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SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.
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Histonas , Neoplasias , Humanos , Histonas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias/tratamiento farmacológico , MetilaciónRESUMEN
BACKGROUND AND PURPOSE: Respiratory movement has an important impact on the radiotherapy for lung tumor. Respiratory gating technology is helpful to improve the accuracy of target delineation. This study investigated the value of prospective and retrospective respiratory gating simulations in target delineation and radiotherapy plan design for solitary pulmonary tumors (SPTs) in radiotherapy. METHODS: The enrolled patients underwent CT simulation with three-dimensional (3D) CT non gating, prospective respiratory gating, and retrospective respiratory gating simulation. The target volumes were delineated on three sets of CT images, and radiotherapy plans were prepared accordingly. Tumor displacements and movement information obtained using the two respiratory gating approaches, as well as the target volumes and dosimetry parameters in the radiotherapy plan were compared. RESULTS: No significant difference was observed in tumor displacement measured using the two gating methods (p > 0.05). However, the internal gross tumor volumes (IGTVs), internal target volumes (ITVs), and planning target volumes (PTVs) based on the retrospective respiratory gating simulation were larger than those obtained using prospective gating (group A: pIGTV = 0.041, pITV = 0.003, pPTV = 0.008; group B: pIGTV = 0.025, pITV = 0.039, pPTV = 0.004). The two-gating PTVs were both smaller than those delineated on 3D non gating images (p < 0.001). V5Gy, V10Gy, V20Gy, V30Gy, and mean lung dose in the two gated radiotherapy plans were lower than those in the 3D non gating plan (p < 0.001); however, no significant difference was observed between the two gating plans (p > 0.05). CONCLUSIONS: The application of respiratory gating could reduce the target volume and the radiation dose that the normal lung tissue received. Compared to prospective respiratory gating, the retrospective gating provides more information about tumor movement in PTV.
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Neoplasias Pulmonares , Planificación de la Radioterapia Asistida por Computador , Humanos , Planificación de la Radioterapia Asistida por Computador/métodos , Masculino , Femenino , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Anciano , Tomografía Computarizada por Rayos X/métodos , Técnicas de Imagen Sincronizada Respiratorias/métodos , Dosificación Radioterapéutica , Carga Tumoral , Adulto , Estudios Retrospectivos , Nódulo Pulmonar Solitario/radioterapia , Nódulo Pulmonar Solitario/diagnóstico por imagen , Estudios Prospectivos , RespiraciónRESUMEN
A multi-component paclitaxel (PTX) -loaded ß-elemene nanoemulsion by transferrin modification (Tf-PE-MEs) was developed to enhance non-small-cell lung cancer (NSCLC) treatment. After transferrin modification, the particle size of Tf-PE-MEs was (14.87 ± 1.84) nm, and the zeta potential was (-10.19 ± 0.870) mV, respectively. In vitro experiments showed that Tf-PE-MEs induced massive apoptosis in A549 cells, indicating that it had significant cytotoxicity to A549 cells. Through transferrin modification, Tf-PE-MEs accumulated at the tumor site efficiently with overexpressed transferrin receptor (TfR) on the surface of A549 cells. This will allow increasing PTX and ß-elemene concentration in the target cells, enhancing the therapeutic effect. Compared to PTX alone, Tf-PE-MEs displayed good anti-tumor efficacy and diminished systemic toxicity in vivo studies. With favourable therapeutic potential, this study provides a new strategy for the combined anticancer treatment of non-small cell lung cancer.
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The precise delivery of therapeutic agents to specific cell populations, including cancer cells, remains a target in modern medicine, to enhance treatment efficacy, while minimizing unintended side effects. This study presents a strategy utilizing bispecific antibodies for the targeted delivery of nucleic acid drugs to the surface of glucose-regulated protein 78 (GRP78)-overexpressing cancer cells. Strong binding affinity of the bispecific antibodies to GRP78-overexpressing cancer cells, including HEPG2 cells, confirmed the tumor-targeting potential of this platform. Functional analyses demonstrated the role of the bispecific antibodies in enhancing lipid nanoparticle (LNP) uptake, causing increased gene expression levels of nucleic acid drugs loaded within LNPs. In vivo imaging confirmed the potency of the bispecific-antibody-modified LNPs in delivering nucleic acid drugs to tumors and sustaining therapeutic expression levels. In vivo therapy results indicated that the bispecific antibodies improved the antitumor activity of PE38-loaded LNPs in tumors overexpressing surface GRP78. This study pioneered a bispecific-antibody-centered platform for the targeted delivery of nucleic acid drugs. The robust antigen-antibody binding affinity, tumor-selective interactions, enhanced cellular uptake, and proficient gene expression promise to advance precision therapeutics in oncology. Continued refinement and translation of this drug delivery strategy are important to unlock its full clinical potential.
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Anticuerpos Biespecíficos , Liposomas , Nanopartículas , Neoplasias , Ácidos Nucleicos , Humanos , Medicina de Precisión , Chaperón BiP del Retículo Endoplásmico , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND AND PURPOSE: To assess the variation of large-volume brain metastases (BMs) boundaries and shapes using enhanced magnetic resonance (MR) scanning with different delay times and to provide a basis for determining the gross tumor target volume (GTV) for radiotherapy of BMs. MATERIALS AND METHODS: We prospectively enrolled 155 patients initially diagnosed with BMs (561 lesions > 1 cm). Contrast-enhanced (CE) T1-weighted imaging scans were performed 1, 3, 5, 10, 18, and 20 min after gadolinium-based contrast agent injection and GTVs were determined as GTV-1min, GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min, respectively, which were subsequently fused in different phases. Fusion of the six GTVs was defined as GTV-total, which was set as the reference GTV. The volume, shape, and signal intensity of the GTVs and brain white matter (BWM) were compared at different delay times. RESULTS: GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min volumes increased by 2.2 %, 3.8 %, 6.5 %, 9.5 %, and 10.6 %, respectively (P < 0.05) compared with GTV-1min. Compared with GTV-total, GTV-1min, GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min volumes reduced by 25.4 %, 22.1 %, 18.7 %, 15.0 %, 11.2 %, and 10.3 %, respectively (P < 0.05). Compared with GTV-total, 29 (51.8 %) fused GTVs had a volume reduction rate < 5 %, 45 (80.4 %) had a Dice similarity coefficient > 0.95, and all contained GTV-10min, GTV-18min or GTV-20min. The signal intensity ratio between the GTV and BWM peaked at 5 min (0.351 ± 0.24). CONCLUSION: Enhanced MR scans with different delay times show significant differences in the boundaries and shapes of large-volume BMs, and time-delayed multi-phase CE scanning should be used in GTV determination, with time phases ≥ 10 min being mandatory.
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Neoplasias Encefálicas , Medios de Contraste , Imagen por Resonancia Magnética , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/patología , Femenino , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Masculino , Anciano , Estudios Prospectivos , Adulto , Carga Tumoral , Factores de Tiempo , Anciano de 80 o más AñosRESUMEN
Recently, the substance P (SP)/neurokinin-1 receptor (NK-1R) system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019 (COVID-19). Besides, studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis. These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy. This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers, as well as the underlying mechanisms. Furthermore, the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized, such as solid dispersion systems, nanonization, and nanoencapsulation. As a radiopharmaceutical therapeutic, the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors. However, combining NK-1R antagonists with other drugs can produce a synergistic effect, thereby enhancing the therapeutic effect, alleviating the symptoms, and improving patients quality of life in several diseases and cancers.