Signal Transduction and Targeted Therapy最新文献

The prognostic implications of TP53 alterations in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) treated with chimeric antigen receptor (CAR) T-cell therapy remain inadequately characterized, particularly with respect to long-term outcomes. We report extended follow-up (median: 77.77 months) of 122 patients with r/r B-NHL who received either dual-targeted CD19/CD22 CAR-T-cell therapy alone (cohort A, n = 65) or following sequential autologous stem cell transplantation (ASCT; cohort B, n = 57). TP53 alterations were identified in 59 patients (48.4%). Within both cohorts, overall survival (OS) and progression-free survival (PFS) did not significantly differ between the TP53-altered subgroup and the wild-type subgroup (P >0.05). Notably, compared with CAR-T-cell monotherapy, the sequential ASCT-CAR-T-cell approach (cohort B) was associated with improved 5-year OS (70.2% vs. 40.0%) and PFS (64.9% vs. 35.4%). The 5-year cumulative incidence of nonrelapse mortality was 10.7% overall (9.2% in cohort A vs. 12.3% in cohort B). Secondary malignancies occurred in 2.5% of patients, whereas serious infection-related events beyond 3 months post-infusion were observed in 13.6%, supporting a favorable long-term safety profile. Multivariate analysis identified treatment options and the presence of bulky disease as independent adverse prognostic factors for OS and PFS. These findings suggest that dual-target CD19/CD22 CAR-T-cell therapy, particularly when integrated with ASCT, may mitigate the adverse prognostic influence of TP53 alterations, offering sustained clinical benefit with manageable long-term toxicity in r/r aggressive B-NHL.

Coronaviruses have repeatedly emerged in recent years, causing significant and ongoing threats to global public health. The development of therapeutic agents and strategies capable of responding to future outbreaks caused by emerging coronavirus variants remain an ongoing priority. Here, we engineered a single-stranded DNA aptamer (NApt8-3) that selectively binds to the conserved nucleocapsid (N) protein shared among multiple coronaviruses, including SARS-CoV-2 (wild-type, beta, omicron variant), SARS-CoV, MERS-CoV, HCoV-OC43 and HCoV-229E, and strongly inhibits N protein-induced inflammatory cytokine expression. Mechanistically, NApt8-3 effectively binds to the N protein and blocks its interaction with the NLRP3 inflammasome, a key mediator of coronavirus-induced inflammation. To enable intracellular delivery and evaluate its therapeutic potential, we developed a proof-of-concept anti-SARS-CoV-2 agent-circSASON, a circular trivalent aptamer-antisense oligonucleotide (ASO) chimera-combining NApt8-3, an antispike protein aptamer, and an ASO that silences the N gene. In vitro experiments demonstrated that circSASON effectively inhibits SARS-CoV-2 replication and suppresses N protein-induced cytokine expression in host cells. The intranasal administration of circSASON significantly decreased the level of SARS-CoV-2 and alleviated SARS-CoV-2-induced pulmonary inflammation and inflammatory cytokine expression in mice. Therefore, our findings highlight NApt8-3 as a broad-spectrum anti-inflammatory agent that targets the conserved coronavirus N protein. The therapeutic design strategy employed, together with the N aptamer developed in this study, may offer a framework for the rapid development of treatments to combat future pandemics caused by emerging coronavirus variants.

RNA modifications represent a dynamic layer of gene expression regulation, RNA stability, and translation with profound implications for cellular function and disease. However, the critical regulation and functions of RNA-modifying proteins (RMPs) remain poorly understood. Here, we present a large-scale characterization of RMPs through 378 multiomics datasets encompassing genomics, bulk and single-cell transcriptomics, epitranscriptomics, proteomics, and posttranslational modifications (PTMs) across 63 human tissues. Our analysis of experimental perturbations of RMPs revealed dynamic differential modification peaks and expressed genes. We applied nonnegative matrix factorization to annotate RMP-mediated cell types in single-cell transcriptomes. Functional annotations in acute myeloid leukemia (AML) revealed RMPs such as ALKBH5 as critical mediators of m6A dynamics, influencing pathways involved in translation initiation, immune regulation, and tumorigenesis. We revealed cell type-specific modification patterns, including those in ALKBH5-enriched AML stem cells with special ligand‒receptor interactions and genetic variations modulated by m6A. We integrated proteogenomic data to uncover PTM-associated regulatory, mutation, and protein‒protein interaction networks linked to RMPs. We developed RMzyme, a platform that consolidates our findings and provides insights into RMPs and their downstream effects. This resource is expected to facilitate biomedical research into the molecular mechanisms of human diseases through the lens of RNA modifications and multiomics data integration.

Ulcerative colitis (UC) is the most common chronic inflammatory disease of the intestinal tract in clinical practice, and long-term chronic inflammation leads to repeated damage to and repair of the colonic mucosa, which may progress to malignancy through atypical hyperplasia. However, there are currently no fully targeted drugs for the treatment of UC. In this review, we discuss several cellular processes, such as autophagy, endoplasmic reticulum stress, mitochondrial dysfunction, macrophage polarization, ferroptosis and the Th/Treg cell balance, which are associated with the occurrence and development of UC. Many molecular targets and signaling pathways, such as nuclear factor kappa-B (NF-κB), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), Wnt/β-catenin, adenosine 5'-monophosphate-activated protein kinase (AMPK), toll-like receptor (TLR), Janus kinase/signal transducer and activator of transcription (JAK/STAT), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs), play crucial roles in the progression of UC. We also summarize the common treatment strategies for UC, including lifestyle interventions, aminosalicylic acid preparations, corticosteroid drugs, biologics, fecal microbiota transplantation, and other drugs for symptomatic treatment. This review provides a detailed theoretical basis for the pathology and treatment of UC. Future research could focus on optimizing the treatment plan and achieving more precise and personalized treatment with multiple targets in multiple aspects.

Ocular neovascular and neurodegenerative diseases, such as diabetic retinopathy and age-related macular degeneration, are characterized by abnormal angiogenesis, vascular leakage, and progressive retinal neurodegeneration, ultimately leading to irreversible vision loss. Here, we present a tetrahedral framework DNA-based bioswitchable Tri-miR-22 mimic delivery system (BiRDS), which is specifically engineered for extraocular administration. In vitro, BiRDS can penetrate the cell membrane within 24 h and accumulate extensively in the cytoplasm. Through transscleral-choroidal-retinal penetration, BiRDS achieves robust delivery to the choroid and retina within 18 h without the need for intravitreal injection in mice. The BiRDS can effectively inhibit the proliferation, tube formation and migration abilities of human umbilical vein endothelial cells. In murine models of choroidal neovascularization and oxygen-induced retinopathy, BiRDS not only suppresses retinal pathological neovascularization with efficacy comparable to that of current anti-VEGF agents, but also possesses unique effects that current agents lack, such as improved retinal perfusion and preserved neuronal integrity, thereby contributing to the protection of visual function. Furthermore, transcriptomic profiling and molecular validation revealed that BiRDS exerts its therapeutic efficacy by inhibiting the Wnt/β-catenin pathway, a key driver of mediating the aforementioned pathological processes. This study highlights BiRDS as a next-generation RNA nanotherapy with broad clinical potential, offering site specific, multitargeted modulation via a minimally invasive and patient-friendly route.