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BACKGROUND: Clinical trials support the efficacy of immune checkpoint blockades (ICBs) plus chemotherapy in a subset of patients with metastatic gastric cancer (mGC). To identify the determinants of response, we developed a TMEscore model to assess tumor microenvironment (TME), which was previously proven to be a biomarker for ICBs. METHODS: A reference database of TMEscore assays was established using PCR assay kits containing 30 TME genes. This multi-center prospective clinical trial (NCT#04850716) included patients with mGC who were administered ICB combined with chemotherapy as a first-line regimen. Eighty-six tumor samples extracted from five medical centers before treatment were used to estimate the TMEscore, PD-L1 (CPS), and mismatch repair deficiency. FINDINGS: The objective response rate (ORR) and median PFS of the cohort were 31.4% and six months. Enhanced ORR was observed in TMEscore-high mGC patients (ORR = 59%). The survival analysis demonstrated that high TMEscore was significantly associated with a more favorable PFS and OS. Moreover, TMEscore was found to be a predictive biomarker that surpassed MSI and CPS (AUC = 0.873, 0.511, and 0.524, respectively). By integrating the TMEscore and clinical variables, the fused model further enhances the predictive efficiency and translational application in a clinical setting. CONCLUSIONS: This prospective clinical study indicates that the TMEscore assay is a robust biomarker for screening patients with mGC who may derive survival benefits from ICB plus chemotherapy. FUNDING: Guangdong Basic and Applied Basic Research Foundation (2023A1515011214), Science and Technology Program of Guangzhou (202206080011), and Guangzhou Science and Technology Project (2023A03J0722 and 2023A04J2357).
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BACKGROUND: Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential. METHODS: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors. RESULTS: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice. CONCLUSIONS: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
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Antígenos CD , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Macrófagos , Metaloproteinase 9 da Matriz , Receptores de Superfície Celular , Animais , Camundongos , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Receptores de Superfície Celular/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunoterapia Adotiva/métodosRESUMO
Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor-ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.
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Angiogenesis is one of the characteristics of malignant tumors, and persistent generation of abnormal tumor blood vessels is an important factor contributing to tumor treatment resistance. Epstein-Barr virus (EBV) is a highly prevalent DNA oncogenic virus that is associated with the development of various epithelial malignancies. However, the relationship between EBV infection and tumor vascular abnormalities as well as its underlying mechanisms is still unclear. In this study, we found that compared to EBV-uninfected tumors, EBV-infected tumors were more angiogenic, but the neovascularization was mostly immature vessels without pericyte attachment in both clinical patient tumor samples and mouse xenograft models; These immature vessels exhibited aberrant functionality, characterized by poor blood perfusion and increased vascular permeability. The vascular abnormalities caused by EBV infection exacerbated tumor hypoxia and was responsible for accelerated tumor growth. Mechanistically, EBV infection upregulated ANXA3-HIF-1α-VEGF pathway. Silencing the ANXA3 gene or neutralizing ANXA3 with an antibody can diminish vascular abnormalities, thereby increasing immune cell infiltration and alleviating treatment resistance. Finally, a new therapy combining ANXA3 blockade and NK cell + PD1 antibody significantly inhibited the growth of EBV-infected xenografts in mice. In conclusion, our study identified a previously unrecognized role for EBV infection in tumor vascular abnormalities and revealed its underlying mechanism that upregulated the ANXA3-HIF-1α-VEGF pathway. ANXA3 is a potential therapeutic target for EBV-infected tumors and ANXA3 blockade to improve vascular conditions, in combination with NK cell + PD1 antibody therapy, holds promise as an effective treatment strategy for EBV-associated epithelial malignancies.
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Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular , Humanos , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Patológica/virologia , Neovascularização Patológica/metabolismo , Linhagem Celular Tumoral , Regulação para Cima , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
The exploration of sonodynamic therapy (SDT) as a possible replacement for antibiotics by creating reactive oxygen species (ROS) is suggested as a non-drug-resistant theranostic method. However, the low-efficiency ROS generation and complex tumor microenvironment which can deplete ROS and promote tumor growth will cause the compromised antibacterial efficacy of SDT. Herein, through an oxygen vacancy engineering strategy, TiO2- x microspheres with an abundance of Ti3+ are synthesized using a straightforward reductant co-assembly approach. The narrow bandgaps and Ti3+/Ti4+-mediated multiple-enzyme catalytic activities of the obtained TiO2- x microspheres make them suitable for use as sonosensitizers and nanozymes. When graphene quantum dot (GQD) nanoantibiotics are deposited on TiO2- x microspheres, the resulting GQD/TiO2- x shows an increased production of ROS, which can be ascribed to the accelerated separation of electron-hole pairs, as well as the peroxidase-like catalytic activity mediated by Ti3+, and the depletion of glutathione mediated by Ti4+. Moreover, the catalytic activities of TiO2- x microspheres are amplified by the heterojunctions-accelerated carrier transfer. In addition, GQDs can inhibit Topo I, displaying strong antibacterial activity and further enhancing the antibacterial activity. Collectively, the combination of GQD/TiO2- x-mediated SDT/NCT with nanoantibiotics can result in a synergistic effect, allowing for multimodal antibacterial treatment that effectively promotes wound healing.
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Fluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6-18.0) for the immunotherapy group compared with 9.9 months (8.0-11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40-0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3-32.8) for the control group (HR, 0.57 [95% CI, 0.33-0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.
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Neoplasias do Colo , Neoplasias Colorretais , Oxaloacetatos , Humanos , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Oxaliplatina , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , ImunoterapiaRESUMO
Hepatocellular carcinoma (HCC) has a pathogenesis that remains elusive with restricted therapeutic strategies and efficacy. This study aimed to investigate the role of SMG5, a crucial component in nonsense-mediated mRNA decay (NMD) that degrades mRNA containing a premature termination codon, in HCC pathogenesis and therapeutic resistance. We demonstrated an elevated expression of SMG5 in HCC and scrutinized its potential as a therapeutic target. Our findings revealed that SMG5 knockdown not only inhibited the migration, invasion, and proliferation of HCC cells but also influenced sorafenib resistance. Differential gene expression analysis between the control and SMG5 knockdown groups showed an upregulation of methionine adenosyltransferase 1A in the latter. High expression of methionine adenosyltransferase 1A, a catalyst for S-adenosylmethionine (SAM) production, as suggested by The Cancer Genome Atlas data, was indicative of a better prognosis for HCC. Further, an ELISA showed a higher concentration of SAM in SMG5 knockdown cell supernatants. Furthermore, we found that exogenous SAM supplementation enhanced the sensitivity of HCC cells to sorafenib alongside changes in the expression of Bax and Bcl-2, apoptosis-related proteins. Our findings underscore the important role of SMG5 in HCC development and its involvement in sorafenib resistance, highlighting it as a potential target for HCC treatment.
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Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Sorafenibe , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Sorafenibe/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proliferação de Células/efeitos dos fármacos , Camundongos , Animais , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismoRESUMO
Netrins, a family of secreted and membrane-associated proteins, can regulate axonal guidance, morphogenesis, angiogenesis, cell migration, cell survival, and tumorigenesis. Four secreted netrins (netrin 1, 3, 4 and 5) and two glycosylphosphatidylinositols-anchored membrane proteins, netrin-G1 and G2, have been identified in mammals. Netrins and their receptors can serve as a biomarker and molecular therapeutic target for pathological differentiation, diagnosis and prognosis of malignant cancers. We review here the potential roles of the netrins family and their receptors in cancer.
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Neoplasias , Animais , Netrinas , Transporte Biológico , Carcinogênese , Diferenciação Celular , Proteínas de Membrana , MamíferosRESUMO
The main proteinase (Mpro) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of Mpro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to Mpro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of Mpro, thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of Mpro dimer, resulting in a rigid Mpro, which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro. These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors.
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Aminoquinolinas , Compostos de Anilina , COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/química , Simulação de Acoplamento Molecular , Cisteína Endopeptidases/metabolismo , Simulação de Dinâmica Molecular , Antivirais/farmacologia , Antivirais/químicaRESUMO
Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFß1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression. SIGNIFICANCE: TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.
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Linfócitos T CD8-Positivos , Carcinoma Hepatocelular , Armadilhas Extracelulares , Neoplasias Hepáticas , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Humanos , Camundongos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , DNA/imunologia , DNA/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linhagem Celular Tumoral , MasculinoRESUMO
Netrin G1 (NTNG1) is a member of the Netrin family and plays a crucial role in various human cancers. However, the molecular functions of NTNG1 in HCC and the underlying mechanisms remain unclear. HCC expression data was obtained from the GEO database and analyzed using various bioinformatics tools. The expression of NTNG1 in HCC tissues and liver cancer cells was evaluated through RT-qPCR and western blotting. Cells with stable NTNG1 overexpression and knockdown were established, and CCK-8, colony formation, and flow cytometry assays were conducted in vitro. The xenograft model was utilized to verify the tumorigenesis capacity of NTNG1 in vivo. IHC was employed to analyze the expression of NTNG1 and CD163 proteins. HCC-specific genes were screened, followed by functional enrichment and immune cell infiltration analysis. Finally, the Co-IP was used to detect the interaction between NTNG1 and N-cadherin. NTNG1 was highly expressed in HCC tissues and liver cancer cells, and associated with significantly poorer OS rates. In addition, NTNG1 overexpression in liver cancer cells significantly increased their proliferation, colony growth, invasion, migration, and EMT, while inhibiting apoptosis. Bioinformatics analyses indicated that NTNG1 was closely related to EMT and tumor infiltration. IHC staining revealed a positive correlation between NTNG1 expression and CD163 in HCC tissues. Additionally, an EMT inhibitor attenuated the expression levels of EMT-related markers and counteracted the effects of NTNG1 overexpression in liver cancer cells. This study is the first to identify NTNG1 as a potential therapeutic target in HCC, promoting tumor development and progression by regulating EMT.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Netrinas , Humanos , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Ligadas por GPI/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Netrinas/genética , Netrinas/metabolismoRESUMO
Extracellular vesicles (EVs) are a class of nanoparticles that mediate signaling molecules delivery between donor and recipient cells. Heterogeneity in the content of EVs and their membrane surface proteins determines their unique targetability. Their low immunogenicity, capability to cross various biological barriers, and superior biocompatibility enable engineering-modified EVs to be ideal drug delivery carriers. In addition, the engineered EVs that emerge in recent years have become a powerful tool for cancer treatment through the selective delivery of bioactive molecules to therapeutic targets, such as tumor cells and stroma. Our review focuses on the various types of EV modifications and their promoting therapeutic capabilities, which provide an innovative means for cancer precision therapy.
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Vesículas Extracelulares , Nanopartículas , Neoplasias , Vesículas Extracelulares/metabolismo , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/metabolismo , Transdução de Sinais , Proteínas de Membrana/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Elevated impulsivity has been frequently reported in individuals with opioid addiction receiving methadone maintenance therapy (MMT), but the underlying neural mechanisms and cognitive subprocesses are not fully understood. We acquired functional magnetic resonance imaging (fMRI) data from 37 subjects with heroin addiction receiving long-term MMT and 33 healthy controls who performed a probabilistic reversal learning task, and measured their resting-state brain glucose using fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET). Subjects receiving MMT exhibited significantly elevated self-reported impulsivity, and computational modeling revealed a marked impulsive decision bias manifested as switching more frequently without available evidence. Moreover, this impulsive decision bias was associated with the dose and duration of methadone use, irrelevant to the duration of heroin use. During the task, the switch-related hypoactivation in the left rostral middle frontal gyrus was correlated with the impulsive decision bias while the function of reward sensitivity was intact in subjects receiving MMT. Using prior brain-wide receptor density data, we found that the highest variance of regional metabolic abnormalities was explained by the spatial distribution of µ-opioid receptors among 10 types of neurotransmitter receptors. Heightened impulsivity in individuals receiving prolonged MMT is manifested as atypical choice bias and noise in decision-making processes, which is further driven by deficits in top-down cognitive control, other than reward sensitivity. Our findings uncover multifaceted mechanisms underlying elevated impulsivity in subjects receiving MMT, which might provide insights for developing complementary therapies to improve retention during MMT.
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Dependência de Heroína , Humanos , Dependência de Heroína/tratamento farmacológico , Metadona/uso terapêutico , Heroína/efeitos adversos , Encéfalo/diagnóstico por imagem , Comportamento ImpulsivoRESUMO
Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.
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BACKGROUND: CD133 is considered a marker for cancer stem cells (CSCs) in several types of tumours, including hepatocellular carcinoma (HCC). Chimeric antigen receptor-specific T (CAR-T) cells targeting CD133-positive CSCs have emerged as a tool for the clinical treatment of HCC, but immunogenicity, the high cost of clinical-grade recombinant viral vectors and potential insertional mutagenesis limit their clinical application. METHODS: CD133-specific CAR-T cells secreting PD-1 blocking scFv (CD133 CAR-T and PD-1 s cells) were constructed using a sleeping beauty transposon system from minicircle technology, and the antitumour efficacy of CD133 CAR-T and PD-1 s cells was analysed in vitro and in vivo. RESULTS: A univariate analysis showed that CD133 expression in male patients at the late stage (II and III) was significantly associated with worse progression-free survival (PFS) (P = 0.0057) and overall survival (OS) (P = 0.015), and a multivariate analysis showed a trend toward worse OS (P = 0.041). Male patients with advanced HCC exhibited an approximately 20-fold higher PD-L1 combined positive score (CPS) compared with those with HCC at an early stage. We successfully generated CD133 CAR-T and PD-1 s cells that could secrete PD-1 blocking scFv based on a sleeping beauty system involving minicircle vectors. CD133 CAR-T and PD-1 s cells exhibited significant antitumour activity against HCC in vitro and in xenograft mouse models. Thus, CD133 CAR-T and PD-1 s cells may be a therapeutically tractable strategy for targeting CD133-positive CSCs in male patients with advanced HCC. CONCLUSIONS: Our study provides a nonviral strategy for constructing CAR-T cells that could also secrete checkpoint blockade inhibitors based on a Sleeping Beauty system from minicircle vectors and revealed a potential benefit of this strategy for male patients with advanced HCC and high CD133 expression (median immunohistochemistry score > 2.284).
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptores de Antígenos Quiméricos , Humanos , Masculino , Animais , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Receptor de Morte Celular Programada 1 , Receptores de Antígenos Quiméricos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Modelos Animais de Doenças , Linfócitos TRESUMO
Introduction: The limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms. Methods: The effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging. Results: There was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRß complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth. Conclusions: Our study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Camundongos , Humanos , Carcinoma Hepatocelular/patologia , Antineoplásicos/uso terapêutico , Neoplasias Hepáticas/patologia , Células Endoteliais/metabolismo , Modelos Animais de DoençasRESUMO
Effective and safe delivery of small interfering RNA (siRNA) by nanomaterials to cancer cells is one of the main challenges in cancer treatment. In this study, we constructed the selenium nanoparticles conjugated with RGDfC (one tumor-targeted polypeptide) to prepare a biocompatible gene vector (RGDfC-SeNPs) and then loaded with siDCBLD2 to synthesize the RGDfC-Se@siDCBLD2 for colorectal cancer (CRC) therapy. As expected, RGDfC-SeNPs could enhance the cellular uptake of siDCBLD2 in human HCT-116 colon cancer cells by targeting polypeptide RGDfC on the surface of colon cancer cells. RGDfC-Se@siDCBLD2 could be effectively internalized by HCT-116 cells mainly through a clathrin-related endocytosis pathway. In addition, RGDfC-Se@siDCBLD2 exhibited high siRNA release efficiency in an acidic tumor environment. Moreover, RGDfC-Se@siDCBLD2 could inhibit the proliferation and induce apoptosis in HCT-116 cells by special silencing gene DCBLD2 expression. RGDfC-Se@siDCBLD2 could be specifically accumulated to the tumor sites and exhibited significantly anti-CRC efficacy on HCT-116 tumor-bearing mice without obvious side effects. Taken together, these results suggest that selenium nanoparticles can be used as an effective gene vector with good biocompatibility, and RGDfC-Se@siDCBLD2 provides a promising strategy for combining tumor-target and siRNA delivery in treating CRC.
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Background: Radiomics can be used to noninvasively predict molecular markers to address the clinical dilemma that some patients cannot accept invasive procedures. This research evaluated the prognostic significance of the expression level of ribonucleotide reductase regulatory subunit M2 (RRM2) in individuals with hepatocellular carcinoma (HCC) and established a radiomics model for predicting the RRM2 expression level. Methods: Genomic data for HCC patients and corresponding computed tomography (CT) images were accessed at The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA), which were utilized for prognosis analysis, radiomic feature extraction and model construction, respectively. The maximum relevance minimum redundancy algorithm (mRMR) and recursive feature elimination (RFE) were used for feature selection. Following feature extraction, a logistic regression algorithm was fitted to establish a dichotomous model that predicts RRM2 gene expression. Establishment of the radiomics nomogram was carried out using the Cox regression model. Receiver operating characteristic (ROC) curve analysis was employed to assess the model performance. Clinical utility was determined by decision curve analysis (DCA). Results: High RRM2 expression acted as a risk factor for overall survival (OS) [hazard ratio (HR) =2.083, P<0.001] and was implicated in regulation of the immune response. Four optimal radiomics features were selected for prediction of RRM2 expression. A predictive nomogram was established using the clinical variables and radiomics score (RS), and the areas under the ROC curve (AUCs) of the time-dependent ROC curve of the model were 0.836, 0.757, and 0.729 for the 1-, 3-, and 5-year periods, respectively. DCA confirmed that the nomogram had good clinical usefulness. Conclusions: The RRM2 expression level in HCC can considerably affect prognosis of these patients. Expression levels of RRM2 and prognosis of HCC individuals can be predicted through radiomics features by utilizing CT scan data.