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BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.
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Aterosclerose , Modelos Animais de Doenças , Fator Regulador 3 de Interferon , Peptídeos e Proteínas de Sinalização Intracelular , Macrófagos , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Mitocôndrias , NF-kappa B , Proteínas de Ligação a Fosfato , Piroptose , Transdução de Sinais , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteínas de Ligação a Fosfato/metabolismo , Proteínas de Ligação a Fosfato/genética , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Camundongos , NF-kappa B/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos Knockout para ApoE , Placa Aterosclerótica , Doenças da Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/prevenção & controle , GasderminasRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a 5-year survival rate of 12%. The abundant mesenchyme is partly responsible for the malignancy. The antifibrotic therapies have gained attention in recent research. However, the role of pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, remains unclear in PDAC. METHODS: Data from RNA-seq of patient-derived xenograft (PDX) models treated with pirfenidone were integrated using bioinformatics tools to identify the target of cell types and genes. Using confocal microscopy, qRT-PCR and western blotting, we validated the signalling pathway in tumour cells to regulate the cytokine secretion. Further cocultured system demonstrated the interplay to regulate stroma fibrosis. Finally, mouse models demonstrated the potential of pirfenidone in PDAC. RESULTS: Pirfenidone can remodulate multiple biological pathways, and exerts an antifibrotic effect through inhibiting the secretion of PDGF-bb from tumour cells by downregulating the TGM2/NF-kB/PDGFB pathway. Thus, leading to a subsequent reduction in collagen X and fibronectin secreted by CAFs. Moreover, the mice orthotopic pancreatic tumour models demonstrated the antifibrotic effect and potential to sensitise gemcitabine. CONCLUSIONS: Pirfenidone may alter the pancreatic milieu and alleviate fibrosis through the regulation of tumour-stroma interactions via the TGM2/NF-kB/PDGFB signalling pathway, suggesting potential therapeutic benefits in PDAC management.
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Carcinoma Ductal Pancreático , Fibrose , Neoplasias Pancreáticas , Piridonas , Piridonas/farmacologia , Piridonas/uso terapêutico , Humanos , Animais , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Camundongos , Fibrose/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Gencitabina , Proteína 2 Glutamina gama-Glutamiltransferase , Microambiente Tumoral/efeitos dos fármacos , NF-kappa B/metabolismoRESUMO
BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.
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Adenocarcinoma , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/mortalidade , Adulto , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Junção Esofagogástrica/patologia , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Imidazóis/efeitos adversos , Idoso de 80 Anos ou mais , Estudos de CoortesRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and its molecular mechanisms are unclear. Nucleolar and spindle-associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development of several types of tumors. The biological function and molecular mechanism of NUSAP1 in PDAC remain controversial. This study explored the effects and mechanism of NUSAP1 in PDAC. METHODS: Differentially expressed genes (DEGs) were screened. A proteinâprotein interaction (PPI) network was constructed to identify hub genes. Experimental studies and tissue microarray (TMA) analysis were performed to investigate the effects of NUSAP1 in PDAC and explore its mechanism. RESULTS: Network analysis revealed that NUSAP1 is an essential hub gene in the PDAC transcriptome. Genome heterogeneity analysis revealed that NUSAP1 is related to tumor mutation burden (TMB), loss of heterozygosity (LOH) and homologous recombination deficiency (HRD) in PDAC. NUSAP1 is correlated with the levels of infiltrating immune cells, such as B cells and CD8 T cells. High NUSAP1 expression was found in PDAC tissues and was associated with a poor patient prognosis. NUSAP1 promoted cancer cell proliferation, migration and invasion, drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation. CONCLUSIONS: NUSAP1 is an essential hub gene that promotes PDAC progression and leads to a dismal prognosis by drives the epithelial-mesenchymal transition and reduces AMPK phosphorylation.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Ductal Pancreático/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/patologia , Fosforilação , PrognósticoRESUMO
BACKGROUND: Hemorrhagic varicella (HV) is a particular form of chicken pox.,with high mortality in adults. This form of the disease is rare, to date, approximately 4 cases have been reported. Occasional cases of HV have been documented in adults with hematologic disorders or other diseases. While there is one reported case of simultaneous reactivation of cytomegalovirus in an adult with chickenpox, there is a lack of information regarding changes in liver function indicators for such patients. This is unfortunate, as CMV reactivation can further exacerbate liver failure and increase mortality. In this report, we present a case of hemorrhagic varicella reactivation with cytomegalovirus and provide some relevant discussions. CASE PRESENTATION: We present the case of a 25-year-old male with HV, who had a history of nephrotic syndrome generally controlled with orally administered prednisone at a dosage of 50 mg per day for two months. The patient arrived at the emergency room with complaints of abdominal pain and the presence of hemorrhagic vesicles on his body for the past 3 days. Despite medical evaluation, a clear diagnosis was not immediately determined. Upon admission, the leukocyte count was recorded as 20.96 × 109/L on the first day, leading to the initiation of broad-spectrum antibiotic treatment. Despite the general interpretation that a positive IgG and a negative IgM indicate a previous infection, the patient's extraordinarily elevated IgG levels, coupled with a markedly increased CMV DNA quantification, prompted us to suspect a reactivation of the CMV virus. In light of these findings, we opted for the intravenous administration of ganciclovir as part of the treatment strategy. Unfortunately,,the patient succumbed to rapidly worsening symptoms and passed away. Within one week of the patient's demise, chickenpox gradually developed in the medical staff who had been in contact with him. In such instances, we speculate that the patient's diagnosis should be classified as a rare case of hemorrhagic varicella. CONCLUSION: Swift identification and timely administration of suitable treatment for adult HV are imperative to enhance prognosis.
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Varicela , Coinfecção , Infecções por Citomegalovirus , Citomegalovirus , Humanos , Masculino , Adulto , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , Varicela/tratamento farmacológico , Varicela/complicações , Varicela/virologia , Varicela/diagnóstico , Coinfecção/virologia , Coinfecção/tratamento farmacológico , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Hemorragia/virologia , Hemorragia/etiologia , Herpesvirus Humano 3/isolamento & purificação , Ativação ViralRESUMO
OBJECTIVE: To identify major contributors, current research status, and to forecast research trends and future development prospects on acupuncture and moxibustion therapy for herpes zoster (HZ) and postherpetic neuralgia (PHN). METHODS: A systematic search was conducted on the China National Knowledge Infrastructure (CNKI), Weipu, WanFang databases, and the Web of Science Core Collection (WoSCC), PubMed, and Scopus databases. The search strategy included relevant terms for HZ, PHN, acupuncture, and moxibustion. The reference type was limited to articles or reviews, with a publication date from January 1, 2014 to December 31, 2023. Data analysis was performed using CiteSpace software, focusing on author, institution, source, and keyword distributions, and temporal trends. RESULTS: A total of 1612 publications were identified from both Chinese and English databases. The analysis revealed a rising trend in publication numbers in the English database, with a significant increase observed in 2020. In the Chinese database, publication activity exhibited two peaks in 2019 and 2023. Guohua Lin and Jingchun Zeng were the most prolific authors in the Chinese and English databases, respectively. The Chengdu University of TCM and Zhejiang Chinese Medicine University were the most active institutions. The keyword analysis revealed "herpes zoster" as the most frequent keyword in the Chinese database, while "postherpetic neuralgia," "acupuncture," and "management" were prominent in the English database. The study also identified several therapeutic approaches, including fire needle therapy and electroacupuncture, which have shown efficacy in treating HZ and PHN. Animal studies provided insights into the mechanisms of these therapies, suggesting potential modulation of neuroinflammatory markers and intracellular signaling pathways. CONCLUSION: The bibliometric analysis underscores the growing interest in acupuncture and moxibustion therapy for HZ and PHN. It highlights the contributions of key authors and institutions while pinpointing potential areas for future research. The study advocates for the necessity of large-scale, multi-center clinical trials and further basic mechanical research to optimize these therapies. Moreover, it also emphasizes the importance of international collaboration to strengthen the evidence base and expand the global impact of this traditional treatment modality.
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Terapia por Acupuntura , Bibliometria , Herpes Zoster , Moxibustão , Neuralgia Pós-Herpética , Humanos , Terapia por Acupuntura/métodos , Terapia por Acupuntura/estatística & dados numéricos , Moxibustão/métodos , Neuralgia Pós-Herpética/terapia , Herpes Zoster/terapiaRESUMO
The Warburg Effect is one of the most well-known cancer hallmarks. This metabolic pattern centered on lactate has extremely complex effects on various aspects of tumor microenvironment, including metabolic remodeling, immune suppression, cancer cell migration, and drug resistance development. Based on accumulating evidence, metabolites are likely to participate in the regulation of biological processes in the microenvironment and to form a feedback loop. Therefore, further revealing the key mechanism of lactate-mediated oncological effects is a reasonable scientific idea. The discovery and refinement of histone lactylation in recent years has laid a firm foundation for the above idea. Histone lactylation is a post-translational modification that occurs at lysine sites on histones. Specific enzymes, known as "writers" and "erasers", catalyze the addition or removal, respectively, of lactacyl group at target lysine sites. An increasing number of investigations have reported this modification as key to multiple cellular procedures. In this review, we discuss the close connection between histone lactylation and a series of biological processes in the tumor microenvironment, including tumorigenesis, immune infiltration, and energy metabolism. Finally, this review provides insightful perspectives, identifying promising avenues for further exploration and potential clinical application in this field of research.
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Histonas , Neoplasias , Humanos , Epigênese Genética/genética , Lisina , Neoplasias/genética , Ácido Láctico , Microambiente Tumoral/genéticaRESUMO
Schizophrenia significantly impacts cognitive and behavioral functions and is primarily treated with second-generation antipsychotics (SGAs) such as olanzapine. Despite their efficacy, these drugs are linked to serious metabolic side effects which can diminish patient compliance, worsen psychiatric symptoms and increase cardiovascular disease risk. This study explores the hypothesis that SGAs affect the molecular determinants of synaptic plasticity and brain activity, particularly focusing on the lateral septum (LS) and its interactions within hypothalamic circuits that regulate feeding and energy expenditure. Utilizing functional ultrasound imaging, RNA sequencing, and weighted gene co-expression network analysis, we identified significant alterations in the functional connection between the hypothalamus and LS, along with changes in gene expression in the LS of mice following prolonged olanzapine exposure. Our analysis revealed a module closely linked to increases in body weight and adiposity, featuring genes primarily involved in lipid metabolism pathways, notably Apoa1, Apoc3, and Apoh. These findings suggest that olanzapine may influence body weight and adiposity through its impact on lipid metabolism-related genes in the LS. Therefore, the neural circuits connecting the LS and LH, along with the accompanying alterations in lipid metabolism, are likely crucial factors contributing to the weight gain and metabolic side effects associated with olanzapine treatment.
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Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.
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Genes Essenciais , Neoplasias Pancreáticas , Humanos , Cromatina/genética , Neoplasias Pancreáticas/genética , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transcrição GênicaRESUMO
Living therapy based on bacterial cells has gained increasing attention for their applications in tumor treatments. Bacterial cells can naturally target to tumor sites and active the innate immunological responses. The intrinsic advantages of bacteria attribute to the development of biohybrid living carriers for targeting delivery toward hypoxic environments. The rationally engineered bacterial cells integrate various functions to enhance the tumor therapy and reduce toxic side effects. In this review, the antitumor effects of bacteria and their application are discussed as living therapeutic agents across multiple antitumor platforms. The various kinds of bacteria used for cancer therapy are first introduced and demonstrated the mechanism of antitumor effects as well as the immunological effects. Additionally, this study focused on the genetically modified bacteria for the production of antitumor agents as living delivery system to treat cancer. The combination of living bacterial cells with functional nanomaterials is then discussed in the cancer treatments. In brief, the rational design of living therapy based on bacterial cells highlighted a rapid development in tumor therapy and pointed out the potentials in clinical applications.
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Background: Mounting evidence underscores the importance of cell communication within the tumor microenvironment, which is pivotal in tumor proliferation, invasion, and metastasis. Exosomes play a crucial role in cell-to-cell communication. Although single-cell RNA sequencing (scRNA-seq) provides insights into individual cell transcriptional characteristics, it falls short of comprehensively capturing exosome-mediated intercellular communication. Method: We analyzed Pancreatic Ductal Adenocarcinoma (PDAC) tissues, separating supernatant and precipitate for exosome purification and single-cell nucleus suspension. We then constructed Single-nucleus RNA sequencing (snRNA-seq) and small RNA-seq libraries from these components. Our bioinformatic analysis integrated these sequences with ligand-receptor analysis and public miRNA data to map the cell communication network. Results: We established intercellular communication networks using bioinformatic analysis to track exosome miRNA effects and ligand-receptor pairs. Significantly, hsa-miR-1293 emerged as a prognostic biomarker for pancreatic cancer, linked to immune evasion, increased myeloid-derived suppressor cells, and poorer prognosis. Targeting this miRNA may enhance anti-tumor immunity and improve outcomes. Conclusion: Our study offers a novel approach to constructing intercellular communication networks using snRNA-seq and exosome-small RNA sequencing. By integrating miRNA tracing with ligand-receptor analysis, we illuminate the complex interactions in the pancreatic cancer microenvironment, highlighting the pivotal role of miRNAs and identifying potential biomarkers and therapeutic targets.
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BACKGROUND: Although we have made progress in treatment and have increased the 5-year survival by ≤30% in pancreatic cancer, chemotherapy resistance remains a major obstacle. However, whether reprogrammed lipid metabolism contributes to chemoresistance still needs to be further studied. METHODS: Gene expression was determined using Western blotting and quantitative reverse transcription polymerase chain reaction. Cell cloning formation assay, Cell Counting Kit-8, EdU assay, wound healing assay, transwell assay, and flow cytometry were used to detect apoptosis, cell proliferation capacity, migration capacity, and cytotoxicity of gemcitabine. Confocal fluorescence microscopy, transmission electron microscopy, etc., were used to detect the changes in intracellular reactive oxygen species, glutathione, lipid peroxidation level, and cell morphology. An animal study was performed to evaluate the effect of CPT1B knockdown on tumor growth and gemcitabine efficacy. RESULTS: In our study, we observed that the CPT1B expression level was higher in pancreatic ductal adenocarcinoma tissues than in normal tissues and correlated with a low rate of survival. Moreover, silencing of CPT1B significantly suppressed the proliferative ability and metastasis of pancreatic cancer cells. Furthermore, we discovered that CPT1B interacts with Kelch-like ECH-associated protein 1, and CPT1B knockdown led to decreased NRF2 expression and ferroptosis induction. In addition, CPT1B expression increased after gemcitabine treatment, and it was highly expressed in gemcitabine-resistant pancreatic ductal adenocarcinoma cells. Finally, we discovered that ferroptosis induced by CPT1B knockdown enhanced the gemcitabine toxicity in pancreatic ductal adenocarcinoma. CONCLUSION: CPT1B may act as a promising target in treating patients with gemcitabine-resistant pancreatic ductal adenocarcinoma .
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Carcinoma Ductal Pancreático , Carnitina O-Palmitoiltransferase , Ferroptose , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Neoplasias Pancreáticas , Animais , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Gencitabina , Homeostase , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Neoplasias Pancreáticas/genéticaRESUMO
Currently, chemotherapy remains occupying a pivotal place in the treatment of pancreatic ductal adenocarcinoma (PDAC). Nonetheless, the emergence of drug resistance in recent years has limited the clinical efficacy of chemotherapeutic agents, especially gemcitabine (GEM). Through bioinformatics analysis, AT-rich Interactive Domain-containing Protein 3A (ARID3A), one of transcription factors, is discovered to possibly participate in this progress. This study thoroughly investigates the potential role of ARID3A in the malignant progression and GEM chemoresistance of PDAC and explores the underlying mechanisms. The results indicate that ARID3A knockdown suppresses tumor development and enhances the sensitivity of PDAC cells to GEM in vitro and vivo. Mechanically, CUT&Tag profiling sequencing, RNA-sequencing and functional studies demonstrates that decreased ARID3A expression alleviates the transcriptional inhibition of phosphatase and tensin homolog (PTEN), consequently leading to glutathione peroxidase 4 (GPX4) depletion and increased lipid peroxidation levels. Activated ferroptosis induced by the inhibition of GPX4 subsequently restricts tumor progression and reduces GEM resistance in PDAC. This research identifies the ferroptosis regulatory pathway of ARID3A-PTEN-GPX4 axis and reveals its critical role in driving the progression and chemoresistance of pancreatic cancer. Notably, both inhibition of ARID3A and enhancement of ferroptosis can increase chemosensitivity to GEM, which offers a promising opportunity for developing therapeutic strategies to combat acquired chemotherapy resistance in pancreatic cancer.
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Proteínas de Ligação a DNA , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase , Neoplasias Pancreáticas , Fatores de Transcrição , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gencitabina , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genéticaRESUMO
Background: Pancreatic adenocarcinoma (PAAD) is referred to as an immunologically "cold" tumor that responds poorly to immunotherapy. A fundamental theory that explains the low immunogenicity of PAAD is the dramatically low tumor mutation burden (TMB) of PAAD tumors, which fails to induce sufficient immune response. Alternative splicing of pre-mRNA, which could alter the proteomic diversity of many cancers, has been reported to be involved in neoantigen production. Therefore, we aim to identify novel PAAD antigens and immune subtypes through systematic bioinformatics research. Methods: Data for splicing analysis were downloaded from The Cancer Genome Atlas (TCGA) SpliceSeq database. Among the available algorithms, we chose CIBERSORT to evaluate the immune cell distribution among PAADs. The TCGA-PAAD expression matrix was used to construct a co-expression network. Single-cell analysis was performed based on the Seurat workflow. Results: Integrated analysis of aberrantly upregulated genes, alternatively spliced genes, genes associated with nonsense-mediated RNA decay (NMD) factors, antigen presentation and overall survival (OS) in TCGA-PAAD revealed that PLEC is a promising neoantigen for PAAD-targeted therapy. We identified a C2 TCGA-PAAD subtype that had better prognosis and more CD8+ T-cell infiltration. We propose a novel immune subtyping system for PAAD to indicate patient prognosis and opportunities for immunotherapy, such as immune checkpoint (ICP) inhibitors. Conclusions: In conclusion, the present study used a transcriptome-guided approach to screen neoantigen candidates based on alternative splicing, NMD factors, and antigen-presenting signatures for PAAD. A prognosis model with guidance of immunotherapy will aid in patient selection for appropriate treatment.
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Recent evidence suggests that glia maturation factor ß (GMFß) is important in the pathogenesis of pulmonary arterial hpertension (PAH), but the underlying mechanism is unknown. To clarify whether GMFß can be involved in pulmonary vascular remodeling and to explore the role of the IL-6-STAT3 pathway in this process, the expression of GMFß in PAH rats is examined and the expression of downstream molecules including periostin (POSTN) and interleukin-6 (IL-6) is measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The location and expression of POSTN is also tested in PAH rats using immunofluorescence. It is proved that GMFß is upregulated in the lungs of PAH rats. Knockout GMFß alleviated the MCT-PAH by reducing right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and pulmonary vascular remodeling. Moreover, the inflammation of the pulmonary vasculature is ameliorated in PAH rats with GMFß absent. In addition, the IL-6-STAT3 signaling pathway is activated in PAH; knockout GMFß reduced POSTN and IL-6 production by inhibiting the IL-6-STAT3 signaling pathway. Taken together, these findings suggest that knockout GMFß ameliorates PAH in rats by inhibiting the IL-6-STAT3 signaling pathway.
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Fator de Maturação da Glia , Interleucina-6 , Remodelação Vascular , Animais , Remodelação Vascular/genética , Remodelação Vascular/fisiologia , Ratos , Masculino , Interleucina-6/metabolismo , Interleucina-6/genética , Fator de Maturação da Glia/metabolismo , Fator de Maturação da Glia/genética , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Transdução de Sinais , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Modelos Animais de DoençasRESUMO
BACKGROUND: The widespread involvement of tumor-infiltrating B cells highlights their potential role in tumor behavior. However, B cell heterogeneity in PDAC remains unexplored. Studying TIL-Bs in PDAC aims to identify new treatment strategies. METHODS: We performed single-cell RNA sequencing to study the heterogeneity of B cells in PDAC. The prognostic and immunologic value of the identified CD38+ B cells was explored in FUSCC (n = 147) and TCGA (n = 176) cohorts. Flow cytometry was conducted to characterize the relationship between CD38+ B cells and other immune cells, as well as their phenotypic features. In vitro and in vivo experiments were performed to assess the putative effect of CD38+ B cells on antitumor immunity. FINDINGS: The presence of CD38+ B cells in PDAC was associated with unfavorable clinicopathological features and poorer overall survival (p < 0.001). Increased infiltration of CD38+ B cells was accompanied by reduced natural killer (NK) cells (p = 0.021) and increased regulatory T cells (p = 0.016). Molecular profiling revealed high expression of IL-10, IL-35, TGF-ß, GZMB, TIM-1, CD5 and CD21, confirming their putative regulatory B cell-like features. Co-culture experiments demonstrated suppression of NK cell cytotoxicity by CD38+ B cell-derived IL-10 (p < 0.001). Finally, in vivo experiments suggested adoptive transfer of CD38+ B cells reduced antitumor immunity and administration of a CD38 inhibitor hampered tumor growth (p < 0.001). INTERPRETATION: We discovered regulatory B cell-like CD38+ B cell infiltration as an independent prognostic factor in PDAC. The use of CD38 inhibitor may provide new possibilities for PDAC immunotherapy. FUNDING: This study was supported by the National Natural Science Foundation of China (U21A20374), Shanghai Municipal Science and Technology Major Project (21JC1401500), Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), Special Project for Clinical Research in the Health Industry of the Shanghai Health Commission (No. 20204Y0265) and Natural Science Foundation of Shanghai (23ZR1479300).
Assuntos
ADP-Ribosil Ciclase 1 , Carcinoma Ductal Pancreático , Humanos , ADP-Ribosil Ciclase 1/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Animais , Camundongos , Prognóstico , Antígenos CD19/metabolismo , Antígenos CD19/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Feminino , Masculino , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Linhagem Celular Tumoral , Microambiente Tumoral/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Pessoa de Meia-Idade , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Terapia de ImunossupressãoRESUMO
B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.
Assuntos
Linfócitos B , Centro Germinativo , Linfócitos do Interstício Tumoral , Neoplasias , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunoterapia , Transcriptoma , Análise de Célula Única , Epigênese Genética , Imunidade Humoral , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos B/imunologiaRESUMO
BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib revealed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumours in a phase I study. PATIENTS AND METHODS: This was an open-label, single-arm, multi-cohort phase II study in China. Patients with advanced neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) or mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) who had failed or were intolerable of standard treatment were given surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary end-point was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end-points included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled into two cohorts by tumour types (NET, n = 19; NEC-MiNEN, n = 21). ORRs (95% CIs) were 21.1% (6.1-45.6) and 23.8% (8.2-47.2) in the NET and NEC-MiNEN cohorts, respectively. Median DoR was 7.1 months (6.9-not evaluable [NE]) and 4.1 months (3.0-NE), respectively. Median PFS was 9.6 months (4.1-NE) and 4.1 months (1.5-5.5); median OS was 27.3 (15.3-NE) and 10.9 months (9.1-14.6), respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 18 (45.0%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed antitumour activity and a tolerable safety profile in patients with previously treated NETs/NECs/MiNENs. Further study of this combination regimen is ongoing for advanced NECs, for which current therapeutic options remain limited. CLINICALTRIALS: gov: NCT04169672.
Assuntos
Carcinoma Neuroendócrino , Indóis , Tumores Neuroendócrinos , Pirimidinas , Sulfonamidas , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Neuroendócrino/tratamento farmacológicoRESUMO
Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.