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Scalable generation of genuine multipartite entanglement with an increasing number of qubits is important for both fundamental interest and practical use in quantum-information technologies1,2. On the one hand, multipartite entanglement shows a strong contradiction between the prediction of quantum mechanics and local realization and can be used for the study of quantum-to-classical transition3,4. On the other hand, realizing large-scale entanglement is a benchmark for the quality and controllability of the quantum system and is essential for realizing universal quantum computing5-8. However, scalable generation of genuine multipartite entanglement on a state-of-the-art quantum device can be challenging, requiring accurate quantum gates and efficient verification protocols. Here we show a scalable approach for preparing and verifying intermediate-scale genuine entanglement on a 66-qubit superconducting quantum processor. We used high-fidelity parallel quantum gates and optimized the fidelitites of parallel single- and two-qubit gates to be 99.91% and 99.05%, respectively. With efficient randomized fidelity estimation9, we realized 51-qubit one-dimensional and 30-qubit two-dimensional cluster states and achieved fidelities of 0.637 ± 0.030 and 0.671 ± 0.006, respectively. On the basis of high-fidelity cluster states, we further show a proof-of-principle realization of measurement-based variational quantum eigensolver10 for perturbed planar codes. Our work provides a feasible approach for preparing and verifying entanglement with a few hundred qubits, enabling medium-scale quantum computing with superconducting quantum systems.
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Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3-5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.
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Neoplasias , Humanos , Camundongos , Animais , Microambiente TumoralRESUMO
Controlling matter-light interactions with cavities is of fundamental importance in modern science and technology1. This is exemplified in the strong-coupling regime, where matter-light hybrid modes form, with properties that are controllable by optical-wavelength photons2,3. By contrast, matter excitations on the nanometre scale are harder to access. In two-dimensional van der Waals heterostructures, a tunable moiré lattice potential for electronic excitations may form4, enabling the generation of correlated electron gases in the lattice potentials5-9. Excitons confined in moiré lattices have also been reported10,11, but no cooperative effects have been observed and interactions with light have remained perturbative12-15. Here, by integrating MoSe2-WS2 heterobilayers in a microcavity, we establish cooperative coupling between moiré-lattice excitons and microcavity photons up to the temperature of liquid nitrogen, thereby integrating versatile control of both matter and light into one platform. The density dependence of the moiré polaritons reveals strong nonlinearity due to exciton blockade, suppressed exciton energy shift and suppressed excitation-induced dephasing, all of which are consistent with the quantum confined nature of the moiré excitons. Such a moiré polariton system combines strong nonlinearity and microscopic-scale tuning of matter excitations using cavity engineering and long-range light coherence, providing a platform with which to study collective phenomena from tunable arrays of quantum emitters.
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Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.
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COVID-19/prevenção & controle , COVID-19/virologia , Imunoglobulina M/administração & dosagem , Imunoglobulina M/imunologia , SARS-CoV-2/classificação , SARS-CoV-2/imunologia , Administração Intranasal , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , COVID-19/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/efeitos adversos , Imunoglobulina M/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Engenharia de Proteínas , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , SARS-CoV-2/genética , Tratamento Farmacológico da COVID-19RESUMO
Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.
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Colágeno/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral , Animais , Linhagem Celular Tumoral , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/deficiência , Receptor com Domínio Discoidina 1/genética , Modelos Animais de Doenças , Matriz Extracelular/imunologia , Feminino , Deleção de Genes , Técnicas de Inativação de Genes , Humanos , Imunocompetência/imunologia , Imunoterapia , Camundongos , Linfócitos T/citologia , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
Nonlinear physics is one of the most important research fields in modern physics and materials science. It offers an unprecedented paradigm for exploring many fascinating physical phenomena and realizing diverse cutting-edge applications inconceivable in the framework of linear processes. Here we review the recent theoretical and experimental progress concerning the nonlinear physics of synthetic quantum moiré superlattices. We focus on the emerging nonlinear electronic, optical and optoelectronic properties of moiré superlattices, including but not limited to the nonlinear anomalous Hall effect, dynamically twistable harmonic generation, nonlinear optical chirality, ultralow-power-threshold optical solitons and spontaneous photogalvanic effect. We also present our perspectives on the future opportunities and challenges in this rapidly progressing field, and highlight the implications for advances in both fundamental physics and technological innovations.
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Two-dimensional semiconductors have emerged as a new class of materials for nanophotonics owing to their strong exciton-photon interaction1,2 and their ability to be engineered and integrated into devices3. Here we take advantage of these properties to engineer an efficient lasing medium based on direct-bandgap interlayer excitons in rotationally aligned atomically thin heterostructures4. Lasing is measured from a transition-metal dichalcogenide heterobilayer (WSe2-MoSe2) integrated in a silicon nitride grating resonator. An abrupt increase in the spatial coherence of the emission is observed across the lasing threshold. The work establishes interlayer excitons in two-dimensional heterostructures as a gain medium with spatially coherent lasing emission and potential for heterogeneous integration. With electrically tunable exciton-photon interaction strengths5 and long-range dipolar interactions, these interlayer excitons are promising for application as low-power, ultrafast lasers and modulators and for the study of many-body quantum phenomena6.
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Bright, scalable, and deterministic single-photon emission (SPE) is essential for quantum optics, nanophotonics, and optical information systems. Recently, SPE from hexagonal boron nitride (h-BN) has attracted intense interest because it is optically active and stable at room temperature. Here, we demonstrate a tunable quantum emitter array in h-BN at room temperature by integrating a wafer-scale plasmonic array. The transient voltage electrophoretic deposition (EPD) reaction is developed to effectively enhance the filling of single-crystal nanometals in the designed patterns without aggregation, which ensures the fabricated array for tunable performances of these single-photon emitters. An enhancement of â¼500% of the SPE intensity of the h-BN emitter array is observed with a radiative quantum efficiency of up to 20% and a saturated count rate of more than 4.5 × 106 counts/s. These results suggest the integrated h-BN-plasmonic array as a promising platform for scalable and controllable SPE photonics at room temperature.
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Anaplastic lymphoma kinase (ALK) rearrangements have been identified as key oncogenic drivers of a subset of nonsmall cell lung cancer (NSCLC). The final chimeric protein of the fusion gene can be constitutively activated, which accounts for the growth and proliferation of ALK-rearranged tumors and thus strongly associates with cancer invasion and metastasis. Diagnostic tools enabling the visualization of ALK activity in a structure-function-based approach are highly desirable to determine ALK status and guide ALK tyrosine kinase inhibitor (ALK-TKI) treatment making. Here, we describe the design, synthesis, and application of a new environment-sensitive fluorescent probe HX16 by introducing an environment-sensitive fluorophore 4-sulfonamidebenzoxadiazole to visualize ALK activity in living cancer cells and tumor tissue slices (mouse model and human biopsy sample). HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity. Using flow cytometry and confocal microscopy, HX16 enables visualization of ALK activity in various cancer cells with distinct ALK fusion genes, as well as xenograft mouse models. Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Quinase do Linfoma Anaplásico/genética , Corantes Fluorescentes , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinases , Inibidores de Proteínas Quinases/farmacologiaRESUMO
High-throughput screening (HTS) is pivotal in the discovery of small molecules that bind to DNA, yet there are limited sensing mechanisms available for designing HTS assays for DNA binders. Herein, we introduce a binder-responsive toehold-mediated DNA strand displacement (BR-TMSD) technique featuring programmable reaction kinetics in response to DNA-binder interactions. When two DNA binders are used, BR-TMSD is initiated through a rapid binder displacement, followed by the DNA strand displacement. The orthogonal displacement reactions of BR-TMSD enables a high-fidelity, dual-channel HTS assay, returning 19 new DNA binders from a library of 1,170 compounds.
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Helicobacter pylori (H. pylori) is the major etiological factor of a variety of gastric diseases. However, the treatment of H. pylori is challenged by the destruction of targeted drugs by gastric acid and pepsin. Herein, a dual-targeted cascade catalytic nanozyme PtCo@Graphene@Hemin-2(L-arginine) (PtCo@G@H2A) is designed for the treatment of H. pylori. The dual-targeting ability of PtCo@G@H2A is derived from directly targeting the receptor protein of H. pylori through hemin and responding to the acidic environment to cause charge reversal (protonation of L-arginine) to capture H. pylori, achieving efficient targeting effect. Compared with the single-targeting strategy relying on hemin, the dual-targeting strategy can greatly improve the targeting rate, achieving an increase of 850% targeting rate. At the concentration of NaHCO3 in intestinal fluid, the surface potential of PtCo@G@H2A can be quickly restored to avoid side effects. Meanwhile, PtCo@G@H2A has pH-responsive oxidase-like activity, which can generate nitric oxide (NO) through a cascade catalytic process that first generates reactive oxygen species (ROS) with oxygen, and further oxidizes L-arginine through ROS, realizing a superior acid-selective bactericidal effect. Overall, it proposes a promising strategy for the treatment of H. pylori that maintains high targeting and therapeutic effects in the environment of gastric acid and pepsin.
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Grafite , Helicobacter pylori , Helicobacter pylori/metabolismo , Pepsina A/farmacologia , Espécies Reativas de Oxigênio , Grafite/farmacologia , Hemina , Arginina/metabolismo , Arginina/farmacologiaRESUMO
Drought, especially terminal drought, severely limits wheat growth and yield. Understanding the complex mechanisms behind the drought response in wheat is essential for developing drought-resistant varieties. This study aimed to dissect the genetic architecture and high-yielding wheat ideotypes under terminal drought. An automated high-throughput phenotyping platform was used to examine 28 392 image-based digital traits (i-traits) under different drought conditions during the flowering stage of a natural wheat population. Of the i-traits examined, 17 073 were identified as drought-related. A genome-wide association study (GWAS) identified 5320 drought-related significant single-nucleotide polymorphisms (SNPs) and 27 SNP clusters. A notable hotspot region controlling wheat drought tolerance was discovered, in which TaPP2C6 was shown to be an important negative regulator of the drought response. The tapp2c6 knockout lines exhibited enhanced drought resistance without a yield penalty. A haplotype analysis revealed a favored allele of TaPP2C6 that was significantly correlated with drought resistance, affirming its potential value in wheat breeding programs. We developed an advanced prediction model for wheat yield and drought resistance using 24 i-traits analyzed by machine learning. In summary, this study provides comprehensive insights into the high-yielding ideotype and an approach for the rapid breeding of drought-resistant wheat.
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Secas , Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único , Triticum , Triticum/genética , Triticum/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Haplótipos/genética , Característica Quantitativa Herdável , Adaptação Fisiológica/genética , Resistência à SecaRESUMO
Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.
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Mieloma Múltiplo , NF-kappa B , Animais , NF-kappa B/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Proteínas Ribossômicas/genética , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Resistência a Medicamentos , Linhagem Celular TumoralRESUMO
BACKGROUND: Cancer stem cells (CSCs) are critical factors that limit the effectiveness of gastric cancer (GC) therapy. Circular RNAs (circRNAs) are confirmed as important regulators of many cancers. However, their role in regulating CSC-like properties of GC remains largely unknown. Our study aimed to investigate the role of circUBA2 in CSC maintenance and the underlying mechanisms. METHODS: We identified circUBA2 as an upregulated gene using circRNA microarray analysis. qRT-PCR was used to examine the circUBA2 levels in normal and GC tissues. In vitro and in vivo functional assays were performed to validate the role of circUBA2 in proliferation, migration, metastasis and CSC-like properties of GC cell. The relationship between circUBA2, miR-144-5p and STC1 was characterised using bioinformatics analysis, a dual fluorescence reporter system, FISH, and RIP assays. RESULTS: CircUBA2 expression was significantly increased in GC tissues, and patients with GC with high circUBA2 expression had a poor prognosis. CircUBA2 enhances CSC-like properties of GC, thereby promoting cell proliferation, migration, and metastasis. Mechanistically, circUBA2 promoted GC malignancy and CSC-like properties by acting as a sponge for miR-144-5p to upregulate STC1 expression and further activate the IL-6/JAK2/STAT3 signaling pathway. More importantly, the ability of circUBA2 to enhance CSC-like properties was inhibited by tocilizumab, a humanised Interleukin-6 receptor (IL-6R) antibody. Thus, circUBA2 knockdown and tocilizumab synergistically inhibited CSC-like properties. CONCLUSIONS: Our study demonstrated the critical role of circUBA2 in regulating CSC-like properties in GC. CircUBA2 may be a promising prognostic biomarker for GC.
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In this paper, CH4, C2H2, H2, and CO adsorbed on intrinsic MoTe2 monolayer and transition metal atom (Ta, V)-doped MoTe2 monolayer have been investigated with density functional theory based on first-principles study. The adsorption energy, geometries, band structures, and density of states of four gases (CH4, C2H2, H2, and CO) adsorbed on the MoTe2 and doped MoTe2 surfaces were analyzed. The results shown that the gas adsorption performance of transition metal atom (Ta, V)-doped MoTe2 monolayers is more superior than that of intrinsic MoTe2, and the adsorption energy and charge transfer of the adsorbed gases on the TM-MoTe2 monolayer are significantly increased in comparison with both sides. Among them, Ta-MoTe2 has the largest Eads value in the adsorbed CO system with a very small adsorption distance, as well as a more suitable recovery time of CO at room temperature, so Ta-MoTe2 can be a candidate material for CO detection. New atoms were introduced during the doping process, which increased the carrier density and carrier mobility of the material, thus improving the charge transfer at the surface of the material. which provides a direction for the gas-sensitive properties of metal Ta-modified MoTe2 materials.
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BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.
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Miastenia Gravis , Humanos , Miastenia Gravis/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Resultado do Tratamento , Receptores Colinérgicos/imunologiaRESUMO
INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant gastrointestinal tumors worldwide with a dismal prognosis and high relapse rate. PDAC is considered a "cold cancer" for which immunotherapy is not effective. Therefore, to improve the prognosis for PDAC patients, it is urgent to explore the mechanism driving its insensitivity to immunotherapy. MATERIALS AND METHODS: We conducted pancancer analyses to test IGF2BP family expression and survival in patients with different cancers via TCGA and GETx databases. Then, we determined the immunological role and prognostic value of IGF2BP2 in vitro, in vivo and in clinical specimens. RESULTS: In the present study, we found that the m6A reader IGF2BP2 was the most clinically relevant member of the IGF2BP family for pancreatic cancer. High expression of IGF2BP2 was most associated with poor prognosis and an immunosuppressive microenvironment in PDAC. By IGF2BP2 knockdown, we found that tumor cell proliferation and invasive ability were significantly diminished. Importantly, we found that IGF2BP2 expression was closely associated with high expression of immunosuppressive molecules such as PD-L1. IGF2BP2 modulated downstream PD-L1 expression by regulating its mRNA stability via m6A methylation control, and we obtained the same verification in animal experiments and human tissue specimens. CONCLUSION: Our study contributes to existing knowledge regarding the IGF2BP2-regulated PD-L1 signaling pathway as a potential prognostic and immune biomarker in pancreatic cancer.
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Adenina/análogos & derivados , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Antígeno B7-H1/genética , Prognóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Microambiente Tumoral , Proteínas de Ligação a RNARESUMO
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
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Amidas , Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Inibidores Enzimáticos , Monoacilglicerol Lipases , Monoacilglicerol Lipases/antagonistas & inibidores , Monoacilglicerol Lipases/metabolismo , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Naftalenos/farmacologia , Naftalenos/síntese química , Naftalenos/química , Relação Dose-Resposta a Droga , Simulação de Acoplamento MolecularRESUMO
Immune checkpoint blockade therapy has been successful in treating some types of cancer but has not shown clinical benefits for treating leukaemia1. This result suggests that leukaemia uses unique mechanisms to evade this therapy. Certain immune inhibitory receptors that are expressed by normal immune cells are also present on leukaemia cells. Whether these receptors can initiate immune-related primary signalling in tumour cells remains unknown. Here we use mouse models and human cells to show that LILRB4, an immunoreceptor tyrosine-based inhibition motif-containing receptor and a marker of monocytic leukaemia, supports tumour cell infiltration into tissues and suppresses T cell activity via a signalling pathway that involves APOE, LILRB4, SHP-2, uPAR and ARG1 in acute myeloid leukaemia (AML) cells. Deletion of LILRB4 or the use of antibodies to block LILRB4 signalling impeded AML development. Thus, LILRB4 orchestrates tumour invasion pathways in monocytic leukaemia cells by creating an immunosuppressive microenvironment. LILRB4 represents a compelling target for the treatment of monocytic AML.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Evasão Tumoral/imunologia , Animais , Apolipoproteínas E/metabolismo , Arginase/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores Imunológicos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Textbook outcome (TO) has been widely employed as a comprehensive indicator to assess the short-term prognosis of patients with cancer. Preoperative malnutrition is a potential risk factor for adverse surgical outcomes in patients with gastric cancer (GC). This study aimed to compare the TO between robotic-assisted gastrectomy (RAG) and laparoscopic-assisted gastrectomy (LAG) in malnourished patients with GC. METHODS: According to the diagnostic consensus of malnutrition proposed by Global Leadership Initiative on Malnutrition (GLIM) and Nutrition Risk Index (NRI), 895 malnourished patients with GC who underwent RAG (n = 115) or LAG (n = 780) at a tertiary referral hospital between January 2016 and May 2021 were included in the propensity score matching (PSM, 1:2) analysis. RESULTS: After PSM, no significant differences in clinicopathological characteristics were observed between the RAG (n = 97) and LAG (n = 194) groups. The RAG group had significantly higher operative time and lymph nodes harvested, as well as significantly lower blood loss and hospital stay time compared to the LAG group. More patients in the RAG achieved TO. Logistic regression analysis revealed that RAG was an independent protective factor for achieving TO. There were more adjuvant chemotherapy (AC) cycles in the RAG group than in the LAG group. After one year of surgery, a higher percentage of patients (36.7% vs. 22.8%; P < 0.05) in the RAG group recovered from malnutrition compared to the LAG group. CONCLUSIONS: For malnourished patients with GC, RAG performed by experienced surgeons can achieved a higher rate of TO than those of LAG, which directly contributed to better AC compliance and a faster restoration of nutritional status.