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This article examines the development of modern nursing education in China through a case study of the Xiangya School of Nursing in Changsha between 1909 and 1926. Founded in 1911 by the Yale-in-China Association, a non-denominational mission, Xiangya was among the earliest nursing schools in China to promote undergraduate nursing education and public health nursing. Drawing on archival materials, published primary sources, and Chinese and English historiography, we analyze the cultural, political, and gendered challenges that shaped the school's development under the leadership of American nurse Nina Gage. While Gage initially sought to implement an Americanized model of nursing education, she and her colleagues adapted admission policies, educational goals, and curricula to local social and cultural conditions. Recognizing the need for Chinese nursing leadership, they prioritized the establishment of a Bachelor of Science degree to prepare nurses for teaching, administration, and public health roles. By 1926, Xiangya had trained approximately 16% of China's qualified nurses and had become one of only two schools in China offering university-level nursing education. This history highlights the interplay of transnational influence, cultural adaptation, and gendered reform in the professionalization of nursing in early 20th-century China.
Hepatocellular carcinoma (HCC) is a leading global malignant tumor with poor prognosis. Immune checkpoint inhibitors (ICIs) have become a breakthrough treatment for HCC, but a systematic landscape analysis of global ICI clinical trials is lacking. Four international clinical trial databases were systematically searched up to February 14, 2026. After screening, 132 eligible trials were included and analyzed for geographic distribution, molecular targets, clinical phases, trial status and result publication rate using R 4.5.1. Trials displayed a China-US dual-core pattern (95 vs. 16). PD-1/PD-L1 inhibitors were the predominant targets, while CTLA-4 inhibitor trials were scarce. Phase II was the most frequent clinical phase (59 trials). Over 80% were interventional studies; most were recruiting or of unknown status, with only 6 terminated or withdrawn. The overall result publication rate was extremely low, with 71 PD1-targeting trials and 71.4% CTLA-4 trials were unpublished. Global HCC ICIs trials are highly concentrated geographically and by target, with stable research progress. However, major challenges include low result translation efficiency, unbalanced target development, insufficient early/late-phase trials and uneven global collaboration. Targeted optimization is needed to promote clinical translation.
This study investigated the associations between dynamic blood pressure (BP) trajectories during pregnancy and adverse birth outcomes using data from the China-US Collaborative Project on Neural Tube Defect Prevention. Among 281,224 pregnant women (mean age 25.07 ± 3.57 years), group-based trajectory modeling (GBTM) identified three distinct systolic (SBP) and diastolic (DBP) BP patterns: "Low-stable", "Fast-increasing", and "High-stable". Compared to the Low-stable SBP group, women with Fast-increasing or High-stable SBP trajectories had significantly elevated risks of adverse outcomes, including an 16% higher risk of preterm birth (adjusted OR = 1.16, 95% CI:1.09-1.23) and 37% increased risk of low birth weight (LBW) (aOR=1.37,1.27-1.49) in the High-stable group. For DBP, the Fast-increasing trajectory showed the strongest associations, with a 19% higher preterm birth risk (aOR=1.19,1.11-1.26) and 63% increased LBW risk (aOR=1.63,1.51-1.76). Each 10 mmHg rise in SBP and DBP from mid-to-late pregnancy was independently linked to higher risks of preterm birth (SBP: aOR=1.10,1.06-1.12; DBP: aOR=1.16,1.13-1.20) and low birth weight (SBP: aOR=1.12,1.09-1.14; DBP: aOR=1.22,1.18-1.26). These findings highlight that dynamic BP changes during pregnancy are robust predictors of adverse birth outcomes, underscoring the importance of continuous BP monitoring for early risk identification and intervention.
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive malignancy with poor prognosis and no established standard therapy. This study aimed to map the research landscape of SMARCA4-UT through bibliometric analysis to guide clinical decision-making and research prioritization. Publications on thoracic SMARCA4-UT were retrieved from the Web of Science Core Collection and Scopus from 2000 to 2025. After screening, 132 articles and reviews were included. Bibliometrix and CiteSpace were used to analyze publication trends, geographic and institutional distribution, author productivity, collaboration networks, keyword evolution, thematic structure, and highly cited articles. SMARCA4-UT research expanded rapidly, with 31.95% annual growth rate and 32.25 average citations per article, reflecting rising academic impact. China (28.8%) and Japan (23.5%) led global output, forming a China-US dual-core collaboration network. Mechanistic studies on the SWI/SNF complex and BRG1 are mature, while clinical and therapeutic research remains underdeveloped. Temporal analysis revealed a shift toward diagnostic standardization after the 2021 WHO classification. SMARCA4-UT research is in a rapid growth phase, with a substantial gap between mechanistic advances and clinical translation. Immunochemotherapy is the current first-line backbone, while targeted and combinatorial strategies remain exploratory. These findings provide evidence-based guidance for clinical practice and research design, highlighting the urgent need for biomarker-driven therapy and large-scale international collaboration to improve patient outcomes.
Zinc ions (Zn2+) are crucial for cellular homeostasis, with their intracellular concentrations tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. Zinc dysregulation has been implicated in esophageal squamous cell carcinoma (ESCC), yet the oncogenic roles of zinc transporters remain poorly understood. We herein identify SLC30A7 as a zinc transporter markedly elevated in ESCC and associated with poor prognosis. Genetic deletion of Slc30a7 significantly suppressed 4NQO-induced esophageal tumorigenesis, whereas SLC30A7 knockdown inhibited ESCC cell proliferation, migration, and tumor progression. Mechanistically, ERK1 specifically binds SLC30A7 and phosphorylates SLC30A7 at T297 site, driving the redistribution of zinc (Zn2+) from the cytosol into the Golgi lumen. SLC30A7 cooperates with the zinc metallochaperone ZNG1 to mobilize Golgi-resident zinc toward matrix metalloproteinases MMP2/3/9 activation, leading to E-cadherin degradation, β-catenin nuclear translocation, and MYC transcription. In ESCC PDX models, a tumor-targeted biomimetic ERK inhibitor nanoplatform (Q3ME@PBA-NPs) significantly restrained tumor growth and disrupted the ERK1-SLC30A7-MMP2/3/9-β-catenin-c-Myc axis. These findings reveal a previously unrecognized zinc-dependent oncogenic pathway in ESCC and highlight SLC30A7 as a valuable therapeutic target in cancer.
TOPK (T-LAK cell-originated protein kinase), also known as PDZ-binding kinase, is a serine/threonine kinase belonging to the mitogen-activated protein kinase family. It is a critical regulator of essential cellular processes, including survival, proliferation, apoptosis, inflammation, and autophagy. As an oncogenic kinase, TOPK is predominantly expressed in actively proliferating cells, where its dysregulation contributes to the pathogenesis of various cancers. Through phosphorylation, TOPK activates key signaling pathways such as ERK/RSK/c-Jun, which in turn promote cancer cell proliferation, migration, and resistance to apoptosis. Furthermore, TOPK has been implicated in the regulation of the tumor microenvironment and immune evasion. This review provides an in-depth examination of the molecular structure of TOPK, the role of TOPK in tumorigenesis, and the underlying mechanisms that support its oncogenic activity. Given its central role in cancer progression, TOPK represents a promising candidate for novel cancer therapies. Additionally, we explore the therapeutic potential of targeting TOPK in cancer treatment, highlighting ongoing research efforts and the challenges in translating TOPK inhibition into clinical practice.
We conducted a comprehensive pan-cancer analysis of gene mutation frequencies across 45,259 samples from 41,988 patients, which were classified into three categories: TP53_top, TP53_plus, and Non_TP53. Intersection analysis of mutated genes revealed heterogeneous overlaps among 61 cancers. Based on sample quantity, mutation frequency, and distribution patterns, 95 significantly mutated genes with 80,524 unique mutations were identified and categorized into three groups: SinglePoint-SingleCan, SinglePoint-MultiCan, and MultiPoints-MultiCan. These findings delineate two strategies for precision medicine development: SinglePoint specificity and MultiPoints compatibility. Furthermore, we identified 26 mutated transcription factors (TFs) and 476 downstream targets across 19 regulatory networks, which were categorized into three groups: TP53-Solo, TP53-Multi, and Non_TP53. Additionally, we mapped 47 mutated signaling pathway networks across 52 cancers, highlighting diverse dysregulated phenotypes and potential therapeutic targets downstream or upstream of these mutated genes. The integration of pan-cancer genotypes and phenotypes provides a blueprint for developing precision therapies tailored to mutation-specific, multi-variant, and context-dependent targeting.
Nearly thirty years ago, T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK), also known as PDZ-binding kinase, was first identified as a serine/threonine kinase with limited known functions. Over time, this molecule has gradually revealed a far more striking role in cancer biology. Initially detected mainly in proliferative tissues such as testes and activated lymphocytes, TOPK is now recognized as a protein that becomes aberrantly overexpressed in many human cancers, where it is consistently linked to aggressive tumor behavior and poor clinical outcomes. Research accumulated over the past three decades shows that TOPK governs a wide range of oncogenic processes, including proliferation, metastasis, cell cycle progression, DNA damage repair, resistance to apoptosis, autophagy regulation, inflammatory signaling, and immune modulation. Mechanistic studies reveal that TOPK communicates extensively with major signaling molecules such as extracellular signal-regulated kinase (ERK), β-catenin, the tyrosine-protein kinase Src/glycogen synthase kinase 3 beta/signal transducer and activator of transcription 3 (Src/GSK3β/STAT3), phosphoinositide 3-kinase/phosphatase and tensin homolog/protein kinase B (PI3K/PTEN/AKT), TGF-β/small mother against decapentaplegic (SMAD), NF-κB/Snail, and HIF-1α. Positive feedback interactions with ERK2, Src and other oncogenic regulators further intensify its tumor-promoting activity. TOPK also contributes to resistance to anti-cancer agents such as doxorubicin, gefitinib, oxaliplatin, and sorafenib through its influence on activator protein-1, phosphatase and tensin homolog, sirtuin 1 (SIRT1), p53, and additional downstream effectors. In the tumor immune microenvironment, TOPK enhances programmed cell death ligand 1 (PD-L1) expression and reduces CD8+ T-cell infiltration, promoting immune evasion. Although numerous natural and synthetic inhibitors of TOPK have been identified, their clinical application remains at an early stage. Overall, current evidence presents TOPK as a promising biomarker and therapeutic target with broad relevance across diverse cancer types.
Traditional Chinese medicine (TCM) has garnered increasing attention globally, with its modernization becoming a prominent research focus both within China and internationally. However, the lack of a precise definition for TCM modernization has hindered clear guidance for its development. Additionally, cancer remains a significant global public health challenge, largely untreatable with current methods. Therefore, a comprehensive understanding of TCM modernization is crucial for its evolution, revolution, drug discovery, and cancer therapy. This study provides an overview of the history, theory, characteristics, and evolution of TCM, highlighting its potential in cancer prevention and treatment. We propose a definition for TCM modernization, innovative Chinese medicine (ICM), and elucidate strategies to elevate TCM from a supporting role to a leading one. Electronic databases such as PubMed, Web of Science, ScienceDirect, and Clinical Trials were utilized to retrieve relevant literature spanning from 1979 to 2024, with most publications being from the last five years, using keywords like "Traditional Chinese medicine", "Cancer", "Mechanism", and "Clinical trial". In this study, we introduce the theory of TCM modernization following target identification and initial compound screening: ICM, defined by "3 D" elements: definite active ingredient composition and content, determined functional mechanism, and detection through evidence-based medicine. Overall, the "3 D" definition of ICM will establish a standard for ICM, accelerate TCM modernization, enhance drug discovery targeting cancer and various human diseases, and benefit patients worldwide.
Neoadjuvant chemotherapy (NACT), a key strategy for various cancers, markedly improves patient prognosis and 5-year survival rates. However, numerous patients develop resistance to NACT and thus fail to benefit from it. Therefore, identifying reliable biomarkers to predict patient responsiveness to NACT remains a critical challenge. Here, we demonstrate that elevated expression of INCENP and CDCA8 contributes to poor NACT responsiveness across multiple cancers. Mechanistically, the 5'UTR (GGACT at position 113) of INCENP and the 3'UTR (GGACT at position 1041) of CDCA8 undergo m⁶A methylation and are recognized by YTHDF3, which facilitates their translation through interaction with eIF3A, ultimately driving poor response to NACT. Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.
Overcoming drug resistance remains essential for improving clinical outcomes in non-small cell lung cancer (NSCLC). This study explores the differential susceptibility of drug-resistant cancer cells, utilizing gefitinib (GEF)-resistant HCC827GR NSCLC cells as a model system. We observed that HCC827GR cells inherently display elevated levels of reactive oxygen species (ROS) and increased expression of ferroptosis-related markers when compared with GEF-sensitive cells. Accordingly, the HCC827GR lineage showed heightened responsiveness to erastin-mediated cytotoxicity, as determined by MTT and soft-agar assays. Our mechanistic investigations established that erastin treatment resulted in non-apoptotic cell death, accompanied by mitochondrial dysfunction and G2/M phase arrest in the cell cycle. In-depth analysis demonstrated that erastin notably raised intracellular iron and ROS concentrations and induced lipid peroxidation. Pretreatment with N-acetyl cysteine (NAC) validated the crucial involvement of ROS, and the use of ferrostatin-1 conclusively verified ferroptosis as the predominant mode of cell death. In summary, GEF-resistant HCC827GR cells exhibit increased sensitivity to erastin-induced ferroptosis compared with the parental line. This distinct vulnerability should be further studied as a potential therapeutic approach for targeting drug-resistant NSCLC.
The mechanisms by which cancer cells survive and adapt under high levels of reactive oxygen species (ROS) remain poorly understood, especially in the context of redox homeostasis. This study reveals increased oxidative stress in esophageal squamous cell carcinoma (ESCC), with serine/arginine-rich splicing factor 6 (SRSF6) playing a crucial role in maintaining redox homeostasis. SRSF6 binds to the exonic splicing enhancer (ESE) motif in nuclear factor erythroid 2-related factor 1 (NFE2L1) Exon 4, preventing exon skipping and promoting the production of specific isoforms that promote ESCC cell proliferation. This interaction enhances cellular antioxidant capacity, thereby influencing redox balance. Moreover, reducing SRSF6 increases the levels of NFE2L1-S, the isoform produced by exon 4 skipping in the NFE2L1 gene, which elevates ROS levels and induces apoptosis and ferroptosis. Notably, SRSF6 and NFE2L1 form a positive feedback loop: NFE2L1 serves as the transcription factor for SRSF6, while SRSF6 acts as the splicing factor for NFE2L1. Antisense oligonucleotides (ASOs) targeting SRSF6 significantly suppress ESCC cell growth. Importantly, inhibiting this feedback loop also enhances cisplatin (CDDP) sensitivity, increasing the therapeutic efficacy of CDDP. Our findings highlight the critical role of the SRSF6-NFE2L1 axis in redox homeostasis and tumor progression, positioning SRSF6 as a distinctive therapeutic target to improve treatment outcomes in ESCC.
A visible-light-mediated intramolecular dearomative macrocyclization of indoles is described. Utilizing tertiary amines as radical precursors and 4CzIPN as an organic photocatalyst, this protocol facilitates the construction of 11- to 20-membered indoline-fused macrocycles. The reaction scope encompasses various linkers, including those derived from amino acids, and extends to benzothiophene and benzofuran derivatives. X-ray crystallographic analysis confirmed a trans-diastereoselective outcome for the 2,3-disubstituted indoline core. Mechanistic studies suggest a radical-mediated pathway initiated by single-electron transfer (SET). Preliminary biological evaluation identified representative macrocycles with antiproliferative activity against human cancer cell lines, with IC50 values ranging from 5.3 to 6.6 μM.
Ovarian cancer (OC) and cervical cancer (CC) are major causes of gynecological malignancy mortality, but their spatially resolved metabolic features and shared progression-driving metabolic reprogramming remain unexplored. This study integrated spatial metabolomics, proteomics, and targeted metabolomics with in vitro assays to explore their metabolic reprogramming and therapeutic targets. The results revealed that OC exhibits intratumoral metabolic heterogeneity and suppresses tryptophan and vitamin B6 metabolism, with ferroptosis-related proteins upregulated in metastatic lesions and ALDH7A1/GATM knockdown promoting its cell proliferation and migration. CC progression was marked by amino acid and bile acid accumulation and neomenthol-driven cell proliferation. Purine metabolism activation was identified as a shared hallmark of both cancers, and purine nucleoside phosphorylase (PNP) knockdown was found to inhibit the proliferation of both OC and CC cells. This work identifies stage-specific metabolic vulnerabilities and PNP as a conserved therapeutic target, providing a framework for developing tailored gynecological cancer therapies.
Sinensetin, a polymethoxylated flavone abundant in citrus fruits, has been recognized for its broad biological activities and wide use in traditional medicine around the world. Emerging clinical evidence from flavonoid-enriched orange juice interventions indicates antioxidant and anti-inflammatory effects, aligning with extensive preclinical data. In this review, we explored in vitro and in vivo findings on the anti-inflammatory and anticancer actions of sinensetin and delineated the underlying cellular pathways, especially in terms of proposed targets for sinensetin. In inflammatory settings, sinensetin attenuates NF-κB activation, lowers pro-inflammatory cytokines (e.g., TNF-α, IL-6), and enhances antioxidant defenses, supporting its reported antioxidant, anti-bacterial, anti-viral, and anti-obesity properties. Across multiple tumor models, sinensetin suppresses oncogenic signaling-including β-catenin, PI3K/AKT, VEGF, NRF2, P53, and MKK6-concomitant with reduced proliferation, migration, and survival signaling. We further discuss emerging immunological effects, including modulation of innate immune cell activation and cytokine production, which may contribute to tumor microenvironment reprogramming and inflammation resolution. Together, these mechanistic insights position sinensetin as a promising lead for chemopreventive and adjunct therapeutic strategies. Our efforts aim to provide insights into the future translational development and clinical evaluation of sinensetin and its derivatives.
Background: Obesity is a global epidemic that remains inadequately addressed by healthcare systems. The gut microbiota offers a promising metabolic target, yet systematic reviews of clinical trials on microbiome modulators for obesity are scarce. Using the Trialtrove database (September 16, 2025), we performed a registry-based systematic review with the strategy: "(Disease: Obesity) AND (Mechanism: Microbiome modulator)." We included interventional trials targeting overweight/obese populations with defined microbiome-modulating mechanisms; observational and withdrawn/suspended trials were excluded. Extracted data covered phase, status, intervention type, sponsor, location, and participant characteristics. Descriptive analyses used R software (v4.4.3). Among 217 included trials, 131 (60%) were completed and 37 (17%) ongoing., Academic institutions led sponsorship (157 trials), followed by commercial (45) and government (14). Trials rose sharply after 2011, peaking at 34 in 2023 (over 80% of Phase IV trials that year). Probiotics dominated (141 trials), followed by synbiotics (21) and FMT (22). China (52) and the US (24) led research. Probiotics prevailed in Phases III/IV, whereas FMT concentrated in Phases II/IV with a higher termination rate. This study reveals a rapidly growing yet uneven landscape. Probiotics remain the primary focus, academic institutions the main sponsors, and China/US the core hubs. The field has entered a post-marketing evaluation phase dominated by Phase IV studies. Limitations include reliance on a single database and lack of efficacy data, but the study highlights rapid expansion and heterogeneity in this field. Future research should integrate multiple data sources and quality assessments for more comprehensive evidence.
Alternative splicing is a fundamental mechanism that expands transcriptomic and proteomic diversity and contributes to multiple biological processes, including immune regulation. Increasing evidence shows that dysregulated alternative splicing influences tumor immunogenicity, the immune landscape of the tumor microenvironment, and responses to cancer immunotherapy. Alternative splicing can alter the expression and peptide repertoire of tumor antigens, modulate major histocompatibility complex-mediated antigen presentation, and generate immunomodulatory isoforms that promote immune evasion. In addition, cell type-specific splicing programs regulate the phenotypes and functions of intratumoral immune and stromal cells, including T cells, antigen-presenting cells, myeloid cells, and fibroblasts. Splicing signatures and isoform-level alterations are also associated with clinical responses to immunotherapy, particularly immune checkpoint blockade. A better understanding of splicing dysregulation in tumor immunity may improve biomarker development, patient stratification, and therapeutic targeting of aberrant RNA processing. Overall, alternative splicing is an important regulator of tumor-immune interactions and a potential target in cancer immunotherapy.
Chemotherapy resistance remains a significant obstacle in the treatment of colorectal cancer (CRC) patients. Here, we examined the ferroptosis susceptibility of the chemotherapy-resistant CRC cell line HCT116-OxR relative to its parental counterpart. The increased basal levels of reactive oxygen species (ROS) and ferroptosis-associated proteins observed in HCT116-OxR cells rendered them more sensitive to erastin-induced cell death, as determined by the MTT and soft agar assays. Mechanistically, erastin elicited a reduction in mitochondrial membrane potential (MMP). Notably, this loss of MMP was not accompanied by detectable apoptotic changes, suggesting that a non-apoptotic cell death pathway may be involved. Rather, erastin elevated intracellular iron and ROS concentrations, resulting in lipid peroxidation consistent with ferroptosis. The pivotal involvement of ROS was supported by N-Acetyl-L-cysteine pretreatment, and ferrostatin-1 pretreatment further verified that erastin-induced cell death was mediated by ferroptosis. The heightened erastin sensitivity of HCT116-OxR cells suggests a therapeutic vulnerability that could be exploited to induce ferroptosis in chemotherapy-resistant CRC. This ferroptosis susceptibility may offer a promising strategy for overcoming treatment resistance and improving therapeutic outcomes.
The de novo purine biosynthesis (DNPB) pathway is increasingly recognized as a key driver of tumor progression. Nevertheless, its precise role in regulating esophageal squamous cell carcinoma (ESCC) growth, radiosensitivity, and therapeutic response has not been fully elucidated. This study aimed to determine contribution of phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of the DNPB pathway, in ESCC progression and potential therapeutic benefit of PPAT-targeted intervention. Single-cell RNA sequencing and untargeted metabolomics analyses were used to characterize PPAT-associated metabolic changes in ESCC. Structure-based virtual screening was performed to identify potential PPAT inhibitors. The interaction and degradation of PPAT by Cucurbitacin B (CuB) were investigated using docking, pull-down, CETSA, and ubiquitination assays, and its anti-tumor and radiosensitizing effects were evaluated in vitro and in vivo. We identified PPAT as a critical modulator of ESCC malignancy. PPAT promoted the production of energy-related nucleotides, including AMP, GMP, ADP, GDP, ATP, and GTP, thereby fueling ESCC tumor growth in vitro and in vivo. Moreover, CuB specifically targeted PPAT and induced its polyubiquitin-mediated degradation via TRIM38, thereby suppressing the DNPB pathway and inhibiting tumor growth. Importantly, CuB also functioned as a radiosensitizer, significantly enhancing the therapeutic efficacy of radiotherapy in ESCC. In conclusion, our findings reveal that targeting PPAT is a promising therapeutic strategy to suppress ESCC progression and enhance the efficacy of radiotherapy.
Prostate cancer is a leading malignancy among men worldwide and an increasing challenge for emerging economies. The expanded BRICS nations represent regions undergoing rapid demographic and epidemiological transitions, yet data on their comparative disease and economic burden remain limited. We analyzed data from the GBD 2021 study to estimate prostate cancer incidence, mortality, DALYs, and mortality-to-incidence ratios (MIRs) from 1990 to 2021 across BRICS+. Temporal patterns were assessed through EAPC. Productivity losses due to premature mortality were calculated using the Human Capital Approach. Incidence and mortality rose sharply in Russia and Egypt, while China and India showed declining mortality despite increasing incidence. MIRs decreased overall, reflecting improved survival, though Ethiopia and Egypt remained high. In 2021, productivity losses were greatest in China (US$73.1 billion) and Russia (US$19.5 billion), with comparatively lower losses in Ethiopia, Saudi Arabia, Egypt, and the UAE. Prostate cancer imposes a heterogeneous but rising health and economic burden across BRICS+ nations. Effective strategies integrating prevention, early detection, equitable treatment-access, and recognition of economic impact are critical to reduce disparities and improve outcomes.