Differences in the effect of adolescents' strategies for expressing academic emotions on academic emotions and peer acceptance in competitive and cooperative situations.

Two studies were conducted to explore the differences in the effect of adolescents' strategies for expressing academic emotions. In Study 1 a total of 65 adolescents participated in the study of the relationship between academic emotions and strategies for expressing them in competitive and cooperative situations. In Study 2 a total of 113 adolescents participated in the study of the relationship between the strategies and peer acceptance in competitive and cooperative situations. The results showed that the relationship between academic emotions and strategies for expressing them in competitive and cooperative situations was situation stable while the relationship between the strategies and peer acceptance was situation specific. Furthermore, emotional expression may be more adaptive when experiencing positive academic emotions. When adolescents experience negative academic emotions, expressing them is more adaptive from the perspective of their own academic emotional experience; whereas suppressing them is more adaptive from the perspective of peer acceptance. These findings (a) clarify how to use more adaptive strategies for emotional expression in various situations and (b) serve as a guide for helping adolescents use strategies to express emotions flexibly according to the situation.

Amplifying Chinese physicians' emphasis on patients' psychological states beyond urologic diagnoses with ChatGPT-A multi-center cross-sectional study.

BACKGROUND: Artificial intelligence (AI) technologies, particularly large language models (LLMs), have been widely employed by the medical community. In addressing the intricacies of urology, ChatGPT offers a novel possibility to aid in clinical decision-making. This study aimed to investigate the decision-making ability of LLMs in solving complex urology-related problems and assess its effectiveness in providing psychological support to patients with urological disorders. MATERIALS AND METHODS: This study evaluated the clinical and psychological support capabilities of ChatGPT 3.5 and 4.0 in the field of urology. A total of 69 clinical and 30 psychological questions were posed to the AI models, and their responses were evaluated by both urologists and psychologists. As a control, clinicians from Chinese medical institutions provided responses under closed-book conditions. Statistical analyses were conducted separately for each subgroup. RESULTS: In multiple-choice tests covering diverse urological topics, ChatGPT 4.0, performed comparably to the physician group, with no significant overall score difference. Subgroup analyses revealed variable performance, based on disease type and physician experience, with ChatGPT 4.0 generally outperforming ChatGPT 3.5 and exhibiting competitive results against physicians. When assessing the psychological support capabilities of AI, it is evident that ChatGPT4.0 outperforms ChatGPT3.5 across all urology-related psychological problems. CONCLUSIONS: The performance of LLMs in dealing with standardized clinical problems and providing psychological support has certain advantages over clinicians. AI stands out as a promising tool for potential clinical aid.

Bacterial outer membrane vesicle nanorobot.

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains.

Omicron neutralization character in patients with breast cancer and liver cancer after the nationwide omicron outbreak.

BACKGROUND: The surge in omicron variants has caused nationwide breakthrough infections in mainland China since the December 2022. In this study, we report the neutralization profiles of serum samples from the patients with breast cancer and the patients with liver cancer who had contracted subvariant breakthrough infections. METHODS: In this real-world study, we enrolled 143 COVID-19-vaccinated (81 and 62 patients with breast and liver cancers) and 105 unvaccinated patients with cancer (58 and 47 patients with breast and liver cancers) after omicron infection. Anti-spike receptor binding domain (RBD) IgGs and 50% pseudovirus neutralization titer (pVNT50) for the preceding (wild type), circulating omicron (BA.4-BA.5, and BF.7), and new subvariants (XBB.1.5) were comprehensively analyzed. RESULTS: Patients with liver cancer receiving booster doses had higher levels of anti-spike RBD IgG against circulating omicron (BA.4-BA.5, and BF.7) and a novel subvariant (XBB.1.5) compared to patients with breast cancer after breakthrough infection. Additionally, all vaccinated patients produced higher neutralizing antibody titers against circulating omicron (BA.4-BA.5, and BF.7) compared to unvaccinated patients. However, the unvaccinated patients produced higher neutralizing antibody against XBB.1.5 than vaccinated patients after Omicron infection, with this trend being more pronounced in breast cancer than in liver cancer patients. Moreover, we found that there was no correlation between anti-spike RBD IgG against wildtype virus and the neutralizing antibody titer, but a positive correlation between anti-spike RBD IgG and the neutralizing antibody against XBB.1.5 was found in unvaccinated patients. CONCLUSION: Our study found that there may be differences in vaccine response and protective effect against COVID-19 infection in patients with liver and breast cancer. Therefore, we recommend that COVID-19 vaccine strategies should be optimized based on vaccine components and immunology profiles of different patients with cancer.

Twisted splitting and propagation factor of superimposed twisted Hermite-Gaussian Schell-model beams in turbulent atmosphere.

We believe this to be a new superposition twisted Hermite-Gaussian Schell-model (STHGSM) beam hat is proposed. Analytic formulas for the intensity distribution and propagation factor of the STHGSM beam in non-Kolmogorov turbulence are derived by utilizing the generalized Huygens-Fresnel principle (HFP) and the Wigner function. The evolution characteristics of STHGSM beams propagating are numerically calculated and analyzed. Our findings indicate that the light intensity of the STHGSM beam gradually undergoes splitting and rotation around the axis during propagation through non-Kolmogorov turbulence, eventually evolving into a diagonal lobe shape at a certain distance of transmission. The anti-turbulence capability of the beam strengthens with higher beam order or twist factor values.

Comparison of bladder carcinogenesis biomarkers in the urine of traditional cigarette users and e-cigarette users.

Background: During the use of electronic cigarettes (e-cigarettes), users are still exposed to carcinogens similar to those found in tobacco products. Since these carcinogens are metabolized and excreted in urine, they may have carcinogenic effects on the bladder urinary tract epithelium. This meta-analysis aimed to compare bladder cancer carcinogens in the urine of tobacco users and e-cigarette users using a large number of samples. Methods: A systematic meta-analysis was performed using data obtained from several scientific databases (up to November 2023). This cumulative analysis was performed following the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) and Assessing the Methodological Quality of Systematic Evaluations (AMSTAR) guidelines, according to a protocol registered with PROSPERO. This study was registered on PROSPERO and obtained the unique number: CRD42023455600. Results: The analysis included 10 high-quality studies that considered polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs) and tobacco-specific nitrosamines (TSNAs). Statistical indicators show that there is a difference between the tobacco user group and the e-cigarette user group in terms of 1-Hydroxynaphthalene (1-NAP) [weighted mean difference (WMD)10.14, 95% confidence interval (CI) (8.41 to 11.88), p < 0.05], 1-Hydroxyphenanthrene (1-PHE) [WMD 0.08, 95% CI (-0.14 to 0.31), p > 0.05], 1-Hydroxypyrene (1-PYR) [WMD 0.16, 95% CI (0.12 to 0.20), p < 0.05], 2-Hydroxyfluorene (2-FLU) [WMD 0.69, 95% CI (0.58 to 0.80), p < 0.05], 2-Hydroxynaphthalene (2-NAP) [WMD 7.48, 95% CI (4.15 to 10.80), p < 0.05], 3-Hydroxyfluorene (3-FLU) [WMD 0.57, 95% CI (0.48 to 0.66), p < 0.05], 2-Carbamoylethylmercapturic acid (AAMA) [WMD 66.47, 95% CI (27.49 to 105.46), p < 0.05], 4-Hydroxy-2-buten-1-yl-mercapturic acid (MHBMA) [WMD 287.79, 95% CI (-54.47 to 630.04), p > 0.05], 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNAL) [WMD 189.37, 95% CI (78.45 to 300.29), p < 0.05], or N0-nitrosonornicotine (NNN) [WMD 11.66, 95% CI (7.32 to 16.00), p < 0.05]. Conclusion: Urinary bladder cancer markers were significantly higher in traditional tobacco users than in e-cigarette users.Systematic review registration: PROSPERO (CRD42023455600: https://www.crd.york.ac.uk/PROSPERO/).

Shape Transformation of Polymer Vesicles.

Life activities, such as respiration, are accomplished through the continuous shape modulation of cells, tissues, and organs. Developing smart materials with shape-morphing capability is a pivotal step toward life-like systems and emerging technologies of wearable electronics, soft robotics, and biomimetic actuators. Drawing inspiration from cells, smart vesicular systems have been assembled to mimic the biological shape modulation. This would enable the understanding of cellular shape adaptation and guide the design of smart materials with shape-morphing capability. Polymer vesicles assembled by amphiphilic molecules are an example of remarkable vesicular systems. The chemical versatility, physical stability, and surface functionality promise their application in nanomedicine, nanoreactor, and biomimetic systems. However, it is difficult to drive polymer vesicles away from equilibrium to induce shape transformation due to the unfavorable energy landscapes caused by the low mobility of polymer chains and low permeability of the vesicular membrane. Extensive studies in the past decades have developed various methods including dialysis, chemical addition, temperature variation, polymerization, gas exchange, etc., to drive shape transformation. Polymer vesicles can now be engineered into a variety of nonspherical shapes. Despite the brilliant progress, most of the current studies regarding the shape transformation of polymer vesicles still lie in the trial-and-error stage. It is a grand challenge to predict and program the shape transformations of polymer vesicles. An in-depth understanding of the deformation pathway of polymer vesicles would facilitate the transition from the trial-and-error stage to the computing stage. In this Account, we introduce recent progress in the shape transformation of polymer vesicles. To provide an insightful analysis, the shape transformation of polymer vesicles is divided into basic and coupled deformation. First, we discuss the basic deformation of polymer vesicles with a focus on two deformation pathways: the oblate pathway and the prolate pathway. Strategies used to trigger different deformation pathways are introduced. Second, we discuss the origin of the selectivity of two deformation pathways and the strategies used to control the selectivity. Third, we discuss the coupled deformation of polymer vesicles with a focus on the switch and coupling of two basic deformation pathways. Last, we analyze the challenges and opportunities in the shape transformation of polymer vesicles. We envision that a systematic understanding of the deformation pathway would push the shape transformation of polymer vesicles from the trial-and-error stage to the computing stage. This would enable the prediction of deformation behaviors of nanoparticles in complex environments, like blood and interstitial tissue, and access to advanced architecture desirable for man-made applications.

Characteristics of urban network and city functions in the Yangtze River Delta Region: A multi-scale perspective.

The development of cities and regions emerges from the complex associations at various spatial levels, highlighting the importance of a multi-scale approach to analyzing regional urban networks. This study attempts to establish a new analysis framework encompassing national, regional, and local dimensions by employing a population flow network in the Yangtze River Delta in China. It explores the inter-city connections and spatial structures of regional urban networks as well as the correlations and differentiations of urban functions under multi-scale interaction. The results indicate that: (1) Regional network demonstrates notable multi-scale interactions with an explicit hierarchical structure; (2) The roles and positions of different cities vary significantly across scales due to economic, administrative, locational, and transportation differences; (3) Different city types can drive their evolution by navigating through rescaling in a diverse multi-scale environment; (4) A positive correlation is observed when comparing the functional behaviors of cities across various scales. This study provides insights for cities to identify their strategic roles and adapt development strategies within the wider network framework, offering theoretical and practical contributions to multi-scale urban networks analysis.

A real-world comparison of circulating tumor cells in breast cancer from China: Novel device, CTC counts and its overall survival.

Background: Both CellSearch and CellCollector have been accepted as the proper devices to capture CTC by domestic approval department. However, there is little article about the comparison between these two devices around the world. Herein, we conducted the real-world study to compare with these two devices and to re-verify the efficacy of CTC counts. Methods: Patients who meet the following points should be included in the analysis. 1. Female, aged 18 years or older; 2. Eastern Cooperative Oncology Group (ECOG) score 0-2; 3. With at least one measurable tumor lesion; 4. Clear immunohistochemistry result; 5. Accept at least one CTC test. Patients were excluded in the analysis if they had a history of malignant tumors, incomplete follow-up information. Results: 536 metastatic breast cancer patients who had been detected for CTC at least once by CellSearch or CellCollector were included in the analysis. CellCollector in vivo CTC detection technology has a higher detection rate than the CellSearch system (69.2% vs 57.4%, P = 0.009). However, the proportion of CTC≥5 detected by CellSearch was higher than CellCollector (37.4% vs 16.3%, P < 0.001). There was a statistically significant difference in overall survival of patients with CTC negative and CTC positive (mOS:49.8 months vs 26.9 months). After 4 weeks of treatment, when CTC decreased by more than 50%, there was a significant difference in survival between the two groups (40.1 months vs 25.8 months, HR = 0.588, 95% CI: 0.350-0.933). In addition, for HER2-positive patients, Patients with CTC HER2 positive had longer overall survival than patients with CTC HER2 negative (median OS: 26.7 months vs 17.3 month, HR = 0.528, 95% CI: 0.269-0.887). Conclusions: Real-world data indicate that CTC is an independent prognostic factor, and CellCollector and CellSearch have their own advantages in CTC detection.

Rhizosphere-Associated Anammox Bacterial Diversity and Abundance of Nitrogen Cycle-Related Functional Genes of Emergent Macrophytes in Eutrophic Wetlands.

Rhizospheric microbial community of emergent macrophytes plays an important role in nitrogen removal, especially in the eutrophic wetlands. The objective of this study was to identify the differences in anammox bacterial community composition among different emergent macrophytes and investigate revealed the the main factors affecting on the composition, diversity, and abundance of anammox bacterial community. Results showed that the composition, diversity, and abundance of the anammox community were significantly different between the vegetated sediments of three emergent macrophytes and unvegetated sediment. The composition of the anammox bacterial community was different in the vegetated sediments of different emergent macrophytes. Also, the abundance of nitrogen cycle-related functional genes in the vegetated sediments was found to be higher than that in the unvegetated sediment. Canonical correspondence analysis (CCA) and structural equation models analysis (SEM) showed that salinity and pH were the main environmental factors influencing the composition and diversity of the anammox bacterial community and NO2--N indirectly affected anammox bacterial community diversity by affecting TOC. nirK-type denitrifying bacteria abundance had significant effects on the bacterial community composition, diversity, and abundance of anammox bacteria. The community composition of anammox bacteria varies with emergent macrophyte species. The rhizosphere of emergent macrophytes provides a favorable environment and promotes the growth of nitrogen cycling-related microorganisms that likely accelerate nitrogen removal in eutrophic wetlands.

Thermophoretic glycan profiling of extracellular vesicles for triple-negative breast cancer management.

Triple-negative breast cancer (TNBC) is a highly metastatic and heterogeneous type of breast cancer with poor outcomes. Precise, non-invasive methods for diagnosis, monitoring and prognosis of TNBC are particularly challenging due to a paucity of TNBC biomarkers. Glycans on extracellular vesicles (EVs) hold the promise as valuable biomarkers, but conventional methods for glycan analysis are not feasible in clinical practice. Here, we report that a lectin-based thermophoretic assay (EVLET) streamlines vibrating membrane filtration (VMF) and thermophoretic amplification, allowing for rapid, sensitive, selective and cost-effective EV glycan profiling in TNBC plasma. A pilot cohort study shows that the EV glycan signature reaches 91% accuracy for TNBC detection and 96% accuracy for longitudinal monitoring of TNBC therapeutic response. Moreover, we demonstrate the potential of EV glycan signature for predicting TNBC progression. Our EVLET system lays the foundation for non-invasive cancer management by EV glycans.

Estimation of wheat protein content and wet gluten content based on fusion of hyperspectral and RGB sensors using machine learning algorithms.

The protein content (PC) and wet gluten content (WGC) are crucial indicators determining the quality of wheat, playing a pivotal role in evaluating processing and baking performance. Original reflectance (OR), wavelet feature (WF), and color index (CI) were extracted from hyperspectral and RGB sensors. Combining Pearson-competitive adaptive reweighted sampling (CARs)-variance inflation factor (VIF) with four machine learning (ML) algorithms were used to model accuracy of PC and WGC. As a result, three CIs, six ORs, and twelve WFs were selected for PC and WGC datasets. For single-modal data, the back-propagation neural network exhibited superior accuracy, with estimation accuracies (WF > OR > CI). For multi-modal data, the random forest regression paired with OR + WF + CI showed the highest validation accuracy. Utilizing the Gini impurity, WF outweighed OR and CI in the PC and WGC models. The amalgamation of MLs with multimodal data harnessed the synergies among various remote sensing sources, substantially augmenting model precision and stability.

Acyl carrier protein OsMTACP2 confers rice cold tolerance at the booting stage.

Low temperatures occurring at the booting stage in rice (Oryza sativa L.) often result in yield loss by impeding male reproductive development. However, the underlying mechanisms by which rice responds to cold at this stage remain largely unknown. Here, we identified MITOCHONDRIAL ACYL CARRIER PROTEIN 2 (OsMTACP2), the encoded protein of which mediates lipid metabolism involved in the cold response at the booting stage. Loss of OsMTACP2 function compromised cold tolerance, hindering anther cuticle and pollen wall development, resulting in abnormal anther morphology, lower pollen fertility, and seed setting. OsMTACP2 was highly expressed in tapetal cells and microspores during anther development, with the encoded protein localizing to both mitochondria and the cytoplasm. Comparative transcriptomic analysis revealed differential expression of genes related to lipid metabolism between the wild type and the Osmtacp2-1 mutant in response to cold. Through a lipidomic analysis, we demonstrated that wax esters, which are the primary lipid components of the anther cuticle and pollen walls, function as cold-responsive lipids. Their levels increased dramatically in the wild type but not in Osmtacp2-1 when exposed to cold. Additionally, mutants of two cold-induced genes of wax ester biosynthesis, ECERIFERUM1 and WAX CRYSTAL-SPARSE LEAF2, showed decreased cold tolerance. These results suggest that OsMTACP2-mediated wax ester biosynthesis is essential for cold tolerance in rice at the booting stage.

A Modified Arthroscopic Triple-row Repair Technique for L-shaped Delaminated Rotator Cuff Tears.

OBJECTIVE: To compare the clinical outcomes of a modified arthroscopic triple-row (TR) repair technique with the suture bridge (SB) repair technique in treating L-shaped delaminated rotator cuff tears. Various surgical techniques for L-shaped delaminated rotator cuff tears have been reported, many of which aid in increasing the contact area and pressure of the rotator cuff. However, there is still debate over which technique yields superior results. METHODS: From January 2017 to March 2020, 61 cases of L-shaped delaminated rotator cuff tears were included in this study. Of these, 34 cases underwent the modified arthroscopic triple-row repair technique, while 27 cases were addressed with the suture bridge repair technique. Functional assessment was conducted using the American Shoulder and Elbow Surgeons (ASES) score, the University of California Los Angeles (UCLA) shoulder score, the Constant score (CS), and the visual analogue scale (VAS) score. Magnetic Resonance Imaging (MRI) assessments for rotator cuff healing were performed at the 24-month postoperative mark. Statistical evaluations were conducted using SPSS for Windows (Version 25.0, IBM, Armonk, NY, USA), employing the Wilcoxon signed-rank test to compare preoperative and postoperative data and ROM differences, and the Mann-Whitney U test for statistical differences in clinical outcome scores between the two groups. A p-value of less than 0.05 was considered statistically significant. RESULTS: Comparative analysis of the preoperative and final follow-up scores revealed a substantial enhancement in shoulder function, as indicated by the ASES, UCLA, CS, and VAS scores, with statistical significance (p < 0.001). At both the preoperative stage and final follow-up, no notable differences were observed in ASES, UCLA, CS, and VAS scores between the two groups. However, the TR repair group exhibited lower VAS scores than the SB group at 1 and 3 months postoperatively. Active range of motion (ROM) showed significant improvement in both groups. No significant differences in ROM were noted between the two groups either before the surgery or at the final follow-up. CONCLUSION: The study demonstrates that both the modified arthroscopic TR and SB techniques for L-shaped delaminated cuff tears yield satisfactory outcomes, with no significant differences in overall clinical performance. Notably, early postoperative pain management appears more effective with the modified TR technique, suggesting its potential for enhanced early recovery experiences. This technique's design, promoting securer fixation and optimal contact conditions, is implied to facilitate superior long-term healing, warranting further investigation into its long-term benefits.

Electroactive nanofibrous membrane with antibacterial and deodorizing properties for air filtration.

Water vapor from respiration can severely accelerate the charge dissipation of the face mask, reducing filtration efficiency. Moreover, the foul odor from prolonged mask wear tends to make people remove their masks, leading to the risk of infection. In this study, an electro-blown spinning electroactive nanofibrous membrane (Zn/CB@PAN) with antibacterial and deodorization properties was prepared by adding zinc (Zn) and carbon black (CB) nanoparticles to the polyacrylonitrile (PAN) nanofibers, respectively. The filtration efficiency of Zn/CB@PAN for PM0.3 was > 99% and could still maintain excellent durability within 4 h in a high-humidity environment (25 â„ƒ and RH = 95%). Moreover, the bacterial interception rate of the Zn/CB@PAN could reach 99.99%, and it can kill intercepted bacteria. In addition, the deodorization rate of Zn/CB@PAN in the moist state for acetic acid was 93.75% and ammonia was 95.23%, respectively. The excellent filtering, antibacterial, and deodorizing performance of Zn/CB@PAN can be attributed to the synergistic effect of breath-induced Zn/CB galvanic couples' electroactivity, released metal ions, and generated reactive oxygen species. The developed Zn/CB@PAN could capture and kill airborne environmental pathogens under humid environments and deodorize odors from prolonged wear, holding promise for broad applications as personal protective masks.

Enhanced Artificial Intelligence Strategies in Renal Oncology: Iterative Optimization and Comparative Analysis of GPT 3.5 Versus 4.0.

BACKGROUND: The rise of artificial intelligence (AI) in medicine has revealed the potential of ChatGPT as a pivotal tool in medical diagnosis and treatment. This study assesses the efficacy of ChatGPT versions 3.5 and 4.0 in addressing renal cell carcinoma (RCC) clinical inquiries. Notably, fine-tuning and iterative optimization of the model corrected ChatGPT's limitations in this area. METHODS: In our study, 80 RCC-related clinical questions from urology experts were posed three times to both ChatGPT 3.5 and ChatGPT 4.0, seeking binary (yes/no) responses. We then statistically analyzed the answers. Finally, we fine-tuned the GPT-3.5 Turbo model using these questions, and assessed its training outcomes. RESULTS: We found that the average accuracy rates of answers provided by ChatGPT versions 3.5 and 4.0 were 67.08% and 77.50%, respectively. ChatGPT 4.0 outperformed ChatGPT 3.5, with a higher accuracy rate in responses (p < 0.05). By counting the number of correct responses to the 80 questions, we then found that although ChatGPT 4.0 performed better (p < 0.05), both versions were subject to instability in answering. Finally, by fine-tuning the GPT-3.5 Turbo model, we found that the correct rate of responses to these questions could be stabilized at 93.75%. Iterative optimization of the model can result in 100% response accuracy. CONCLUSION: We compared ChatGPT versions 3.5 and 4.0 in addressing clinical RCC questions, identifying their limitations. By applying the GPT-3.5 Turbo fine-tuned model iterative training method, we enhanced AI strategies in renal oncology. This approach is set to enhance ChatGPT's database and clinical guidance capabilities, optimizing AI in this field.

Efficacy, Safety, and Population Pharmacokinetics of MW032 Compared With Denosumab for Solid Tumor-Related Bone Metastases: A Randomized, Double-Blind, Phase 3 Equivalence Trial.

Importance: The bioequivalence of denosumab biosimilar has yet to be studied in a 53-week, multicenter, large-scale, and head-to-head trial. A clinically effective biosimilar may help increase access to denosumab in patients with solid tumor-related bone metastases. Objectives: To establish the biosimilarity of MW032 to denosumab in patients with solid tumor-related bone metastases based on a large-scale head-to-head study. Design, Setting, and Participants: In this 53-week, randomized, double-blind, phase 3 equivalence trial, patients with solid tumors with bone metastasis were recruited from 46 clinical sites in China. Overall, 856 patients were screened and 708 eligible patients were randomly allocated to receive either MW032 or denosumab. Interventions: Patients were randomly assigned (1:1) to receive MW032 or reference denosumab subcutaneously every 4 weeks until week 49. Main Outcomes and Measures: The primary end point was percentage change from baseline to week 13 of natural logarithmic transformed urinary N-telopeptide/creatinine ratio (uNTx/uCr). Results: Among the 701 evaluable patients (350 in the MW032 group and 351 in the denosumab group), the mean (range) age was 56.1 (22.0-86.0) years and 460 patients were women (65.6%). The mean change of uNTx/uCr from baseline to week 13 was -72.0% (95% CI, -73.5% to -70.4%) in the MW032 group and -72.7% (95% CI, -74.2% to -71.2%) in the denosumab group. These percent changes corresponded to mean logarithmic ratios of -1.27 and -1.30, or a difference of 0.02. The 90% CI for the difference (-0.04 to 0.09) was within the equivalence margin (-0.13 to 0.13); the mean changes of uNTx/uCr and bone-specific alkaline phosphatase (s-BALP) at each time point were also similar during 53 weeks. The differences of uNTx/uCr change were 0.015 (95% CI, -0.06 to 0.09), -0.02 (95% CI, -0.09 to 0.06), -0.05 (95% CI, -0.13 to 0.03) and 0.001 (95% CI, -0.10 to 0.10) at weeks 5, 25, 37, and 53, respectively. The differences of s-BALP change were -0.006 (95% CI, 0.06 to 0.05), 0.00 (95% CI, -0.07 to 0.07), -0.085 (95% CI, -0.18 to 0.01), -0.09 (95% CI, -0.20 to 0.02), and -0.13 (95% CI, -0.27 to 0.004) at weeks 5, 13, 25, 37 and 53, respectively. No significant differences were observed in the incidence of skeletal-related events (-1.4%; 95% CI, -5.8% to 3.0%) or time to first on-study skeletal-related events (unadjusted HR, 0.86; P = .53; multiplicity adjusted HR, 0.87; P = .55) in the 2 groups. Conclusions and Relevance: MW032 and denosumab were biosimilar in efficacy, population pharmacokinetics, and safety profile. Availability of denosumab biosimilars may broaden the access to denosumab and reduce the drug burden for patients with advanced tumors. Trial Registration: ClinicalTrials.gov Identifier: NCT04812509.

Continuous genetic monitoring of transient mesenchymal gene activities in distal tubule and collecting duct epithelial cells during renal fibrosis.

Epithelial cells (ECs) have been proposed to contribute to myofibroblasts or fibroblasts through epithelial-mesenchymal transition (EMT) during renal fibrosis. However, since EMT may occur dynamically, transiently, and reversibly during kidney fibrosis, conventional lineage tracing based on Cre-loxP recombination in renal ECs could hardly capture the transient EMT activity, yielding inconsistent results. Moreover, previous EMT research has primarily focused on renal proximal tubule ECs, with few reports of distal tubules and collecting ducts. Here, we generated dual recombinases-mediated genetic lineage tracing systems for continuous monitoring of transient mesenchymal gene expression in E-cadherin+ and EpCAM+ ECs of distal tubules and collecting ducts during renal fibrosis. Activation of key EMT-inducing transcription factor (EMT-TF) Zeb1 and mesenchymal markers αSMA, vimentin, and N-cadherin, were investigated following unilateral ureteral obstruction (UUO). Our data revealed that E-cadherin+ and EpCAM+ ECs did not transdifferentiate into myofibroblasts, nor transiently expressed these mesenchymal genes during renal fibrosis. In contrast, in vitro a large amount of cultured renal ECs upregulated mesenchymal genes in response to TGF-ß, a major inducer of EMT.