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N1-methyladenosine (m1A) modification is an epigenetic change that occurs on RNA molecules, regulated by a suite of enzymes including methyltransferases (writers), demethylases (erasers), and m1A-recognizing proteins (readers). This modification significantly impacts the function of RNA and various biological processes by affecting the structure, stability, translation, metabolism, and gene expression of RNA. Thereby, m1A modification is closely associated with the occurrence and progression of cancer. This review aims to explore the role of m1A modification in tumor immunity. m1A affects tumor immune responses by directly regulating immune cells and indirectly modulating tumor microenvironment. Besides, we also discuss the implications of m1A-mediated metabolic reprogramming and its nexus with immune checkpoint inhibitors, unveiling promising avenues for immunotherapeutic intervention. Additionally, the m1AScore, established based on the expression patterns of m1A modification, can be used to predict tumor prognosis and guide personalized therapy. Our review underscores the significance of m1A modification as a burgeoning frontier in cancer biology and immuno-oncology, with the potential to revolutionize cancer treatment strategies.

UTX is known as a general factor that activates gene transcription during development. Here, we demonstrate an additional essential role of UTX in the DNA damage response, in which it upregulates the expression of ku80 in Drosophila, both in cultured cells and in third instar larvae. We further showed that UTX mediates the expression of ku80 by the demethylation of H3K27me3 at the ku80 promoter upon exposure to ionizing radiation (IR) in a p53-dependent manner. UTX interacts physically with p53, and both UTX and p53 are recruited to the ku80 promoter following IR exposure in an interdependent manner. In contrast, the loss of utx has little impact on the expression of ku70, mre11, hid and reaper, suggesting the specific regulation of ku80 expression by UTX. Thus, our findings further elucidate the molecular function of UTX.

Currently, fatigue-resistance topology optimization has received ever increasing attention, in which most of the literature considers this issue as a simple extension of stress-based topology optimization. However, previous approaches may not be applicable when considering general loads, as the conventional uniaxial rainflow counting method, commonly employed in prior studies, can result in significant errors. Furthermore, the inclusion of general loads introduces additional nonlinearity to fatigue-resistant topology optimization, posing challenges in identifying the optimal solution. To this end, a novel methodology for fatigue-resistance topology optimization considering general loads is proposed in this paper. The independent rainflow counting method is utilized during the process of structural damage estimation. The damage penalization model is subsequently adopted to reduce the nonlinearity by scaling the value of fatigue damage. To illustrate the necessity of an independent rainflow counting method, an example of a double L -shaped structure subjected to general loads is presented. The augmented Lagrangian (AL) approach is introduced to transform numerous damage constraint equations into the objective function, generating a sequence of box-constrained optimization sub-problems. After employing the typical SIMP technique, the relative sensitivities of the AL function regarding design variables are derived, which facilitates the efficient solution using the method of moving asymptotes (MMA). Through 2D and 3D numerical tests, the effectiveness of the proposed method is validated in comparison to the traditional method. Further investigation is conducted into the influences of general loads, damage penalization model, and manufacturing error robustness. In addition, the fatigue-resistance performance of a bearing support of a wind turbine is improved by the suggested approach, and its overall weight is decreased by 25.40%. The proposed method addresses the nonlinear and localized nature of fatigue-resistant topology optimization more efficiently. The results indicate that the proposed method can develop a lightweight design for structures under general loads.

This paper aims to propose a topology optimization method on generating porous structures comprising multiple materials. The mathematical optimization formulation is established under the constraints of individual volume fraction of constituent phase or total mass, as well as the local volume fraction of all phases. The original optimization problem with numerous constraints is converted into a box-constrained optimization problem by incorporating all constraints to the augmented Lagrangian function, avoiding the parameter dependence in the conventional aggregation process. Furthermore, the local volume percentage can be precisely satisfied. The effects including the global mass bound, the influence radius and local volume percentage on final designs are exploited through numerical examples. The numerical results also reveal that porous structures keep a balance between the bulk design and periodic design in terms of the resulting compliance. All results, including those for irregular structures and multiple volume fraction constraints, demonstrate that the proposed method can provide an efficient solution for multiple material infill structures.

Cellular structure can possess superior mechanical properties and low density simultaneously. Additive manufacturing has experienced substantial progress in the past decades, which promotes the popularity of such bone-like structure. This paper proposes a methodology on the topological design of porous structure. For the typical technologies such as the p-norm aggregation and implicit porosity control, the violation of the maximum local volume constraint is inevitable. To this end, the primary optimization problem with bounds of local volume constraints is transformed into unconstrained programming by setting up a sequence of minimization sub-problems in terms of the augmented Lagrangian method. The approximation and algorithm using the concept of moving asymptotes is employed as the optimizer. Several numerical tests are provided to illustrate the effectiveness of the proposed approach in comparison with existing approaches. The effects of the global and local volume percentage, influence radius and mesh discretization on the final designs are investigated. In comparison to existing methods, the proposed method is capable of accurately limiting the upper bound of global and local volume fractions, which opens up new possibilities for additive manufacturing.

Oral squamous cell carcinoma (OSCC) is a highly aggressive head and neck malignancy with a poor prognosis associated with its complex tumor microenvironment. Cancer-associated fibroblasts (CAFs) contribute to tumor progression by secreting various signaling molecules. This study investigates the molecular mechanism through which Z-DNA-binding protein 1 (ZBP1) promotes OSCC development through CAF regulation. To this end, orthotopic MOC1 transplantation and 4NQO-induced carcinogenesis OSCC models were established with Zbp1 −/− mice. Single-cell RNA sequencing (scRNA-seq) analyzed cellular heterogeneity and signaling network alterations in the tumor microenvironment. An in vitro CAF induction model combined with a Transwell co-culture system clarified the molecular mechanism of ZBP1. Finally, the role of the ZBP1–CCL7/CCR1 signaling axis in promoting OSCC progression was evaluated via in vivo recombinant CCL7 protein rescue and CCR1 antagonist (BX471) intervention. ZBP1 is highly expressed in OSCC tissues, while its deficiency inhibits tumor growth and proliferation. Proliferation-related pathways (e.g., E2F targets, MYC targets, cell cycle) are downregulated while immune activation signatures (e.g., interferon response, p53 pathway, TNF-α/NF-κB signaling) are upregulated in Zbp1 −/− tumor cells. Cellular interaction analysis and ligand–receptor network profiling demonstrated significant attenuation of the CCL7–CCR1 signaling axis between CAFs and tumor cells. ZBP1 deficiency reduces CCL7 expression in CAFs, diminishing their ability to promote tumor cell proliferation, migration, and invasion via the CCL7/CCR1 axis. Exogenous CCL7 supplementation partially restores tumor growth in Zbp1 −/− mice, indicating that ZBP1 bridges CAF–tumor cell communication through the CCL7–CCR1 axis. This study highlights ZBP1 as crucial for OSCC progression by regulating CCL7 expression in CAFs to activate CCR1 signaling in tumor cells. This provides insights into the regulatory mechanisms within the OSCC microenvironment, offering a potential therapeutic strategy for targeted interventions.

Despite landmark therapy of chronic myelogenous leukemia (CML) with tyrosine kinase inhibitors (TKIs), drug resistance remains problematic. Cancer pathogenesis involves epigenetic dysregulation and in particular, histone lysine demethylases (KDMs) have been implicated in TKI resistance. We sought to identify KDMs with altered expression in CML and define their contribution to imatinib resistance. Bioinformatics screening compared KDM expression in CML versus normal bone marrow with shRNA knockdown and flow cytometry used to measure effects on imatinib-induced apoptosis in K562 cells. Transcriptomic analyses were performed against KDM6A CRISPR knockout/shRNA knockdown K562 cells along with gene rescue experiments using wildtype and mutant demethylase-dead KDM6A constructs. Co-immunoprecipitation, luciferase reporter and ChIP were employed to elucidate mechanisms of KDM6A-dependent resistance. Amongst five KDMs upregulated in CML, only KDM6A depletion sensitized CML cells to imatinib-induced apoptosis. Re-introduction of demethylase-dead KDM6A as well as wild-type KDM6A restored imatinib resistance. RNA-seq identified NTRK1 gene downregulation after depletion of KDM6A. Moreover, NTRK1 expression positively correlated with KDM6A in a subset of clinical CML samples and KDM6A knockdown in fresh CML isolates decreased NTRK1 encoded protein (TRKA) expression. Mechanistically, KDM6A was recruited to the NTRK1 promoter by the transcription factor YY1 with subsequent TRKA upregulation activating down-stream survival pathways to invoke imatinib resistance. Contrary to its reported role as a tumor suppressor and independent of its demethylase function, KDM6A promotes imatinib-resistance in CML cells. The identification of the KDM6A/YY1/TRKA axis as a novel imatinib-resistance mechanism represents an unexplored avenue to overcome TKI resistance in CML.

UTX is known as a general factor that activates gene transcription during development. Here, we demonstrate an additional essential role of UTX in the DNA damage response, in which it upregulates the expression of ku80 in Drosophila, both in cultured cells and in third instar larvae. We further showed that UTX mediates the expression of ku80 by the demethylation of H3K27me3 at the ku80 promoter upon exposure to ionizing radiation (IR) in a p53-dependent manner. UTX interacts physically with p53, and both UTX and p53 are recruited to the ku80 promoter following IR exposure in an interdependent manner. In contrast, the loss of utx has little impact on the expression of ku70, mre11, hid and reaper, suggesting the specific regulation of ku80 expression by UTX. Thus, our findings further elucidate the molecular function of UTX.

Background Tumor metastasis is responsible for the high mortality rate of patients with oral squamous cell carcinoma (OSCC). Although many hypotheses have been proposed to elucidate the mechanism of tumor metastasis, the origin of the metastatic tumor cells remains unclear. In this study, we explored the role of cell fusion in the formation of OSCC metastatic tumor cells. Methods Murine OSCC tumor cells and macrophages were fused in vitro, and the cell proliferation, migration, and phagocytosis abilities of hybrid cells and parental cells were compared. Subsequently, we compared the transcriptome differences between hybrid and parental cells. Results Murine OSCC tumor cells and macrophages were successfully fused in vitro. The cytological and molecular experimental results revealed that OSCC tumor cells obtained a migration‐related phenotype after fusion with macrophages, and the migration ability of hybrid cells was related to the activation of the “chemokine signal pathway”. Conclusion After fusion with macrophages, the chemokine signaling pathway in OSCC tumor cells was activated, leading to metastasis.

Oral squamous cell carcinoma (OSCC) has a poor prognosis due to its immunosuppressive tumor microenvironment (TME), in which tumor-associated macrophages (TAMs) play a pivotal role in promoting disease progression and therapeutic resistance. This study examines whether Prussian blue nanoparticles (PB NPs) could reprogram TAMs and block tumor-stroma communication in OSCC. PB NPs were synthesized using polyvinylpyrrolidone-assisted coprecipitation and characterized by transmission electron microscopy, dynamic light scattering, and UV-Vis spectroscopy. In vitro, their effects on macrophage polarization were assessed via immunofluorescence, Western blotting (CD206/CD86), and ELISA (TGF-β1/IL-6/TNF-α). The impact on OSCC-macrophage interaction was evaluated using CCK-8 assays, transwell co-culture systems with conditioned media. In vivo, xenograft-bearing mice were used to assess PB NP effects on OSCC-TAM crosstalk. Tumor growth, Ki67 proliferation index, and TAM phenotypes (CD206 /CD86 ) were analyzed. Systemic biocompatibility was further assessed through CCK-8 in vitro and hematological profiling and histopathological examination in vivo. PB NPs (diameter 57.43 ± 22.25 nm; zeta potential -17.36mV) were successfully made and showed good biocompatibility in vitro and in vivo. In vitro, they shifted M2 TAMs toward anti-tumor M1 phenotypes, reducing CD206 and TGF-β1 while increasing CD86 and pro-inflammatory cytokines (IL-6, TNF-α). This change disrupted OSCC-TAM communication, limiting tumor growth and migration. In vivo, PB NPs reduced tumor volume, lowered the Ki67 cell ratio, and increased the intratumoral M1/M2 macrophage ratio. Prussian blue nanoparticles effectively modulate the immunosuppressive TME in OSCC by shifting TAM polarization from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype, thereby interrupting critical tumor-stroma interactions. Given their intrinsic immunomodulatory properties and favorable biosafety profile, PB NPs represent a promising and safe therapeutic strategy targeting the TME in OSCC.