Roles of serum uric acid on the association between arsenic exposure and incident metabolic syndrome in an older Chinese population.

Growing evidences showed that heavy metals exposure may be associated with metabolic diseases. Nevertheless, the mechanism underlying arsenic (As) exposure and metabolic syndrome (MetS) risk has not been fully elucidated. So we aimed to prospectively investigate the role of serum uric acid (SUA) on the association between blood As exposure and incident MetS. A sample of 1045 older participants in a community in China was analyzed. We determined As at baseline and SUA concentration at follow-up in the Yiwu Elderly Cohort. MetS events were defined according to the criteria of the International Diabetes Federation (IDF). Generalized linear model with log-binominal regression model was applied to estimate the association of As with incident MetS. To investigate the role of SUA in the association between As and MetS, a mediation analysis was conducted. In the fully adjusted log-binominal model, per interquartile range increment of As, the risk of MetS increased 1.25-fold. Compared with the lowest quartile of As, the adjusted relative risk (RR) of MetS in the highest quartile was 1.42 (95% confidence interval, CI: 1.03, 2.00). Additionally, blood As was positively associated with SUA, while SUA had significant association with MetS risk. Further mediation analysis demonstrated that the association of As and MetS risk was mediated by SUA, with the proportion of 15.7%. Our study found higher As was remarkably associated with the elevated risk of MetS in the Chinese older adults population. Mediation analysis indicated that SUA might be a mediator in the association between As exposure and MetS.

Four-Direction Procedures Involving Tibial Tubercle Osteotomy for Habitual Dislocation of the Patella: A Case Report.

CASE: A 22-year-old man with habitual dislocation of the patella (HDP), characterized by lateral dislocation in flexion with spontaneous relocation with extension, presented with right knee pain and inability to actively extend. Imaging revealed lateral patellar dislocation, flat articular surface of the patella, and trochlear dysplasia. His symptoms persisted despite physical therapy. A 4-directional patellar stabilization surgery, incorporating lateral release, medial tibial tuberosity osteotomy, quadriceps muscle lengthening, and medial patellofemoral ligament reconstruction, was performed, with significant improvement in pain and function postoperatively. CONCLUSION: The procedure could be feasible in cases of severe HDP when conservative measures failed to relieve the patient's symptoms.

Bioinspired Bouligand-Structured Cellulose Nanocrystals/Poly(vinyl alcohol) Composite Hydrogel for Enhanced Impact Resistance.

Impact-protective materials are gaining importance because of the widespread occurrence of impact damage. Hydrogels have emerged as promising candidates owing to their lightweight and flexible nature. However, achieving soft impact-resistant hydrogels with exceptional stiffness, strength, and toughness remains a challenge. Inspired by the Bouligand structure found in the smasher dactyl club of stomatopods, we propose a straightforward multiscale hierarchical structural design strategy. This strategy integrates self-assembly and salting-out techniques to enhance the impact resistance of soft hydrogels. Rigid cellulose nanocrystals (CNCs) self-assemble into Bouligand-like structures within soft poly(vinyl alcohol) (PVA) matrix via supramolecular interactions. This rational structural design combines the CNC Bouligand structure with a cross-linked network of soft PVA crystalline domains, resulting in a composite hydrogel with impressive mechanical properties: high tensile fracture strength (30.2 MPa), elastic modulus (62.7 MPa), and fracture energy (75.6 kJ m-2), surpassing those of other tough hydrogels. Moreover, the multiscale hierarchical structure facilitates various energy dissipation mechanisms, including crack twisting, tortuous crack paths, and PVA chain orientation, resulting in notable force attenuation (80.4%) in the composite hydrogel. This biomimetic design strategy opens new avenues for developing soft and lightweight impact-resistant materials.

Homoharringtonine promotes non-small-cell lung cancer cell death via modulating HIF-1α/ERß/E2F1 feedforward loop.

OBJECTIVES: Hypoxia conditions promote the adaptation and progression of non-small-cell lung cancer (NSCLC) via hypoxia-inducible factors (HIF). HIF-1α may regulate estrogen receptor ß (ERß) and promote the progression of NSCLC. The phytochemical homoharringtonine (HHT) exerts strong inhibitory potency on NSCLC, with molecular mechanism under hypoxia being elusive. METHODS: The effects of HHT on NSCLC growth were determined by cell viability assay, colony formation, flow cytometry, and H460 xenograft models. Western blotting, molecular docking program, site-directed mutagenesis assay, immunohistochemical assay, and immunofluorescence assay were performed to explore the underlying mechanisms of HHT-induced growth inhibition in NSCLC. KEY FINDINGS: HIF-1α/ERß signaling-related E2F1 is highly expressed and contributes to unfavorable survival and tumor growth. The findings in hypoxic cells, HIF-1α overexpressing cells, as well as ERß- or E2F1-overexpressed and knockdown cells suggest that the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC cell growth. HHT suppresses HIF-1α/ERß/E2F1 signaling via the ubiquitin-proteasome pathway, which is dependent on the inhibition of the protein expression of HIF-1α and ERß. Molecular docking and site-directed mutagenesis revealed that HHT binds to the GLU305 site of ERß. HHT inhibits cell proliferation and colony formation and promotes apoptosis in both NSCLC cells and xenograft models. CONCLUSION: The formation of the HIF-1α/ERß/E2F1 feedforward loop promotes NSCLC growth and reveals a novel molecular mechanism by which HHT induces cell death in NSCLC.

Clinical efficacy and safety of acupuncture combined with statin in dyslipidemia: A meta-analysis and system review.

BACKGROUND: This study aims to systematically evaluate the clinical efficacy and safety of acupuncture in combination with statin therapy compared to statin monotherapy for the treatment of dyslipidemia. METHODS: A comprehensive search for relevant randomized controlled trials assessing the clinical efficacy of acupuncture and statin combination in the treatment of dyslipidemia was conducted. Databases including PubMed, EMbase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, Wanfang database, and China Science and Technology Journal Database were searched up to October 27, 2023. RESULTS: Sixteen Chinese-language studies involving a total of 1333 subjects were included for analysis. The meta-analysis revealed that the total effective rate of acupuncture combined with statin was significantly higher than that of statin alone (odds ratios = 3.32, 95% confidence intervals [CI] = 2.33 to 4.72). Furthermore, the combination of acupuncture with statin treatment resulted in a significant reduction in triglyceride levels (mean differences [MD] = -0.72 mmol/L, 95% CI = -1.05 to -0.4), total cholesterol levels (MD = -0.79 mmol/L, 95% CI = -1.07 to -0.51), low-density lipoprotein cholesterol levels (MD = -0.61 mmol/L, 95% CI = -0.95 to -0.27) and traditional Chinese medicine syndrome integral (MD = -1.32, 95% CI = -1.75 to -0.89), compared to statin treatment alone. Additionally, the high-density lipoprotein cholesterol level was higher in the combined acupuncture and statin treatment group than in the statin treatment alone group (MD = 0.44 mmol/L, 95% CI = 0.09 to 0.79). Notably, the rate of adverse reactions reported with combined acupuncture and statin treatment was lower than that with statin therapy alone. CONCLUSION: Our findings support the potential of acupuncture combined with statin as a viable clinical treatment option for dyslipidemia. However, it is important to note that current research on the mechanism of acupuncture for lipid-lowering has not yielded definitive results, and there are inherent biases in the conducted clinical studies.

Pyroptosis-associated genes and tumor immune response in endometrial cancer.

The occurrence and progression of tumors are linked to the process of pyroptosis. However, the precise involvement of pyroptosis-associated genes (PRGs) in endometrial cancer (EC) remains uncertain. 29 PRGs were identified as being either up-regulated or down-regulated in EC. PRGs subgroup analysis demonstrated distinct survival outcomes and diverse responses to chemotherapy and immune checkpoint blockade therapy. A higher expression of GPX4 and NOD2, coupled with lower levels of CASP6, PRKACA, and NLRP2, were found to be significantly associated with higher overall survival (OS) rates (p < 0.05). Conversely, lower expression of NOD2 was linked to lower progression-free survival (p = 0.021) and advanced tumor stage(p = 0.0024). NOD2, NLRP2, and TNM stages were identified as independent prognostic factors (p < 0.001). The LASSO prognostic model exhibited a notable decrease in OS among EC patients in the high-risk score group (ROC-AUC10-years: 0.799, p = 0.00644). Furthermore, NOD2 displayed a positive correlation with the infiltration of immune cells and the expression of immune checkpoints (p < 0.001). GPX4 and CASP6 are significantly associated with TMB and MSI (RTMB = 0.39; RMSI = 0.23). Additionally, a substantial upregulation of NOD2 was confirmed in both EC cells and tissue, indicating a positive relationship between advanced TNM stage (p < 0.0001) and infiltration of M1 phenotype macrophages. Nonetheless, its impact on patient OS did not reach statistical significance (p = 0.141). Our findings have contributed to the advancement of a prognostic model for EC patients. NOD2 receptor-mediated pyroptosis mechanism potentially regulates tumor immunity and promotes the transformation of macrophages from the M2 phenotype to the M1 phenotype, which significantly impacts the progression of EC.

The Potential of Gemini and GPTs for Structured Report Generation based on Free-Text 18F-FDG PET/CT Breast Cancer Reports.

RATIONALE AND OBJECTIVE: To compare the performance of large language model (LLM) based Gemini and Generative Pre-trained Transformers (GPTs) in data mining and generating structured reports based on free-text PET/CT reports for breast cancer after user-defined tasks. MATERIALS AND METHODS: Breast cancer patients (mean age, 50 years ± 11 [SD]; all female) who underwent consecutive 18F-FDG PET/CT for follow-up between July 2005 and October 2023 were retrospectively included in the study. A total of twenty reports from 10 patients were used to train user-defined text prompts for Gemini and GPTs, by which structured PET/CT reports were generated. The natural language processing (NLP) generated structured reports and the structured reports annotated by nuclear medicine physicians were compared in terms of data extraction accuracy and capacity of progress decision-making. Statistical methods, including chi-square test, McNemar test and paired samples t-test, were employed in the study. RESULTS: The structured PET/CT reports for 131 patients were generated by using the two NLP techniques, including Gemini and GPTs. In general, GPTs exhibited superiority over Gemini in data mining in terms of primary lesion size (89.6% vs. 53.8%, p < 0.001) and metastatic lesions (96.3% vs 89.6%, p < 0.001). Moreover, GPTs outperformed Gemini in making decision for progress (p < 0.001) and semantic similarity (F1 score 0.930 vs 0.907, p < 0.001) for reports. CONCLUSION: GPTs outperformed Gemini in generating structured reports based on free-text PET/CT reports, which is potentially applied in clinical practice. DATA AVAILABILITY: The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Parametric modeling and engineering application of the high-speed continuous beam bridge based on Building Information Modeling.

To improve the informatization and intelligence level of high-speed railway (HSR) bridge construction, a parametric modeling method for continuous beam bridges based on Building Information Modeling (BIM) is proposed in this study. By this method, the parametric families of continuous beam components and key construction machinery are established, and the rapid modeling of overall continuous beam bridge and the simulation of critical construction process are realized as well. Taking the Caoxian-Shangqiu bridge of Xiong'an-Shangqiu HSR as a case study, the parametric modeling method is applied to conduct the engineering application on the prestressed duct layout and rebar clash detection. The results indicate that the modeling efficiencies of HSR continuous beam bridge and construction machinery are significantly increased by the established parametric modeling method. Based on the BIM model of continuous beam bridge, the improvement in the precision of prestressed duct layout and the elimination of rebar clash points can be achieved. The research achievement can guide the visualization of construction disclosure, enhance construction efficiency, and provide reference and technical support for the construction management and control of HSR continuous beam bridges.

Effect of methylprednisolone in reducing severe COVID-19 and mortality in high-risk patients: A retrospective study.

Introduction: The treatment of COVID-19 patients, especially high-risk patients, remains a large challenge. Glucocorticoids have been accepted as effective medicines for severe COVID-19. However, the glucocorticoid usage guidelines do not cover all the indications for high-risk patients. Objective: To identify more effective treatments for high-risk patients with COVID-19, this retrospective study analyzed routine epidemiological, clinical, and laboratory data from 33 high-risk patients with COVID-19 in Beijing Gobroad Boren Hospital, Beijing, China, most of whom responded well to treatment. Methods: Severe acute respiratory syndrome coronavirus-2 infection was confirmed via real-time reverse transcriptase polymerase chain reaction assays. Outcome measures such as duration of mechanical ventilation, intensive care unit length of stay, and 28-day mortality were analyzed. Patients were divided into two groups: mild to moderate COVID-19 (n = 26) and severe COVID-19 (n = 7). Chest computed tomography images were used to guide methylprednisolone administration or withdrawal. Results: Upon intensive care unit admission, 12.1% of patients were mechanically ventilated with an average partial pressure of oxygen/fraction of inspired oxygen(PaO2/FiO2) ratio of 279 ± 146. No coinfections with other endemic viruses were observed. The duration of mechanical ventilation was 16 days (interquartile range: 8-28); the intensive care unit length of stay was 11 (interquartile range: 2-33) days; and the 28-day total mortality was 3.0%. Conclusion: Multivariate regression analysis revealed that low-dose, timely methylprednisolone administration was associated with a lower severe COVID-19 rate and mortality in high-risk patients. For high-risk patients, once there are ground-glass opacities (GGO) in the computed tomography image, continuous and low-dose methylprednisolone administration promotes inflammation remission and protects them from severe COVID-19 or mortality.

Enhanced IL-37-IL-1R8 axis is negatively associated with inflammatory and clinical severity of chronic rhinosinusitis with nasal polyps.

Background: The importance of IL-37 and downstream signal in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) demanding further investigation. Objective: We sought to address the potential importance of the IL-37-IL-1R8 axis in regulating inflammatory response in patients with CRSwNP. Methods: Nasal polyp (NP) tissues and control sinonasal tissues were obtained from adult CRSwNP, chronic rhinosinusitis without nasal polyps patients and healthy control subjects. The mRNA and protein levels of IL-37 and IL-1R8 in nasal tissues were examined by using quantitative PCR, immunohistochemical staining, and immunoblotting. In addition, the regulation of IL-1R8 expression was evaluated in human nasal epithelial cells (HNECs) in the presence of different stimuli. Results: The mRNA and protein levels of IL-37 and IL-1R8 were significantly elevated in nasal polyps compared with that in control tissues. IL-37 and IL-1R8 were mainly distributed in the epithelial layer and lamina propria of tissues. IL-1R8 mRNA level in nasal polys was negatively associated with eosinophil and neutrophil infiltration, as well as endoscopic score and computed tomography score. Moreover, the mRNA expression of IL-1R8 in HNECs was significantly increased by toll-like receptor agonists, but significantly inhibited by proinflammatory cytokines, which can be rescued by using steroid (DEX). Conclusion: Our findings showed that enhanced IL-37-IL-1R8 axis in NP tissues was negatively associated with inflammatory and clinical severity of CRSwNP patients, which could be considered as a future therapeutic target in CRSwNP patients.

High-purity butoxydibutylborane catalysts enable the low-exothermic polymerization of PMMA bone cement with enhanced biocompatibility and osseointegration.

Polymethyl methacrylate (PMMA) based biomaterials have been widely utilized in clinics. However, currently, PMMA catalyzed by benzoyl peroxide (BPO) exhibits disquieting disadvantages including an exothermic polymerization reaction and a lack of bioactivity. Here, we first designed three industrial-scale synthesis methods for high-purity butoxydibutylborane (BODBB), achieving purity levels greater than 95% (maximum: 97.6%) and ensuring excellent fire safety. By utilizing BODBB as a catalyst, the highest polymerization temperature of PMMA bone cement (PMMA-BODBB) reached only 36.05 °C, ensuring that no thermal damage occurred after implantation. Compared to PMMA catalyzed by BPO and partially oxidized tributylborane (TBBO, catalyst of Super Bond C&B), PMMA-BODBB exhibited superior cell adhesion, proliferation, and osteogenesis, attributed to the reduced release of free radicals and toxic monomer, and moderate bioactive boron release. After injection into a 5 mm defect in the rat cranial bone, PMMA-BODBB demonstrated the highest level of osteointegration. This work not only presents an industrial-scale synthesis of high-purity BODBB, but also offers an innovative PMMA biomaterial system with intrinsic biocompatibility and osseointegration, paving the way for the next generation of PMMA-based biomaterials with broader applications.

Inflammation unleashed: The role of pyroptosis in chronic liver diseases.

Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1ß, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1ß and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration.

Exposure to thimerosal induces behavioral abnormality in the early life stages of zebrafish via altering amino acid homeostasis.

Thimerosal (THI) has become a significant source of organic mercury pollutants in aquatic ecosystems, but there is limited information regarding its adverse effects on fish. In this study, zebrafish embryos were exposed to THI at 0 (control), 5.0, and 50 ng/L from 0-5 days post fertilization (dpf), and variations in their survival, development, behavior, free amino acid contents, and the biochemical responses involved in monoaminergic systems were examined. Although THI exposure did not significantly affect the survival, heart rate, or hatching time of zebrafish embryos, it substantially increased swimming velocity (136-154 % of the control) and reduced exploratory behavior (141-142 % of the control) in zebrafish larvae at 5 dpf. Exposure also significantly altered the amino acid contents (51-209 % of the control) and monoamine levels (70-154 % of the control) in zebrafish larvae, some of which displayed significant correlations with behavioral traits. THI significantly elevated dopamine receptor gene expression and monoamine oxidase activity in zebrafish larvae. Adding extra phenylalanine or tryptophan to the E3 medium facilitates the recovery of zebrafish larvae from the abnormal behaviors induced by THI. These findings reveal for the first time that THI exposure at the level of ng/L is sufficient to induce neurobehavioral toxic effects in the early life stages of zebrafish, and disrupting amino acid homeostasis is a critical underlying mechanism. This study provides valuable insights into the toxicity of THI to fish and highlights the importance of assessing its potential risks to aquatic ecosystems.

Strong and Fatigue-Resistant Carbon Nanotube Composites Enabled by Amorphous/Crystalline Heterophase Shell.

Lightweight materials with high strength and long cyclic lifespan are greatly demanded in practical applications, yet these properties are usually mutually exclusive. Here, we present a strong, lightweight, highly deformation-tolerant, and fatigue-resistant carbon nanotube (CNT) composite enabled by an amorphous/crystalline heterophase carbon shell. In particular, we obtain nanocrystallites with CNT-induced crystalline orientation uniformly embedded within an amorphous matrix by controlled thermal annealing. The heterophase carbon shell effectively alleviates the stress concentration and inhibits crack propagation, which renders our composite superior mechanical properties and high fatigue resistance (106 compression cycles at 20% strain with high stress of 144 kPa, or 5 × 105 cycles at 50% strain with stress up to 260 kPa). This study provides a deep understanding of amorphous-crystalline phase transition and insight into utilizing phase engineering to design and develop other high-performance functional materials such as structural materials and catalysis.

SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma.

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center, was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitive to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also conceptually broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

Oleanolic acid derivative self-assembled aggregates based on heparin and chitosan for breast cancer therapy.

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients.

A transcriptomics-based analysis of mechanisms involved in the sex-dependent effects of diazepam on zebrafish.

Diazepam (DZP) is a universally detected emerging pollutant in aquatic ecosystems. Although the sex-dependent effects of DZP on fish have been properly established, the underlying mechanisms remain unclear. In this study, zebrafish of both sexes were separately exposed to DZP (8 µg/L) for 21 days, and the alteration of the behaviors, brain amino acid neurotransmitter contents, and transcriptomic profiles were investigated. Although DZP exposure showed a sedative effect on both sexes, significantly reduced cumulative duration of high mobility and willingness to encounter the opposite sex were only observed in females. However, DZP significantly enhanced the brain levels of glutamate and glutamine in males but not in females. Transcriptome analysis identified more different expression genes (DEGs) in females (322 up-regulated and 311 down-regulated) than in males (138 up-regulated genes and 38 down-regulated). The DEGs in both sexes were significantly enriched in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway of the synaptic vesicle cycle, indicating a possible pathway for the sedative effects of DZP on zebrafish. DZP exhibited different or even opposing regulatory patterns on gene expression in the brains of females and males, providing some insights into its sex-dependent impacts on the behaviors and brain neurotransmitter contents in zebrafish. Moreover, enrichment analysis also suggested that DZP exposure may affect the oocyte maturation in female zebrafish, which highlights the need to study its reproductive and transgenerational toxicity to fish species.

Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.

Radiomics based on 18F-FDG PET/CT for prediction of pathological complete response to neoadjuvant therapy in non-small cell lung cancer.

Purpose: This study aimed to establish and evaluate the value of integrated models involving 18F-FDG PET/CT-based radiomics and clinicopathological information in the prediction of pathological complete response (pCR) to neoadjuvant therapy (NAT) for non-small cell lung cancer (NSCLC). Methods: A total of 106 eligible NSCLC patients were included in the study. After volume of interest (VOI) segmentation, 2,016 PET-based and 2,016 CT-based radiomic features were extracted. To select an optimal machine learning model, a total of 25 models were constructed based on five sets of machine learning classifiers combined with five sets of predictive feature resources, including PET-based alone radiomics, CT-based alone radiomics, PET/CT-based radiomics, clinicopathological features, and PET/CT-based radiomics integrated with clinicopathological features. Area under the curves (AUCs) of receiver operator characteristic (ROC) curves were used as the main outcome to assess the model performance. Results: The hybrid PET/CT-derived radiomic model outperformed PET-alone and CT-alone radiomic models in the prediction of pCR to NAT. Moreover, addition of clinicopathological information further enhanced the predictive performance of PET/CT-derived radiomic model. Ultimately, the support vector machine (SVM)-based PET/CT radiomics combined clinicopathological information presented an optimal predictive efficacy with an AUC of 0.925 (95% CI 0.869-0.981) in the training cohort and an AUC of 0.863 (95% CI 0.740-0.985) in the test cohort. The developed nomogram involving radiomics and pathological type was suggested as a convenient tool to enable clinical application. Conclusions: The 18F-FDG PET/CT-based SVM radiomics integrated with clinicopathological information was an optimal model to non-invasively predict pCR to NAC for NSCLC.

In-situ synthesis of heteroatom-doped hard carbon for sodium-ion batteries: Dual benefits for green energy and environment.

Heteroatom-doped carbon has been widely investigated as anode materials for sodium-ion batteries (SIBs). However, simplifying the preparation process and precisely controlling their microstructure to achieve excellent Na+ storage performance remain significant challenges. Therefore, in this study, high-performance N, P co-doped Na+ storage carbon anode electrode materials were prepared by one-step carbonization using N, P-rich Eichhornia crassipes (EC) as raw materials and systematically tested for their Na+ storage performance. The doping levels of N and P atoms as well as the spatial structure of the carbon material were adjusted by changing the carbonization temperature during the pyrolysis process. Among them, the anode material corresponding to 1300 °C (EC-PN1300) showed an excellent Na+ storage capacity of 336 ± 4 mAh g-1 (50 mA g-1) and excellent cycling stability (99.8 % retention after 2000 cycles). In addition, the Na+ storage mechanism of EC-PN1300 was systematically analyzed using galvanostatic intermittent titration (GITT), ex-situ XPS and in-situ Raman spectroscopy, providing accurate research directions for developing carbon anode electrode materials with superior electrochemical performance. This study not only provides some insights into the preparation of carbon anode materials in alkali metal batteries and the development of carbon materials in other fields, but also realizes the interaction between environmental protection and new energy development.