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BACKGROUND: Adenomyosis is a common gynecological disease, characterized by overgrowth of endometrial glands and stroma in the myometrium, however its exact pathophysiology still remains uncertain. Emerging evidence has demonstrated the elevated level of arginase 2 (ARG2) in endometriosis and adenomyosis. This study aimed to determine whether ARG2 involved in mitochondrial function and epithelial to mesenchymal transition (EMT) in adenomyosis and its potential underlying mechanisms. MATERIALS AND METHODS: RNA interference was used to inhibit ARG2 gene, and then Cell Counting Kit (CCK-8) assay and flow cytometery were performed to detect the cell proliferation capacity, cell cycle, and apoptosis progression, respectively. The mouse adenomyosis model was established and RT-PCR, Western blot analysis, mitochondrial membrane potential (Δψm) detection and mPTP opening evaluation were conducted. RESULTS: Silencing ARG2 effectively down-regulated its expression at the mRNA and protein levels in endometrial cells, leading to decreased enzyme activity and inhibition of cell viability. Additionally, ARG2 knockdown induced G0/G1 cell cycle arrest, promoted apoptosis, and modulated the expression of cell cycle- and apoptosis-related regulators. Notably, the interference with ARG2 induces apoptosis by mitochondrial dysfunction, ROS production, ATP depletion, decreasing the Bcl-2/Bax ratio, releasing Cytochrome c, and increasing the expression of Caspase-9/-3 and PARP. In vivo study in a mouse model of adenomyosis demonstrated also elevated levels of ARG2 and EMT markers, while siARG2 treatment reversed EMT and modulated inflammatory cytokines. Furthermore, ARG2 knockdown was found to modulate the NF-κB and Wnt/ß-catenin signaling pathways in mouse adenomyosis. CONCLUSION: Consequently, ARG2 silencing could induce apoptosis through a mitochondria-dependent pathway mediated by ROS, and G0/G1 cell cycle arrest via suppressing NF-κB and Wnt/ß-catenin signaling pathways in Ishikawa cells. These findings collectively suggest that ARG2 plays a crucial role in the pathogenesis of adenomyosis and may serve as a potential target for therapeutic intervention.
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Class IIa histone deacetylases (Class IIa HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific roles of each class IIa HDAC isoform is hindered by the pan-inhibitory effect of current inhibitors and a lack of tools to probe their functions beyond epigenetic regulation. In this study, a novel PROTAC-based compound B4 is developed, which selectively targets and degrades HDAC7, resulting in the effective attenuation of a specific set of proinflammatory cytokines in both lipopolysaccharide (LPS)-stimulated macrophages and a mouse model. By employing B4 as a molecular probe, evidence is found for a previously explored role of HDAC7 that surpasses its deacetylase function, suggesting broader implications in inflammatory processes. Mechanistic investigations reveal the critical involvement of HDAC7 in the Toll-like receptor 4 (TLR4) signaling pathway by directly interacting with the TNF receptor-associated factor 6 and TGFß-activated kinase 1 (TRAF6-TAK1) complex, thereby initiating the activation of the downstream mitogen-activated protein kinase/nuclear factor-κB (MAPK/NF-κB) signaling cascade and subsequent gene transcription. This study expands the insight into HDAC7's role within intricate inflammatory networks and highlights its therapeutic potential as a novel target for anti-inflammatory treatments.
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Chemically modified superatoms have emerged as promising candidates in the new periodic table, in which Au13 and its doped M n Au13- n have been widely studied. However, their important counterpart, Ag13 artificial element, has not yet been synthesized. In this work, we report the synthesis of Ag13 nanoclusters using strong chelating ability and rigid ligands, that fills the gaps in the icosahedral superatomic metal clusters. After further doping Ag13 template with different degrees of Au atoms, we gained insight into the evolution of their optical properties. Theoretical calculations show that the kernel metal doping can modulate the transition of the excited-state electronic structure, and the electron transfer process changes from local excitation (LE) to charge transfer (CT) to LE. This study not only enriches the families of artificial superatoms, but also contributes to the understanding of the electronic states of superatomic clusters.
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Neoantigens are crucial in distinguishing cancer cells from normal ones and play a significant role in cancer immunotherapy. The field of bioinformatics prediction for tumor neoantigens has rapidly developed, focusing on the prediction of peptide-HLA binding affinity. In this chapter, we introduce a user-friendly tool named DeepHLApan, which utilizes deep learning techniques to predict neoantigens by considering both peptide-HLA binding affinity and immunogenicity. We provide the application of DeepHLApan, along with the source code, docker version, and web-server. These resources are freely available at https://github.com/zjupgx/deephlapan and http://pgx.zju.edu.cn/deephlapan/ .
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Biología Computacional , Aprendizaje Profundo , Antígenos HLA , Péptidos , Programas Informáticos , Humanos , Péptidos/inmunología , Péptidos/química , Biología Computacional/métodos , Antígenos HLA/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Unión Proteica , Neoplasias/inmunologíaRESUMEN
This perspective reviews the recent advances in martian water and other volatiles and addresses the associated scientific questions for future martian exploration missions.
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Manganese oxide-based aqueous zinc-ion batteries (ZIBs) are attractive energy storage devices, owing to their good safety, low cost, and ecofriendly features. However, various critical issues, including poor conductivity, sluggish reaction kinetics, and unstable structure still restrict their further development. Oxygen defect engineering is an effective strategy to improve the electrochemical performance of manganese oxides, but challenging in the accurate regulation of oxygen defects. In this work, an effective and controllable defect engineering strategy-controllable electrochemical lithium-ion intercalation - is proposed to tackle this issue. The incorporation of lithium ions and oxygen defects can promote the conductivity, lattice spacing, and structural stability of Mn2O3 (MO), thus improving its capacity (232.7 mAh g-1), rate performance, and long-term cycling stability (99.0% capacity retention after 3000 cycles). Interestingly, the optimal ratio of intercalated lithium-ion varies at different temperature or mass-loading of MO, which provides the possibility to customize diverse ZIBs to meet different application conditions. In addition, the fabricated ZIBs present good flexibility, superior safety, and admirable adaptability under extreme temperatures (-20-100 °C). This work provides an inspiration on the structural customization of metal oxide nanomaterials for diverse ZIBs, and sheds light on the construction of future portable electronics.
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FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.
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Flexible supercapacitors can potentially power next-generation flexible electronics. However, the mechanical and electrochemical stability of flexible supercapacitors under different flexible conditions is limited by the weak bonding between adjacent layers, posing a significant hindrance to their practical applicability. Herein, based on the uninterrupted 3D network during the growth of bacterial cellulose (BC), a flexible all-in-one supercapacitor is cultivated through a continuous biosynthesis process. This strategy ensures the continuity of the 3D network of BC throughout the material, thereby forming a continuous electrode-separator-electrode structure. Benefitting from this bioinspired structure, the all-in-one supercapacitor not only achieves a high areal capacitance (3.79 F cm-2) of electrodes but also demonstrates the integration of high tensile strength (2.15 MPa), high shear strength (more than 54.6 kPa), and high bending resistance, indicating a novel pathway toward high-performance flexible power sources.
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Delayed luminescence (DF), including phosphorescence and thermally activated delayed fluorescence (TADF), and circularly polarized luminescence (CPL) exhibit common and broad application prospects in optoelectronic displays, biological imaging, and encryption. Thus, the combination of delayed luminescence and circularly polarized luminescence is attracting increasing attention. The encapsulation of guest emitters in various host matrices to form host-guest systems has been demonstrated to be an appealing strategy to further enhance and/or modulate their delayed luminescence and circularly polarized luminescence. Compared with conventional liquid crystals, polymers, and supramolecular matrices, porous crystalline frameworks (PCFs) including metal-organic frameworks (MOFs), covalent-organic frameworks (COFs), zeolites and hydrogen-bonded organic frameworks (HOFs) can not only overcome shortcomings such as flexibility and disorder but also achieve the ordered encapsulation of guests and long-term stability of chiral structures, providing new promising host platforms for the development of DF and CPL. In this review, we provide a comprehensive and critical summary of the recent progress in host-guest photochemistry via the encapsulation engineering of guest emitters in PCFs, particularly focusing on delayed luminescence and circularly polarized luminescence. Initially, the general principle of phosphorescence, TADF and CPL, the combination of DF and CPL, and energy transfer processes between host and guests are introduced. Subsequently, we comprehensively discuss the critical factors affecting the encapsulation engineering of guest emitters in PCFs, such as pore structures, the confinement effect, charge and energy transfer between the host and guest, conformational dynamics, and aggregation model of guest emitters. Thereafter, we summarize the effective methods for the preparation of host-guest systems, especially single-crystal-to-single-crystal (SC-SC) transformation and epitaxial growth, which are distinct from conventional methods based on amorphous materials. Then, the recent advancements in host-guest systems based on PCFs for delayed luminescence and circularly polarized luminescence are highlighted. Finally, we present our personal insights into the challenges and future opportunities in this promising field.
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Circularly polarized light (CPL) detection is of great significance in various applications such as drug identification, sensing and imaging. Atomically precise chiral metal nanoclusters with intense circular dichroism (CD) signals are promising candidates for CPL detection, which can further facilitate device miniaturization and integration. Herein, we report the preparation of a pair of optically active chiral silver nanoclusters [Ag7(R/S-DMA)2(dpppy)3] (BF4)3 (R/S-Ag7) for direct CPL detection. The crystal structure and molecular formula of R/S-Ag7 clusters are confirmed by single-crystal X-ray diffraction and high-resolution mass spectrometry. R/S-Ag7 clusters exhibit strong CD spectra and CPL both in solution and solid states. When used as the photoactive materials in photodetectors, R/S-Ag7 enables effective discrimination between left-handed circularly polarized and right-handed circularly polarized light at 520â nm with short response time, high responsivity and considerable discrimination ratio. This study is the first report on using atomically precise chiral metal nanoclusters for CPL detection.
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BACKGROUND: Previous studies have revealed the critical functions of NEK2 in controlling the cell cycle which is linked to poor prognosis in multiple tumor types, but less research has been devoted to clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded clinical data from the gene expression omnibus (GEO) and TCGA databases together with transcriptional and mutational datasets. Strongly coexpressed genes with NEK2 were extracted from TCGA-KIRC cohort, and were submitted to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analyses. According to NEK2 levels, the survival status, mutational characteristics, response to immunotherapy and sensitivity to drugs of the patients were studied. The potential correlations between NEK2 levels and immune cell state as well as immune cell infiltration were examined using the GEPIA, TIMER and TISIDB databases. Double immunofluorescence (IF) was performed to identify the NEK2 overexpression and relationship with CD8 in ccRCC. RESULTS: The NEK2 gene was overexpressed and would enhance the nuclear division and cell cycle activities in ccRCC. ccRCC patients with high NEK2 expression had worse clinical outcomes, higher mutation burden and better therapeutic response. Moreover, NEK2 gene overexpression was positively related to various immune cell marker sets, which was also proved by validation cohort, and more infiltration of various immune cells. CONCLUSION: ccRCC patients with NEK2 high expression have a poorer prognosis than those with NEK2 low expression, resulting from its function of promoting proliferation, accompanied by increased infiltration of CD8â +â T cells and Tregs and T-cell exhaustion and will respond better to proper treatments.
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Carcinoma de Células Renales , Neoplasias Renales , Quinasas Relacionadas con NIMA , Microambiente Tumoral , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Quinasas Relacionadas con NIMA/genética , Quinasas Relacionadas con NIMA/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Microambiente Tumoral/inmunología , Pronóstico , Masculino , Regulación Neoplásica de la Expresión Génica , Femenino , Mutación , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Bases de Datos GenéticasRESUMEN
Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , Epítopos , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Anticuerpos Neutralizantes/inmunología , Epítopos/inmunología , Epítopos/química , Epítopos/genética , Coronavirus/inmunología , Coronavirus/genética , Bases de Datos Factuales , Reacciones Cruzadas/inmunologíaRESUMEN
In eukaryotes, cytosine methylation is a primary heritable epigenetic modification of the genome that regulates many cellular processes. In invertebrate, methylated cytosine generally located on specific genomic elements (e.g., gene bodies and silenced repetitive elements) to show a "mosaic" pattern. While in jawed vertebrate (teleost and tetrapod), highly methylated cytosine located genome-wide but only absence at regulatory regions (e.g., promoter and enhancer). Many studies imply that the evolution of DNA methylation reprogramming may have helped the transition from invertebrates to jawed vertebrates, but the detail remains largely elusive. In this study, we used the whole-genome bisulfite-sequencing technology to investigate the genome-wide methylation in three tissues (heart, muscle, and sperm) from the sea lamprey, an extant agnathan (jawless) vertebrate. Strikingly, we found that the methylation level of the sea lamprey is very similar to that in sea urchin (a deuterostome) and sea squirt (a chordate) invertebrates. In sum, the global pattern in sea lamprey is intermediate methylation level (around 30%), that is higher than methylation level in the genomes of pre-bilaterians and protostomes (1%-10%), but lower than methylation level appeared in jawed vertebrates (around 70%, teleost and tetrapod). We anticipate that, in addition to genetic dynamics such as genome duplications, epigenetic dynamics such as global methylation reprograming was also orchestrated toward the emergence and evolution of vertebrates.
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Metilación de ADN , Genoma , Petromyzon , Animales , Petromyzon/genética , Invertebrados/genética , MasculinoRESUMEN
Sepsis-induced neuroinflammation is significantly associated with sepsis-related brain dysfunction. Remimazolam is a novel ultra-short-acting benzodiazepine anesthetic with multiple organ protective effects. However, it is unknown whether remimazolam can ameliorate LPS-induced brain impairment. In this study, Lipopolysaccharide (5 mg/kg, LPS) severely impaired Sprague-Dawley rats spatial learning ability, memory, and cognitive function. However, remimazolam treatment showed a protective effect on LPS-induced cognitive dysfunction. Remimazolam partly reversed LPS-induced splenomegaly, decreased serum cytokine expression, suppressed hippocampal M1 microglial activation, and mitigated oxidative stress injury and neuroinflammation. Electroacupuncture (EA) or PNU282987 treatment improved LPS-induced cognitive dysfunction and also significantly inhibited neuroinflammation and systemic inflammation. However, MLA, ML385, or subdiaphragmatic vagus nerve (SDV) treatment abolished the protective effects of remimazolam. Further mechanistic studies showed that remimazolam induces protective effects by activating subdiaphragmatic vagus nerve target α7nAChR-mediated Nrf2/HO-1 signaling pathway. These results demonstrate that remimazolam can up-regulate α7nAChR, Cyto-Nrf2, HO-1, and cognitive-related (CREB, BDNF, PSD95) protein expressions, suppress M1 microglia, ameliorate neuroinflammation or systemic inflammation, and reverse cognitive dysfunction. Therefore, this study provides insight into a new therapeutic target for the treatment of sepsis-induced cerebral dysfunction.
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Disfunción Cognitiva , Sepsis , Ratas , Animales , Ratas Sprague-Dawley , Lipopolisacáridos/toxicidad , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedades Neuroinflamatorias , Transducción de Señal , Benzodiazepinas/efectos adversos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Nervio Vago/metabolismoRESUMEN
Glycemic and body weight control gained from GLP-1R agonists remains an unmet need for diabetes and obesity treatment, leading to the development of GLP-1R/GIPR co-agonists. An imbalance in GLP-1R/GIPR agonism may extensively maximize the glucose- and weight-lowering effects. Hence, we prepared a potent and imbalanced GLP-1R/GIPR co-agonist, and refined its action time through a site-specific N-terminal PEGylation strategy. The pharmacological efficacy of these resulting long-acting co-agonists was interrogated both in vitro and in vivo. The results showed that peptide 1 possessed potent and imbalanced receptor-stimulating potency favoring GIP activity, but its hypoglycemic action was disrupted probably resulting from its short half-life. After PEGylation to improve the pharmacokinetics, the pharmacological effects were amplified compared to native peptide 1. Among the resulting derivatives, D-5K exhibited significant glycemic, HbA1c, body-weight, and food-intake control, outperforming GLP-1R mono-agonists. Based on its excellent pharmacological profiles, D-5K may hold the great therapeutic potential for diabetes and obesity treatment.
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Although metal single-atom (SA)-based nanomaterials are explored as sonosensitizers for sonodynamic therapy (SDT), they normally exhibit poor activities and need to combine with other therapeutic strategies. Herein, the deposition of metal SAs on oxygen vacancy (OV)-rich WO3- x nanosheets to generate a synergistic effect for efficient SDT is reported. Crystalline WO3 and OV-rich WO3- x nanosheets are first prepared by simple calcination of the WO3·H2O nanosheets under an air and N2 atmosphere, respectively. Pt, Cu, Fe, Co, and Ni metal SAs are then deposited on WO3- x nanosheets to obtain metal SA-decorated WO3- x nanocomposites (M-WO3- x). Importantly, the Cu-WO3- x sonosensitizer exhibits a much higher activity for ultrasound (US)-induced production of reactive oxygen species than that of the WO3- x and Cu SA-decorated WO3, which is also higher than other M-WO3- x nanosheets. Both the experimental and theoretical results suggest that the excellent SDT performance of the Cu-WO3- x nanosheets should be attributed to the synergistic effect between Cu SAs and WO3- x OVs. Therefore, after polyethylene glycol modification, the Cu-WO3- x can quickly kill cancer cells in vitro and effectively eradicate tumors in vivo under US irradiation. Transcriptome sequencing analysis and further molecular validation suggest that the Cu-WO3- x-mediated SDT-activated apoptosis and TNF signaling pathways are potential drivers of tumor apoptosis induction.
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Óxidos , Tungsteno , Terapia por Ultrasonido , Tungsteno/química , Humanos , Óxidos/química , Terapia por Ultrasonido/métodos , Animales , Ratones , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Nanoestructuras/química , Apoptosis/efectos de los fármacos , Antineoplásicos/química , Antineoplásicos/farmacología , Cobre/químicaRESUMEN
We report a case of a 20-year-old young woman with a large stucco keratosis in the mons veneris, one of the clinical variants of Seborrheic keratoses (SKs). Periodic acid-Schiff staining revealed a large number of Malassezia spores in the stratum corneum. After oral antifungal treatment with itraconazole for 4 weeks, the benign tumor was completely cleared without residue or recurrence, which may open a new perspective for exploring the pathogenesis of SKs.
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Although the global pandemic of SARS-CoV-2 has passed, there are still regional outbreaks that continue to jeopardize human health. Hence, there is still a great deal of interest in developing an efficient vaccine that can quickly and effectively prevent reemerging outbreaks of SARS-CoV-2. Delta variant was once a dominant strain in the world in 2021, and we first constructed a recombinant RBDdelta-Fc fusion vaccine by coupling the RBD of Delta variant with the human Fc fragment. This Fc fusion strategy increases the immunogenicity of the recombinant RBD vaccine, with a long-lasting high level of IgG antibodies and neutralizing antibodies induced by RBDdelta-Fc vaccine. This RBDdelta-Fc vaccine, as well as the RBD-Fc vaccine prepared in our previously study, could trigger a durable immune effect by the heterologous boosting immunity, and the RBD-Fc induced a quicker humoral immune response than the homologous immunization with inactivated vaccines. In conclusion, the Fc fusion strategy has a significant role in enhancing the immunogenicity of recombinant protein vaccines, thus promising the development of a safe and efficient vaccine for the heterologous boosting against SARS-CoV-2.
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Although gene/genome duplications in the early stage of vertebrates have been thought to provide major resources of raw genetic materials for evolutionary innovations, it is unclear whether they continuously contribute to the evolution of morphological complexity during the course of vertebrate evolution, such as the evolution from two heart chambers (fishes) to four heart chambers (mammals and birds). We addressed this issue by our heart RNA-Seq experiments combined with published data, using 13 vertebrates and one invertebrate (sea squirt, as an outgroup). Our evolutionary transcriptome analysis showed that number of ancient paralogous genes expressed in heart tends to increase with the increase of heart chamber number along the vertebrate phylogeny, in spite that most of them were duplicated at the time near to the origin of vertebrates or even more ancient. Moreover, those paralogs expressed in heart exert considerably different functions from heart-expressed singletons: the former are functionally enriched in cardiac muscle and muscle contraction-related categories, whereas the latter play more basic functions of energy generation like aerobic respiration. These findings together support the notion that recruiting anciently paralogous genes that are expressed in heart is associated with the increase of chamber number in vertebrate evolution.
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Evolución Molecular , Vertebrados , Animales , Vertebrados/genética , Invertebrados/genética , Peces/genética , Duplicación de Gen , Filogenia , Familia de Multigenes , Mamíferos/genéticaRESUMEN
Bystander-killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody-drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander-killing payloads, this model is utilized for score-directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti-tumor efficacy and bystander-killing effect in vivo and in vitro. The optimal conjugate T-VEd9 exhibited therapeutic efficacy superior to DS-8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity.