Atomic-Layer IrOx Enabling Ligand Effect Boosts Water Oxidation Electrocatalysis.

An in situ formed IrOx (x ≤ 2) layer driven by anodic bias serves as the essential active site of Ir-based materials for oxygen evolution reaction (OER) electrocatalysis. Once being confined to atomic thickness, such an IrOx layer possesses both a favorable ligand effect and maximized active Ir sites with a lower O-coordination number. However, limited by a poor understanding of surface reconstruction dynamics, obtaining atomic layers of IrOx remains experimentally challenging. Herein, we report an idea of material design using intermetallic IrVMn nanoparticles to induce in situ formation of an ultrathin IrOx layer (O-IrVMn/IrOx) to enable the ligand effect for achieving superior OER electrocatalysis. Theoretical calculations predict that a strong electronic interaction originating from an orderly atomic arrangement can effectively hamper the excessive leaching of transition metals, minimizing vacancies for oxygen coordination. Linear X-ray absorption near edge spectra analysis, extended X-ray absorption fine structure fitting outcomes, and X-ray photoelectron spectroscopy collectively confirm that Ir is present in lower oxidation states in O-IrVMn/IrOx due to the presence of unsaturated O-coordination. Consequently, the O-IrVMn/IrOx delivers excellent acidic OER performances with an overpotential of only 279 mV at 10 mA cm-2 and a high mass activity of 2.3 A mg-1 at 1.53 V (vs RHE), exceeding most Ir-based catalysts reported. Moreover, O-IrVMn/IrOx also showed excellent catalytic stability with only 0.05 at. % Ir dissolution under electrochemical oxidation, much lower than that of disordered D-IrVMn/IrOx (0.20 at. %). Density functional theory calculations unravel that the intensified ligand effect optimizes the adsorption energies of multiple intermediates involved in the OER and stabilizes the as-formed catalytic IrOx layer.

A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway.

Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

Fourier-Based Frequency Space Disentanglement and Augmentation for Generalizable Face Anti-Spoofing.

Generalizing face anti-spoofing (FAS) models to unseen distributions is challenging due to domain shifts. Previous domain generalization (DG) based FAS methods focus on learning invariant features across domains in the spatial space, which may be ineffective in detecting subtle spoof patterns. In this paper, we propose a novel approach called Frequency Space Disentanglement and Augmentation (FSDA) for generalizable FAS. Specifically, we leverage Fourier transformation to analyze face images in the frequency space, where the amplitude spectrum captures low-level texture information that forms distinct visual appearances, and the phase spectrum corresponds to the content information. We hypothesize that the liveness of a face is more related to these low-level patterns rather than high-level content information. To locate spoof traces, we disentangle the amplitude spectrum into domain-related and spoof-related components using either empirical or learnable strategies. We then propose a frequency space augmentation technique that mixes the disentangled components of two images to synthesize new variations. By imposing a distillation loss and a consistency loss on the augmented samples, our model learns to capture spoof patterns that are robust to both domain and spoof type variations. Extensive experiments on four FAS datasets demonstrate the superiority of our method in improving the generalization ability of FAS models in various unseen scenarios.

Lanthanide-regulating Ru-O covalency optimizes acidic oxygen evolution electrocatalysis.

Precisely modulating the Ru-O covalency in RuOx for enhanced stability in proton exchange membrane water electrolysis is highly desired. However, transition metals with d-valence electrons, which were doped into or alloyed with RuOx, are inherently susceptible to the influence of coordination environment, making it challenging to modulate the Ru-O covalency in a precise and continuous manner. Here, we first deduce that the introduction of lanthanide with gradually changing electronic configurations can continuously modulate the Ru-O covalency owing to the shielding effect of 5s/5p orbitals. Theoretical calculations confirm that the durability of Ln-RuOx following a volcanic trend as a function of Ru-O covalency. Among various Ln-RuOx, Er-RuOx is identified as the optimal catalyst and possesses a stability 35.5 times higher than that of RuO2. Particularly, the Er-RuOx-based device requires only 1.837 V to reach 3 A cm-2 and shows a long-term stability at 500 mA cm-2 for 100 h with a degradation rate of mere 37 µV h-1.

Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents.

To discover new Werner (WRN) helicase inhibitors, a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives were designed and synthesized through a structural optimization strategy, and the anticancer activities of 25 new target compounds against PC3, K562, and HeLa cell lines were evaluated by the MTT assay. Some of these compounds exhibited excellent inhibitory activity against three different cancer cell lines. Compounds 6a, 8i, and 13a showed better antiproliferative activity against K562 cells, with IC50 values of 3871.5, 613.6 and 134.7 nM, respectively, than did paclitaxel (35.6 nM), doxorubicin (2689.0 nM), and NSC 617145 (20.3 nM). To further verify whether the antiproliferative activity of these compounds is dependent on WRN, PC3 cells overexpressing WRN (PC3-WRN) were constructed to further study their antiproliferative potency in vitro, and the inhibition ratio and IC20 values showed that compounds 6a, 8i, and 13a were more sensitive to PC3-WRN than were the control group cells (PC3-NC). The IC20 ratios of compounds 6a, 8i, and 13a to PC3-NC and PC3-WRN were 94.3, 153.4 and 505.5, respectively. According to the docking results, the compounds 6a, 8i, and 13a overlapped well with the binding pocket of 6YHR. Further study demonstrated that among the tested compounds, 13a was the most sensitive to PC3-WRN. In summary, our research identified a series of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential WRN-dependent anticancer agents.

Psychological factors enhanced heterogeneous learning interactive graph knowledge tracing for understanding the learning process.

Introduction: With the rapid expansion of online education, there is a burgeoning interest within the EdTech space to offer tailored learning experiences that cater to individual student's abilities and needs. Within this framework, knowledge tracing tasks have garnered considerable attention. The primary objective of knowledge tracing is to develop a model that assesses a student's proficiency in a particular skill based on their historical performance in exercises, enabling predictions regarding the likelihood of correct responses in future exercises. While existing knowledge tracing models often incorporate information such as students' exercise answering history and skill mastery level, they frequently overlook the students' mental states during the learning process. Methods: This paper addresses this gap by introducing a novel psychological factors-enhanced heterogeneous learning interactive graph knowledge tracing model (Psy-KT). This model delineates the interactions among students, exercises, and skills through a heterogeneous graph, supplementing it with four psychological factors that capture students' mental states during the learning process: frustration level, confusion level, concentration level, and boredom level. In the modeling of students' learning processes, we incorporate the forgetting curve and construct relevant cognitive parameters from the features. Additionally, we employ the Item Response Theory (IRT) model to predict students' performance in answering exercises at the subsequent time step. This model not only delves into the psychological aspects of students during the learning process but also integrates the simulation of forgetting, a natural phenomenon in the learning journey. The inclusion of cognitive parameters enhances the description of changes in students' abilities throughout the learning process. This dual focus allows for a more comprehensive understanding of students' learning behaviors while providing a high level of interpretability for the model. Results and discussion: Empirical validation of the Psy-KT model is conducted using four publicly available datasets, demonstrating its superior performance in predicting students' future performance. Through rigorous experimentation, the integration of psychological and forgetting factors in the Psy-KT model not only improves predictive accuracy but also enables educators to offer more targeted tutoring and advice, enhancing the overall efficacy of the learning experience.

Effects of geopolitical risk on environmental sustainability and the moderating role of environmental policy stringency.

This study investigates the impact of geopolitical risk (GPR) on consumption-based carbon (CCO2) emissions as well as the moderating role of environmental policy stringency (EPS) on the above relationship. Based on data collected from 27 countries from 1990 to 2020, the basic results from the sample of the study indicate that GPR accelerates CCO2 emissions. Quantile regression results reveal that the effect of GPR is more pronounced in countries with higher CCO2 emissions. Moreover, EPS weakens the escalating effect of GPR on CCO2 emissions. The robust test results validate the findings reported in the basic regression model. The heterogeneity test indicates that the impact of GPR on CCO2 emissions is greater in developing countries compared in developed countries. The study also proposes these policy implications based on the findings: (1) countries should ensure a stable political environment, establish a robust legal system and promote energy transition; and (2) the scope of environmental taxes should be expanded where different tax rates should be imposed in order to be useful in reducing CCO2 emissions.

Synaptotagmins family affect glucose transport in retinal pigment epithelial cells through their ubiquitination-mediated degradation and glucose transporter-1 regulation.

BACKGROUND: Synaptotagmins (SYTs) are a family of 17 membrane transporters that function as calcium ion sensors during the release of Ca2+-dependent neurotransmitters and hormones. However, few studies have reported whether members of the SYT family play a role in glucose uptake in diabetic retinopathy (DR) through Ca2+/glucose transporter-1 (GLUT1) and the possible regulatory mechanism of SYTs. AIM: To elucidate the role of the SYT family in the regulation of glucose transport in retinal pigment epithelial cells and explore its potential as a therapeutic target for the clinical management of DR. METHODS: DR was induced by streptozotocin in C57BL/6J mice and by high glucose medium in human retinal pigment epithelial cells (ARPE-19). Bioinformatics analysis, reverse transcriptase-polymerase chain reaction, Western blot, flow cytometry, ELISA, HE staining, and TUNEL staining were used for analysis. RESULTS: Six differentially expressed proteins (SYT2, SYT3, SYT4, SYT7, SYT11, and SYT13) were found between the DR and control groups, and SYT4 was highly expressed. Hyperglycemia induces SYT4 overexpression, manipulates Ca2+ influx to induce GLUT1 fusion with the plasma membrane, promotes abnormal expression of the glucose transporter GLUT1 and excessive glucose uptake, induces ARPE-19 cell apoptosis, and promotes DR progression. Parkin deficiency inhibits the proteasomal degradation of SYT4 in DR, resulting in SYT4 accumulation and enhanced GLUT1 fusion with the plasma membrane, and these effects were blocked by oe-Parkin treatment. Moreover, dysregulation of the myelin transcription factor 1 (Myt1)-induced transcription of SYT4 in DR further activated the SYT4-mediated stimulus-secretion coupling process, and this process was inhibited in the oe-MYT1-treated group. CONCLUSION: Our study reveals the key role of SYT4 in regulating glucose transport in retinal pigment epithelial cells during the pathogenesis of DR and the underlying mechanism and suggests potential therapeutic targets for clinical DR.

Sub-2 nm Microstrained High-Entropy-Alloy Nanoparticles Boost Hydrogen Electrocatalysis.

High-entropy alloys (HEAs) confine multifarious elements into the same lattice, leading to intense lattice distortion effect. The lattice distortion tends to induce local microstrain at atomic level and thus affect surface adsorptions toward different adsorbates in various electrocatalytic reactions, yet remains unexplored. Herein, this work reports a class of sub-2 nm IrRuRhMoW HEA nanoparticles (NPs) with distinct local microstrain induced by lattice distortion for boosting alkaline hydrogen oxidation (HOR) and evolution reactions (HER). This work demonstrates that the distortion-rich HEA catalysts with optimized electronic structure can downshift the d-band center and generate uncoordinated oxygen sites to enhance the surface oxophilicity. As a result, the IrRuRhMoW HEA NPs show a remarkable HOR kinetic current density of 8.09 mA µg-1 PGM at 50 mV versus RHE, 8.89, 22.47 times higher than those of IrRuRh NPs without internal strain and commercial Pt/C, respectively, which is the best value among all the reported non-Pt based catalysts. IrRuRhMoW HEA NPs also display great HER performances with a turnover frequency (TOF) value of 5.93 H2 s-1 at 70 mV versus RHE, 4.6-fold higher than that of Pt/C catalyst, exceeding most noble metal-based catalysts. Experimental characterizations and theoretical studies collectively confirm that weakened hydrogen (Had) and enhanced hydroxyl (OHad) adsorption are achieved by simultaneously modulating the hydrogen adsorption binding energy and surface oxophilicity originated from intensified ligand effect and microstrain effect over IrRuRhMoW HEA NPs, which guarantees the remarkable performances toward HOR/HER.

Ultrasonic-Assisted Extraction of Dictyophora rubrovolvata Volva Proteins: Process Optimization, Structural Characterization, Intermolecular Forces, and Functional Properties.

Dictyophora rubrovolvata volva, an agricultural by-product, is often directly discarded resulting in environmental pollution and waste of the proteins' resources. In this study, D. rubrovolvata volva proteins (DRVPs) were recovered using the ultrasound-assisted extraction (UAE) method. Based on one-way tests, orthogonal tests were conducted to identify the effects of the material-liquid ratio, pH, extraction time, and ultrasonic power on the extraction rate of DRVPs. Moreover, the impact of UAE on the physicochemical properties, structure characteristics, intermolecular forces, and functional attributes of DRVPs were also examined. The maximum protein extraction rate was achieved at 43.34% under the best extraction conditions of UAE (1:20 g/mL, pH 11, 25 min, and 550 W). UAE significantly altered proteins' morphology and molecular size compared to the conventional alkaline method. Furthermore, while UAE did not affect the primary structure, it dramatically changed the secondary and tertiary structure of DRVPs. Approximately 13.42% of the compact secondary structures (α-helices and ß-sheets) underwent a transition to looser structures (ß-turns and random coils), resulting in the exposure of hydrophobic groups previously concealed within the molecule's core. In addition, the driving forces maintaining and stabilizing the sonicated protein aggregates mainly involved hydrophobic forces, disulfide bonding, and hydrogen bonding interactions. Under specific pH and temperature conditions, the water holding capacity, oil holding capacity, foaming capacity and stability, emulsion activity, and stability of UAE increased significantly from 2.01 g/g to 2.52 g/g, 3.90 g/g to 5.53 g/g, 92.56% to 111.90%, 58.97% to 89.36%, 13.85% to 15.37%, and 100.22% to 136.53%, respectively, compared to conventional alkali extraction. The findings contributed to a new approach for the high-value utilization of agricultural waste from D. rubrovolvata.

Di-n-butyl phthalate induces toxicity in male fetal mouse testicular development by regulating the MAPK signaling pathway.

"White pollution" has a significant impact on male reproduction. Di-n-butyl phthalate (DBP) is one of the most important factors in this type of pollution. Currently, research from international sources has demonstrated the significant reproductive toxicity of DBP. However, most of these studies have focused mainly on hormones expression at the protein and mRNA levels and the specific molecular targets of DBP and its mechanisms of action remain unclear. In this study, we established a Sprague Dawley pregnant mouse model exposed to DBP, and all male offspring were immediately euthanized at birth and bilateral testes were collected. We found through transcriptome sequencing that cell apoptosis and MAPK signaling pathway are the main potential pathways for DBP induced reproductive toxicity. Molecular biology analyses revealed a significant increase in the protein levels of JNK1(MAPK8) and BAX, as well as a significant increase in the BAX/BCL2 ratio after DBP exposure. Therefore, we propose that DBP induces reproductive toxicity by regulating JNK1 expression to activate the MAPK signaling pathway and induce reproductive cell apoptosis. In conclusion, our study provides the first evidence that the MAPK signaling pathway is involved in DBP-induced reproductive toxicity and highlights the importance of JNK1 as a potential target of DBP in inducing reproductive toxicity.

A novel α,ß-unsaturated ketone inhibits leukemia cell growth as PARP1 inhibitor.

Leukemia is a malignant disease of the hematopoietic system, in which clonal leukemia cells accumulate and inhibit normal hematopoiesis in the bone marrow and other hematopoietic tissues as a result of uncontrolled proliferation and impaired apoptosis, among other mechanisms. In this study, the anti-leukemic effect of a compound (SGP-17-S) extracted from Chloranthus multistachys, a plant with anti-inflammatory, antibacterial and anti-tumor effects, was evaluated. The effect of SGP-17-S on the viability of leukemic cell was demonstrated by MTT assay, cell cycle, and apoptosis were assessed by flow cytometry using PI staining and Annexin V/PI double staining. Combinations of network pharmacology and cellular thermal shift assay (CETSA) with western blot were used to validate agents that act on leukemia targets. The results showed that SGP-17-S inhibited the growth of leukemia cells in a time- and dose-dependent manner. SGP-17-S blocked HEL cells in the G2 phase, induced apoptosis, decreased Bcl-2 and caspase-8 protein expression, and increased Bax and caspase-3 expression. In addition, CETSA revealed that PARP1 is an important target gene for the inhibition of HEL cell growth, and SGP-17-S exerted its action on leukemia cells by targeting PARP1. Therefore, this study might provide new solutions and ideas for the treatment of leukemia.

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Derivatives Possessing a Trifluoromethyl Moiety as Potential Antitumor Agents.

A novel series of trifluoromethyl-containing quinazoline derivatives with a variety of functional groups was designed, synthesized, and tested for their antitumor activity by following a pharmacophore hybridization strategy. Most of the 20 compounds displayed moderate to excellent antiproliferative activity against five different cell lines (PC3, LNCaP, K562, HeLa, and A549). After three rounds of screening and structural optimization, compound 10 b was identified as the most potent one, with IC50 values of 3.02, 3.45, and 3.98 µM against PC3, LNCaP, and K562 cells, respectively, which were comparable to the effect of the positive control gefitinib. To further explore the mechanism of action of 10 b against cancer, experiments focusing on apoptosis induction, cell cycle arrest, and cell migration assay were conducted. The results showed that 10 b was able to induce apoptosis and prevent tumor cell migration, but had no effect on the cell cycle of tumor cells.

Promoting mental health in children and adolescents through digital technology: a systematic review and meta-analysis.

Background: The increasing prevalence of mental health issues among children and adolescents has prompted a growing number of researchers and practitioners to explore digital technology interventions, which offer convenience, diversity, and proven effectiveness in addressing such problems. However, the existing literature reveals a significant gap in comprehensive reviews that consolidate findings and discuss the potential of digital technologies in enhancing mental health. Methods: To clarify the latest research progress on digital technology to promote mental health in the past decade (2013-2023), we conducted two studies: a systematic review and meta-analysis. The systematic review is based on 59 empirical studies identified from three screening phases, with basic information, types of technologies, types of mental health issues as key points of analysis for synthesis and comparison. The meta-analysis is conducted with 10 qualified experimental studies to determine the overall effect size of digital technology interventions and possible moderating factors. Results: The results revealed that (1) there is an upward trend in relevant research, comprising mostly experimental and quasi-experimental designs; (2) the common mental health issues include depression, anxiety, bullying, lack of social emotional competence, and mental issues related to COVID-19; (3) among the various technological interventions, mobile applications (apps) have been used most frequently in the diagnosis and treatment of mental issues, followed by virtual reality, serious games, and telemedicine services; and (4) the meta-analysis results indicated that digital technology interventions have a moderate and significant effect size (g = 0.43) for promoting mental health. Conclusion: Based on these findings, this study provides guidance for future practice and research on the promotion of adolescent mental health through digital technology. Systematic review registration: https://inplasy.com/inplasy-2023-12-0004/, doi: 10.37766/inplasy2023.12.0004.

Effects of macroprudential policies on ecological footprint: the moderating role of environmental policy stringency in the top 11 largest countries.

This study investigates the impact of macroprudential policies on ecological footprint (EF) in the top 11 largest countries. This study uses country-level panel data from these countries, covering the period from 1992 to 2020. Findings indicate that macroprudential policies alleviates ecological footprint in the sample. Macroprudential policies primarily reduce the ecological footprint before medium quantile (50%) while the environmental benefits of the policies end in the later quantiles. Moreover, environmental policy stringency (EPS) amplifies the positive influence of macroprudential policies on environmental sustainability. Estimate results stay the same with basic regression results in the post-global financial crisis (GFC) period while the impact is positive in the pre-GFC period. Finally, other robust tests validate the findings reported in basic regression model. This study suggests that governments should customize various types of macroprudential policies while also considering environmental concerns. The achievement of a sustainable environment can be facilitated by the combined effects of macroprudential policies and EPS.

Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner.

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

The impact of economic uncertainty on bank efficiency-the moderating role of country governance.

This study examined the impact of economic uncertainty (EU) on Islamic banks (IBs) and conventional banks' (CBs) efficiency in countries that meet a standard where 1% share of Islamic banking assets is part of their total domestic banking sector assets. In addition, this study explored the moderating effect of country governance (CG) by employing the quantitative methodology based on secondary data from 2006 to 2021. The data analysis was done through ordinary least square, fixed effect model, and the random effect model. EU was found to enhance bank efficiency based on the basic regression results. CG moderated the positive effect of EU on bank efficiency. Additional robustness tests showed that EU was positively related to both types of banks' efficiency. The value of the paper is unique in that few papers have investigated the moderating effect of CG on the impact of EU on banks' efficiency, which enhances comprehension of EU and CG. These results highlight important policy implications whereby banks should continue to invest in and improve their risk management strategies. In addition, governments and regulatory bodies should prioritise good governance practices as these can improve banks' efficiency.

Assembled RhRuFe Trimetallene for Water Electrolysis.

Industrializing water electrolyzers demands better electrocatalysts, especially for the anodic oxygen evolution reaction (OER). The prevailing OER catalysts are Ir or Ru-based nanomaterials, however, they still suffer from insufficient stability. An alternative yet considerably less explored approach is to upgrade Rh, a known stable but moderately active element for OER electrocatalysis, via rational structural engineering. Herein, a precise synthesis of assembled RhRuFe trimetallenes (RhRuFe TMs) with an average thickness of 1 nm for boosting overall water splitting catalysis is reported. Favorable mass transport and optimized electronic structure collectively render RhRuFe TMs with an improved OER activity of an overpotential of 330 mV to deliver 10 mA cm-2, which is significantly lower than the Rh/C control (by 601 mV) and reported Rh-based OER electrocatalysts. In particular, the RhRuFe TMs-based water splitting devices can achieve the current density of 10 mA cm-2 at a low voltage of 1.63 V, which is among the best in the Rh-based bifunctional catalysts for electrolyzers. The addition of Fe in RhRuFe TMs can modulate the strain/electron distribution of the multi-alloy, which regulates the binding energies of H* and OH* in hydrogen and oxygen evolution reactions for achieving the enhanced bifunctional OER and HER catalysis is further demonstrated.

Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives.

Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 µM concentration were more than 50 %. The IC50 values of compounds 18a and 18b were 0.3 ± 0.01 µM and 0.05 ± 0.02 µM in K562 cells respectively, compared with HeLa and A549 cells, 18a and 18b were more sensitive to K562 cells. In addition, the PC3 cells with WRN overexpression (PC3-WRN) was constructed, 18a and 18b and 23a were more sensitive to PC3-WRN cells compared with the control group cells (PC3-NC). Then, the cell viability of the novel WRN inhibitors were further assessed by colony formation assay. Compared with PC3-NC cells, 18b and 23a had obvious inhibitory effect on PC3-WRN cell at 1000 nM. In summary, these results indicated that the compounds 18b and 23a could be WRN protein inhibitor with potent anticancer properties in vitro.

A comparison of the postoperative outcomes between intraoperative leak testing and no intraoperative leak testing for gastric cancer surgery: a systematic review and meta-analysis.

BACKGROUND: Postoperative anastomotic leakage (PAL) is a serious complication of gastric cancer surgery. Although perioperative management has made considerable progress, anastomotic leakage (AL) cannot always be avoided. The purpose of this study is to evaluate whether intraoperative leak testing (IOLT) can reduce the incidence of PAL and other postoperative outcomes in gastric cancer surgery. MATERIALS AND METHODS: In this meta-analysis, we searched the PubMed, Embase, and Cochrane Library databases for clinical trials to assess the application of IOLT in gastric cancer surgery. All patients underwent laparoscopic radical gastrectomy for gastric cancer surgery. Studies comparing the postoperative outcomes of IOLT and no intraoperative leak testing (NIOLT) were included. Quality assessment, heterogeneity, risk of bias, and the level of evidence of the included studies were evaluated. PAL, anastomotic-related complications, 30-day mortality, and reoperation rates were compared between the IOLT and NIOLT group. RESULTS: Our literature search returned 721 results, from which six trials (a total of 1,666 patients) were included in our meta-analysis. Statistical heterogeneity was low. The primary outcome was PAL. IOLT reduced the incidence of PAL [2.09% vs 6.68%; (RR = 0.31, 95% Cl 0.19-0.53, P < 0.0001]. Anastomotic-related complications, which included bleeding, leakage, and stricture, were significantly higher in the NIOLT group than in the IOLT group [3.24% VS 10.85%; RR = 0.30, 95% Cl 0.18-0.53, P < 0.0001]. Moreover, IOLT was associated with lower reoperation rates [0.94% vs 6.83%; RR = 0.18, 95% CI 0.07-0.43, P = 0.0002]. CONCLUSION: Considering the observed lower incidence of postoperative anastomotic leakage (PAL), anastomotic-related complications, and reoperation rates, IOLT appears to be a promising option for gastric cancer surgery. It warrants further study before potential inclusion in future clinical guidelines.