Acute Dose Research Articles

A comparison of the chemo- and radiotoxicity of thorium and uranium at different enrichment grades

Uranium and thorium are heavy metals, and all of their isotopes are radioactive, so it is impossible to study chemical effects entirely independent of the radiation effects. In the present study, we tried to compare the chemo- and radiotoxicity of both metals, taking into account deterministic radiation damages reflected by acute radiation sickness and stochastic radiation damages leading to long-term health impairments (e.g., tumor induction). We made at first a literature search on acute median lethal doses that may be expected to be caused by chemical effects, as even acute radiation sickness as a manifestation of acute radiotoxicity occurs with latency. By simulations based on the biokinetic models of the International Commission on Radiological Protection and using the Integrated Modules for Bioassay Analysis software, we determined the amounts of uranium at different enrichment grades and thorium-232 leading to a short-term red bone marrow equivalent dose of 3.5 Sv considered to cause 50% lethality in humans. Different intake pathways for incorporation were considered, and values were compared to the mean lethal doses by chemotoxicity. To assess stochastic radiotoxicity, we calculated the uranium and thorium amounts leading to a committed effective dose of 200 mSv that is often considered critical. Mean lethal values for uranium and thorium are in the same order of magnitude so that the data do not give evidence for substantial differences in acute chemical toxicity. When comparing radiotoxicity, the reference units (activity in Bq or weight in g) must always be taken into account. The mean lethal equivalent dose to the red bone marrow of 3.5 Sv is reached by lower activities of thorium compared to uranium in soluble compounds. However, for uranium as well as thorium-232, acute radiation sickness is expected only after incorporation of amounts exceeding the mean lethal doses by chemotoxicity. Thus, acute radiation sickness is not a relevant clinical issue for either metal. Concerning stochastic radiation damages, thorium-232 is more radiotoxic than uranium if incorporating the same activities. Using weight units for comparison show that for soluble compounds, thorium-232 is more radiotoxic than low-enriched uranium in the case of ingestion but even more toxic than high-enriched uranium after inhalation or intravenous administration. For insoluble compounds, the situation differs as the stochastic radiotoxicity of thorium-232 ranges between depleted and natural uranium. For acute effects, the chemotoxicity of uranium, even at high enrichment grades, as well as thorium-232 exceeds deterministic radiotoxicity. Simulations show that thorium-232 is more radiotoxic than uranium expressed in activity units. If the comparison is based on weight units, the rankings depend on the uranium enrichment grades and the route of intake.

Lifetime of Mayak workers after acute radiation syndrome of various severity levels

Assessment of the impact of radiation exposure on human lifetime is an actual problem in radiation medicine. The aim of the study was to assess lifetime in Mayak PA workers who had developed acute radiation syndrome following accidental acute high-dose external exposure and in those individuals who had taken part in nuclear accidents but had not developed the syndrome. Study analyses considered 58 deceased Mayak PA workers (50 males and 8 females) and were performed using STATISTICA 10 software. Five indicators of lifetime were studied: static – before and after acute exposure, total lifetime, as well as potential – potential years of life lost and the proportion of people who lived less than 35 years. The study demonstrated significant decrease in static indicators excluding lifetime before acute exposure and increase in potential indicators of lifetime in workers with severe and especially with extreme acute radiation syndrome compared to workers with moderate and modest acute radiation syndrome and to workers free of the syndrome. The reason for the decrease of lifetime in workers with extreme acute radiation syndrome was extremely severe course of the disease. Decrease of lifetime in cases with severe level of the syndrome was mainly due to early death from malignancies. A significant linear regression association with natural logarithm of acute radiation dose in Gy was observed for lifetime indicators. At 1 logarithm of the radiation dose, the lifetime after acute exposure was reduced by 8.3 years, total lifetime by 8.8 years, and potential years of life lost increased by 8.4 years. The relative risk of the increase of the proportion of workers with less than 35 years of life was considerably higher in workers with extreme and severe acute radiation syndrome and in workers with acute radiation doses above 10 Gy compared to other groups of workers: 26.8 and 18.8 (95% CI: 3.8–191.1 and 2.7–129.8; p<0.001), respectively. Thus, for the first time, a reduction in lifetime after acute radiation syndrome was found among Mayak PA workers.

The Effects of Two Weeks of Oral PeakATP® Supplementation on Performance during a Three-Minute All out Test

Exogenous ATP has been shown to increase total weight lifted during resistance training interventions and attenuate fatigue during repeated Wingate assessments. However, the influence of exogenous ATP on single bout maximal effort performance has yet to be examined. The purpose of this study was to investigate the effects of PeakATP® supplementation on performance during a 3-min all-out test (3MT). Twenty adults (22.3 ± 4.4 years, 169.9 ± 9.5 cm, 78.7 ± 14.6 kg) completed two identical 3MT protocols in a double-blind, counter-balanced, crossover design. Participants were randomized to either PeakATP® (400 mg·day-1) or placebo (PLA) treatments and consumed their assigned supplement for 14 days and ingested an acute dose 30 min before each 3MT. A 14-day wash-out period was completed between each supplementation period and subsequent 3MT. Peak power, time to peak power, work above end power, end power, and fatigue index were assessed during each 3MT. Dependent t-tests and Hedge's g effect sizes were used to assess differences between treatments. No significant differences were observed between treatments for 3MT performance (p > 0.05). These findings indicate that 3MT performance was not significantly impacted by PeakATP® supplementation. This may be due in part to the continuous nature of the 3MT as disodium ATP has been shown to be beneficial for repeated bout activities.

Argyrophilic nucleolar organizer regions as a promising biomarker for the detection of brain hypoxia levels caused by different doses of carbon monoxide poisoning.

The purpose of the study is to investigate whether there is any relationship between mean argyrophilic nucleolar organizing regions (AgNOR) number and total AgNOR area/total nuclear area (TAA/TNA) ratio and the levels of brain hypoxia after exposure to different acute doses of carbon monoxide (CO) gas. Each experimental group was exposed to CO gas (concentrations of 1,000, 3,000 and 5,000 ppm). Then, the rats were anesthetized, and blood samples were taken from the right jugular vein for carboxyhemoglobin levels detection. The rats were sacrificed on seventh day. AgNOR staining was applied to brain tissues. TAA/TNA and mean AgNOR number were detected for each nucleus. Significant differences were detected among all groups for TAA/TNA ratio, mean AgNOR number and carboxyhemoglobin level. According to a double comparison of groups, the differences between control and 1,000 ppm, control and 3,000 ppm, control and 5,000 ppm, and between 1,000 and 5,000 ppm were significant for TAA/TNA ratio. When mean AgNOR number was considered, significant differences were detected between control and 1,000 ppm, control and 3,000 ppm, control and 5,000 ppm, and between 1,000 and 3,000 ppm. AgNOR proteins may be used for early detection of the duration, intensity, and damage of brain injury caused by CO poisoning. Thus, effective treatment strategies can be developed for the prevention of hypoxic conditions.

Dose rate dependent reduction in chromatin accessibility at transcriptional start sites long time after exposure to gamma radiation

ABSTRACT Ionizing radiation (IR) impact cellular and molecular processes that require chromatin remodelling relevant for cellular integrity. However, the cellular implications of ionizing radiation (IR) delivered per time unit (dose rate) are still debated. This study investigates whether the dose rate is relevant for inflicting changes to the epigenome, represented by chromatin accessibility, or whether it is the total dose that is decisive. CBA/CaOlaHsd mice were whole-body exposed to either chronic low dose rate (2.5 mGy/h for 54 d) or the higher dose rates (10 mGy/h for 14 d and 100 mGy/h for 30 h) of gamma radiation (60Co, total dose: 3 Gy). Chromatin accessibility was analysed in liver tissue samples using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-Seq), both one day after and over three months post-radiation (>100 d). The results show that the dose rate contributes to radiation-induced epigenomic changes in the liver at both sampling timepoints. Interestingly, chronic low dose rate exposure to a high total dose (3 Gy) did not inflict long-term changes to the epigenome. In contrast to the acute high dose rate given to the same total dose, reduced accessibility at transcriptional start sites (TSS) was identified in genes relevant for the DNA damage response and transcriptional activity. Our findings link dose rate to essential biological mechanisms that could be relevant for understanding long-term changes after ionizing radiation exposure. However, future studies are needed to comprehend the biological consequence of these findings.

Residues and dietary risk assessment of fluazinam in root mustard after field experiments.

The residue levels of fluazinam in root mustard were investigated by using a quick, easy, cheap, effective, rugged, and safe (QuEChERS) technique with ultra-performance liquid chromatography tandem mass spectrometry. Samples of leaf and root mustard were analyzed. The recoveries of fluazinam were 85.2-110.8% for leaf mustard with the coefficient of variation of 1.0-7.2%, and 88.8-93.3% for root mustard with the coefficient of variation of 1.9-12.4%. The suspension concentrate formulation of fluazinam was applied on root mustard at 262.5g a.i. ha-1 in accordance with good agricultural practice (GAP), respectively. After the final application, the root mustard samples were collected at 3, 7, and 14days. Fluazinam residues in root mustard were less than 0.01-0.493mgkg-1. The dietary risk of fluazinam was predicted by comparing intake amounts with the toxicological data, namely acceptable daily intake (ADI) and acute reference dose (ARfD). The risk quotient (RQ) was 72.2-74.3%, for ordinary consumers, which showed negligible risk. According to the maximum residue limit (MRL) and dietary risk assessment, it is suggested that the pre-harvest interval (PHI) of 3days; meanwhile, the MRL of 2mgkg-1 was suggested for fluazinam in root mustard, which indicates that the dietary risk of fluazinam 500g L-1 suspension concentrate (SC) with the recommended usage on root mustard is negligible. This study provided basic data on the use and safety of fluazinam in root mustard to help the Chinese government formulate a maximum residue level for fluazinam in root mustard.

Parasite and Pesticide Impacts on the Bumblebee (Bombus terrestris) Haemolymph Proteome

Pesticides pose a potential threat to bee health, especially in combination with other stressors, such as parasites. However, pesticide risk assessment tests pesticides in isolation from other stresses, i.e., on otherwise healthy bees. Through molecular analysis, the specific impacts of a pesticide or its interaction with another stressor can be elucidated. Molecular mass profiling by MALDI BeeTyping® was used on bee haemolymph to explore the signature of pesticidal and parasitic stressor impacts. This approach was complemented by bottom-up proteomics to investigate the modulation of the haemoproteome. We tested acute oral doses of three pesticides-glyphosate, Amistar and sulfoxaflor-on the bumblebee Bombus terrestris, alongside the gut parasite Crithidia bombi. We found no impact of any pesticide on parasite intensity and no impact of sulfoxaflor or glyphosate on survival or weight change. Amistar caused weight loss and 19-41% mortality. Haemoproteome analysis showed various protein dysregulations. The major pathways dysregulated were those involved in insect defences and immune responses, with Amistar having the strongest impact on these dysregulated pathways. Our results show that even when no response can be seen at a whole organism level, MALDI BeeTyping® can detect effects. Mass spectrometry analysis of bee haemolymph provides a pertinent tool to evaluate stressor impacts on bee health, even at the level of individuals.

Is acute low-dose gamma irradiation an effective elicitor for secondary metabolism in Leontopodium alpinum (Cass.) callus culture?

Leontopodium alpinum Cass. (Edelweiss) is a protected species in some European countries and has become of growing interest for exploitation by the food supplements and cosmetics industry, due to its valuable composition in bioactive and biocompatible compounds. Small scale field cultivation and in vitro biotechnological approaches are economically viable alternatives to the production via chemical synthesis. In this study, we aimed to compare two performant L. alpinum callus culture lines and to investigate the effect of acute low dose gamma irradiation on biomass accumulation (Gi), total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity (DPPH) and secondary metabolites’ profile. A purple, pigmented line (PC) was obtained under lightning conditions and in the absence of light, an unpigmented greenish line (GC) was established. Both lines displayed impressive proliferative capacity after 14 days of culture, with an 18.31 ( ± 1.83) fold mass increase for PC and a 13.27 ( ± 2.42) for GC. In respect to Gi, TPC, TFC and DPPH, the purple callus line significantly outperformed the unpigmented line. According to the UPLC-HRMS analysis of the methanolic extracts, both callus lines displayed similar metabolic profiles, having similar quantities of 3,5-dicaffeoylquinic acid, leontopodic acids A and B, but 60% higher concentration of chlorogenic acid in the GC line. In the methanolic callus extracts, 9 economically important phenylpropanoid derivatives were identified. The two callus lines responded differently to low dose gamma irradiation. Although the control values measured for Gi, TPC, TFC and DPPH were significantly higher in the PC line, this line was generally negatively impacted by the gamma treatments. On the contrary, higher, but not significant, values were registered in some GC variants post irradiation with 25, 30 and 40 Gy. UPLC-HRMS investigations emphasized the overproduction of 7 compounds, post irradiation with all doses, for the PC line, while for the unpigmented line only one compound was stimulated by all irradiation treatments. The highest stimulative effect was obtained for the 35 and 40 Gy experimental variants, in the GC line, where dihydroxybenzoic acid glucoside accumulation was increased by 160%. The results of this study showed, for the first time, the different responses of two distinct L. alpinum callus lines using gamma irradiation elicitation method, which can be successfully applied to stimulate the production of certain industrially important compounds as chlorogenic acid, dicaffeoylquinic acid isomers or characteristic glucaric acids.

Excretion and residue depletion of cannabinoids in beef cattle fed hempseed cake for 111 days

Thirty-two crossbred heifers were fed either a control diet or 20% (dry matter basis) hempseed cake in a complete ration for 111 days; of the cattle fed hempseed cake, four each were harvested with 0, 1, 4, and 8-day withdrawal periods. Urine and plasma were collected during the feeding and withdrawal periods and liver, kidney, skeletal muscle, and adipose tissue were collected at harvest. Total cannabinoid (n = 10) concentration of hempseed cake averaged 11.3 ± 11.7 mg kg−1 across the feeding period with total cannabidiol and tetrahydrocannabinol (CBD/THC) concentrations of 1.3 ± 0.8 mg kg−1. Neutral cannabinoids (cannabinol [CBN], CBD/THC, and cannabidivarin [CBDV]) were not detected in plasma or urine, but CBD/THC was measured in adipose tissue at all withdrawal periods (6.3 ± 2.1 to 10.1 ± 2.5 ng g−1). In contrast, cannabinoid acids (cannabinolic acid [CBNA], cannabidiolic acid [CBDA]/tetrahydrocannabinolic acid [THCA], cannabichromenic acid [CBCA], and cannabidivarinic acid [CBDVA]) were sporadically detected (<15 ng mL−1) in plasma and urine of cattle fed hempseed cake. Cannabinoid acids were depleted from liver by withdrawal day 4, but could still be measured (<1 ng g−1) in kidney of some animals harvested on withdrawal day 8. Assessment of human exposures to CBD/THC residues through the consumption of beef fat from animals fed hempseed cake suggests that the probability of consuming the equivalent of an acute reference dose (ARfD) is remote, even with the use of a conservative reference dose ARfD (1 μg kg−1 body weight).

Comparative analysis of Acomyscahirinus and Musmusculus responses to genotoxicity, oxidative stress, and inflammation

The Egyptian spiny mouse, Acomyscahirinus, is a recently described model organism for regeneration studies. It has surprising powers of regeneration with relatively fast repairing mechanisms and reduced inflammation form compared to other mammals. Although several studies have documented the exceptional capabilities of Acomys to regenerate different tissues after injury, its response to different cellular and genetic stresses is not yet investigated. Therefore, the current study aimed to investigate Acomys abilities to resist genotoxicity, oxidative stress and inflammation induced by acute and subacute treatments with lead acetate. Responses of Acomys were compared with those of the lab mouse (Musmusculus), which displays signatures of the “typical” mammalian response to various stressors. Cellular and genetic stresses were induced by using acute and subacute doses of Lead acetate (400 mg/kg and 50 mg/kg for 5 days, respectively). The assessment of genotoxicity was carried out by using comet assay, while oxidative stress was evaluated by measuring the biomarkers; MDA, GSH and antioxidant enzymes CAT and SOD. Moreover, inflammation was assessed by analyzing the expression of some inflammatory-regeneration-related genes: CXCL1, IL1-β, and Notch2 and immunohistochemical staining of TNF-α protein in brain tissue, in addition to histopathological examination of brain, liver, and kidneys. The obtained results revealed a unique resistance potency of Acomys to genotoxicity, oxidative stress, and inflammation in certain tissues in comparison to Mus. Altogether, the results revealed an adaptive and protective response to cellular and genetic stresses in Acomys.

Copper sulfate induces clinico-hematological, oxidative stress, serum biochemical and histopathological changes in freshwater fish rohu (Labeo rohita).

Despite being an essential trace element for numerous metabolic processes and micronutrients, copper (Cu) has induced adverse effects on the environment and public health due to its continuous and widespread use for the last several decades. The current study assessed the hematological and histopathological alterations in the freshwater fish (Labeo rohita) exposed to graded concentrations of copper sulfate. For this purpose, L. rohita fish (n = 72), weighing ~200-215 g, were randomly divided into four experimental groups and then exposed to acute doses of CuSO4, i.e., control, 0.28, 0.42, and 0.56 μgL-1. For comparative analysis of hematological and biochemical changes, blood/serum samples were obtained on 12, 24, and 36 days. Overall, the body weight of fish decreased with the time and dose of CuSO4; as the dose increases, body weight decreases. Dose and time-dependent results were observed in other parameters also. Results showed a significant increase in leukocytes, whereas red blood cells count, Hb, and Hct were significantly reduced in treated groups compared to the control. The mean corpuscular hemoglobin (MHC) and mean corpuscular hemoglobin concentration (MCHC) showed a non-significant decrease in treated groups compared to the control group. Serum biochemical parameters, including total proteins, albumin, and globulin, decreased significantly (p < 0.05). At the same time, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glucose, and cholesterol were significantly (p < 0.05) increased in the treated groups compared to the control group. Significantly (p < 0.05) increased levels of lipid peroxidation while decreased values of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (RGSH) in the blood of fish were recorded. Histopathological examination of fish gills, liver, and kidneys showed inflammation and degenerative changes due to CuSO4 exposure. In the brain tissue, degenerative changes like neuron necrosis, intracellular edema, cytoplasmic vacuolization, and congestion were observed. In conclusion, the study indicates that exposure to copper sulfate, even in smaller concentrations, can cause adverse hematological and histopathological changes in L. rohita fish.

Characterization, Preclinical Efficacy and Toxicity Evaluations of Flavonoids Glycosides based Standardized Fenugreek Seed Extract (FEFLG)

Introduction: Fenugreek seeds, a natural food chain raw material, is known to have many flavonoid glycosides. Objective: Characterization, preclinical efficacy, and safety evaluation of flavonoid glycosidebased standardized fenugreek seed extract (FEFLG). Methods: FEFLG was characterized for a group of flavonoid glycoside marker compounds by HPLC. The CD38+ enzyme inhibition efficacy was assessed in vitro. In addition, acute oral toxicity (AOT) and subchronic, 90-day repeated-dose oral toxicity (in vivo), mutagenicity (AMES test, in vitro) and chromosome aberration test (in vitro) of FEFLG were evaluated. Results: The FEFLG was found to have 49.85% of total flavonoid glycosides content in FEFLG (25.15% of Group 1: vitexin, isovitexin and vitexin 2-o- rhamnoside and 24.70% of Group 2 (vicenin derivatives, schaftoside, iso-schaftoside, orientin and iso-orientin). FEFLG showed CD38+ enzyme inhibition in vitro (IC50= 0.96 μg/ml) equivalent to the positive control, apigenin. FEFLG did not show any toxicity at an acute oral dose of more than 2000 mg/kg (median lethal dose, LD50) with a limit dose of 5000 mg/kg. The 90-day repeated-dose oral administration of FEFLG did not induce significant toxicological changes till the maximum dose of 1000 mg/kg in male and female rats, indicating no observed adverse effect level, NOAEL ≥ 1000 mg/kg. FEFLG did not show mutagenicity (up to a concentration of 5000 μg/plate) or structural chromosomal aberrations (up to 5000 μg /ml). Conclusion: The CD38+ enzyme inhibitor efficacy in vitro, oral safety in vivo and absence of mutagenicity or genotoxicity of FEFLG indicated its potential for anti-aging applications.

Dietary Arginine and Citrulline Supplements for Cardiovascular Health and Athletic Performance: A Narrative Review.

The global market for nutritional supplements (NS) is growing rapidly, and the use of L-arginine (Arg), L-citrulline (Cit), and citrulline malate (CitMal) supplements has been shown to enhance cardiovascular health and athletic performance. Over the past decade, Arg, Cit, and CitMal supplements have received considerable attention from researchers in the field of exercise nutrition, who have investigated their potential effects on hemodynamic function, endothelial function, aerobic and anaerobic capacity, strength, power, and endurance. Previous studies were reviewed to determine the potential impact of Arg, Cit, and CitMal supplements on cardiovascular health and exercise performance. By synthesizing the existing literature, the study aimed to provide insight into the possible uses and limitations of these supplements for these purposes. The results showed that both recreational and trained athletes did not see improved physical performance or increased nitric oxide (NO) synthesis with 0.075 g or 6 g doses of Arg supplement per body weight. However, 2.4 to 6 g of Cit per day for 7 to 16 days of various NSs had a positive impact, increasing NO synthesis, enhancing athletic performance indicators, and reducing feelings of exertion. The effects of an 8 g acute dose of CitMal supplement were inconsistent, and more research is needed to determine its impact on muscle endurance performance. Based on the positive effects reported in previous studies, further testing is warranted in various populations that may benefit from nutritional supplements, including aerobic and anaerobic athletes, resistance-trained individuals, elderly people, and clinical populations, to determine the impact of different doses, timing of ingestion, and long-term and acute effects of Arg, Cit, and CitMal supplements on cardiovascular health and athletic performance.

Abstract Number ‐ 132: Stent‐assisted repair of the intracranial aneurysms with loading dose of antiplanets and perioperative events.

Introduction Introduction: Thromboemboembolic event (TEE) remains the mail perioperative challenge in addition to the potential intracranial hemorrhage (IH) in stent‐assisted repair of intracranial aneurysms (IA), and there are no standard antiplatelet strategies. Bases on the data, antiplatelets effects are more pronounce in first 4 hours after administration of antiplatelets. Objectives: To evaluate the effect of acute loading doses of aspirin and clopidogrel (LDAC) in TEE and hemorrhagic events associate with stent‐assisted repair of intracranial aneurysm. Additionally, to review the outcome of those patient who underwent stent‐assisted coiling using LDAC. Methods Consecutive patients underwent stent‐assisted repair of aneurysm using loading doses of aspirin 324 mg (4 baby aspirin) and clopidogrel 300 mg 2 to 4 hours before the procedure were enrolled from 2011 to 2022. Patients demographics including intra‐operative and post operative events were recorded. Outcome was measured using modified Rankin Scale (mRS) score. Results 96 patients (6 had baseline mRS 2) with mean age of 53 ± 13 underwent 98 stent‐assisted procedures including two Y‐stent neck reconstructions to treat 98 (6 ruptured and 41 symptomatic aneurysms) IA. Aneurysms are Right internal carotid artery (ICA) 25, left ICA 30, middle cerebral artery (MCA) 22, basilar artery 17 and anterior communicating artery 2.Stent deployment was achieved in all cases. Coil prolapsed and stretching occurred in one right ICA case, required deployment of additional 3 intracranial stents and one carotid artery stent with no clinical events. There was no intra‐operative rupture or IH. A small perioperative left hemispheric subarachnoid hemorrhage was observed on a right MCA aneurysm on day 3 after discharged, which resolved spontaneously without stopping antiplatelet. Intra‐operative stent thrombosis developed in one who had two aneurysms in right ICA with significant cerebrovascular risk factors; resolved with intraarterial integrilin followed by intravenous for infusion with no clinical consequences immediately and 12 months follow‐up; was resistant to clopidrogel and placed on ticagrelor.Post‐operative TEE were observed in 2 cases (2%); first event was observed on day 2 in a 42 years old woman with a giant right ICA giant aneurysm with NIHSS 6 and who recovered completely (NIHSS 0, mRS 1) in 90 days. The second event was visual distortion and diplopia (NIHSS 0) developed on day 2 in a 66 years old woman with basilar artery aneurysm. Her symptoms resolved completely and return to nursing job. All ruptured and symptomatic aneurysms were secure immediately and there are no subarachnoid hemorrhages during follow‐up. TEE was associated withperiorerative smoking. Immediate complete and near complete obliteration of aneurysm was observed in 66% and subtotal in 34%. There was no mortality or permanent disability in our series. 90 days mRankins 0 and 1 was observed in 96% and mRS 2 in 7% (baseline mRS) Conclusions Our study revealed that LDAC in stent‐assisted repair of IA is associated with a low TEE without added risk of IH with clinical good outcome. Our antiplatelets loading regimen may be an option in stent‐assisted repair of IA, especially when patients are unreliable and aneurysms are symptomatic. Further studies are required.

Histopathological Evaluation of Nanocurcumin for Mitigation of Radiation- Induced Small Intestine Injury.

In the current study, we aimed to mitigate radiation-induced small intestinal toxicity using post-irradiation treatment with nano-micelle curcumin. Small intestine is one of the most radiosensitive organs within the body. Wholebody exposure to an acute dose of ionizing radiation may lead to severe injuries to this tissue and may even cause death after some weeks. This study aimed to evaluate histopathological changes in the small intestine following whole-body irradiation and treatment with nanocurcumin. Forty male Nordic Medical Research Institute mice were grouped into control, treatment with 100 mg/kg nano-micelle curcumin, whole-body irradiation with cobalt-60 gamma-rays (dose rate of 60 cGy/min and a single dose of 7 Gy), and treatment with 100 mg/kg nano-micelle curcumin 1 day after whole-body irradiation for 4 weeks. Afterward, all mice were sacrificed for histopathological evaluation of their small intestinal tissues. Irradiation led to severe damage to villi, crypts, glands as well as vessels, leading to bleeding. Administration of nano-micelle curcumin after whole-body irradiation showed a statistically significant improvement in radiation toxicity of the duodenum, jejunum and ileum (including a reduction in infiltration of polymorphonuclear cells, villi length shortening, goblet cells injury, Lieberkühn glands injury and bleeding). Although treatment with nano-micelle curcumin showed increased bleeding in the ileum for non-irradiated mice, its administration after irradiation was able to reduce radiation-induced bleeding in the ileum. Treatment with nano-micelle curcumin may be useful for mitigation of radiationinduced gastrointestinal system toxicity via suppression of inflammatory cells' infiltration and protection against villi and crypt shortening.

Exposure of Shewanella oneidensis MR-1 to Sublethal Doses of Ionizing Radiation Triggers Short-Term SOS Activation and Longer-Term Prophage Activation.

Currently, there is a lack of bacterial biomarkers indicative of exposure to ionizing radiation (IR). IR biomarkers have applications for medical treatment planning, population exposure surveillance, and IR sensitivity studies. In this study, we compared the utility of signals originating from prophages and the SOS regulon as biomarkers of IR exposure in the radiosensitive bacterium Shewanella oneidensis. Using RNA sequencing, we demonstrated that 60 min after exposure to acute doses of IR (40, 1, 0.5, and 0.25 Gy), the transcriptional activation of the SOS regulon and the lytic cycle of the T-even lysogenic prophage So Lambda are comparable. Using quantitative PCR (qPCR), we showed that 300 min after exposure to doses as low as 0.25 Gy, the fold change of transcriptional activation of the So Lambda lytic cycle surpassed that of the SOS regulon. We observed an increase in cell size (a phenotype of SOS activation) and plaque production (a phenotype of prophage maturation) 300 min after doses as low as 1 Gy. While the transcriptional responses of the SOS and So Lambda regulons have been examined in S. oneidensis after lethal IR exposures, the potential of these (and other transcriptome-wide) responses as biomarkers of sublethal levels of IR (<10 Gy) and the longer-term activity of these two regulons have not been investigated. A major finding is that after exposure to sublethal doses of IR, the most upregulated transcripts are associated with a prophage regulon and not with a DNA damage response. Our findings suggest that prophage lytic cycle genes are a promising source of biomarkers of sublethal DNA damage. IMPORTANCE The bacterial minimum threshold of sensitivity to ionizing radiation (IR) is poorly understood, which hinders our understanding of how living systems recover from the doses of IR experienced in medical, industrial, and off-world environments. Using a transcriptome-wide approach, we studied how in the highly radiosensitive bacterium S. oneidensis, genes (including the SOS regulon and the So Lambda prophage) are activated after exposure to low doses of IR. We found that 300 min after exposure to doses as low as 0.25 Gy, genes within the So Lambda regulon remained upregulated. As this is the first transcriptome-wide study of how bacteria respond to acute sublethal doses of IR, these findings serve as a benchmark for future bacterial IR sensitivity studies. This is the first work to highlight the utility of prophages as biomarkers of exposure to very low (i.e., sublethal) doses of IR and to examine the longer-term impacts of sublethal IR exposure on bacteria.

Heroin- and Fentanyl-Induced Respiratory Depression in a Rat Plethysmography Model: Potency, Tolerance, and Sex Differences.

The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized the magnitude and duration of respiratory depression, the leading cause of death in opioid overdose cases, induced by heroin or fentanyl and the development of tolerance in male and female rats. We used whole-body plethysmography to first establish dose-response curves by recording breathing for 60 minutes post-intravenous opioid injection. We then tested the development of respiratory tolerance to acute heroin or fentanyl over several weeks and to chronic fentanyl with acute fentanyl or heroin challenge. Heroin and fentanyl each provoked dose-dependent respiratory depression. Heroin caused prolonged (45-60 minute) respiratory depression in female and male rats, characterized by decreased frequency, tidal volume, and minute ventilation and increased inspiratory time and apneic pause. Fentanyl produced similar changes with a shorter duration (10-15 minutes). High-dose heroin or fentanyl produced robust respiratory depression that was slightly more severe in females and, when given intermittently (acute doses 2 to 3 weeks apart), did not lead to tolerance. In contrast, chronic fentanyl delivered with an osmotic minipump resulted in tolerance to acute fentanyl and heroin, characterized by a shorter duration of respiratory depression. This effect persisted during withdrawal in males only. Our model and experimental design will allow for investigation of the neurobiology of opioid-induced respiratory depression and for testing potential therapeutics to reverse respiratory depression or stimulate breathing. SIGNIFICANCE STATEMENT: Fentanyl was more potent and had shorter duration in producing respiratory depression than heroin in both sexes, whereas female rats were more sensitive than males to heroin-induced respiratory depression. Tolerance/cross-tolerance develops in chronic fentanyl administration but is minimized with long interadministration intervals.

Transcriptomic analysis reveals differential adaptation of colorectal cancer cells to low and acute doses of cisplatin

Over the years, the landscape of cisplatin-based cancer treatment options has undergone continuous transitions. Currently, there is much debate over the optimum dose of cisplatin to be administered to cancer patients. In clinical practice, it can extend from repeated low sub-toxic doses to a few cycles of acute high drug doses. Herein, the molecular understanding of the overall cellular response to such differential doses of cisplatin becomes crucial before any decision making; and it has been a grey area of research. In this study, colorectal cancer (CRC) cells were treated with either- a low sub-toxic dose (LD; 30 µM) or a ten times higher acute dose (HD; 300 µM) of cisplatin, and thereafter, the cellular response was mapped through RNA sequencing followed by transcriptomic analysis. Interestingly, we observed that the tumor cells’ response to varying doses of cisplatin is distinctly different, and they activate unique transcriptional programs. The analysis of differentially regulated or uniquely expressed transcripts and corresponding pathways revealed a preferential enrichment of genes associated with chromatin organization, oxidative stress, senescence-associated signaling, and developmentally-active signaling pathways in HD; whereas, modulation of autophagy, protein homeostasis, or differential expression of ABC transporters was primarily enriched in LD. This study is the first of its kind to highlight cellular transcriptomic adaptations to different doses of cisplatin in CRC cells. Consequently, since, protein homeostasis was found to be deeply affected after cisplatin treatment, we further analyzed one of the primary cellular protein homeostatic mechanisms- autophagy. It was activated upon LD, but not HD, and served as a pro-survival strategy through the regulation of oxidative stress. Inhibition of autophagy improved sensitivity to LD. Overall, our study provides a holistic understanding of the distinct molecular signatures induced in CRC cells in response to differential cisplatin doses. These findings might facilitate the design of tailored therapy or appropriate drug dose for enhanced efficacy against CRCs.

Angelica herbal supplement AGN-CognI.Q acute dose safety and pharmacokinetics (PK) dose-response in patients with prostate cancer (PK Dose Trial).

TPS404 Background: There are currently no FDA approved modalities for intercepting biochemically recurrent prostate cancer (PCa) after standard of care surgery and radiation therapies to delay or prevent the need of androgen deprivation therapy (ADT) for localized disease. Preclinical modeling has suggested herbal alcoholic extracts of Angelica gigas Nakai (AGN) root, their signature pyranocoumarins and metabolite decursinol, as potential novel modalities to address this unmet clinical need. We hypothesize that CognI.Q at the higher doses has an acceptable safety profile in prostate cancer patients and pharmacokinetics (PK) exposure metrics will be increased proportional to dose increment. Methods: This is a single institution, phase 1 PK study, N=12. Primary objective- PK, pharmacodynamic (PD) biomarkers with a single ascending dose (SAD)-PK response design. After a subject is enrolled, a 14-day gap must occur before the next subject can be enrolled. If one subject develops a dose limiting toxicity (DLT) at any dose level, that subject will stop participation; If a 2nd subject develops DLT at the same dose level, the trial will be stopped, and the dose level below will be the maximum tolerated dose (MTD). Any subject at a higher dose level at the time of occurrence of 2nd DLT will also stop participation. All subjects will initially start at the 800 mg x 1dose, with further single dose escalation to 1200mg, 1600mg, 2000mg doses of AGN-CognI.Q; each dose will be 1-2 weeks apart. Inclusion criteria: Treated PCa, not on ADT; no active cancer. Subjects will be assessed for safety- clinical, labs (CBC, CMP, baseline and after 24hrs) and EKGs. PK blood will be taken at hourly intervals from 2-7hrs and 24hrs. Plasma pyranocoumarin content will be measured by LC-MS. Immunophenotyping of NK and T cell subtypes will be assessed at baseline and 24 h. Primary Endpoint: MTD. Secondary Endpoint: PK metrics; genotype CYP 2C19 and 3A4 metabolizer status and explore relationship to PK metrics and safety metrics; NK and inflammatory and immune cytokines as PD biomarkers. Trial is now open to accrual (Clinical trial registration NCT05375539). We anticipate that the acute dose safety and PK/PD information will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials. Research Support: MPI 1R01CA260901-01A. Clinical trial information: Clinical trial registration NCT05375539 .

Risk assessment of short-term intake of pyrrolizidine alkaloids in food: derivation of an acute reference dose

Pyrrolizidine alkaloids (PA) are phytochemicals that are known to act as human hepatotoxins and are also considered to be genotoxic carcinogens. Several plant-derived foods are frequently contaminated with PA, like teas and herbal infusions, spices and herbs or certain food supplements. With respect to the chronic toxicity of PA, the carcinogenic potential of PA is generally regarded as the critical toxicological effect. The risk assessment of the short-term toxicity of PA, however, is internationally less consistent. The characteristic pathological syndrome of acute PA toxicity is hepatic veno-occlusive disease. High PA exposure levels may lead to liver failure and even death as documented by several case reports. In the present report, we suggest a risk assessment approach for the derivation of an acute reference dose (ARfD) for PA of 1 µg/kg body weight per day based on a sub-acute animal toxicity study in rats after oral PA administration. The derived ARfD value is further supported by several case reports describing acute human poisoning following accidental PA intake. The here derived ARfD value may be used for PA risk assessment in cases where the short-term toxicity of PA is of interest in addition to the assessment of the long-term risks.