Mechanical properties, cytotoxicity, and protein adsorption of three-dimensionally printable hybrid resin containing zwitterionic polymer and silicate-based composites for dental restorations.

OBJECTIVE: To evaluate the mechanical and biological properties of three-dimensionally (3D) printable resins filled with 2-methacryloyloxyethyl phosphorylcholine (MPC) and silicate-based composites and compare with those of a commercially available 3D-printable resin for definitive restorations. METHODS: A group of 3D-printable hybrid resins (HRs) filled with 6 wt% MPC and three different compositions of silicate-based composites (barium silicate to zirconium silicate ratios: 1.50:1 for HR1, 0.67:1 for HR2, and 0.25:1 for HR3) were prepared. The HR groups were compared with the commercially available unfilled 3D-printable resin (CR) marketed for definitive restorations in terms of flexural strength and modulus, fracture toughness, surface roughness, Vickers hardness, light transmittance (all, n = 15), cytotoxicity, and protein adsorption (both, n = 3). All data were analyzed by using non-parametric Kruskal-Wallis and Dunn's tests (α=0.05). RESULTS: The HR groups had significantly higher flexural strength, modulus, fracture toughness, and hardness values than the CR (P < 0.001). HR3 had the highest surface roughness and light transmittance among the groups (P ≤ 0.006). None of tested resins showed cytotoxicity. Both HR2 and HR3 showed significantly lower protein adsorption than the CR, with a difference of approximately 60% (P ≤ 0.026). CONCLUSION: Both HR2 and HR3 exhibited superior mechanical properties (flexural strength, flexural modulus, fracture toughness, and Vickers hardness), light transmittance, and protein-repellent activity than the CR, with no impact on cytotoxicity. CLINICAL SIGNIFICANCE: The MPC/silicate-based composite-filled resins may be a suitable alternative for definitive restorations, given their higher mechanical properties and promising biological properties to prevent microbial adhesion and subsequent biofilm formation, as well as their non-cytotoxic properties.

Effect of postpolymerization time and atmosphere on surface properties and biofilm formation in additively manufactured resins for definitive restorations.

OBJECTIVES: To investigate how postpolymerization time (PPT) and atmosphere (PPA) influence the surface properties, protein adsorption, and microbial adhesion of two types of additively manufactured (AM) resins used for definitive restorations. METHODS: Two different types of commercially available AM resins for definitive restorations (UR and CR) were used to create disk-shaped specimens. These specimens were divided into eight groups based on resin type (UR and CR), PPT (standard or extended), and PPA (air or nitrogen). After postpolymerization, the surface roughness (Ra and Sa) and surface free energy (SFE) of all specimens were measured. The study also evaluated protein adsorption, microbial attachment, and cytotoxicity. A non-parametric factorial analysis of variance with post-hoc analyses was conducted, using a significance level (α) of 0.05. RESULTS: The Ra and Sa values for CR were higher than those for UR, regardless of PPT or PPA (P < 0.05). For UR, SFE was higher with extended PPT compared to standard PPT. CR had higher SFE than UR under standard PPT. The interaction between PPT and PPA had a significant effect on protein adsorption (P < 0.05). When PPT was standard, nitrogen significantly increased protein adsorption compared to air. The interaction between resin type and PPA, and between resin type and PPT, significantly affected microbial adhesion (P < 0.05). The changes in PPT or PPA did not affect the cytotoxicity of either AM resin. CONCLUSION: Surface properties, protein adsorption, and microbial attachment were influenced by the interactions among PPT, PPA, and resin type. These factors can have implications for resin-based definitive restorations. CLINICAL SIGNIFICANCES: Clinicians should understand the impact of PPT and PPA on the surface properties of AM resins for definitive restorations, particularly regarding protein adsorption and microbial adhesion. Additionally, the type of AM resin (based on chemical composition) could affect its biological properties.

Effect of barium silicate on mechanical properties, transmittance, and protein adsorption of resin for additive manufacturing containing zwitterionic polymer.

STATEMENT OF PROBLEM: Studies on the effect of barium silicate on the material properties of additively manufactured (AM) resins containing 2-methacryloyloxyethyl phosphorylcholine (MPC) for dental applications are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the mechanical properties, transmittance, and protein adsorption of MPC-containing AM resin incorporated with different barium silicate contents and to compare these findings with those of a commercially available unfilled AM resin marketed for definitive restorations. MATERIAL AND METHODS: Resins incorporating 6 wt% MPC and 4 different concentrations of barium silicate (10 wt%, MB10; 20 wt%, MB20; 30 wt%, MB30; and 40 wt%, MB40) were prepared. An MPC-containing resin with no filler was also prepared (0 wt%, MBN). Surface roughness (n=15), Vickers hardness (n=15), flexural strength and modulus (n=15), fracture toughness (n=15), transmittance (n=15), and protein adsorption (n=3) of the filled resin specimens were measured and compared with those of commercially available unfilled resin specimens. All data were analyzed using the Kruskal-Wallis and Dunn tests (α=.05). RESULTS: All experimental resins had higher surface roughness than the unfilled resin (P≤.048). MB40 had higher hardness, flexural strength, flexural modulus, and fracture toughness than most other groups (P≤.047). MB10 had higher transmittance than most other groups (P≤.012). All experimental resins had lower protein adsorption than the unfilled resin, regardless of the barium silicate content (P≤.023). CONCLUSIONS: The experimental resin containing 6 wt% MPC and 40 wt% barium silicate showed better mechanical properties and lower protein adsorption than the resin with no MPC or ceramic fillers. Transmittance decreased with the increase of barium silicate in the resins.

Image segmentation of impacted mesiodens using deep learning.

This study aimed to evaluate the performance of deep learning algorithms for the classification and segmentation of impacted mesiodens in pediatric panoramic radiographs. A total of 850 panoramic radiographs of pediatric patients (aged 3-9 years) was included in this study. The U-Net semantic segmentation algorithm was applied for the detection and segmentation of mesiodens in the upper anterior region. For enhancement of the algorithm, pre-trained ResNet models were applied to the encoding path. The segmentation performance of the algorithm was tested using the Jaccard index and Dice coefficient. The diagnostic accuracy, precision, recall, F1-score and time to diagnosis of the algorithms were compared with those of human expert groups using the test dataset. Cohen's kappa statistics were compared between the model and human groups. The segmentation model exhibited a high Jaccard index and Dice coefficient (>90%). In mesiodens diagnosis, the trained model achieved 91-92% accuracy and a 94-95% F1-score, which were comparable with human expert group results (96%). The diagnostic duration of the deep learning model was 7.5 seconds, which was significantly faster in mesiodens detection compared to human groups. The agreement between the deep learning model and human experts is moderate (Cohen's kappa = 0.767). The proposed deep learning algorithm showed good segmentation performance and approached the performance of human experts in the diagnosis of mesiodens, with a significantly faster diagnosis time.

Photoluminescence of MoS2 on Plasmonic Gold Nanoparticles Depending on the Aggregate Size.

Transition metal dichalcogenides (TMDs) are promising candidates for ultrathin functional semiconductor devices. In particular, incorporating plasmonic nanoparticles into TMD-based devices enhances the light-matter interaction for increased absorption efficiency and enables control of device performance such as electronic, electrical, and optical properties. In this heterohybrid structure, manipulating the number of TMD layers and the aggregate size of plasmonic nanoparticles is a straightforward approach to tailoring device performance. In this study, we use photoluminescence (PL) spectroscopy, which is a commonly employed technique for monitoring device performance, to analyze the changes in electronic and optical properties depending on the number of MoS2 layers and the size of the gold nanoparticle (AuNP) aggregate under nonresonant and resonant excitation conditions. The PL intensity in monolayer MoS2/AuNPs increases as the size of aggregates increases irrespective of the excitation conditions. The strain induced by AuNPs causes a red shift, but as the aggregates grow larger, the effect of p-doping increases and the blue shift becomes prominent. In multilayer MoS2/AuNPs, quenched PL intensity is observed under nonresonant excitation, while enhancement is noted under resonant excitation, which is mainly contributed by p-doping and LSPR, respectively. Remarkably, the alteration in the spectral shape due to resonant excitation is evident solely in small aggregates of AuNPs across all layers.

Color stability and translucency of newly developed composites for splinting teeth.

This study aimed to investigate the colorimetric properties of newly developed composites for dental trauma splints using various staining solutions during the clinical splinting period. The clear shades of G-Fix (GF), Ortho Connect Flow (OC), Light Fix (LF), and Filtek Z350XT (FZ) were fabricated into 96 disk-shaped specimens. Specimens from each composite group were stored in distilled water, coffee, tea, and red wine solutions at 37ºC. CIE values were measured using a spectrophotometer at 24 h after specimen preparation and at 1 day, 1 week, 2 weeks, 3 weeks, and 4 weeks after storage in each solution. Color differences and translucency parameters were calculated using the initial and measured values. Within the experiment period, the color differences of GF, OC, and LF compared to the initial measurement were smaller than that for FZ for all staining solutions except distilled water. There were no significant color differences between the GF, OC, and LF groups.

Fully automated deep learning approach to dental development assessment in panoramic radiographs.

BACKGROUND: Dental development assessment is an important factor in dental age estimation and dental maturity evaluation. This study aimed to develop and evaluate the performance of an automated dental development staging system based on Demirjian's method using deep learning. METHODS: The study included 5133 anonymous panoramic radiographs obtained from the Department of Pediatric Dentistry database at Seoul National University Dental Hospital between 2020 and 2021. The proposed methodology involves a three-step procedure for dental staging: detection, segmentation, and classification. The panoramic data were randomly divided into training and validating sets (8:2), and YOLOv5, U-Net, and EfficientNet were trained and employed for each stage. The models' performance, along with the Grad-CAM analysis of EfficientNet, was evaluated. RESULTS: The mean average precision (mAP) was 0.995 for detection, and the segmentation achieved an accuracy of 0.978. The classification performance showed F1 scores of 69.23, 80.67, 84.97, and 90.81 for the Incisor, Canine, Premolar, and Molar models, respectively. In the Grad-CAM analysis, the classification model focused on the apical portion of the developing tooth, a crucial feature for staging according to Demirjian's method. CONCLUSIONS: These results indicate that the proposed deep learning approach for automated dental staging can serve as a supportive tool for dentists, facilitating rapid and objective dental age estimation and dental maturity evaluation.

Paroxysmal dystonia results from the loss of RIM4 in Purkinje cells.

Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell-type specific role in cerebellar Purkinje cells that is essential for normal motor function. In the absence of RIM4, Purkinje cell intrinsic firing is reduced and caffeine-sensitive, and dendritic integration of climbing fibre input is disturbed. Mice lacking RIM4, but not mice lacking RIM1/2, selectively in Purkinje cells exhibit a severe, hours-long paroxysmal dystonia. These episodes can also be induced by caffeine, ethanol or stress and closely resemble the deficits seen with mutations of the PNKD (paroxysmal non-kinesigenic dystonia) gene. Our data reveal essential postsynaptic functions of RIM proteins and show non-overlapping specialized functions of a small isoform despite high homology to a single domain in the full-length proteins.

Correlation between dental and skeletal maturity in Korean children based on dental maturity percentile: a retrospective study.

BACKGROUND: The correlation between dental maturity and skeletal maturity has been proposed, but its clinical application remains challenging. Moreover, the varying correlations observed in different studies indicate the necessity for research tailored to specific populations. AIM: To compare skeletal maturity in Korean children with advanced and delayed dental maturity using dental maturity percentile. DESIGN: Dental panoramic radiographs and cephalometric radiographs were obtained from 5133 and 395 healthy Korean children aged between 4 and 16 years old. Dental maturity was assessed with Demirjian's method, while skeletal maturity was assessed with the cervical vertebral maturation method. Standard percentile curves were developed through quantile regression. Advanced (93 boys and 110 girls) and delayed (92 boys and 100 girls) dental maturity groups were defined by the 50th percentile. RESULTS: The advanced group showed earlier skeletal maturity in multiple cervical stages (CS) in both boys (CS 1, 2, 3, 4, and 6) and girls (CS 1, 3, 4, 5, and 6). Significant differences, as determined by Mann-Whitney U tests, were observed in CS 1 for boys (p = 0.004) and in CS 4 for girls (p = 0.037). High Spearman correlation coefficients between dental maturity and cervical vertebral maturity exceeded 0.826 (p = 0.000) in all groups. CONCLUSION: A correlation between dental and skeletal maturity, as well as advanced skeletal maturity in the advanced dental maturity group, was observed. Using percentile curves to determine dental maturity may aid in assessing skeletal maturity, with potential applications in orthodontic diagnosis and treatment planning.

Non-Electroconductive Polymer Coating on Graphite Mitigating Electrochemical Degradation of PTFE for a Dry-Processed Lithium-Ion Battery Anode.

Polytetrafluoroethylene (PTFE)-based dry process for lithium-ion batteries is gaining attention as a battery manufacturing scheme can be simplified with drastically reducing environmental damage. However, the electrochemical instability of PTFE in a reducing environment has hampered the realization of the high-performance dry-processed anode. In this study, we present a non-electroconductive and highly ionic-conductive polymer coating on graphite to mitigate the electrochemical degradation of the PTFE binder and minimize the coating resistance. Poly(ethylene oxide) (PEO) and poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) (P(VDF-TrFE-CFE)) coatings on the anode material effectively inhibit the electron transfer from graphite to PTFE, thereby alleviating the PTFE breakdown. The graphite polymer coatings improved initial Coulombic efficiencies of full cells from 67.2% (bare) to 79.1% (PEO) and 77.8% (P(VDF-TrFE-CFE)) and increased initial discharge capacity from 157.7 mAh g(NCM)-1 (bare) to 185.1 mAh g(NCM)-1 (PEO) and 182.5 mAh g(NCM)-1 (P(VDF-TrFE-CFE)) in the full cells. These outcomes demonstrate that PTFE degradation in the anode can be surmounted by adjusting the electron transfer to the PTFE.

Neighbor List Artifacts in Molecular Dynamics Simulations.

Molecular dynamics (MD) simulations are widely used in biophysical research. To aid nonexpert users, most simulation packages provide default values for key input parameters. In MD simulations using the GROMACS package with default parameters, we found large membranes to deform under the action of a semi-isotropically coupled barostat. As the primary cause, we identified overly short outer cutoffs and infrequent neighbor list updates that resulted in missed nonbonded interactions. Small but systematic imbalances in the apparent pressure tensor then induce unphysical asymmetric box deformations that crumple the membrane. We also observed rapid oscillations in averages of the instantaneous pressure tensor components and traced these to the use of a dual pair list with dynamic pruning. We confirmed that similar effects are present in MD simulations of neat water in atomistic and coarse-grained representations. Whereas the slight pressure imbalances likely have minimal impact in most current atomistic MD simulations, we expect their impact to grow in studies of ever-larger systems with coarse-grained representation, in particular, in combination with anisotropic pressure coupling. We present measures to diagnose problems with missed interactions and guidelines for practitioners to avoid them, including estimates for appropriate values for the outer cutoff rl and the number of time steps nstlist between neighbor list updates.

The microRNA-mediated gene regulatory network in the hippocampus and hypothalamus of the aging mouse.

Aging leads to time-dependent functional decline of all major organs. In particular, the aging brain is prone to cognitive decline and several neurodegenerative diseases. Various studies have attempted to understand the aging process and underlying molecular mechanisms by monitoring changes in gene expression in the aging mouse brain using high-throughput sequencing techniques. However, the effect of microRNA (miRNA) on the post-transcriptional regulation of gene expression has not yet been comprehensively investigated. In this study, we performed global analysis of mRNA and miRNA expression simultaneously in the hypothalamus and hippocampus of young and aged mice. We identified aging-dependent differentially expressed genes, most of which were specific either to the hypothalamus or hippocampus. However, genes related to immune response-related pathways were enriched in upregulated differentially expressed genes, whereas genes related to metabolism-related pathways were enriched in downregulated differentially expressed genes in both regions of the aging brain. Furthermore, we identified many differentially expressed miRNAs, including three that were upregulated and three that were downregulated in both the hypothalamus and hippocampus. The two downregulated miRNAs, miR-322-3p, miR-542-3p, and the upregulated protein-encoding coding gene C4b form a regulatory network involved in complement and coagulation cascade pathways in the hypothalamus and hippocampus of the aging brain. These results advance our understanding of the miRNA-mediated gene regulatory network and its influence on signaling pathways in the hypothalamus and hippocampus of the aging mouse brain.

Histology and morphometry of the skin of purple spaghetti-eel Moringua raitaborua (Anguilliformes, Moringuidae).

The purple spaghetti-eel Moringua raitaborua lives on the sandy or muddy bottoms of estuaries, which are subject to rapid and wide changes in salinity, pH, and osmoregulatory and hypoxic conditions due to the influx of organic materials from sources of freshwater. The species has adapted to hypoxic environments by developing a thicker epidermis with stratified polygonal cells, club cells, two types of mucous cells (goblet and, oval cells), stratified cuboidal cells and dermis with abundant blood capillaries. Among them, histological modification of thinner dorsal, lateral, and ventral body skin to include abundant capillaries and well-developed dermal vascularization may provide cutaneous respiration, permitting survival in brackish waters with low levels of oxygen and variable environmental parameters.

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase.

Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression. SIGNIFICANCE: The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.

Criteria for early diagnosis of mandibular third molar agenesis based on the developmental stages of mandibular canine, first and second premolars, and second molar: a retrospective cohort study.

BACKGROUND: Permanent first molars with severe dental caries, developmental defects, or involved in oral pathologies are at risk of poor prognosis in children. Accordingly, using the third molar to replace the first molar can be a good treatment option when third molar agenesis is predicted early. Thus, this retrospective cohort study aimed to develop criteria for early detection of mandibular third molar (L8) agenesis based on the developmental stages of mandibular canine (L3), first premolar (L4), second premolar (L5), and second molar (L7). METHOD: Overall, 1,044 and 919 panoramic radiographs of 343 males and 317 females, respectively, taken between the ages of 6 and 12 years were included. All developmental stages of L3, L4, L5, L7, and L8 were analyzed based on the dental age, as suggested by Demirjian et al. The independent t-test was used to assess age differences between males and females. The rank correlation coefficients were examined using Kendall's tau with bootstrap analysis and Bonferroni's correction to confirm the teeth showing developmental stages most similar to those of L8s. Finally, a survival analysis was performed to determine the criteria for the early diagnosis of mandibular third molar agenesis. RESULTS: Some age differences were found in dental developmental stages between males and females. Correlation coefficients between all stages of L3, L4, L5, and L7 and L8 were high. In particular, the correlation coefficient between L7 and L8 was the highest, whereas that between L3 and L8 was the lowest. CONCLUSION: If at least two of the following criteria (F stage of L3, F stage of L4, F stage of L5, and E stage of L7) are met in the absence of L8 crypt, agenesis of L8 can be confirmed.

Rationally Designed Solution-Processible Conductive Carbon Additive Coating for Sulfide-based All-Solid-State Batteries.

Sulfide-based all-solid-state batteries (ASSBs) have emerged as promising candidates for next-generation energy storage systems owing to their superior safety and energy density. A conductive agent is necessarily added in the cathode composite of ASSBs to facilitate electron transport therein, but it causes the decomposition of the solid electrolyte and ultimately the shortening of lifetime. To resolve this dilemmatic situation, herein, we report a rationally designed solution-processible coating of zinc oxide (ZnO) onto vapor-grown carbon fiber as a conductive agent to reduce the contact between the carbon additive and the solid electrolyte and still maintain electron pathways to the active material. ASSBs with the carbon additive with an optimal coating of ZnO have markedly improved cycling performance and rate capability compared to those with the bare conductive agent, which can be attributed to hindering the decomposition of the solid electrolytes. The results highlight the usefulness of controlling the interparticle contacts in the composite cathodes in addressing the challenging interfacial degradation of sulfide-based ASSBs and improving their key electrochemical properties.

Nutrition and Theriogenology: A Glimpse Into Nutrition and Nutritional Supplementation During Gestation, Lactation, Weaning and Breeding Dogs and Cats.

Feeding during normal reproduction is often not thought of until there is a problem with conception or gestational losses. Energy demands of lactation and early puppy/kitten are of concern, particularly in large and giant breed dogs where mineral balance is crucial to normal development. There is a paucity of information around optimizing feeding during conception and gestation with many myths around ingredients which will be explored in this article along with supplements that may be able to support spermatogenesis and conception which primarily comes from the human literature and may have validity in times of difficult conception.

Carbamate JNK3 Inhibitors Show Promise as Effective Treatments for Alzheimer's Disease: In Vivo Studies on Mouse Models.

We have been developing new inhibitors for c-Jun N-terminal kinase 3 (JNK3) as a potential treatment for Alzheimer's disease (AD). We identified potential JNK3 inhibitors through pharmacodynamic optimization studies, including benzimidazole compounds 2 and 3, but their unreliable pharmacokinetic properties led us to develop carbamate inhibitors 2h and 3h. In vitro studies validated carbamate inhibitors 2h and 3h as potent and highly selective JNK3 inhibitors with favorable pharmacokinetic profiles. Oral administration of 2h and 3h to both APP/PS1 and 3xTg AD mouse models improved cognitive function, indicating their potential as effective treatments for Alzheimer's disease. Carbamate JNK3 inhibitor 3h, in particular, restored cognitive function to near-normal levels in the 3xTg mice model of AD and led to pTau reduction in the hippocampal tissues of 3xTg-AD mice during in vivo behavioral evaluations. We intend to further develop these carbamate JNK3 inhibitors in preclinical studies as a potential first-in-class treatment for AD.

Graph approaches for analysis of brain connectivity during dexmedetomidine sedation.

Sedation is commonly used to relieve fear and anxiety during procedures. Dexmedetomidine (DEX), approved by the US Food and Drug Administration in 1999 for short-term sedation, is a selective alpha2-adrenoreceptor agonist. The use of DEX is increasing due to minimal respiratory depression and easy and quick awakening from sedation. Its sedative mechanisms are suggested to be related to changes in the interaction between brain regions. In this study, we used graph theory to investigate whether the altered network connection is associated with sedation. Electroencephalogram (EEG) recordings of 32 channels were acquired during awake and DEX-induced sedation for 20 participants. We extracted EEG epochs from the awake and the DEX sedation state. Using the graph theory, we compared the changes in the network connection parameters with the awake state. We observed that the slopes in 1/f dynamics, which indicate overall brain network characteristics, were greater during DEX-induced sedation compared to the awake state, suggesting a transition towards a random network behavior. In addition, network connections from the perspective of information processing were significantly disturbed in the alpha frequency band, unlike other frequency bands augmenting network connections. The alpha frequency band plays a prominent role in the function and interaction of cognitive activities. These results collectively indicate that changes in the brain network critical to cognition during DEX administration may also be related to the mechanism of sedation.

Structural optimization of novel Ras modulator for treatment of Colorectal cancer by promoting ß-catenin and Ras degradation.

Ras protein has been considered a fascinating target for anticancer therapy because its malfunction is closely related to cancer. However, Ras has been considered undruggable because of the failure to regulate its malfunction by controlling the Ras activation mechanism. Recently, Lumakras targeting the G12C mutation was approved, and therapeutic interest in Ras for anticancer therapy has been rejuvenated. Here, we present a series of compounds that inhibit Ras via a unique mechanism of action that exploits the relationship between the Wnt/ß-catenin pathway and Ras. KYA1797K (1) binds to axin to stabilize the ß-catenin destruction complex that causes the phosphorylation and subsequent degradation of Ras, similar to canonical ß-catenin regulation. Based on the chemical structure of 1, we performed a structural optimization and identified 3-(2-hydroxyethyl)-5-((6-(4-nitrophenyl)pyridin-2-yl)methylene)thiazolidine-2,4-dione (13d) as the most potent compound. 13d displayed antitumor effects in a colorectal cancer model with enhanced inhibition activity on Ras. The results of this study suggest that the further development of 13d could contribute to the development of Ras inhibitors with novel mechanisms of action.