Volume 139  ·  Issue 21  ·  2026

The human body is a complex and irregular system that generates diverse physiological signals. In the era of wearable technology, an increasing number of physiological signals can be continuously monitored, generating rich time series data that capture the dynamic physiological fluctuations and may reveal subtle signs of dysregulation. For example, continuous glucose monitoring (CGM) systems generate glucose time series data. As such, new metrics harnessing the time series nature of physiological signals may serve as sensitive markers of health. Of them, complexity focuses more on the dynamical characteristics of physiological signals and can reveal hidden information that linear methods may miss, allowing for the handling of nonstationary data and providing a more precise capture of individual differences. Importantly, the complexity of physiological signals may reflect the regulatory capacity, adaptability, and functional reserves of the body, which are often impaired in chronic diseases and during aging. Using CGM-derived glucose complexity as a representative example, this review discusses the clinical significance and applications of complexity in chronic diseases and aging. Finally, we outline future directions for complexity-related research, particularly regarding the roles of artificial intelligence (AI), wearable devices, and clinical translation.

Conventional two-dimensional (2D) pathology relies on a limited number of tissue sections and therefore provides information from isolated planes, which can introduce sampling bias and lead to the loss of axial details, making it difficult to accurately capture the full structural organization of tumors and their microenvironment. In recent years, the integration of three-dimensional (3D) imaging technologies, such as tissue clearing and light-sheet fluorescence microscopy, combined with virtual staining, artificial intelligence, and spatial omics, has enabled the acquisition and analysis of volumetric biological information while preserving the overall architecture of the tissue. Following the theme of "advancing from planar observation to 3D quantitative analysis", this paper outlines the major technical pathways of 3D pathology, from sample clearing and fluorescent labeling to 3D imaging and visualization and then to an analytical framework for 3D pathological data. Based on this, we further examined representative applications, including tumor staging, lesion detection, and immune microenvironment profiling, to illustrate the advantages and potential clinical value of 3D pathology over conventional 2D approaches in precision diagnosis, prognostic assessment, and therapeutic decision-making. We also highlight key challenges that remain for 3D pathology, such as storage and computational costs, workflow and diagnostic standardization, and clinical implementation. Overall, AI-enabled 3D pathological imaging holds promise as an important direction for pathology, although its integration into routine clinical decision-making will require continued technological development and translational research.

The treatment landscape for advanced prostate cancer (PCa) has significantly evolved in recent years, marked by the introduction of several novel therapies. Targeting the androgen receptor (AR) remains a cornerstone of treatment, with drugs, such as abiraterone and next-generation antiandrogens, providing substantial benefits. Poly (ADP-ribose) polymerase (PARP) inhibitors, both as monotherapies and in combination with other agents, have demonstrated promise, particularly for patients with deoxyribonucleic acid (DNA) repair defects. While immunotherapy has historically shown limited efficacy in the treatment of PCa, recent findings from the CONTACT-2 study suggest a potential breakthrough, demonstrating improved patient outcomes with the combined use of atezolizumab and cabozantinib. Additionally, emerging therapies targeting cyclin-dependent kinases 4 and 6 (CDK4/6), the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, and epigenetic modifications offer new treatment possibilities. These advancements, coupled with ongoing research into combination therapies and novel drug targets, hold the potential to further enhance outcomes for patients with advanced PCa. This article review summarizes the latest transformative therapies in PCa care.

Background: Mental disorders contribute significantly to the global disease burden, with marked regional variations. This study provides the most up-to-date assessment of trends in the burden of mental disorders worldwide and in China and compares the burden of mental disorders between China and other regions. Methods: We conducted a descriptive secondary analysis of publicly available estimates from the updated Global Burden of Disease Study 2023 (GBD 2023) for the period 1990-2023, covering the 6 World Health Organization (WHO) regions and China. We summarized prevalence, disability-adjusted life years (DALYs), age-standardized prevalence rates (ASPRs), and age-standardized DALY rates (ASDRs) by year, region, age, and sex. Future trends were projected using a Bayesian age-period-cohort model with second-order random-walk priors, and uncertainty was described using 95% uncertainty or credible intervals. Results: In 2023, 1171.64 million people suffered from mental disorders globally, resulting in 171.27 million DALYs. China accounted for 16.32% of global cases and 15.39% of global DALYs, ranking second worldwide for both measures. In China, mental disorders were the fourth leading cause of DALYs. Among these, anxiety and depressive disorders were the most prevalent and the leading contributors to the burden. From 2010 to 2023, the ASDR increased by 16.18%, with the largest increase in anxiety disorders (38.37%), eating disorders (21.84%), and autism spectrum disorders (ASDs, 21.20%). Anxiety and depressive disorders were more prevalent in females, whereas attention-deficit/hyperactivity disorder (ADHD), ASDs, and conduct disorders were more prevalent in males. Although the burden was concentrated on older adults, notable increases were also observed among young people. By 2035, the numbers of mental disorder cases and associated DALYs in China are projected to reach 209.6 million and 28.7 million, respectively. Conclusions: China faces a growing burden of mental health issues, particularly anxiety disorders, eating disorders, and ASD. Immediate development and implementation of comprehensive strategies are crucial to address the escalating mental health crisis in China.

Background: Lymph node metastasis is a well-established prognostic factor in renal cell carcinoma (RCC); however, the prognosis varies among patients with nodal metastases. Subclassification by T category may improve the prognostic stratification. Methods: This study aimed to refine the prognostic stratification of advanced RCC by analyzing the overall survival and cancer-specific survival of patients classified as pT1-3N1M0. We retrospectively analyzed data from 364 patients with American Joint Committee on Cancer (AJCC) stage III and IV RCC who underwent nephrectomy with lymphadenectomy at multiple centers between 2010 and 2023. Five-year survival rates were estimated using Kaplan-Meier analysis, and the concordance index (C-index) was used to assess the stratification ability of the different staging systems. Multivariable analyses were conducted to adjust for potential confounders. Additionally, 194 and 1513 patients from The Cancer Genome Atlas and Surveillance, Epidemiology, and End Results databases were used to validate the prognostic values. Results: Patients with pT1-2N1M0 had significantly better 5-year survival rates than those with pT3N1M0 (overall survival: 62.4% vs. 31.5%, P = 0.003; cancer-specific survival: 62.4% vs. 38.5%, P = 0.008). Reclassifying pT3N1M0 from AJCC stage III to IV improved prognostic discrimination, as reflected by higher C-index values compared to the AJCC staging (8th edition) (∆C-index: 0.03-0.10, all P values <0.05). The modified staging system demonstrated comparable performance to the previous system while avoiding the over-staging of patients with pT1-2N1M0 (∆C-index: 0-0.04, most P values >0.05), as confirmed across local and external cohorts. These findings were supported by the multivariable analyses. Conclusion: Reclassifying pT3N1M0 as stage IV improves prognostic stratification in RCC.

Background: Programmed death-1/programmed death ligand-1 inhibitors exert a unique delayed effect in clinical practice, although the exact duration of this delay remains inconclusive. To address this, we aimed to develop an algorithm—SOTA (Superiority Onset-Time Algorithm) to quantify the delayed effect and estimate the post-onset therapeutic benefit and applied it based on a meta-analysis of randomized controlled trials (RCTs) to calculate the delayed effect of PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). Methods: SOTA reconstructs Kaplan-Meier curves from published figures, recovers individual-level data, and applies a piecewise Cox model to identify the optimal breakpoint as superiority onset time (SOT). It also enables the estimation of post-onset efficacy of PD-1/PD-L1 inhibitors by using landmark analysis to estimate the hazard ratio (HR) after the SOT. The code is available at: https://github.com/qihanfan/SOTA. Then we applied SOTA in a meta-analysis of phase II/III RCTs in NSCLC, identified through a systematic search up to Mar 9, 2025. Data extraction and quality assessment were conducted in accordance with Cochrane guidelines. Pooled estimates of SOT and post-onset HR were obtained. Results: Simulation studies confirmed the accuracy of the SOTA. For survival data reconstruction, the average value of mean absolute error (MAE), root mean square error (RMSE), and maximum deviation between the raw and reconstructed data were 0.008, 0.011, and 0.050, respectively. For the estimation of the SOT, SOTA accurately recovered the true change point of the HR, with relative errors predominantly within ± 5% and coverage probabilities ≥95% across all scenarios. In the meta-analysis, 25 RCTs were included after screening. The estimated SOT was 3.64 months for overall survival (OS) and 3.26 months for progression-free survival (PFS). The corresponding post-onset HRs for OS and PFS were 0.68 and 0.47, respectively. Conclusions: PD-1/PD-L1 inhibitors show a unique delayed effect compared to chemotherapy. The SOTA algorithm provides a quantitative framework for assessing this delay, offering valuable insights for estimating treatment effects and clinical trial design.

Background: Hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA) have a higher risk of recurrence and metastasis, which is mainly caused by sublethal heat stress due to insufficient RFA (IRFA). This study aimed to investigate the molecular mechanisms by which sublethal heat stress enhances HCC progression to improve therapeutic strategies and patient outcomes in HCC management. Methods: Cell-based and mouse models of insufficient thermal ablation in HCC were established via sublethal heat stress treatment. Twenty-four BALB/c nude mice were randomly divided into four groups, with six mice per group. RNA sequencing was used for transcriptional profiling. Messenger RNA (mRNA) and protein levels were quantified using quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Metastatic lesions in mouse liver and lung tissues were identified by hematoxylin and eosin staining. Proliferative, migratory, and invasive characteristics of tumor cells were probed via colony formation, 5-ethynyl-2′-deoxyuridine incorporation, scratch wound healing, and Transwell assays. Interactions between related genes were determined using dual-luciferase reporter, chromatin immunoprecipitation, co-immunoprecipitation, and RNA immunoprecipitation assays. Methylated RNA immunoprecipitation was used to detect N6-methyladenosine (m6A) levels in heat shock transcription factor 4 (HSF4). Results: HSF4 was identified as a key gene that was upregulated in sublethal heat stress-treated cells (6.20-fold increase in Huh7 cells and 8.34-fold increase in Hep3B cells; P <0.001). HSF4 knockdown inhibited sublethal heat stress-induced cell proliferation by 61.09% in Huh7 cells and 47.28% in Hep3B cells (P <0.001 and P <0.01), migration by 31.64% in Huh7 cells and 17.01% in Hep3B cells (P <0.05), invasion by 29.68% in Huh7 cells and 47.03% in Hep3B cells (P <0.05 and P <0.001), and epithelial-mesenchymal transition (EMT). Furthermore, HSF4 knockdown repressed liver (reduced liver weight-to-body weight ratio by 32.46%, P <0.001) and lung (decreased metastatic nodules from 10.5 to 5.17 per section, P <0.001) metastases in vivo. Mechanistically, HSF4 increased cell cycle and apoptosis regulator 1 (CCAR1) levels and activated β-catenin pathway by binding to CCAR1 promoter. CCAR1 overexpression counteracted the suppressive effects of HSF4 knockdown on cell proliferation, migration, invasion, and EMT following sublethal heat stress. In addition, sublethal heat stress increased the HSF4 levels by upregulating guanine-rich RNA sequence binding factor 1 (GRSF1) (2.92-fold in Huh7 cells and 2.87-fold in Hep3B cells, P <0.001) in an insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-m6A-dependent manner. HSF4 overexpression blocked the inhibitory effects of GRSF1 knockdown on HCC cell proliferation and metastasis following sublethal heat stress. Conclusion: Sublethal heat stress increased HSF4 expression by upregulating GRSF1 through IGF2BP2-mediated m6A modification, thereby increasing CCAR1 levels and activating β-catenin pathway, ultimately facilitating HCC proliferation and metastasis.

Background: E2F transcription factor 7 (E2F7) has been implicated in the tumorigenesis and progression of multiple cancer types; however, the molecular mechanisms through which E2F7 regulates malignant phenotypes in cancer cells remain largely undefined. In this study, we investigated the biological functions and underlying mechanisms of E2F7 in lung adenocarcinoma (LUAD). Methods: E2F7 expression in LUAD was analyzed using The Cancer Genome Atlas (TCGA) datasets and further validated in clinical specimens via quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. The effects of E2F7 on cancer cell self-renewal and epithelial-mesenchymal transition (EMT) were assessed using sphere formation and Transwell assays, respectively. In vivo tumorigenicity and metastasis were evaluated using xenograft models combined with extreme limiting dilution analysis to assess tumor-initiating capacity. Wnt/β-catenin pathway activity was measured using T-cell factor optimal promoter luciferase reporter plasmid/far-from optimal promoter luciferase reporter plasmid (TOP/FOP) flash reporter assays. β-Catenin expression, stability, and ubiquitination were examined via western blotting, cycloheximide chase assays, and ubiquitination assays. Protein-protein interactions among E2F7, β-catenin, and glycogen synthase kinase 3 beta (GSK3β) were verified through co-immunoprecipitation (Co-IP), glutathione S-transferase (GST) pull-down, and immunofluorescence assays. Truncated mutants were generated to map the functional binding domains of E2F7. In vitro immunoprecipitation and kinase assays were further performed to confirm that E2F7 regulates GSK3β autophosphorylation and β-catenin phosphorylation. Results: Bioinformatic analyses revealed that E2F7 was significantly upregulated in LUAD tissues, and elevated E2F7 expression correlated with poor patient prognosis. Functional assays demonstrated that E2F7 promoted LUAD cell self-renewal and EMT. Mechanistically, cytoplasmic E2F7 directly associated with β-catenin through its DNA-binding domain (DBD) and PHA03247 domain. E2F7 modulated β-catenin phosphorylation at Ser675 and Ser33/37/T41, thereby inhibiting ubiquitin-mediated degradation and enhancing β-catenin protein stability. Furthermore, E2F7 interacted with GSK3β and suppressed its autophosphorylation at Tyr216, concomitant with reduced β-catenin phosphorylation at Ser33/37/T41 and its accumulation. Conclusion: Collectively, these findings indicate that E2F7 drives LUAD malignant progression through regulation of the GSK3β/β-catenin signaling axis and stabilization of β-catenin. This study unveils a novel oncogenic mechanism of E2F7 in LUAD and identifies E2F7 as a promising therapeutic target for clinical intervention in LUAD.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) with a poor prognosis in advanced stages. One of the major challenges in ccRCC treatment is the resistance to tyrosine kinase inhibitors or immune checkpoint inhibitors. Asparagine-linked glycosyltransferase 6 (ALG6) is a glycosyltransferase whose biological role in tumorigenesis remains largely unknown. Therefore, this study aims to investigate its function in ccRCC and its potential involvement in therapeutic resistance. Methods: We first analyzed 30 paired ccRCC and adjacent normal tissues from Shandong Provincial Hospital, correlating ALG6 expression with clinicopathological features (age, sex, tumor size, Tumor-Node-Metastasis [TNM] stage). In vitro, CCK-8, colony formation, and apoptosis assays were performed to assess the functional role of ALG6 in ccRCC cell lines. In vivo, a subcutaneous C57BL/6J mouse model and flow cytometry was used to evaluate the effect of ALG6 on the immune microenvironment and anti-PD-1 antibody sensitivity. Results: In this study, we found that ALG6 was significantly overexpressed in ccRCC. Elevated ALG6 expression was positively correlated with tumor size and TNM stage, but negatively associated with overall survival in patients with ccRCC. Functional experiments demonstrated that downregulation of endogenous ALG6 markedly suppressed ccRCC cell viability and promoted apoptosis both in vitro and in vivo. Mechanistically, knockdown of ALG6 triggered endoplasmic reticulum (ER) stress, as evidenced by the upregulation of glucose-regulated protein 78 (GRP78) and activation of C/EBP homologous protein (CHOP) in ccRCC cells. Notably, knockdown of ALG6 significantly reduced programmed cell death ligand 1 (PD-L1) expression by inhibiting PD-L1 glycosylation and promoting its ubiquitin-mediated degradation. Furthermore, in vivo experiments demonstrated that ALG6 depletion destabilized PD-L1, enhanced antitumor T-cell immunity, and improved the therapeutic efficacy of anti-PD-1 treatment. Conclusions: This study demonstrates that downregulation of ALG6 induces ER stress-mediated apoptosis and enhances antitumor immunity by regulating PD-L1 expression in ccRCC. These findings suggest that ALG6 may serve as a potential therapeutic target for ccRCC.

Background: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. The immunosuppressive tumor microenvironment (TME) and limited response to immune checkpoint blockade (ICB) therapy remain major obstacles to improving HCC prognosis. Interleukin-33 (IL-33) is a multifunctional cytokine that plays critical roles in cancer development; however, its function in HCC remains unclear. Methods: Cell proliferation was evaluated using colony formation and 5-ethynyl-2′-deoxyuridine (EdU) staining assays. Tumor-bearing models were established in both immunocompetent and immunodeficient mice. Multiplex immunofluorescence and flow cytometry were performed to assess TME characteristics. RNA sequencing and Western blot analyses were conducted to investigate the underlying mechanisms. Results: We found that IL-33 downregulation was significantly associated with shorter survival in patients with HCC. IL-33 treatment markedly inhibited tumor progression, whereas endogenous IL-33 blockade accelerated tumor growth in immunocompetent mice. However, IL-33 showed no significant effect on cell proliferation in vitro and failed to suppress tumor growth in immunodeficient mice lacking T cells. IL-33 administration notably reduced immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells, while substantially increasing CD8+ T cells, particularly functional interferon (IFN)-γ+CD8+ T cells, within the TME. Mechanistically, IL-33 activated the stimulator of interferon genes/interferon regulatory factor signaling axis, enhanced IFN-γ secretion, and inhibited Rictor and programmed death 1 expression in mouse tumors. Furthermore, HCC specimens with high IL-33 expression exhibited more tertiary lymphoid structures. In addition, combined IL-33 and anti-programmed death ligand-1 therapy synergistically reduced tumor burden and further enhanced antitumor immunity in vivo. Conclusion: These findings indicate that IL-33 alleviates immunosuppression and enhances ICB efficacy, providing novel insights into its role in HCC immunotherapy.