2025年 · 第138卷第16期

The gut, a key component of the human digestive system, not only undertakes the heavy task of absorbing nutrients but also serves as an important hub for sensing the environment and transmitting information. As an important structure of the intestine, intestinal epithelium cells (IECs) play an indispensable role in maintaining the stability of the intestinal environment and regulating the physiological functions. Traditionally, research on the physiological functions of IECs has been focused on nutrient absorption. Recent studies have suggested that IECs may actively communicate with other organs. The novel communication medium derived from IECs has the potential to unlock unprecedented avenues for the regulation of physiological homeostasis.

Chimeric antigen receptor (CAR)-T cell therapy has become a crucial treatment modality for hematopoietic malignancies. Because of the complex treatment procedures of CAR-T cell therapy and its specific severe immune-related adverse events, a multidisciplinary integrated case management approach is necessary. Focusing on how to improve the efficacy and safety of CAR-T cell therapy, we developed this consensus to establish a standardized approach for managing and applying the multidisciplinary teams (MDT) model in CAR-T cell therapy for B-cell non-Hodgkin lymphoma. Full-length version of the consensus can be seen in supplementary file, http://links.lww.com/CM9/B961.

Gastric tumors represent a significant subset of gastrointestinal pathologies. Among these, gastric cancer is the most common malignancy, ranking fifth in global incidence and third in cancer-related mortality within China.^[1]The increasing adoption of endoscopic procedures has contributed to an increasing annual rate of early gastric cancer (EGC).^[2,3]Additionally, gastric submucosal tumors (SMTs), which are primarily composed of stromal tumors and leiomyomas, originate from protruding lesions in the nonmucosal layer and are being detected with increasing frequency.^[4]

Cholangiocarcinoma (CCA) is a fatal malignancy with steadily increasing incidence and poor prognosis. Since most CCA cases are diagnosed at an advanced stage, systemic therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, play a crucial role in the management of unresectable CCA. The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA. This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA, summarizes crucial clinical trials, and describes the efficacy and safety of different drugs, which may help further develop precision and individualization in the clinical treatment of unresectable CCA.

Cancer represents a major worldwide disease burden marked by escalating incidence and mortality. While therapeutic advances persist, developing safer and precisely targeted modalities remains imperative. Nanomedicines emerges as a transformative paradigm leveraging distinctive physicochemical properties to achieve tumor-specific drug delivery, controlled release, and tumor microenvironment modulation. By synergizing passive enhanced permeation and retention effect-driven accumulation and active ligand-mediated targeting, nanoplatforms enhance pharmacokinetics, promote tumor microenvironment enrichment, and improve cellular internalization while mitigating systemic toxicity. Despite revolutionizing cancer therapy through enhanced treatment efficacy and reduced adverse effects, translational challenges persist in manufacturing scalability, longterm biosafety, and cost-efficiency. This review systematically analyzes cutting-edge nanoplatforms, including polymeric, lipidic, biomimetic, albumin-based, peptide engineered, DNA origami, and inorganic nanocarriers, while evaluating their strategic advantages and technical limitations across three therapeutic domains: immunotherapy, chemotherapy, and radiotherapy. By assessing structure-function correlations and clinical translation barriers, this work establishes mechanistic and translational references to advance oncological nanomedicine development.

Ischemic stroke (IS) ranks as a leading cause of death and disability globally. The blood-brain barrier (BBB) poses significant challenges for effective drug delivery to brain tissues. Recent decades have seen the development of targeted nanomedicine and biomimetic technologies, sparking substantial interest in biomimetic drug delivery systems for treating IS. These systems are devised by utilizing or replicating natural cells and their derivatives, offering promising new pathways for detection and transport across the BBB. Their multifunctionality and high biocompatibility make them effective treatment options for IS. In addition, the incorporation of engineering techniques has provided these biomimetic drug delivery systems with active targeting capabilities, enhancing the accumulation of therapeutic agents in ischemic tissues and specific cell types. This improvement boosts drug transport and therapeutic efficacy. However, it is crucial to thoroughly understand the advantages and limitations of various engineering strategies employed in constructing biomimetic delivery systems. Selecting appropriate construction methods based on the characteristics of the disease is vital to achieving optimal treatment outcomes. This review summarizes recent advancements in three types of engineered biomimetic drug delivery systems, developed from natural cells and their derivatives, for treating IS. It also discusses their effectiveness in application and potential challenges in future clinical translation.

Microbial-derived metabolites are important mediators of host–microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.

Urolithiasis is a widespread disease with a high prevalence worldwide. This study aims to evaluate the disease burden of urolithiasis and its trends from 1990 to 2021 globally, based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 database.

The numbers and age-standardized rates (ASRs) of incidence, disability-adjusted life years (DALYs), and mortality of urolithiasis were extracted from GBD 2021 to represent the disease burden. Joinpoint regression analyses were conducted to assess the temporal trends in the burden of urolithiasis. The male-to-female ASR ratio indices were used to evaluate sex disparities. Additionally, we explored the relationship between the ASR ratio and the sociodemographic index (SDI).

The total numbers of incidence, DALY, and mortality of urolithiasis were 105,983,780 cases (95% uncertainty interval [UI] = 88,349,356–128,645,155 cases), 693,444 cases (95% UI = 567,765–850,490 cases), and 17,672 cases (95% UI = 13,932–21,241 cases), respectively, in 2021. There is an increasing trend in the number of these measures globally, whereas the ASRs have decreased over the past 30 years. The age-standardized incidence rate (ASIR) and age-standardized mortality rate (ASMR) were significantly higher in males than in females in 2021. The sex disparities in the age-standardized DALY rate (ASDR) and ASMR of urolithiasis were negatively correlated with the SDI. In 2021, the ASIR of urolithiasis was 964.70 (95% UI = 801.26–1175.09) per 100,000 people in China, which is much lower than the global average (1242.84 [95% UI = 1034.94–1506.99] per 100,000 people). Compared with the global average, a more pronounced decline in ASIR was observed in China from 1793.16 (1446.0–2235.14) in 1990 to 964.70 (801.26–1175.09) per 100,000 people in 2021.

Urolithiasis poses a significant healthcare burden worldwide. More robust global and national strategies are warranted to address the prevention and treatment, especially in low SDI countries and regions.

Neoadjuvant therapy enhances the possibility of achieving radical resection and improves the prognosis for locally advanced gastric cancer (GC). However, there is a lack of evidence regarding the optimal extent of resection for locally advanced proximal GC after neoadjuvant therapy.

In this study, 330 patients underwent resection in Peking University Cancer Hospital, with curative intent after neoadjuvant therapy for histologically confirmed proximal GC from January 2009 to December 2022.

In this study, 45 patients underwent proximal gastrectomy (PG), while 285 underwent total gastrectomy (TG). After propensity-score matching, 110 patients (71 TG and 39 PG) were included in the analysis. No significant differences between PG and TG regarding short-term outcomes and long-term prognosis were found. Specifically, PG demonstrated comparable overall survival to TG (P = 0.47). Subgroup analysis revealed that although not statistically significant, PG showed a potential advantage over TG in overall survival for patients with tumor-long diameters less than 4 cm (P = 0.31). However, for those with a long diameter larger than 4 cm, TG had a better survival probability (P = 0.81). No substantial differences were observed in baseline characteristics, surgical safety, postoperative recovery, and postoperative complications.

For locally advanced proximal GC with objective response to neoadjuvant therapy (long diameter <4 cm), PG is an alternative surgical procedure.

Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens.

Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ.

This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 (COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival.

P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.

Macrophage polarization anomalies and dysfunction play a crucial role in the pathogenesis of immune thrombocytopenia (ITP). Itaconate is a Krebs cycle-derived immunometabolite synthesized by myeloid cells to modulate cellular metabolism and inflammatory responses. This study aimed to evaluate the immunoregulatory effects of an itaconate derivative on macrophages in patients with ITP.

Peripheral blood-derived macrophages from patients with ITP and healthy controls were treated with 4-octyl itaconate (4-OI), a derivative of itaconate that can penetrate the cell membrane. Macrophage polarization, antigen-presenting functions, and phagocytic capability were measured via flow cytometry and enzyme-linked immunosorbent assay (ELISA). Macrophage glycolysis in patients with ITP and the metabolic regulatory effect of 4-OI were detected using a Seahorse XFe96 Analyzer. An active murine model of ITP was used to evaluate the therapeutic effects of 4-OI in vivo.

4-OI reduced the levels of CD80 and CD86 in M1 macrophages and suppressed the release of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 pro-inflammatory cytokines, suggesting that 4-OI could hinder the polarization of macrophages toward an M1 phenotype. We found that 4-OI pretreated M1 macrophages reduced the proliferation of CD4⁺ T cells and promoted the differentiation of regulatory T cells. In addition, after 4-OI treatment, the phagocytic capacity of M1 macrophages toward antibody-coated platelets decreased significantly in patients with ITP. In addition, the glycolytic function of M1 macrophages was elevated in individuals with ITP compared to those in healthy controls. 4-OI treatment downregulated glycolysis in M1 macrophages. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) also inhibited the polarization of M1 macrophages and restored their functions. In vivo, 4-OI treatment significantly increased platelet counts in the active ITP murine model.

Itaconate derivative 4-OI inhibited M1 macrophage polarization and restored impaired functions through metabolic reprogramming. This study provides a novel therapeutic option for ITP.

Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment.

Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models.

Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin (OMD), apolipoprotein A4 (APOA4), and insulin like growth factor binding protein 6 (IGFBP6) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells.

Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD, APOA4, and IGFBP6 may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders.

The potential impact of pre-existing coronary artery stenosis (CAS) on right ventricular (RV) function during acute pulmonary embolism (PE) episodes remains underexplored. This study aimed to investigate the association between pre-existing CAS and RV dysfunction in patients with acute PE.

In this multicenter, case-control study, 89 cases and 176 controls matched for age were enrolled at three study centers (Peking Union Medical College Hospital, Fuwai Hospital, and the Second Affiliated Hospital of Harbin Medical University) from January 2016 to December 2020. The cases were patients with acute PE with CAS, and the controls were patients with acute PE without CAS. Coronary artery assessment was performed using coronary computed tomographic angiography. CAS was defined as ≥50% stenosis of the lumen diameter in any coronary vessel >2.0 mm in diameter. Conditional logistic regression analysis was used to evaluate the association between CAS and RV dysfunction.

The percentages of RV dysfunction (19.1% [17/89] vs. 44.6% [78/176], P <0.001) and elevated systolic pulmonary artery pressure (sPAP) (19.3% [17/89] vs. 39.5% [68/176], P = 0.001) were significantly lower in the case group than those in the control group. In the multivariable logistic regression model, CAS was independently and negatively associated with RV dysfunction (adjusted odds ratio [OR]: 0.367; 95% confidence interval [CI]: 0.185–0.728; P = 0.004), and elevated sPAP (OR: 0.490; 95% CI: 0.252–0.980; P = 0.035), respectively.

Pre-existing CAS was significantly and negatively associated with RV dysfunction and elevated sPAP in patients with acute PE. This finding provides new insights into RV dysfunction in patients with acute PE with pre-existing CAS.

To the Editor: Sepsis is the leading cause of death in hospitalized patients.^[1]Organ dysfunction is a central feature of sepsis. The sequential organ failure assessment (SOFA) score, which is most commonly used in the diagnosis and treatment of sepsis, is based on the assessment of organ function.^[2]The study of organ injury is currently a hot topic in the field of sepsis research.^[3]Clarifying the distribution status of multiple organ dysfunction and mortality in sepsis is highly important for further research in these fields. We designed this study to analyze the distribution of multiple organ dysfunction syndrome (MODS) in sepsis patients based on SOFA scores. The diagnosis of sepsis was based on the third international consensus definition of sepsis and septic shock.^[4]Each patient was reevaluated and given a SOFA score based on the raw data. In this survey, patients with sepsis in eICU database, Medical Information Mart for Intensive Care (MIMIC)-IV database and admitted to Peking Union Medical College Hospital (PUMCH) were enrolled. The exclusion criteria were as follows: patients aged less than 18 years, patients not at first admission, and patients who were unable to have SOFA scores. The data in the PUMCH database were collected from June 8, 2013 to October 12, 2022. MIMIC is the largest free clinical database in critical care medicine. MIMIC-IV (version 1.0) is the latest version and contains data from 2008 to 2019. The eICU database included more than 200,000 admissions to 335 ICUs from 208 hospitals in 2014 and 2015. We obtained the corresponding certificate to use the above databases. The protocol was approved by the Central Institutional Review Board at Peking Union Medical College Hospital (No. I-23PJ1416). The requirement for individual informed consent for this retrospective analysis was waived because all protected health information was anonymized. Patients with sepsis (2984 in the PUMCH database, 12,943 in the eICU database, and 10,150 in the MIMIC-IV database) were ultimately enrolled. The basic information and comorbidities are shown in Supplementary Table 1, http://links.lww.com/CM9/C490.A SOFA score of a single system ≥1 is defined as impairment of organ function, and a score of ≥3 is defined as severe impairment of organ function. All the analyses were conducted via R software (version 3.4.3, R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were summarized as medians and interquartile ranges, while categorical variables were expressed as frequencies and percentages.

To the Editor: The global prevalence of chronic spontaneous urticaria (CSU) is estimated to be approximately 0.5–1%, with approximately 0.75% in China.^[1,2]Secondgeneration H1-antihistamines (H1AHs) at a standard dose are currently the preferred first-line treatment for CSU. In the case of an inadequate response to H1AHs after 1–2 weeks of treatment, the dose of the same H1AH could be increased to a maximum of 4-fold, or it could be combined with other antihistamines. For patients with CSU who remain intolerant or unresponsive despite 2–4 weeks of treatment with increased doses of antihistamines, omalizumab, a humanized recombinant anti-immunoglobulin E (IgE) monoclonal antibody (300 mg every 4 weeks), is recommended as third-line treatment.^[3]

To the Editor: As antiretroviral therapy (ART) transforms HIV into a chronic condition, metabolic abnormalities, particularly hyperglycemia, have become a significant concern for people living with HIV (PLWH). Although PLWH are at higher risk for hyperglycemia due to both ART and HIV-related factors, the prevalence and associated factors of hyperglycemia and diabetes in treatment-naive PLWH in China remain underexplored. This study aims to investigate the trend of hyperglycemia and diabetes prevalence in newly diagnosed PLWH in Shenzhen, China, from 2013 to 2019.

To the Editor: Subthreshold depression (SD), which often precedes major depressive disorder (MDD), is broadly defined as scoring above the cutoff point on a depression questionnaire without meeting the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria.^[1]SD was estimated to have a prevalence rate ranging between 5.3% and 29.2%.^[2,3]In addition, SD was linked to adverse outcomes in both physical and mental well-being, as well as poor academic, social, and mood results for children and adolescents.^[4]Consequently, addressing SD with appropriate treatment was of paramount importance. Psychological interventions have shown some impact on reducing depressive symptoms in adolescents with SD but faced obstacles such as inaccessibility, high costs, and stigma of mental illness.^[4]Digital (i.e., internet- and computer-based) psychological interventions offer potential solutions to address these barriers and promote mental health care for youth. However, previous studies presented mixed results concerning the efficacy of these interventions. An evaluation of extant evidence for the efficacy of digital psychotherapy programs for youth experiencing SD will provide important evidence for primary healthcare.