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[Display omitted] • A novel discrete element model considering micro-roughness was developed for adhesive joints. • The microscale crack initiation, coalescence and propagation of adhesive and adhesion interface can be captured. • Micro-mechanisms due to surface roughness on the micro/macroscale behaviour were found. • Key statistical features such as root mean square roughness, correlation length, skewness were discussed. Micro-roughness at adhesion surface yields significant influences on the structural behaviour of adhesive joints. Investigations into the micromechanical mechanism are extremely limited. This works developed a novel particle-based model of joints with stochastic microstructural features of roughness, which can capture refined multi-scale responses as first of this kind. Aluminium adherends with mechanical surface treatments were firstly scanned using 3D laser scanning microscope. The statistical features and reconstruction method of micro-roughness profiles were determined. Single lap shear tests on joints made of epoxy adhesive (Loctite EA 9497) and treated aluminium adherends were performed to provide testing data and observations on failure modes. The refined numerical models were subsequently developed to examine the influences of the actual micro-roughness on the micromechanical behaviors and failure mechanism. The mechanical interlocking, mitigation on crack propagation due to the irregular roughness were investigated. It is followed by introducing the reconstructed roughness of various magnitudes and further numerically examining the micromechanical responses by key stochastic parameters such as root mean square roughness and correlation length. The results indicate that the mechanical interlocking contribute more to enhancing the joint strength than the increase of adhesion area by micro-roughness. A rougher surface in either horizontal or vertical directions does not exhibit a consistent improvement of joint strength, which also depends on the threshold of roughness and the surface skewness triggering the transition of failure modes. [ABSTRACT FROM AUTHOR]

Discrete element (DE) model has a great feasibility in modelling the microstructural behaviours of adhesive composite joints. However, it demands a sophisticated calibration process to determine microscale bond parameters, which involves massive efforts in both experimental and numerical investigations. This work developed a novel calibration strategy based on DE models and genetic expression programming (GEP) approach for predicting the behaviours of hybrid composite joints encompassing the material nonlinearity, large ductile deformation and multiple fracture modes. In the developed strategy, both the bulk and interlaminar-like properties of ductile adhesives were concerned to suit various joint configurations. GEP modelling was performed based on the datasets from virtual DE experiments. Symbolic regression models were subsequently developed to facilitate the parameters determination. A series lab tests were conducted to validate the numerical results. It shows that the calibrated DE model can adaptively simulate the featured behaviours of both the ductile adhesive and composite joints with different configurations well in most examined occasions. Therefore, it could be suggested to generalize the developed strategy in the development of other DE models for saving the massive efforts in the calibration process of microstructural parameters. [Display omitted] • A novel calibration strategy for discrete element models of ductile adhesive joints was proposed. • Machine learning method was used to facilitate the complex calibration. • The proposed strategy can save massive efforts in the calibration process of microstructural parameters. • Modelling reliability was thoroughly examined with lab tests using Teroson MS 9399 adhesive. • Robust prediction on joint behaviours with material nonlinearity and multiple fracture modes can be achieved. [ABSTRACT FROM AUTHOR]

Particle-based model has strength and flexibility in modelling the microstructures of adhesives and interface in adhesive joints. In this work, a procedure with genetic expression programming (GEP) technique to calibrate the microscale parameters of discrete element (DE) model was proposed for brittle adhesives. Two categories of adhesive properties, the bulk property of thick adhesive and interlaminar-like property of thin adhesive, were discussed. For the bulk property, three target properties of adhesives, i.e. tensile strength, peak strain, secant modulus, were set as the reproduced features. 300 sets of adjustable microscale parameters were produced to run the numerical tests and generate datasets. GEP was then employed to find regression formulas for predicting the target properties as a function of the microscale parameters. For the interlaminar-like property, fracture energies of the cohesive failure of thin adhesives were approximated. A similar procedure of combined DE modelling and GEP was performed to find the regression models to estimate the fracture energy. The developed regression formulas can cover a general range of brittle adhesives. Loctite EA 9497 adhesive was selected to perform a series of lab tests, of which the results were subsequently used to examine the applicability of the DE model with calibrated parameters. The numerical results exhibit good agreements with testing data and observation. • Machine learning based approach was developed to calibrate the microscale parameters of DE models. • The bulk and interlaminar-like properties of brittle adhesives in various joint designs were calibrated. • Symbolic regression models of concerned properties were developed. • The developed DE models were validated with lab tests using brittle epoxy Loctite EA 9497 as example. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel approach of charge and strain engineering on g-C 9 N 7 nanosheets was proposed to achieve efficient CO 2 /C 2 H 2 separation. • Superior performance of CO 2 capture and separation was demonstrated by synergistically regulated g-C 9 N 7 membrane. • The remarkable CO 2 permeance of g-C 9 N 7 nanosheets was higher than that of conventional porous 2D membranes. • The underlying separation and adsorption mechanism of CO 2 was revealed. Efficient CO 2 /C 2 H 2 separation at ambient conditions is an essential but challenging process owing to their similar molecular sizes and physical properties. In this work, a novel approach of charge/strain-regulated gas capture and separation was proposed, which offered the advantages of reversibility and controllable kinetics. Highly selective CO 2 separation from CO 2 /C 2 H 2 with porous g-C 9 N 7 nanosheets were demonstrated with varying charge densities and strains using molecular dynamics (MD) simulations and first-principle density function theory (DFT) calculations. The remarkable CO 2 permeance up to 5.85 × 107 GPU can be achieved by charge engineering. Under the condition of tensile strain, a controllable CO 2 separation performance was exhibited, whose CO 2 permeance increased with increasing the applied strain. The maximum permeance was 3.44 × 107 GPU with 9% strained g-C 9 N 7 membrane. More interestingly, a promising approach combining the charge regulation with strain engineering was explored to investigate the synergistic effect. Under conditions of 2 e- charge and 3% tensile strain on g-C 9 N 7 membrane, the CO 2 permeance reached 4.24 × 107 GPU, which was 1.6 times of CO 2 permeability when only 2 e- was added and 10 times of CO 2 permeance when only 3% strain was added. Additionally, the energy barrier of CO 2 decreased with the increasing degree of regulation (charge and strain engineering) on the g-C 9 N 7 membrane, indicating that the g-C 9 N 7 membrane can be served as an excellent candidate for CO 2 /C 2 H 2 separation. These results provide useful guidance for developing advanced materials and applying new regulation techniques to realize highly tunable and selective CO 2 /C 2 H 2 separation. [ABSTRACT FROM AUTHOR]

• Bridging ability of fractured LG under weathering actions was experimentally investigated. • Novel EVA and hybrid EVA/PC interlayer were adopted to make specimens. • TCT tests and uniaxial tests were performed to examined the bridging behaviours. • Temperatures, damp heat and lighting radiation were considered for weathering treatment. • The degradation of bridging resistance, strength and adhesion energy was identified. Local bridging ability between fragments including bridging force and adhesion concerns the post-fracture performance of laminated glass (LG). Weathering actions such as heat and lighting radiation can greatly damage bridging ability. The bridging behaviour of fractured LG under diverse weathering actions was examined in this work. Material specimens made of single EVA interlayer and hybrid EVA/PC interlayer, which were developed to provide better degradation resistance and long-term post-fracture performance for LG products, were manufactured. Uniaxial tensile tests on the interlayer specimens and through-crack tensile (TCT) tests on fractured LG specimens were performed after the specimens were exposed to the weathering actions including different temperatures, damp heat, and radiations from laboratory light source. Experimental observations, testing data such as bridging force–displacement relationship, normalized force and stress were analysed to discuss the effects of the weathering actions. Finally, the equivalent adhesion energy was determined to describe the failure of interfacial bridging. It is found that temperature rise to over 60 °C will greatly damage the bridging ability even for the specimens with hybrid interlayers, which also present limited bridging effects when temperature increases to nearly 100 °C. Damp heat and lighting treatment are found to have limited effects on the adhesion resistance of hybrid interlayer, although the former may facilitate interlayer rupture and the latter may result in greater degradation of adhesion energy. [ABSTRACT FROM AUTHOR]

• 73 impact attempts with increasing impact velocity were conducted to test multi-layered laminated glass (MLG) panels as the first attempt of this kind. • A nonlinear dynamic analytical model was proposed to calculate the pre-crack impact response of square MLG. • The indentation dominating the impact failure which haven't been considered in the existing analytical works was introduced into the analytical model. • The key feature of experimental impact force variation was determined and validated with the analytical results. • Parametric study was conducted to investigate the influence of the number of glass layers, glass thickness and ratio, panel size on the impact response. This study presents a combined experimental and analytical study on the impact response of multi-layered laminated glass (MLG) under low-velocity hard body impact before glass breakage. The drop weight impact tests using repeated attempts with increasing impact velocities were firstly performed on 12 MLG panels with double PVB or SG interlayers to record the impact response, high speed fracture process. The experimental results identify that: (1) the indentation is the predominant factor for glass fracture in the examined impact scenarios; (2) the key time interval of the pre-crack impact response is within 0.6 ms. The indentation which hasn't been considered in the existing analytical works was hence introduced into the proposed nonlinear analytical model, which employed third order shear deformation theory and obtained the solutions of motion equations by a two-step perturbation method, according to the former finding. The calculated impact response based on the proposed model was validated with the experimental results within 0.6 ms based on the latter finding and showed satisfactory agreement. A parametric study was subsequently conducted to investigate the influence of factors such as the number of glass layers, glass thickness and ratio, panel size on the pre-crack impact response. The results show the increase of peak force and indentation is more sensitive to the increase of total glass thickness after the thickness reaches 24 mm and presents less sensitivity when the thickness approaches 57 mm. The variation of the glass thickness ratio has no influence on the pre-crack behavior once the total glass thickness is fixed. [Display omitted] [ABSTRACT FROM AUTHOR]

The aerospace, automotive and marine industries have witnessed a rapid increase of using adhesive bonded joints due to their advantages in joining dissimilar and/or new engineering materials. Joint strength is the key property in evaluating the capability of the adhesive joint. In this paper, developments of black-box and grey-box machine learning (ML) models are presented to allow accurate predictions of the failure load of single lap joints by considering a mix of continuous and discrete design (geometry and material) variables. Firstly, the failure loads of 300 single lap joint samples with different geometry/material parameters are calculated by FE models to generate a data set of which accuracy is validated by experimental results. Then, a deep neuron network (black-box) and a genetic programming (grey-box) model are developed for accurately predicting the failure load of the joint. Based on both ML models, a case study is conducted to explore the relationships between specific design variables and overall mechanical performances of the single lap adhesive joint, and optimal designs of structure and material can be obtained. [Display omitted] • Development of both deep neuron networks and genetic programming models for predicting the strength of composite joints. • Consideration of geometry (continuous) and material (discrete) variables in the development of machine learning models. • Discussion of the optimal design and the effects of design variables on the overall performance of composite joints. [ABSTRACT FROM AUTHOR]

Adhesively bonding has been increasingly used for numerous industrial applications to meet the high demand for lightweight and safer structures. Debonding of adhesively bonded joints is a typical mixed mode failure process. It is highly depended on the interactional effects of material properties and geometric definitions of the constituents, which is very complicated. The existing studies in identifying fracture modes of joints based on either experiments or finite element analysis are often prohibitively time and computational expensive. This paper proposed an innovate method by combining Finite Element Analysis (FEA), Latin Hypercube Sampling (LHS) and Genetic Programming (GP) to understand the effect of the physical attributes on the fracture modes of adhesively single lap joints. A dataset of 150 adhesive joint samples has been generated using LHS, including different combinations of adherend and adhesive's material properties and thicknesses. The mixed mode ratios of the 150 samples are calculated using Strain Energy Release Rate (SERR) outputs embedded in Linear Elastic Fracture Mechanics (LEFM), which has been validated by experimental tests. Finally, a GP model is developed and trained to provide an extracted explicit expression used for evaluating the early-state failure modes of the adhesively bonded joints against the design variables. [ABSTRACT FROM AUTHOR]

In this study, different single-lap hybrid joints are used to analyse the effects of the stiffness of the adherends and the adhesive on the failure mechanism. The hybrid joints include a combination of (a) different adherends: aluminium (6082 T6) and PolyPhtalamide (PPA) reinforced with 50% of glass fibre (grade HTV-5H1 from Grivory) and (b) different adhesives: epoxy-based adhesive (Loctite EA 9497) and silane-modified polymer-based adhesive (Teroson MS 9399). Six different single-lap joints are fabricated and analysed. The cohesive parameters of different adhesives against different adherends are determined respectively using single-mode coupons and validated with finite element modelling. Single-lap shear tests are conducted to understand different fracture mechanisms of the joints. Finite element (FE) models using the Cohesive Zone Method (CZM) are developed to simulate the failure of the joints and validated by the testing results. Different failure processes obtained from different hybrid joints combinations are discussed further by analysing the stress distributions along the interfaces of the joints. Finally, the relationship between the stiffness of the constituents of a hybrid adhesive joint and its failure mechanism is summarised. The load vs displacement behaviour of the single-lap joints demonstrate that the stiffness of adherends affects the maximum failure load of the joints with rigid adhesive (epoxy). However, the joint with flexible adhesive (polyurethane) is not sensitive to the stiffness of the adherends. In addition, higher shear stress distribution occurs in the interface adjacent to the adherend with lower stiffness, leading to the failure initiation at the PPA side regardless of adhesive types. [ABSTRACT FROM AUTHOR]

The current spatial distribution of the risk of terrestrial gamma radiation in China were investigated by using spatial interpolation. And the driving factors influence on the terrestrial gamma radiation dose (TGRD) distribution were identified using the geographic detector, a new statistical method based on the nonlinear hypothesis. The results showed that the values of TGRD were range from 60 to 195 nGy h−1 with the average of 86.5 nGy h−1, and the higher values were recorded in Qingahi–Tibet Plateau, which were all within the range of background value in China. In addition, the radiological indices, ELCR (Excess Lifetime Cancer Risk), TGRD and AEDE (Annual Effective Dose Equivalent) were also within the acceptable range of values by risk assessment. The results by use of the geographic detector showed that sunshine duration, atmosphere pressure, altitude, and rainfall condition have closely related to the TGRD distribution. In addition, these meteorological factors and altitude had more impact on TGRD than the air pollution-related factors. Our study can provide useful information on studying the influence mechanism of the TGRD distribution, the variability of the natural terrestrial gamma radiation in China, and exposure data for risk assessment from low dose chronic exposures. • In China, gamma radiation has a range of 60–195 nGy h−1, and average 85 nGy h−1. • Higher gamma radiation values were measured in Qinghai–Tibet Plateau. • Radiological indices were all within the range of background values. • Meteorological factors and altitude had more effect on TGRD than air pollutants. [ABSTRACT FROM AUTHOR]

TMPRSS2-ERG gene fusion occurs in approximately 50% of cases of prostate cancer (PCa), and the fusion product is a key driver of prostate oncogenesis. However, how to leverage cellular signaling to ablate TMPRSS2-ERG oncoprotein for PCa treatment remains elusive. Here, we demonstrate that DNA damage induces proteasomal degradation of wild-type ERG and TMPRSS2-ERG oncoprotein through ERG threonine-187 and tyrosine-190 phosphorylation mediated by GSK3β and WEE1, respectively. The dual phosphorylation triggers ERG recognition and degradation by the E3 ubiquitin ligase FBW7 in a manner independent of a canonical degron. DNA damage-induced TMPRSS2-ERG degradation was abolished by cancer-associated PTEN deletion or GSK3β inactivation. Blockade of DNA damage-induced TMPRSS2-ERG oncoprotein degradation causes chemotherapy-resistant growth of fusion-positive PCa cells in culture and in mice. Our findings uncover a previously unrecognized TMPRSS2-ERG protein destruction mechanism and demonstrate that intact PTEN and GSK3β signaling are essential for effective targeting of ERG protein by genotoxic therapeutics in fusion-positive PCa. • DNA damage induces proteasomal degradation of TMPRSS2-ERG oncoprotein • GSK3β and WEE1 mediates ERG T187 and Y190 phosphorylation and degradation • FBW7 recognizes and promotes degradation of dual phosphorylated ERG • PTEN loss confers ERG degradation and tumor growth resistance to genotoxic therapy TMPRSS2-ERG oncoprotein plays a pivotal role in prostate oncogenesis and progression and is a potential therapeutic target of prostate cancer. Hong et al. reveal a previously unrecognized TMPRSS2-ERG protein destruction mechanism, and intact PTEN and GSK3β signaling are essential for effective targeting of TMPRSS2-ERG by genotoxic therapeutics in prostate cancer. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to investigate the behavioral changes in the core features and challenging behaviors of children with Autism Spectrum Disorder (ASD) during the COVID-19 Omicron wave (from December 2022 to January 2023) in China., Patients and Methods: A total of 515 caregivers of children with ASD completed an online survey. This survey was designed to assess the sociodemographic characteristics of the children and their caregivers, the clinical features of COVID-19, the manifestation of core ASD features and challenging behaviors, and the alterations in daily life following the COVID-19 Omicron variant wave., Results: The children with ASD had an average age of 5.4 years, with 79.6% being male. After the Omicron wave, the proportions of participants with worsening core ASD features and challenging behaviors were 22.9% and 37.1%, respectively. Sleep disorders (20.0%), eating problems (18.6%), and inattentive symptoms (17.5%) were the most frequently reported worsening behaviors. The factors associated with the worsening of core ASD features included infection with the Omicron variant of COVID-19, reduced outdoor activity, and a lower score of caregiver health-related quality of life (HRQoL). The worsening of challenging behaviors was associated with infection with the Omicron variant of COVID-19, a lower frequency of rehabilitation training, and a lower score of HRQoL., Conclusion: The outbreak of the COVID-19 Omicron variant had an impact on the behaviors of autistic children. The behavior changes in core ASD features and challenging behaviors differed and were associated with COVID-19 infection and other factors., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Ye et al.)

Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX)., Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA ( NR3C1 ) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography., Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response., Conclusion: The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy., Competing Interests: JTV is currently an employee of GlaxoKlineSmith. GFF reports honorarium for talk from Curio Science, advisory board for GSK, uncompensated advisory board for TTC, and PI of industry-sponsored study for Corcept, Abbvie, Genentech/Roche, Tesaro/GSK, Syndax, 47 inc, Iovance, Syros, Astex, Merck, Sanofi, Sermonix, Compugen, INcyte, Hoffman LaRoche, Eisai. The authors acknowledge supply of Relacorilant from Corcept Therapeutics. SDC and The University of Chicago have been issued patents on methods of measuring GR expression in triple-negative breast cancer (TNBC) and using GR antagonists in TNBC and prostate cancer., (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Ovarian cancer is the deadliest gynecological malignancy, owing to its late-stage diagnosis and high rates of recurrence and resistance following standard-of-care treatment, highlighting the need for novel treatment approaches. Through an unbiased drug screen, we identified the kinase inhibitor, lestaurtinib, as a potent antineoplastic agent for chemotherapy- and PARP-inhibitor (PARPi)-sensitive and -resistant ovarian cancer cells and patient derived xenografts (PDXs). RNA-sequencing revealed that lestaurtinib potently suppressed JAK/STAT signaling and lestaurtinib efficacy was shown to be directly related to JAK/STAT pathway activity in cell lines and PDX models. Most ovarian cancer cells exhibited constitutive JAK/STAT pathway activation and genetic loss of STAT1 and STAT3 resulted in growth inhibition. Lestaurtinib also displayed synergy when combined with cisplatin and olaparib, including in a model of PARPi resistance. In contrast, the most well-known JAK/STAT inhibitor, ruxolitinib, lacked antineoplastic activity against all ovarian cancer cell lines and PDX models tested. This divergent behavior was reflected in the ability of lestaurtinib to block both Y701/705 and S727 phosphorylation of STAT1 and STAT3, whereas ruxolitinib failed to block S727. Consistent with these findings, lestaurtinib additionally inhibited JNK and ERK activity, leading to more complete suppression of STAT phosphorylation. Concordantly, combinatorial treatment with ruxolitinib and a JNK or ERK inhibitor resulted in synergistic antineoplastic effects at dose levels where single agents were ineffective. Taken together, these findings indicate that lestaurtinib, and other treatments that converge on JAK/STAT signaling, are worthy of further pre-clinical and clinical exploration for the treatment of highly aggressive and advanced forms of ovarian cancer., Statement of Significance: Lestaurtinib is a novel inhibitor of ovarian cancer, including chemotherapy- and PARPi-resistant models, that acts through robust inhibition of the JAK/STAT pathway and synergizes with standard-of-care agents at clinically relevant concentrations.

Abscisic acid (ABA) is a conserved and important "sesquiterpene signaling molecule" widely distributed in different organisms with unique biological functions. ABA coordinates reciprocity and competition between microorganisms and their hosts. In addition, ABA also regulates immune and stress responses in plants and animals. Therefore, ABA has a wide range of applications in agriculture, medicine and related fields. The plant pathogenic ascomycete B. cinerea has been extensively studied as a model strain for ABA production. Nevertheless, there is a relative dearth of research regarding the regulatory mechanism governing ABA biosynthesis in B. cinerea . Here, we discovered that H3K9 methyltransferase BcDIM5 is physically associated with the H3K14 deacetylase BcHda1. Deletion of Bcdim5 and Bchda1 in the high ABA-producing B. cinerea TB-31 led to severe impairment of ABA synthesis. The combined analysis of RNA-seq and ChIP-seq has revealed that the absence of BcDIM5 and BcHda1 has resulted in significant global deficiencies in the normal distribution and level of H3K9me3 modification. In addition, we found that the cause of the decreased ABA production in the Δ Bcdim5 and Δ Bchda1 mutants was due to cluster gene repression caused by the emergence of hyper-H3K9me3 in the ABA gene cluster. We concluded that the ABA gene cluster is co-regulated by BcDIM5 and BcHda1, which are essential for the normal distribution of the B. cinerea TB-31 ABA gene cluster H3K9me3. This work expands our understanding of the complex regulatory network of ABA biosynthesis and provides a theoretical basis for genetic improvement of high-yielding ABA strains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wei, Shu, Hou, Li, Li, Luo, Yang and Tan.)

Background: Gout is a common inflammatory arthritis, which is mainly caused by the deposition of monosodium urate (MSU) in tissues. Transcriptomics was used to explore the pathogenesis and treatment of gout in our work., Objective: The objective of the study was to analyze and validate potential therapeutic targets and biomarkers in THP-1 cells that were exposed to MSU., Methods: THP-1 cells were exposed to MSU. The inflammatory effect was characterized, and RNA-Seq analysis was then carried out. The differential genes obtained by RNA-Seq were analyzed with gene expression omnibus (GEO) series 160170 (GSE160170) gout-related clinical samples in the GEO database and gout-related genes in the GeneCards database. From the three analysis approaches, the genes with significant differences were verified by the differential genes' transcription levels. The interaction relationship of long non-coding RNA (lncRNA) was proposed by ceRNA network analysis., Results: MSU significantly promoted the release of IL-1β and IL-18 in THP-1 cells, which aggravated their inflammatory effect. Through RNA-Seq, 698 differential genes were obtained, including 606 differential mRNA and 92 differential `LncRNA. Cross-analysis of the RNA-Seq differential genes, the GSE160170 differential genes, and the gout-related genes in GeneCards revealed a total of 17 genes coexisting in the tripartite data. Furthermore, seven differential genes-C-X-C motif chemokine ligand 8 (CXCL8), C-X-C motif chemokine ligand 2 (CXCL2), tumor necrosis factor (TNF), C-C motif chemokine ligand 3 (CCL3), suppressor of cytokine signaling 3 (SOCS3), oncostatin M (OSM), and MIR22 host gene (MIR22HG)-were verified as key genes that analyzed the weight of genes in pathways, the enrichment of inflammationrelated pathways, and protein-protein interaction (PPI) nodes combined with the expression of genes in RNA-Seq and GSE160170. It is suggested that MIR22HG may regulate OSM and SOCS3 through microRNA 4271 (miR-4271), OSM, and SOCS3m; CCL3 through microRNA 149-3p (miR-149-3p); and CXCL2 through microRNA 4652-3p (miR-4652-3p)., Conclusion: The potential of CXCL8, CXCL2, TNF, CCL3, SOCS3, and OSM as gout biomarkers and MIR22HG as a therapeutic target for gout are proposed, which provide new insights into the mechanisms of gout biomarkers and therapeutic methods., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Although esophageal carcinoma (EC) is one of the most common cancers in the world, details of its pathogenesis remain unclear. Metabolic reprogramming is a main feature of EC. Mitochondrial dysfunction, especially the decrease in mitochondrial complex I (MTCI), plays an important role in the occurrence and development of EC., Objective: The objective of the study was to analyze and validate the metabolic abnormalities and the role of MTCI in esophageal squamous cell carcinoma., Methods: In this work, we collected transcriptomic data from 160 esophageal squamous carcinoma samples and 11 normal tissue samples from The Cancer Genome Atlas (TCGA). The OmicsBean and GEPIA2 were used to conduct an analysis of differential gene expression and survival in clinical samples. Rotenone was used to inhibit the MTCI activity. Subsequently, we detected lactate production, glucose uptake, and ATP production., Results: A total of 1710 genes were identified as being significantly differentially expressed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis suggested that these differentially expressed genes (DEGs) were significantly enriched in various pathways related to carcinoma tumorigenesis and progression. Moreover, we further identified abnormalities in metabolic pathways, in particular, the significantly low expression of multiple subunits of MTCI genes ( ND1, ND2, ND3, ND4, ND4L, ND5 , and ND6 ). Rotenone was used to inhibit the MTCI activity of EC109 cells, and it was found that the decrease in MTCI activity promoted HIF1A expression, glucose consumption, lactate production, ATP production, and cell migration., Conclusion: Our results indicated the occurrence of abnormal metabolism involving decreased mitochondrial complex I activity and increased glycolysis in esophageal squamous cell carcinoma (ESCC), which might be related to its development and degree of malignancy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Oncogene E6 plays a critical role in the development and progression of esophageal cancer caused by human papillomavirus (HPV) infection. Alpha-ketoglutarate (AKG) is a key metabolite in the tricarboxylic acid cycle and has been widely used as a dietary and anti-ageing supplement. In this study, we found that treating esophageal squamous carcinoma cells with a high dose of AKG can induce cell pyroptosis. Furthermore, our research confirms that HPV18 E6 inhibits AKG-induced pyroptosis of esophageal squamous carcinoma cells by lowering P53 expression. P53 downregulates malate dehydrogenase 1 (MDH1) expression; however, MDH1 downregulates L-2-hydroxyglutarate (L-2HG) expression, which inhibits a rise in reactive oxygen species (ROS) levels-as L-2HG is responsible for excessive ROS. This study reveals the actuating mechanism behind cell pyroptosis of esophageal squamous carcinoma cells induced by high concentrations of AKG, and we posit the molecular pathway via which the HPV E6 oncoprotein inhibits cell pyroptosis., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Bromodomain and extraterminal (BET) proteins including BRD4 play important roles in oncogenesis and immune inflammation. Here we demonstrate that cancer cells with loss of the retinoblastoma (RB) tumor suppressor became resistant to small molecule bromodomain inhibitors of BET proteins. We find that RB binds to bromodomain-1 (BD1) of BRD4, but binding is impeded by CDK4/6-mediated RB phosphorylation at serine-249/threonine-252 (S249/T252). ChIP-seq analysis shows RB knockdown increases BRD4 occupancy at genomic loci of genes enriched in cancer-related pathways including the GPCR-GNBIL-CREB axis. S249/T252-phosphorylated RB positively correlates with GNBIL protein level in prostate cancer patient samples. BET inhibitor resistance in RB-deficient cells is abolished by co-administration of CREB inhibitor. Our study identifies RB protein as a bona fide intrinsic inhibitor of BRD4 and demonstrates that RB inactivation confers resistance to small molecule BET inhibitors, thereby revealing a regulatory hub that converges RB upstream signaling onto BRD4 functions in diseases such as cancer., (© 2022. The Author(s).)

PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. SIGNIFICANCE: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Androgen receptor-positive prostate cancer (PCa) and estrogen receptor-positive luminal breast cancer (BCa) are generally less responsive to immunotherapy compared with certain tumor types such as melanoma. However, the underlying mechanisms are not fully elucidated. In this study, we found that FOXA1 overexpression inversely correlated with interferon (IFN) signature and antigen presentation gene expression in PCa and BCa patients. FOXA1 bound the STAT2 DNA-binding domain and suppressed STAT2 DNA-binding activity, IFN signaling gene expression, and cancer immune response independently of the transactivation activity of FOXA1 and its mutations detected in PCa and BCa. Increased FOXA1 expression promoted cancer immuno- and chemotherapy resistance in mice and PCa and BCa patients. These findings were also validated in bladder cancer expressing high levels of FOXA1. FOXA1 overexpression could be a prognostic factor to predict therapy resistance and a viable target to sensitize luminal PCa, BCa, and bladder cancer to immuno- and chemotherapy.

Objective: We describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive., Methods: Patients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies., Results: Forty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models., Conclusion: Ribociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models., Trial Registration Number: ClinicalTrials.gov registry (NCT02657928)., Competing Interests: Competing interests: GC-O and SJW report grants from Novartis during the conduct of the study. MSB reports grants from Immune Design, Pharmacyclics, Marker Therapeutics, Merck, Genentech and Bristol Myers Squibb, outside the submitted work. We certify that the other authors have no financial affiliation/interest (eg, employment, stock holdings, consultant arrangements, honoraria in the subject matter, materials or products) mentioned in this manuscript., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Insulin-like growth factor (IGF) signaling has been implicated in the resistance to hormonal therapy in breast cancer. Using a model of postmenopausal, estrogen-dependent breast cancer, we investigated the antitumor effects of the dual IGF-1R/InsR tyrosine kinase inhibitor BMS-754807 alone and in combination with letrozole or tamoxifen. BMS-754807 exhibited antiproliferative effects in vitro that synergized strongly in combination with letrozole or 4-hydroxytamoxifen and fulvestrant. Similarly, combined treatment of BMS-754807 with either tamoxifen or letrozole in vivo elicited tumor regressions not achieved by single-agent therapy. Notably, hormonal therapy enhanced the inhibition of IGF-1R/InsR without major side effects in animals. Microarray expression analysis revealed downregulation of cell-cycle control and survival pathways and upregulation of erbB in response to BMS-754807 plus hormonal therapy, particularly tamoxifen. Overall, these results offer a preclinical proof-of-concept for BMS-754807 as an antitumor agent in combination with hormonal therapies in hormone-sensitive breast cancer. Cooperative cell-cycle arrest, decreased proliferation, and enhanced promotion of apoptosis may contribute to antitumor effects to be gauged in future clinical investigations justified by our findings.

Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism., (©2010 AACR.)

We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417, in breast and ovarian cancer cell lines. Further studies indicated treatment of OV202 ovarian cancer cells with BMS-554417 increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore, combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924, increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin, respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1 and HER-2 may overcome clinical resistance to IGF-IR inhibitors.

The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via alpha-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel.

Uterine estrogenic actions are biphasic, early (phase I) and late (phase II) responses. However, the molecular linkage between these phases is not known. Although certain phase I responses are considered estrogen receptor (ER)alpha and ERbeta independent, the phase II responses are ERalpha dependent. We previously observed that among several genes Bip is induced by estrogen in the mouse uterus in an ER-independent manner as a phase I response. Bip is a member of the chaperone family and plays roles in protein processing and confers cellular protection. However, its role in estrogen-dependent uterine biology is unknown. We show here a new function of Bip in regulating estrogen signaling in the uterus. Bip, induced during the phase I responses, molecularly interacts with ERalpha required for estrogen-mediated phase II growth responses. Utilizing in vivo and in vitro model systems, we found that adenovirus-driven suppression of Bip antagonizes ERalpha-mediated uterine gene transcription. Importantly, down-regulation of Bip compromises estrogen-dependent phase II growth responses with sustained phase I responses. In conclusion, Bip is critical for coordinating estrogen-elicited biphasic responses and serves as a molecular link between ERalpha-independent and -dependent estrogenic responses in the uterus.

Because uterine cell-specific proliferation, differentiation, and apoptosis are differentially regulated during the periimplantation period, we speculated that negative cell cycle regulators are also operative in the uterus during this period. This prompted us to examine the roles of two negative growth-regulatory genes, cyclin G1 and cyclin G2, in the periimplantation mouse uterus. We show that cyclin G1 and cyclin G2 genes are differentially regulated in the uterus during this period (d 1-8 of pregnancy) in a spatiotemporal manner. The results suggest that cyclin G1 is primarily associated with epithelial cell differentiation before implantation and stromal cell proliferation and differentiation during decidualization, whereas cyclin G2 is associated with terminal differentiation and apoptosis of the luminal epithelial and stromal cells at the site of blastocyst after implantation. Pharmacological and genetic studies provide evidence that the expression of cyclin G1, not cyclin G2, is regulated by progesterone via its nuclear receptor. Furthermore, the expression of these genes is aberrantly up-regulated in homeo box A-10 mutant uteri, suggesting that cyclin G1 and cyclin G2 genes act as downstream targets of homeobox A-10 and negatively impact uterine cell proliferation. Collectively, our present and previous studies suggest that negative cell cycle regulators collaborate with growth-promoting regulators in regulating uterine cell-specific proliferation, differentiation, and apoptosis relevant to implantation and decidualization.

Major biological effects of estrogen in the uterus are thought to be primarily mediated by nuclear estrogen receptors, ERalpha and ERbeta. We show here that estrogen in an ER-independent manner rapidly up-regulates the expression of Wnt4 and Wnt5a of the Wnt family and frizzled-2 of the Wnt receptor family in the mouse uterus. One of the mechanisms by which Wnts mediate canonical signaling involves stabilization of intracellular beta-catenin. We observed that estrogen treatment prompts nuclear localization of active beta-catenin in the uterine epithelium. We also found that adenovirus mediated in vivo delivery of SFRP-2, a Wnt antagonist, down-regulates estrogen-dependent beta-catenin activity without affecting some of the early effects (water imbibition and angiogenic markers) and inhibits uterine epithelial cell growth, suggesting that canonical Wnt signaling is critical to estrogen-induced uterine growth. Our present results provide evidence for a novel role of estrogen that targets early Wnt/beta-catenin signaling in an ER-independent manner to regulate the late uterine growth response that is ER dependent.