=1.16-3.68, p=0.014), while high EQD2s >30 Gy were associated with better FFLP (HR=0.48, 95% CI=0.25-0.93, p=0.031). Bulky tumors treated with EQD2s ≤30 Gy had the lowest median FFLP (4.0 months), while EQD2s >30 Gy had an unreached median FFLP (p=0.0047). ConclusionsBulky r/r DLBCL tumors were associated with less favorable tumor control outcomes in the salvage and palliative settings. RT regimens with higher EQD2s (>30 Gy) should be considered if durable local control of bulky tumors is desired.

Electrophysiological and biochemical effect of zinc oxide nanoparticles on heart functions of male Wistar rats

Zinc oxide nanoparticles (ZnO NPs) are one of the most abundantly used nanomaterials in cosmetics and topical products, and nowadays, they are explored in drug delivery and tissue engineering. Some recent data evidenced that they are responsible for cardiotoxic effects and systemic toxicity. The present study aimed to investigate the toxic effect of ZnO NPs (39 nm) on the heart of Wistar rats and to perform a dose–response relationship using three different dose levels (25, 50, 100 mg/kg bw) of ZnO NPs on the electrocardiogram (ECG) readings, the levels of biochemical function parameters of heart, and the oxidative stress and antioxidant biomarkers. Furthermore, zinc concentration level and histopathological examination of heart tissues were determined. ZnO NPs showed a dose-dependent effect, as the 100 mg/kg bw ZnO NPs treated group showed the most significant changes in ECGs parameters: R–R distance, P–R interval, R and T amplitudes, and increased levels of heart enzymes Creatine Kinase- MB (CK-MB) and Lactate dehydrogenase (LDH). On the other hand, elevated zinc concentration levels, oxidative stress biomarkers MDA and NO, and decreased GSH levels were found also in a dose-dependent manner, the results were supported by impairment in the histopathological structure of heart tissues. While the dose of 100 mg/kg bw of ZnO bulk group showed no significant effects on heart function. The present study concluded that ZnO NPs could induce cardiac dysfunctions and pathological lesions mainly in the high dose.

Circulating lung-cancer-related non-coding RNAs are associated with occupational exposure to hexavalent chromium – A cross-sectional study within the SafeChrom project

BackgroundHexavalent chromium (Cr(Ⅵ)) is classified as a group 1 human carcinogen and increases the risk of lung cancer. Non-coding RNAs (ncRNAs) have key regulatory roles in lung cancer, but less is known about their relation to Cr(Ⅵ) exposure. ObjectivesWe aimed to 1) measure the expression of lung cancer-related circulating ncRNAs in exposed workers and controls; 2) assess associations between ncRNAs expression and Cr concentrations in red blood cells (RBC) and urine; and 3) evaluate correlations between the ncRNAs. MethodsThe study included 111 Cr(VI) exposed workers and 72 controls recruited from the SafeChrom project. Cr concentrations were measured in RBC (biomarker of long-term exposure) and urine (biomarker of short-term exposure) samples. Long ncRNA (lncRNA) and microRNA (miRNA) were extracted from plasma followed by deoxyribonuclease treatment, complementary DNA synthesis, and quantitative real‐time polymerase chain reaction using target-specific assays for three lncRNAs (H19, MALAT1, NORAD), and four miRNAs (miR-142-3p, miR-15b-5p, miR-3940-5p, miR-451a). ResultsExpression levels of lncRNAs MALAT1 and NORAD, and all four miRNAs, were significantly lower in Cr(VI) exposed workers compared with controls, and correlated significantly with RBC-Cr concentrations (rS = −0.16 to −0.38). H19 was non-significantly increased in exposed workers but significantly correlated with miR-142-3p (rS = −0.33) and miR-15b-5p (rS = −0.30), and NORAD was significantly positively correlated with all four miRNAs (rS = 0.17 to 0.46). In multivariate regression models adjusting for confounders, expressions of lncRNAs MALAT1 and NORAD and all miRNAs were still significantly lower in the exposed group compared with controls, and the expression decreased with increasing RBC-Cr concentrations. ConclusionsCr(VI) exposure was inversely and in a dose–response manner associated with the expression of circulating non-coding RNA, which suggests ncRNAs as potential biomarkers for Cr(VI)-induced toxicity. Correlations between miRNAs and lncRNAs suggest that they participate in the same lncRNA-miRNA-messenger RNA regulatory axes, which may play important roles in Cr(VI) carcinogenesis.