Objective: To characterize longitudinal trajectories of testicular development in boys and breast development in girls, so as to provide reference data for understanding patterns of pubertal sexual maturation. Methods: Based on the Shanghai Pudong New Area Cohort Study on Growth, Development and Health in Children and Adolescents, a baseline survey was conducted in 2020 using a mult stage cluster random sampling method. A total of 2 184 children who completed all follow ups during the primary school period from 13 elementary schools in Pudong New Area,Shanghai,with annual follow ups during 2021-2025. Testicular volume and Tanner stage of breast development were assessed by professional physicians using standardized visual inspection and palpation. The age distribution of testicular volume and breast development was fitted by using cumulative link mixed models and Turnbull s nonparametric maximum likelihood estimation method. Results: Median ages for testicular volumes of 2, 3, 4 and 5 mL in boys were 7.07, 9.24, 10.29, and 11.57 years old, respectively. Median ages for Tanner breast stages Ⅱ, Ⅲ, Ⅳ, and Ⅴ in girls were 8.55 , 10.17, 11.18, and 13.78 years old, respectively. Based on overweight and obesity, stratified analysis showed that earlier pubertal onset among overweight/obesity children, and the key milestones for pubertal initiation were testicular volume reaching 4 mL in boys and breast Tanner II in girls for 10.29, 10.83; 8.18, 9.00 years. Conclusion Overweight and obesity are associated with earlier pubertal initiation,but there are certain gender and developmental stage specific patterns.

ObjectiveThis paper aims to observe the syndrome improvement and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome）. MethodsThrough a multi-center randomized controlled methodology design，confirmed influenza cases were collected from October 2022 to April 2023 in the pediatrics department of eight hospitals，such as Dongfang Hospital of Beijing University of Chinese Medicine. A total of 180 children with influenza and heat accumulation in the lung and stomach syndrome conforming to the standard were recruited through the clinic. The sick children meeting the inclusion criteria were randomly divided into groups by a block-randomized method. The children in the experimental group were treated with Qingxuan Daozhi formula for five days，and those in the control group were treated with Oseltamivir Phosphate Granules for five days. The primary efficacy indicator was the negative conversion rate of influenza antigen detection. Secondary efficacy indicators were the Canadian acute respiratory illness and flu scale （CARIFS） and the incidence of complications，severe cases， and critical cases. Follow-up observation was conducted on the day of enrollment，48 hours after medication，72 hours after medication， and （6+1） d after medication. ResultsOne hundred and eighty participants were randomly assigned to the experimental group （90 cases） or the control group （90 cases）. All participants were followed up during the study. Comparison of influenza antigen detection results in the primary efficacy indicators showed that the average time of negative influenza antigen conversion in the experimental group was （5.29±1.25） d，and that in the control group was （5.40±1.68） d，without a statistically significant difference. After five days of intervention，52 cases in the experimental group and 51 cases in the control group converted to negative，without a statistically significant difference. CARIFS score results in the secondary efficacy indicators showed that during 72 hours after intervention，there were statistically significant differences between the experimental group and the control group in three dimensions， including headache，muscle soreness， and the need for extra care （P<0.05）. On the （6+1） days after the intervention，the differences in both the experimental group and the control group were statistically significant in 10 dimensions， including sore throat，bad sleep，uncomfortable feeling，poor spirit and fatigue，crying more than usual，the need for extra care，symptom，function，influence on parents，and total score （P<0.05）. The comparison results within the group in the dimensional scores of symptom， function， and influence on parents，as well as the CARIFS total score showed that with the delay of follow-up time，scores of both groups decreased significantly，with a statistically significant difference （P<0.01）. Inter-group comparison results showed that the mean score of the experimental group was higher than that of the control group at the time of enrollment. With the progress of intervention，the score of the experimental group was significantly decreased compared with that of the control group. At the end of follow-up，the mean score of the experimental group was lower than that of the control group，with no statistically significant difference. In terms of the incidence of complications，severe cases， and critical cases， there were no complications，severe cases， and critical cases in the two groups，without a statistically significant difference. ConclusionThe symptom improvement effect and negative antigen conversion rate of Qingxuan Daozhi formula in the treatment of influenza in children （heat accumulation in the lung and stomach syndrome） are not inferior to Oseltamivir Phosphate granules， and children's acceptance is better. It can be more widely used in clinical treatment of influenza in children （heat accumulation in the lung and stomach syndrome）.

The digitization of traditional Chinese medicine (TCM) has generated vast amounts of data. However, these data are characterized by significant heterogeneity and complex semantic structures, posing substantial challenges for systematic integration and intelligent analysis, and limiting its potential for modern clinical and computational research. To address the challenges posed by the high heterogeneity and complex structure in TCM data, we designed and developed the TCM Data Hub platform, which is powered by the YiYuan large language models (LLMs). This platform aims to enhance intelligent data processing capabilities and unlock the potential for clinical application of TCM data through systematic integration and efficient utilization, thereby bridging the gap between traditional knowledge and modern computational research. This study first analyzed the heterogeneity and complexity of TCM information with respect to data types, structures, and semantics. A standardized data framework was constructed to enhance data integration and interoperability. Based on the TCM Intelligent Computing Platform of the China Academy of Chinese Medical Sciences, we trained the YiYuan LLMs to acquire domain-specific semantic understanding of TCM, thereby improving the platform’s comprehension of specialized terminology and knowledge systems. Leveraging the natural language processing capabilities of the LLMs, we developed a human-in-the-loop data processing system to enable efficient extraction, cleansing, and structured organization of TCM data. In addition, utilizing Vue and Java technologies, we developed multiple LLM-powered intelligent agents and systems, including a human-in-the-loop data processing system, as well as automated prescription mining and network pharmacology analysis agents. Task-specific agents tailored to TCM data processing were developed to enhance the model’s effectiveness in clinical knowledge discovery. System functionality and platform infrastructure were implemented using Java and Vue technologies.The TCM Data Hub platform has completed system construction and core functionality implementation. It supported integrated management and efficient access to 8 key types of TCM data: prescriptions, materia medica, ingredients, targets, diseases (Western medicine), diseases (TCM), syndromes, and therapeutic methods. The human-in-the-loop data processing system achieved an accuracy of 95.34% in structuring TCM data and supported annotation for data requiring manual labeling. The intelligent agent-driven big-data analytics module enabled 1-click, end-to-end workflows for TCM prescription mining, herb-syndrome association analysis, network pharmacology, and molecular biology research, completing a full data mining task in approximately 30 minutes. Users can interact with and manipulate data through a visual front-end interface. The system demonstrated stable performance, strong scalability, and a user-friendly experience. Empowered by the YiYuan LLMs, the TCM Data Hub platform significantly improves the accessibility, usability, and intelligence of TCM data. It effectively bridges traditional TCM knowledge with modern intelligent technologies, providing robust data support and intelligent tools for TCM research and clinical applications.

Objective: To determine the potential genetic causal relationship between sleep related phenotypes and female pubertal onset using the two sample Mendelian randomization approach. Methods: Genetic instrumental variables for sleep and age at menarche were sourced from FinnGen, IEU Open GWAS and GWAS Catalog three publicly available Genome Wide Association Study databases. Causal effects were estimated using the inverse variance weighted method, supplemented by sensitivity analyses and tests for heterogeneity, pleiotropy, and direction. Results: Genetically predicted sleep duration was positively associated with age at menarche ( β =0.61, 95% CI =0.30-0.91, P <0.01). Conversely, overall sleep problems ( β =-0.13, 95% CI =-0.20 to -0.07 ), two specific types of sleep disorders (sleep apnea: β =-0.10, 95% CI =-0.16 to -0.03; insomnia: β =-0.40, 95% CI = -0.69 to -0.11) were causally associated with earlier age at menarche (all P <0.01). Sensitivity analyses confirmed the robustness of these findings with consistent effect directions and no evidence of significant directional pleiotropy. Conclusions The study reveales a genetic causal relationship between sleep and pubertal onset. Adequate sleep duration appears to have a protective effect. These findings suggest that sleep may have a critical regulatory role in the initiation of pubertal development.

With the rapid advancement of medical technology and the increasing complexity of clinical environments, competence in clinical ethical decision-making has become an indispensable core competency for exemplary physicians. However, traditional medical ethics education has long been confronted with the persistent challenges of theory-practice dissociation and the disconnect between pedagogical settings and clinical realities. Thus, how to construct a "Clinical Ethics" curriculum that aligns with the objectives of training high-caliber medical professionals has emerged as a critical and challenging issue in current medical education reform. To effectively address this challenge, the Office of Education at Peking University Third Hospital, since 2021, has assembled a multidisciplinary "Clinical Ethics" teaching and management team comprising faculty from Peking University School of Humanities and key clinical specialists from the hospital. In 2022, the "Clinical Ethics" elective course was formally launched for fourth-year students in the eight-year MD program who had completed coursework in "Medical Ethics" and organ-system-based curricula, with the aim of exploring and operationalizing a pre-clinical ethics education model tailored for senior medical students. The course employs a modular instructional design encompassing "theoretical review-case-based deliberation-clinical workshop", which effectively facilitates the deep integration of medical humanities with clinical practice.Following four years of iterative refinement through the "plan-act-observe-reflect" cycle, the course has demonstrated positive outcomes in enhancing students' ethical awareness and decision-making capabilities, and has preliminarily established a sustainable collaborative mechanism among the multidisciplinary faculty team. This article systematically delineates the course development background, pedagogical model and methodological innovations, and the multidisciplinary collaborative framework, alongside reflections and summaries based on implementation outcomes, with the intent of providing references for the future development of "Clinical Ethics" curricula.

Thrombospondin 4 (THBS4; TSP4), a crucial component of the extracellular matrix (ECM), serves as an important regulator of tissue homeostasis and various pathophysiological processes. As a member of the evolutionarily conserved thrombospondin family, THBS4 is a multidomain adhesive glycoprotein characterized by six distinct structural domains that mediate its diverse biological functions. Through dynamic interactions with various ECM components, THBS4 plays pivotal roles in cell adhesion, proliferation, inflammation regulation, and tissue remodeling, establishing it as a key modulator of microenvironmental organization. The transcription and translation of THBS4 gene, as well as the activity of the THBS4 protein, are tightly regulated by multiple signaling pathways and extracellular cues. Positive regulators of THBS4 include transforming growth factor-β (TGF-β), interferon-γ (IFNγ), granulocyte-macrophage colony-stimulating factor (GM-CSF), bone morphogenetic proteins (BMP12/13), and other regulatory factors (such as B4GALNT1, ITGA2/ITGB1, PDGFRβ, etc.), which upregulate THBS4 at the mRNA and/or protein level. Conversely, oxidized low-density lipoprotein (OXLDL) acts as a potent negative regulator of THBS4. This intricate regulatory network ensures precise spatial and temporal control of THBS4 expression in response to diverse physiological and pathological stimuli. Functionally, THBS4 acts as a critical signaling hub, influencing multiple downstream pathways essential for cellular behavior and tissue homeostasis. The best-characterized pathways include: (1) the PI3K/AKT/mTOR axis, which THBS4 modulates through both direct and indirect interactions with integrins and growth factor receptors; (2) Wnt/β-catenin signaling, where THBS4 functions as either an activator or inhibitor depending on the cellular context; (3) the suppression of DBET/TRIM69, contributing to its diverse regulatory roles. These signaling connections position THBS4 as a master regulator of cellular responses to microenvironmental changes. Substantial evidence links aberrant THBS4 expression to a range of pathological conditions, including neoplastic diseases, cardiovascular disorders, fibrotic conditions, neurodegenerative diseases, musculoskeletal disorders, and atopic dermatitis. In cancer biology, THBS4 exhibits context-dependent roles, functioning either as a tumor suppressor or promoter depending on the tumor type and microenvironment. In the cardiovascular system, THBS4 contributes to both adaptive remodeling and maladaptive fibrotic responses. Its involvement in fibrotic diseases arises from its ability to regulate ECM deposition and turnover. The diagnostic and therapeutic potential of THBS4 is particularly promising in oncology and cardiovascular medicine. As a biomarker, THBS4 expression patterns correlate significantly with disease progression and patient outcomes. Therapeutically, targeting THBS4-mediated pathways offers novel opportunities for precision medicine approaches, including anti-fibrotic therapies, modulation of the tumor microenvironment, and enhancement of tissue repair. This comprehensive review systematically explores three key aspects of THBS4 research(1) the fundamental biological functions of THBS4 in ECM organization; (2) its mechanistic involvement in various disease pathologies; (3) its emerging potential as both a diagnostic biomarker and therapeutic target. By integrating recent insights from molecular studies, animal models, and clinical investigations, this review provides a framework for understanding the multifaceted roles of THBS4 in health and disease. The synthesis of current knowledge highlights critical research gaps and future directions for exploring THBS4-targeted interventions across multiple disease contexts. Given its unique position at the intersection of ECM biology and cellular signaling, THBS4 represents a promising frontier for the development of novel diagnostic tools and therapeutic strategies in precision medicine.

Objective To analyze the effect of Hsa-circ-0101216 on gemcitabine(GEM)chemotherapy resistance in pancreatic cancer and its mechanism.Methods Differentially expressed circRNAs between GEM-resistant pancreatic cancer cells and parent cells were screened using the GEO database.Pancreatic cancer GEM resistant cell lines(BxPC-3-GEM and Capan-1-GEM)were constructed by intermittent concentration gradient method.qRT-PCR was used to detect the expression of Hsa-circ-0101216 in cells.GEM resistant pancreatic cancer cell lines were taken and divided into sh-circ-0101216 group(knockdown of circ-0101216),sh-NC group(transfected with sh-NC),and blank control group(untreated).CCK-8 assay and EdU proliferation assay were used to detect the half inhibitory concentration(IC50)of GEM and proliferation ability of cells in each group.Western blotting was performed to detect the expression of multidrug resistance-related protein 1(MRP1),breast cancer resistance protein(BCRP),and human equilibrative nucleoside transporter-1(hENT-1).A subcutaneous xenograft tumor model of human pancreatic cancer in nude mice was constructed,and sh-NC+GEM group and sh-circ-0101216+GEM group(n=6)were set up.The volume and weight of xenograft tumor in nude mice were compared between the two groups.Western blotting and immunohistochemistry were used to detect the expression of MRP1,BCRP,and hENT-1 proteins in xenograft tumor tissues,and EDU proliferation assay was used to detect the proliferation ability of tumor cells.Results The GEO database screening showed that Hsa-circ-0101216 was up-regulated in GEM-resistant pancreatic cancer cell lines.Pancreatic cancer GEM-resistant cell lines were successfully constructed,and the expression levels of Hsa-circ-0101216 and the IC50 value in GEM-resistant pancreatic cancer cells BxPC-3-GEM and Capan-1-GEM were significantly higher than those in parental cells(P<0.05).In sh-circ-0101216 group,the IC50 values of GEM,cell viability,EdU positivity rate,and the expression levels of MRP1 and BCRP proteins in GEM-resistant pancreatic cancer cells BxPC-3-GEM and Capan-1-GEM were significantly lower than those in blank control group and sh-NC group,while the expression level of hENT-1 protein was significantly higher(P<0.05 or P<0.001).In sh-circ-0101216+GEM group,the weight and volume of subcutaneous xenograft tumors in nude mice,the expression levels and positive expression rates of MRP1 and BCRP proteins in tumor tissues,and the EdU positive rate were significantly lower than those in sh-NC+GEM group,while the expression level and positive expression rate of hENT-1 protein were significantly higher(P<0.05).Conclusions Hsa-circ-0101216 is highly expressed in GEM-resistant pancreatic cancer cell lines.Its knockdown can inhibit the proliferation of pancreatic cancer cells and enhance the chemosensitivity of pancreatic cancer cells to GEM.The mechanism may be related to the regulation of transmembrane transporter protein expression.

Objective To investigate the correlations of calmodulin 1(CNN1)and asymmetric dimethylarginine(ADMA)expression with Wnt/β-catenin pathway in tissues of gastric cancer and their values for prognosis.Methods Surgical specimens and serum samples from 110 patients with gastric cancer,along with serum samples from 60 healthy individuals in the hospital were collected.Immunohistochemistry and real-time fluorescent quantitative PCR were used to detect the expression levels of CNN1 protein and CNN1 mRNA in gastric cancer tissues respectively;the enzyme-linked immunosorbent assay(ELISA)was used to detect the expression of ADMA in the serum of gastric cancer patients.The relationships of the CNN1 and ADMA expression with the clinicopathological characteristics in gastric cancer patients were analyzed.Kaplan-Meier survival curve was used to an-alyze the influence of CNN1 and ADMA expression on prognosis of gastric cancer patients;Cox re-gression analysis was used to explore independent factors affecting the prognosis of gastric cancer pa-tients;the Pearson correlation analysis was used to explore the correlation between CNN1 and ADMA expression in gastric cancer tissues,and to analyze the correlations of CNN1 mRNA and ADMA mRNA with Wnt/β-catenin signaling pathway-related indicators.Results The positive ex-pression rate of CNN1 protein in gastric cancer tissues was 38.18％(42/110),which was signifi-cantly lower than 57.27％(63/110)in adjacent tissues(x2=8.035,P=0.005).The serum ADMA level in gastric cancer patients was(0.54±0.17)μmol/L,which was significantly higher than(0.42±0.14)μmol/L in healthy individuals(t=4.752,P＜0.001).Patients with lymph node metastasis and advanced tumor stages had significantly decreased CNN1 protein positivity in gastric cancer tissues and increased serum ADMA expression(P＜0.05).The survival rate was 73.80％in the high CNN1 expression group(n=42),which was significantly higher than 39.71％in the low CNN1 expression group(n=68)(x2=22.300,P＜0.001);the survival rate was 45.68％in the high ADMA expression group(n=81),which was significantly lower than 72.41％in the low ADMA expression group(n=29)(x2=4.791,P=0.029).Univariate and multivariate Cox regression analysis showed that lymph node metastasis,advanced tumor staging,low CNN1 pro-tein expression,and high serum ADMA expression were independent risk factors for poor prognosis in gastric cancer patients(P＜0.05).The expression level of CNN1 mRNA in gastric cancer tissues was(0.41±0.13),which was significantly lower than(1.16±0.35)in adjacent tissues(t=21.068,P＜0.001).The expression levels of wnt3a mRNA and β-catenin mRNA in gastric cancer tissues were(2.02±0.42)and(2.59±0.58)respectively,both were significantly higher than(1.25±0.28)and(1.18±0.42)in adjacent tissues(t=15.999,P＜0.001;t=20.651,P＜0.001).CNN1 expression in gastric cancer tissues was negatively correlated with serum ADMA ex-pression in gastric cancer patients(r=-0.794,P＜0.001);CNN1 mRNA expression in gastric cancer tissues was negatively correlated with the expression of Wnt/β-catenin signaling pathway-re-lated indicators wnt3a mRNA and β-catenin mRNA(P＜0.001);serum ADMA mRNA expression in gastric cancer patients was positively correlated with the expression of Wnt/β-catenin signaling pathway-related indicators wnt3a mRNA and β-catenin mRNA(r=0.763,P＜0.001;r=0.874,P＜0.001).Conclusion The decreased expression of CNN1 and the increased expression of ser-um ADMA are independent risk factors for poor prognosis in gastric cancer patients,and their ex-pression levels are related to lymph node metastasis and tumor TNM staging.The expression levels of CNN 1 and ADMA are negatively correlated in gastric cancer tissues,which may be mediated by reg-ulating the Wnt/β-catenin signaling pathway.

OBJECTIVE To explore the effects of naringin on the proliferation， apoptosis and immune escape of breast cancer cells through the cyclic GMP-AMP synthase （cGAS）-stimulator of interferon gene （STING） signaling pathway. METHODS The human breast cancer cell line MDA-MB-231 was divided into blank group， naringin low-， medium-， and high-dose groups （50， 100 and 200 μmol/L）， RU.521 group （cGAS inhibitor， 1 μmol/L） and high-dose naringin+RU.521 group （200 μmol/L naringin+1 μmol/L RU.521）. After each group of cells was treated with their respective drug solutions for 48 h， the proliferation of MDA-MB- 231 cells [measured by the positive rate of 5-ethynyl-2′-deoxyuridine （EdU） and the value of optical density （OD450）]， apoptosis status， as well as the protein expression levels of proliferating cell nuclear antigen （PCNA）， p53， B7 homolog 1 （B7H1）， programmed death-1 （PD-1）， cGAS， and STING in the cells were measured. The MDA-MB-231 cells of the above groups were treated with corresponding drugs for 48 h respectively， and then co-incubated with NK cells for 48 h except blank group. The levels of granzyme B， tumor necrosis factor-α （TNF-α）， interferon-γ （IFN-γ） in the supernatant of the co-incubation system and the killing power of NK cells were detected. RESULTS Compared with the blank group， the EdU positive rate， OD450 value， and protein expression levels of PCNA， B7H1 and PD-1 in MDA-MB-231 cells of each dose group of naringin were significantly decreased， while the apoptotic rate and protein expression levels of p53， cGAS， and STING were significantly increased （P＜ 0.05）. The changes of the above indicators in the MDA-MB-231 cells of the RU.521 group were opposite to those in each naringin dose group （P＜0.05）. Compared with the blank+NK group， the levels of granzyme B， TNF-α， IFN-γ and the killing power of NK cells in the supernatant of the co-incubation system of MDA-MB-231 cells treated with different concentrations of naringin and NK cells were significantly increased （P＜0.05）. However， the above indicators in the co-incubation system of MDA-MB-231 cells treated with RU.521 and NK cells were significantly decreased （P＜0.05）. CONCLUSIONS Naringin can inhibit the proliferation and immune escape of MDA-MB-231 cells and induce their apoptosis by activating the cGAS-STING signaling pathway.