Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study.

Breast cancer is a common public health disease causing mortality worldwide. Thus, providing novel chemotherapies that tackle breast cancer is of great interest. In this investigation, novel pyrido[2,3-d]pyrimidine derivatives 3,4,(6a-c),(8a,b),9-20 were synthesized and characterized using a variety of spectrum analyses. The geometric and thermal parameters of the novel thiouracil derivatives 3,4,6a,(8a,b),11,12,17,18, 19 were measured using density functional theory (DFT) via DFT/B3LYP/6-31 + G(d,p) basis set. All synthesized compounds were evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) method using MCF-7 and MDA-MB-231 breast cancerous cells, compound 17 had the maximum anticancer activity against both breast cancerous cells, recording the lowest half-maximal inhibitory concentration (IC50) values (56.712 µg/mL for MCF-7 cells and 48.743 µg/mL for MDA-MB-231 cells). The results were confirmed in terms of the intrinsic mechanism of apoptosis, where compound 17 had the highest percentage in the case of both cancer cells and recorded Bax (Bcl-2 associated X)/Bcl-2 (B-cell lymphoma 2) ratio 17.5 and 96.667 for MCF-7 and MDA-MB-231 cells, while compound 19 came after 17 in the ability for induction of apoptosis, where the Bax/Bcl-2 ratio was 15.789 and 44.273 for both cancerous cells, respectively. Also, compound 11 recorded a high Bax/Bcl-2 ratio for both cells. The safety of the synthesized compounds was applied on normal WI-38 cells, showing minimum cytotoxic effect with undetectable IC50. Compounds 17, 11, and 19 recorded a significant increase of p53 upregulated modulator of apoptosis (PUMA) expression levels in the cancerous cells. The DFT method was also used to establish a connection between the experimentally determined values of the present investigated compounds and their predicted quantum chemical parameters. It was concluded that Compounds 17, 11, and 19 had anti-breast cancer potential through the induction of apoptotic Bax/Bcl-2 and PUMA expression levels.

Monolacunary Wells-Dawson Polyoxometalate as a Novel Contrast Agent for Computed Tomography: A Comprehensive Study on In Vivo Toxicity and Biodistribution.

Polyoxotungstate nanoclusters have recently emerged as promising contrast agents for computed tomography (CT). In order to evaluate their clinical potential, in this study, we evaluated the in vitro CT imaging properties, potential toxic effects in vivo, and tissue distribution of monolacunary Wells-Dawson polyoxometalate, α2-K10P2W17O61.20H2O (mono-WD POM). Mono-WD POM showed superior X-ray attenuation compared to other tungsten-containing nanoclusters (its parent WD-POM and Keggin POM) and the standard iodine-based contrast agent (iohexol). The calculated X-ray attenuation linear slope for mono-WD POM was significantly higher compared to parent WD-POM, Keggin POM, and iohexol (5.97 ± 0.14 vs. 4.84 ± 0.05, 4.55 ± 0.16, and 4.30 ± 0.09, respectively). Acute oral (maximum-administered dose (MAD) = 960 mg/kg) and intravenous administration (1/10, 1/5, and 1/3 MAD) of mono-WD POM did not induce unexpected changes in rats' general habits or mortality. Results of blood gas analysis, CO-oximetry status, and the levels of electrolytes, glucose, lactate, creatinine, and BUN demonstrated a dose-dependent tendency 14 days after intravenous administration of mono-WD POM. The most significant differences compared to the control were observed for 1/3 MAD, being approximately seventy times higher than the typically used dose (0.015 mmol W/kg) of tungsten-based contrast agents. The highest tungsten deposition was found in the kidney (1/3 MAD-0.67 ± 0.12; 1/5 MAD-0.59 ± 0.07; 1/10 MAD-0.54 ± 0.05), which corresponded to detected morphological irregularities, electrolyte imbalance, and increased BUN levels.

Imidazo[1,2-b]pyridazines as inhibitors of DYRK kinases.

Selective inhibitors of DYRK1A are of interest for the treatment of cancer, Type 2 diabetes and neurological disorders. Optimization of imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration and in silico drug design efforts led to the discovery of compound 17 as a potent cellular inhibitor of DYRK1A with selectivity over much of the kinome. The binding mode of compound 17 was elucidated with X-ray crystallography, facilitating the rational design of compound 29, an imidazo [1,2-b]pyridazine with improved kinase selectivity with respect to closely related CLK kinases.

Photocatalytic activation of sulfite by maghemite (γ-Fe2O3) for iohexol degradation and alleviation effect of HCO3- on water acidification.

Photo-catalyzing sulfite (S(IV)) for the generation of sulfate radical (SO4•-) has emerged as a novel advanced oxidation process (AOP) recently. However, both the potential of soil minerals as effective photocatalysts and the process of water acidification due to S(IV) oxidation have been overlooked. Herein, maghemite (γ-Fe2O3), a typical soil iron oxide with excellent photocatalytic reactivity like hematite and magnetic-collectible property like magnetite, was successfully used to activate S(IV) for iohexol degradation under visible light irradiation. As a result, 91.3% of iohexol was eliminated within 15 min at 0.1 g/L maghemite and 0.5 mM S(IV) under neutral conditions. The influencing factors, including initial pH, catalyst dosage, S(IV) amount, co-existing substances and water matrix, were systematically investigated. The maghemite/S(IV)/vis system exhibited superior performance in iohexol degradation at a wide pH range (3-10). It was found that the released proton via S(IV) oxidation led to severe water acidification. Interestingly, a low dose of HCO3- could evidently resist water acidification with little influence on iohexol elimination. Radical quenching experiments and electron spin resonance (ESR) analysis confirmed that SO4•-, •OH and •O2- were involved in iohexol abatement with SO4•- being the dominant reactive species. Compared with hydrogen peroxide, persulfate and peroxymonosulfate, the established maghemite/S(IV)/vis system achieved much more remarkable degradation performance. Furthermore, the reactivity of the catalyst was not obviously reduced even after 10 runs of reaction. This study expands the application of soil iron oxide mineral in S(IV) activation in water treatment and proposes an approach to regulate water acidification in S(IV)-based AOP.

Discovery of a stilbenoid-flavanone hybrid as an antitumor Wnt/ß-catenin signaling pathway inhibitor.

A series of designed stilbenoid-flavanone hybrids featuring sp3-hybridized C2 and C3 atoms of C-ring was evaluated against colorectal cancers presented compounds 4, 17, and 20 as the most potential compounds among explored compounds. Evaluation of the anticancer activity spectrum of compounds 4, 17, and 20 against diverse solid tumors presented compounds 17 and 20 with interesting anticancer spectrum. The potencies of compounds 17 and 20 were assessed in comparison with FDA-approved anticancer drugs. Compound 17 was the, in general, the most potent showing low micromolar GI50 values that were more potent than the standard FDA-approved drugs against several solid tumors including colon, brain, skin, renal, prostate and breast tumors. Compound 17 was subjected for evaluation against normal cell lines and was subjected to a mechanism study in HCT116 colon cancer cells which presented it as an inhibitor of Wnt signaling pathway triggering G2/M cell cycle arrest though activation of p53-p21 pathway as well as intrinsic and extrinsic apoptotic death of colon cancer cells. Compound 17 might be a candidate for further development against diverse solid tumors including colon cancer.

Impact of humanized vancomycin infusion on kidney function and kidney injury in a translational rat model.

Allometric dose scaling aims to create isometric exposures between animals and humans and is often employed in preclinical pharmacokinetic/pharmacodynamic models. Bolus-administration with allometric scaling is the most simple and commonly used strategy in pre-clinical kidney injury studies; however, it is possible to humanize drug exposures. Currently, it is unknown if dose-matched, bolus-administration with allometric scaling results in similar outcomes compared to humanized infusions in the vancomycin induced kidney injury model. We utilized a preclinical Sprague-Dawley rat model to compare traditional allometrically-scaled, dose-matched, bolus-administration of vancomycin to an infusion-pump controlled, humanized infusion scheme to assess for differences in iohexol-measured kidney function and urinary kidney injury biomarkers. Following 24 h of vancomycin administration, rats in the humanized infusion group had equivalent area under the curve exposures to animals in the dose-matched bolus group (93.7 mg·h/L [IQR 90.2-97.2] vs. 99.5 mg·h/L [IQR 95.1-104.0], P = 0.07). No significant differences in iohexol-measured kidney function nor meaningful differences in urinary kidney injury biomarkers, kidney injury molecule-1, clusterin, and osteopontin, were detected. Administration of intravenous vancomycin as either a humanized infusion or dose-matched bolus resulted in similar vancomycin exposures. No differences in iohexol-measured GFR nor meaningful differences in urinary kidney injury biomarkers were observed among male Sprague-Dawley rats.

Microvascular changes following exposure to iodinated contrast media in vitro. A qualitative comparison to serum creatinine concentrations in post-cardiac catheterization patients.

INTRODUCTION: Contrast-associated acute kidney injury (CA-AKI) is characterized as a loss of renal function following radiological contrast media administration. While all contrast media induce variable changes in microvascular endothelial cells in vitro, only few studies report clinical significance of their findings. A comprehensive assessment of the effect of iodinated contrast media on the renal function in vitro and in vivo is essential. The aim of our study was to morphometrically quantify the effect of two different contrast media (Iobitridol and Iodixanol) on vascular endothelial capillaries in vitro and to analyze their effect on the renal function of patients who underwent cardiac catheterization including the intra-arterial administration of contrast media, by measuring serum creatinine concentration (SCr), a byproduct of muscle metabolism, primarily excreted by the kidneys. Our hypothesis suggests that conducting a qualitative comparison of both outcomes will enable identification of differences and similarities between in vitro and in vivo exposure. MATERIAL AND METHODS: In vitro, co-cultures of human dermal fibroblasts and human dermal microvascular endothelial cells forming capillary beds were exposed to a mixture of phosphate buffered saline and either Iobitridol, Iodixanol, or one of their supplements EDTA or Trometamol for 1.5 or 5 min. Negative control co-cultures were exposed exclusively to phosphate buffered saline. Co-cultures were either directly fixed or underwent a regeneration time of 1, 3 or 7 days. An artificial intelligence software was trained for detection of labeled endothelial capillaries (CD31) on light microscope images and measurements of morphometric parameters. In vivo, we retrospectively analyzed data from patients who underwent intra-arterial administration of contrast media and for whom SCr values were available pre- and post-contrast exposition (1, 3, and 7 days following procedure). Temporal development of SCr and incidence of CA-AKI were assessed. Both exposure types were qualitatively compared. RESULTS: In vitro, Iobitridol, Iodixanol and EDTA induced a strong decrease of two morphometric parameters after 3 days of regeneration. In vivo, a significant increase of SCr and incidence of CA-AKI was observed 3 days following procedure in the post-contrast media patients. No difference was observed between groups. DISCUSSION: Two of the morphometric parameters were inversely proportional to the SCr of the patients. If the endothelial damages observed in vitro occur in vivo, it may result in renal hypoxia, inducing a loss of kidney function clinically translated into an increase of SCr. Further development of our in vitro model could allow closer replication of the internal structure of a kidney and bridge the gap between in vitro studies and their clinical findings.

Evaluation of the technique of localization of the epidural space with the aid of a peripheral nerve stimulator and epidurographic, comparing two techniques for determining the infused volume, in rabbits (Oryctolagus Cuniculus).

Veterinary care for rabbits has been growing, and, consequently, the anesthetic and analgesic management of this species must be improved. The aim of the present study was to evaluate the technique of localization of the epidural space with the aid of a peripheral nerve stimulator and epidurographic, comparing two techniques for determining the infused volume in rabbits (Oryctolagus Cuniculus). In a prospective, randomized blinded study, six healthy New Zealand rabbits, adults, and weighing from 2.2 kg to 3.8 kg received two treatments, at 1 week intervals: 0.33 mL/kg (treatment I) or 0.05 mL per centimeter of the spine (treatment II) of ioexol epidurally. In both treatments, a peripheral nerve stimulator (2 Hz, 0.25 mA and 0.1 milliseconds) was used to determine the location of the epidural space. Latero-lateral and ventro-dorsal radiographs were taken after five (T5) and twenty-five minutes (T25) of iohexol administration. The epidural space was correctly accessed in 92% of attempts. Treatment I received a smaller volume of contrast than treatment II, 1.0 ± 0.2 mL versus 2.1 ± 0.1 mL (mean ± standard deviation), respectively (p = 0.007). At T5, the cranial progression of the contrast varied between L4 and L5 in treatment I, and L5 and T10 in treatment II. At T25, no contrast was observed in any rabbit. In conclusion, peripheral nerve stimulator aided in accessing the lumbosacral epidural space, and the administration of 0.05 mL per centimeter of the spine resulted in greater cranial progression of contrast.

Characterizing and Comparing Adverse Drug Events Documented in 2 Spontaneous Reporting Systems in the Lower Mainland of British Columbia, Canada: Retrospective Observational Study.

BACKGROUND: Robust adverse drug event (ADE) reporting systems are crucial to monitor and identify drug safety signals, but the quantity and type of ADEs captured may vary by system characteristics. OBJECTIVE: We compared ADEs reported in 2 different reporting systems in the same jurisdictions, the Patient Safety and Learning System-Adverse Drug Reaction (PSLS-ADR) and ActionADE, to understand report variation. METHODS: This retrospective observational study analyzed reports entered into PSLS-ADR and ActionADE systems between December 1, 2019, and December 31, 2022. We conducted a comprehensive analysis including all events from both reporting systems to examine coverage and usage and understand the types of events captured in both systems. We calculated descriptive statistics for reporting facility type, patient demographics, serious events, and most reported drugs. We conducted a subanalysis focused on adverse drug reactions to enable direct comparisons between systems in terms of the volume and events reported. We stratified results by reporting system. RESULTS: We performed the comprehensive analysis on 3248 ADE reports, of which 12.4% (375/3035) were reported in PSLS-ADR and 87.6% (2660/3035) were reported in ActionADE. Distribution of all events and serious events varied slightly between the 2 systems. Iohexol, gadobutrol, and empagliflozin were the most common culprit drugs (173/375, 46.2%) in PSLS-ADR, while hydrochlorothiazide, apixaban, and ramipril (308/2660, 11.6%) were common in ActionADE. We included 2728 reports in the subanalysis of adverse drug reactions, of which 12.9% (353/2728) were reported in PSLS-ADR and 86.4% (2357/2728) were reported in ActionADE. ActionADE captured 4- to 6-fold more comparable events than PSLS-ADR over this study's period. CONCLUSIONS: User-friendly and robust reporting systems are vital for pharmacovigilance and patient safety. This study highlights substantial differences in ADE data that were generated by different reporting systems. Understanding system factors that lead to varying reporting patterns can enhance ADE monitoring and should be taken into account when evaluating drug safety signals.

Selective electrophilic attack towards organic micropollutants with superior Fenton-like activity by biochar-supported cobalt single-atom catalyst.

The global shortage of freshwater and inadequate supply of clean water have necessitated the implementation of robust technologies for wastewater purification, and Fenton-like chemistry is a highly-promising approach. However, realizing the rapid Fenton-like chemistry for high-efficiency degradation of organic micropollutants (OMs) remains challenging. Herein, one novel system was constructed by a Co single-atom catalyst activating peroxymonosulfate (PMS), and the optimal system (SA-Co-NBC-0.2/PMS) achieved unprecedented catalytic performance towards a model OM [Iohexol (IOH)], i.e., almost 100% decay ratio in only 10 min (the observed rate constant: 0.444 min-1) with high electrophilic species 1O2 (singlet oxygen) generation. Theoretical calculations unveiled that Co-N4 sites preferred to adsorb the terminal-O of PMS (more negative adsorption energy than other O sites: -32.67 kcal/mol), promoting the oxidation of PMS to generate 1O2. Iodine (I)23 (0.1097), I24 (0.1154) and I25 (0.0898) on IOH with higher f- electrophilic values were thus identified as the main attack sites. Furthermore, 16S ribosomal RNA high-throughput sequencing and quantitative structure-activity relationship analysis illustrated the environmentally-benign property of the SA-Co-NBC-0.2 and the tapering ecological risk during IOH degradation process. Significantly, this work comprehensively checked the competence of the SA-Co-NBC-0.2/PMS system for organics abatement in practical wastewater.

Expression of GRP78 and its copartners in HEK293 and pancreatic cancer cell lines (BxPC-3/PANC-1) exposed to MRI and CT contrast agents.

Endoplasmic reticulum (ER) stress-associated chaperones trigger a defense mechanism called as unfolded protein response (UPR) which can manage apoptosis and be determinative in cell fate. Both anticancer drug effects and potential toxicity effects of magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents were aimed to be evaluated. For this purpose, we investigated expression profiles of endoplasmic reticulum stress-associated chaperone molecules in human pancreatic tumor lines BxPC-3 and PANC-1 and control human embryonic kidney cells 293 (HEK293) induced with a variety of gadolinium and iohexol contrast agents. Protein expression levels of ER stress-associated chaperones (master regulator: GRP78/Bip and its copartners: Calnexin, Ero1, PDI, CHOP, IRE1α and PERK) were evaluated with Western blotting. Expression levels at mRNA level were also assessed for GRP78/Bip and CHOP with real-time PCR. Induction of cells was carried out with four different Gd-based contrast agents (GBCAs): (Dotarem, Optimark, Primovist and Gadovist) and two different iohexol agents (Omnipol, Omnipaque). CT contrast agents tested in the study did not result in significant ER stress in HEK293 cells. However, they do not seem to have theranostic potential in pancreas cancer through ER pathway. The potential efficiency of macrocyclic MRI contrast agents to provoke apoptosis via ER stress-associated chaperones in BxPC-3 cells lends credibility for their future theranostic use in pancreas cancer as long as undesired toxicity effects were carefully considered. ER stress markers and/or contrast agents seem to have promising potential to be translated into the clinical practice to manage pancreas cancer progression.

Indocyanine green and iohexol loaded hydroxyapatite in poly(L-lactide-co-caprolactone)-based composite for bimodal near-infrared fluorescence- and X-ray-based imaging.

This study aimed to develop material for multimodal imaging by means of X-ray and near-infrared containing FDA- and EMA-approved iohexol and indocyanine green (ICG). The mentioned contrast agents (CAs) are hydrophilic and amphiphilic, respectively, which creates difficulties in fabrication of functional polymeric composites for fiducial markers (FMs) with usage thereof. Therefore, this study exploited for the first time the possibility of enhancing the radiopacity and introduction of the NIR fluorescence of FMs by adsorption of the CAs on hydroxyapatite (HAp) nanoparticles. The particles were embedded in the poly(L-lactide-co-caprolactone) (P[LAcoCL]) matrix resulting in the composite material for bimodal near-infrared fluorescence- and X-ray-based imaging. The applied method of material preparation provided homogenous distribution of both CAs with high iohexol loading efficiency and improved fluorescence signal due to hindered ICG aggregation. The material possessed profound contrasting properties for both imaging modalities. Its stability was evaluated during in vitro experiments in phosphate-buffered saline (PBS) and foetal bovine serum (FBS) solutions. The addition of HAp nanoparticles had significant effect on the fluorescence signal. The X-ray radiopacity was stable within minimum 11 weeks, even though the addition of ICG contributed to a faster release of iohexol. The stiffness of the material was not affected by iohexol or ICG, but incorporation of HAp nanoparticles elevated the values of bending modulus by approximately 70%. Moreover, the performed cell study revealed that all tested materials were not cytotoxic. Thus, the developed material can be successfully used for fabrication of FMs.

Comparison of Diatrizoate and Iohexol for Patient Acceptance and Fecal-Tagging Performance in Noncathartic CT Colonography.

OBJECTIVE: The aim of this study was to compare diatrizoate and iohexol regarding patient acceptance and fecal-tagging performance in noncathartic computed tomography colonography. METHODS: This study enrolled 284 volunteers with fecal tagging by either diatrizoate or iohexol at an iodine concentration of 13.33 mg/mL and an iodine load of 24 g. Patient acceptance was rated on a 4-point scale of gastrointestinal discomfort. Two gastrointestinal radiologists jointly analyzed image quality, fecal-tagging density and homogeneity, and residual contrast agent in the small intestine. The results were compared by the generalized estimating equation method. RESULTS: Patient acceptance was comparable between the 2 groups (3.95 ± 0.22 vs 3.96 ± 0.20, P = 0.777). The diatrizoate group had less residual fluid and stool than the iohexol group ( P = 0.019, P = 0.004, respectively). There was no significant difference in colorectal distention, residual fluid, and stool tagging quality between the 2 groups (all P 's > 0.05). The mean 2-dimensional image quality score was 4.59 ± 0.68 with diatrizoate and 3.60 ± 1.14 with iohexol ( P < 0.001). The attenuation of tagged feces was 581 ± 66 HU with diatrizoate and 1038 ± 117 HU with iohexol ( P < 0.001). Residual contrast agent in the small intestine was assessed at 55.3% and 62.3% for the diatrizoate group and iohexol group, respectively ( P = 0.003). CONCLUSIONS: Compared with iohexol, diatrizoate had better image quality, proper fecal-tagging density, and more homogeneous tagging along with comparable excellent patient acceptance, and might be more suitable for fecal tagging in noncathartic computed tomography colonography.

Effect and mechanism of phosphate enhanced sulfite activation with cobalt ion for effective iohexol abatement.

Sulfate radical (SO4•-)-based advanced oxidation processes (AOPs) from sulfite activation have recently received attention for abatement of microorganic pollutants in the aquatic environments. Trace-level Co(II) has been demonstrated to be effective for promoting sulfite activation (simplified as the Co(II)/sulfite system) and the corresponding radical formation, yet this process is challenged by the limited valence inter-transformation of Co(II)/Co(III). In order to enhance this valence inter-transformation, a novel Co(II)/HPO42-/sulfite system is developed in this work, because HPO42-, as a typical radical scavenging agent, has the advantage of complexing with Co(II) without quenching effect. In this work, complexation of Co(II) with HPO42- can regulate the electronic structure of Co(II), accelerate electron transfer, and promote valence inter-transformation of Co(II)/Co(III) during the sulfite activation process. The Co(II)/HPO42-/sulfite system exhibits superior iohexol abatement performance under circumneutral conditions. For pH 8.0 and Co(II) dose of 1 µM, the iohexol abatement efficiency is as high as 98%, which is considerably higher than that of the Co(II)/sulfite system (50%). SO4•- is identified as the predominant reactive radical contributing to iohexol abatement. The presence of HPO42- broadens the pH adaptability of the Co(II)/sulfite system for iohexol abatement. In addition, the coexisting Cl- exerts an inhibitory effect on iohexol abatement while the other cations and anions show negligible effect. The Co(II)/HPO42-/sulfite system displays good reusability and adaptability towards various organic pollutants. This study highlights the important role of complexation of Co(II) with HPO42- in sulfite activation and provides a feasible idea for abatement of the microorganic pollutants.

Optical clearing of human skin: Molecular modeling and in vivo OCT study.

The results of in vivo immersion optical clearing of human skin under the action of two different optical clearing agents (OCAs), such as an aqueous sucrose solution and a radiographic contrast agent Omnipaque™ 300 (iohexol), were obtained with the use of optical coherence tomography (OCT) method. The rate of reduction of light scattering coefficient, obtained through an averaged A-scan of the OCT image in the region of dermis within the depths from 350 to 700 µm, were determined to evaluate the efficiency of optical clearing (EOC). The correlations between the EOC and the energy of intermolecular interaction of OCAs with a fragment of collagen peptide have been established as a result of molecular modeling by quantum chemistry methods HF/STO3G/DFT/B3LYP/6-311G(d) of a number of OCAs (glycerol, iohexol, sucrose, ribose, fructose, glucose) with mimetic peptide of collagen (GPH)3 .

Predictors of augmented renal clearance based on iohexol plasma clearance in critically ill children.

BACKGROUND: Augmented renal clearance (ARC) holds a risk of subtherapeutic drug concentrations. Knowledge of patient-, disease-, and therapy-related factors associated with ARC would allow predicting which patients would benefit from intensified dosing regimens. This study aimed to identify ARC predictors and to describe ARC time-course in critically ill children, using iohexol plasma clearance (CLiohexol) to measure glomerular filtration rate (GFR). METHODS: This is a retrospective analysis of data from the "IOHEXOL" study which validated GFR estimating formulas (eGFR) against CLiohexol. Critically ill children with normal serum creatinine were included, and CLiohexol was performed as soon as possible after pediatric intensive care unit (PICU) admission (CLiohexol1) and repeated (CLiohexol2) after 48-72 h whenever possible. ARC was defined as CLiohexol exceeding normal GFR for age plus two standard deviations. RESULTS: Eighty-five patients were included; 57% were postoperative patients. Median CLiohexol1 was 122 mL/min/1.73 m2 (IQR 75-152). Forty patients (47%) expressed ARC on CLiohexol1. Major surgery other than cardiac surgery and eGFR were found as independent predictors of ARC. An eGFR cut-off value of 99 mL/min/1.73 m2 and 140 mL/min/1.73 m2 was suggested to identify ARC in children under and above 2 years, respectively. ARC showed a tendency to persist on CLiohexol2. CONCLUSIONS: Our findings raise PICU clinician awareness about increased risk for ARC after major surgery and in patients with eGFR above age-specific thresholds. This knowledge enables identification of patients with an ARC risk profile who would potentially benefit from a dose increase at initiation of treatment to avoid underexposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179564, registered retrospectively on January 5, 2022.

Effects of Low-Osmolar Contrast Media on Long-Term Renal Impairment After Coronary Angiography: Iohexol Versus Iopromide.

To investigate the long-term effects of 2 commonly used low-osmolar contrast media, iohexol and iopromide, on renal function and survival in patients who underwent coronary angiography. A total of 14,141 cardiology patients from 2006 to 2013 were recruited, of whom 1,793 patients (679 patients on iohexol and 1,114 on iopromide) were evaluated for long-term renal impairment and 5,410 patients (1,679 patients on iohexol and 3,731 on iopromide) were admitted for survival analyses spanning as long as 15 years. Univariate and multivariate logistic regression were used to explore the risk factors for long-term renal impairment. Cox proportional hazard regression was used to investigate the risk factors affecting survival. Propensity score matching and inverse probability of treatment weighting were applied to balance the baseline clinical characteristics. Patients receiving iohexol demonstrated a greater occurrence of renal impairment compared with those who received iopromide. Such difference remained consistent both before and after propensity score matching or inverse probability of treatment weighting, with a statistical significance of p <0.05. Among clinical variables, receiving contrast-enhanced contrast tomography/magnetic resonance imaging during follow-up, antihypertensive medication usage, presence of proteinuria, and anemia were identified as risk factors for long-term renal impairment (p = 0.041, 0.049, 0.006, and 0.029, respectively). During survival analyses, the difference was insignificant after propensity score matching and inverse probability of treatment weighting. In conclusion, administration of iohexol was more likely to induce long-term renal impairment than iopromide, particularly among patients diagnosed with anemia and proteinuria and those taking antihypertensive medication and with additional contrast exposure. The all-cause mortality, however, showed no significant difference between iohexol and iopromide administration.

Structure-Based Drug Design for Targeting IRE1: An in Silico Approach for Treatment of Cancer.

BACKGROUND: Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a key role in cancer progression. The aggregation of incorrectly folded proteins in the ER generates ER stress, which in turn activates the UPR as an adaptive mechanism to fix ER proteostasis. Inositol-requiring enzyme 1 (IRE1) is the most evolutionary conserved ER stress sensor, which plays a pro-tumoral role in various cancers. Targeting its' active sites is one of the most practical approaches for the treatment of cancers. OBJECTIVE: In this study, we aimed to use the structure of 4µ8C as a template to produce newly designed compounds as IRE1 inhibitors. METHODS: Various functional groups were added to the 4µ8C, and their binding affinity to the target sites was assessed by conducting a covalent molecular docking study. The potential of the designed compound for further in vitro and in vivo studies was evaluated using ADMET analysis. RESULTS: Based on the obtained results, the addition of hydroxyl groups to 4µ8C enhanced the binding affinity of the designed compound to the target efficiently. Compound 17, which was constructed by the addition of one hydroxyl group to the structure of 4µ8C, can construct a strong covalent bond with Lys907. The outcomes of ADMET analysis indicated that compound 17 could be considered a drug-like molecule. CONCLUSION: Our results revealed that designed compound 17 could inhibit IRE1 activity. Therefore, this designed compound is a remarkable inhibitor of IRE1 and introduces a promising therapeutic strategy for cancer treatment.