Chinese Medical Journal最新文献

Background: Triple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant subtype of breast cancer, characterized by high rates of metastasis and mortality. This study aimed to identify and evaluate the therapeutic potential of blestriarene C (BC), a novel diphenanthrene compound, in the treatment of TNBC. The study also sought to explore the underlying mechanisms and signaling pathways involved in BC's antitumor effects.

Methods: A multiomics analysis was conducted to identify key genes and pathways involved in TNBC treatment. We performed experiments related to cell viability, ferroptosis, and mitophagy to explore the effects of BC in the treatment of TNBC, utilizing the TNBC cell lines BT-549 and 4T1 cells. The impact of sestrin 2 (SESN2) knockout on BC's effects was also studied. We also conducted in vivo experiments using the patient-derived xenograft (PDX) model in zebrafish to assess the antitumor effects of BC.

Results: The results of RNA sequencing and proteomics showed that ferroptosis and mitophagy may be the main mechanisms of BC acting on TNBC cells. BC could inhibit cell proliferation by modulating the phosphoinositide 3-kinase/protein kinase B/forkhead box O4 and SESN2/mechanistic target of rapamycin signaling pathways, and inducing ferroptosis and mitophagy. SESN2 and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), as hub genes, participated in regulating the therapeutic effect of BC on TNBC. TNBC tumors in zebrafish treated with BC were smaller and lighter, indicating that BC had antitumor effect.

Conclusions: BC emerges as a promising therapeutic agent for TNBC by targeting SESN2 and MAP1LC3B, modulating associated signaling pathways, and inducing ferroptosis and mitophagy. These findings provide the basis for further investigation of BC's potential as a targeted therapy for TNBC.

Background: Autologous chimeric antigen receptor T (CAR-T) cell therapy has demonstrated efficacy in the treatment of acute myeloid leukemia (AML). Nevertheless, the intrinsic characteristics of autologous therapy, such as extended manufacturing timelines and patient-specific limitations, contribute to delays in treatment availability. More critically, relapse due to antigen escape following single-targeted CAR-T therapy constitutes a significant clinical obstacle. To address the dual challenges of delayed treatment accessibility and antigen escape relapse, this study proposes the development of universal tandem CAR-T cells. These cells, engineered to target CD123 and B7-H3 through clustered regularly interspaced short palindromic repeats (CRISPR) gene editing technology, represent an innovative therapeutic strategy for AML.

Methods: In this study, an immune phage display nanobody library was developed for the purpose of screening CD123-specific nanobodies. The CRISPR/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing system was utilized to disrupt the T-cell receptor alpha chain ( TRAC ) and B2M genes present in T cells, resulting in the generation of universal CD123/B7-H3 bispecific universal CAR-T (UCAR-T) cells. The efficacy of these dual-specific UCAR-T cells in combating tumors was subsequently assessed through in vitro and in vivo experiments.

Results: Through four rounds of panning against CD123 from an immunized camelid VHH library, we identified 21 antigen-specific nanobodies. Tandem bispecific UCAR-T engineered with these binders demonstrated CAR transduction efficiencies ranging from 82% to 87%. In vitro functional profiling revealed a significantly enhanced cytotoxicity of bispecific UCAR-Ts against CD123 + /B7-H3 + AML cell lines when compared to single-target constructs, while effectively regulating the secretion of effector cytokines (IL-2, IFN-γ, TNF-α). In AML xenograft models, treatment with bispecific UCAR-T notably inhibited tumor progression, extended the survival of tumor-bearing mice with recurrence-free persistence throughout the observation period, and did not result in significant body weight loss or cytokine release syndrome.

Conclusions: The findings of the study address the issue of tumor antigen evasion in the treatment of AML, circumvent certain constraints associated with autologous CAR-T cell therapy, and offer novel insights and strategies for managing AML.

Abstract: Cardiometabolic risk encompasses the interconnected conditions of cardiovascular diseases (CVDs), type 2 diabetes (T2D), and other metabolic diseases, which are leading global health challenges. The American Heart Association (AHA) has introduced "Life's Essential 8" (LE8), a framework emphasizing eight key lifestyle and health factors, including diet, physical activity, smoking, sleep health, body weight, blood glucose, blood lipids, and blood pressure to optimize cardiovascular health and reduce the burden of cardiometabolic risk. This review examined the associations between individual and combined lifestyle factors and the development and progression of cardiometabolic risk, using CVD and T2D as representative conditions. Evidence highlighted that adherence to healthy lifestyle behaviors, such as maintaining a balanced diet, engaging in physical activity, avoiding smoking, and achieving a healthy weight, significantly reduced the risks of CVD, T2D, and hypertension. Studies showed that adherence to 3-4 healthy lifestyle factors lowers the risk of transition from baseline to diabetes, complications, and mortality. Despite the proven benefits, barriers such as limited access to healthy food and safe environments for physical activity hinder widespread adoption. Addressing these challenges requires innovative public health interventions and personalized strategies targeting high-risk populations. This review underscored the importance of promoting and adhering to LE8 principles to reduce the global burden of cardiometabolic risk and improve overall health outcomes.

Background: Given the high incidence of secondary antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE) and the similarity of clinical manifestations between APS and SLE, validating the 2023 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) antiphospholipid syndrome (APS) classification criteria within this special population is of critical importance. This study aimed to clarify the clinical applicability of the 2023 criteria for classifying secondary APS in Chinese SLE populations.

Methods: SLE patients with available data of antiphospholipid antibodies were retrospectively identified from the Peking University First Hospital Treat SLE to Target (STAR) cohort starting from April 1, 2007. This study included the patients from STAR between April 1, 2007 and May 1, 2024. Patients were independently classified according to both the 2023 criteria and 2006 criteria. For the 2023 criteria, two strategies were implemented (all-in or all-out) to determine whether overlapping manifestations of APS and SLE should be scored as APS when clinical differentiation was not feasible. The "gold standard" for APS classification was independently established by two rheumatologists. Sensitivity and specificity were compared between the two criteria. Subgroup analyses were conducted in terms of gender, age, body mass index, disease duration, and comorbidities.

Results: A total of 1001 SLE patients were included in this study. According to the two scoring strategies, if all overlapping features were considered as APS manifestations, 101 patients (10.1%) met the 2023 criteria, which showed higher sensitivity (0.878 vs. 0.768) but lower specificity (0.968 vs. 0.988) compared to the 2006 criteria. When overlapping features were excluded from APS scoring, 68 patients (6.8%) met the 2023 criteria, which demonstrated similar specificity (0.993 vs. 0.988) but lower sensitivity (0.756 vs. 0.768) compared to the 2006 criteria.

Conclusions: The sensitivity and specificity of 2023 APS classification criteria varied depending on the scoring strategy used. Considering the presence of SLE as a distinct item in future APS classification criteria may be warranted.

Abstract: Epidermal growth factor receptor (EGFR) is a critical driver gene in non-small cell lung cancer (NSCLC). Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Throughout this evolution, EGFR-TKIs have become the cornerstone of treatment for EGFR-mutant NSCLC, extending beyond advanced stages to encompass the entire disease spectrum, including perioperative and maintenance therapies, with combination therapies has further expanded treatment options. These advancements have significantly improved patient survival and quality of life. However, challenges such as acquired resistance remain significant hurdles in achieving long-term disease control. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.

Abstract: The treatment paradigm for lymphoma, a highly heterogeneous group of hematologic malignancies, has been revolutionized by the development of therapies targeting oncogenic signaling pathways. This shift from conventional chemotherapy to precision medicine is driven by a deep molecular understanding of the pathways that govern lymphoma cell survival and proliferation. This review comprehensively surveys the landscape of these targeted therapies, from fundamental molecular mechanisms to clinical breakthroughs. We first dissect the molecular architecture of key oncogenic drivers, covering foundational survival networks such as the B-cell receptor, phosphatidylinositol 3-kinase /protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription, and B-cell lymphoma 2 apoptosis pathways; critical regulatory processes like nuclear export controlled by exportin 1 and epigenetic patterns. For each therapeutic class, we discuss the clinical development of specific inhibitors and the challenge of acquired resistance. Furthermore, we examine emerging concepts in lymphoma, including the context-dependent role of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway, to provide a comprehensive overview of the current therapeutic landscape. A central theme of this review is the integration of these targeted agents into clinical practice. We discuss how the successful targeting of oncogenic signaling pathways has enabled the development of effective chemotherapy-free regimens, which offer durable responses with reduced toxicity and improved quality of life. Although initially transformative for patients with indolent lymphomas or those unfit for intensive chemotherapy, this paradigm is now extending to aggressive lymphomas as well. Another pivotal advance is the use of molecular subtyping and predictive biomarkers to guide treatment. As powerfully demonstrated by recent clinical trials, aligning targeted agents with the specific signaling or epigenetic dependencies of a tumor subtype can significantly enhance the efficacy of standard immunochemotherapy backbones in both B-cell and T-cell lymphomas. Finally, we address the persistent challenges of acquired resistance and discuss future directions, including the development of next-generation agents such as proteolysis-targeting chimeras, the design of rational, synergistic combination strategies, and the leveraging of multiomics and artificial intelligence to decipher complex signaling networks. By continuing to translate molecular insights into clinical practice, the field is steadily moving toward the goal of achieving precision cures for patients with lymphoma.