RESUMEN
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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Aterosclerosis , Modelos Animales de Enfermedad , Factor 3 Regulador del Interferón , Péptidos y Proteínas de Señalización Intracelular , Macrófagos , Proteínas de la Membrana , Ratones Endogámicos C57BL , Mitocondrias , FN-kappa B , Proteínas de Unión a Fosfato , Piroptosis , Transducción de Señal , Animales , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/genética , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Fosfato/genética , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Ratones , FN-kappa B/metabolismo , Mitocondrias/metabolismo , Mitocondrias/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Ratones Noqueados para ApoE , Placa Aterosclerótica , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/prevención & control , GasderminasRESUMEN
Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.
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Diabetes Mellitus Experimental , Retinopatía Diabética , Degeneración Retiniana , Humanos , Ratas , Animales , Degeneración Retiniana/patología , Células Ependimogliales/metabolismo , Estreptozocina/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Crecimiento Transformador beta3/efectos adversos , Factor de Crecimiento Transformador beta3/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Gliosis/patología , Retina/metabolismo , Retinopatía Diabética/patología , ARN Mensajero/metabolismoRESUMEN
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 , Fibrosis , Neoplasias Pancreáticas , Piridonas , Piridonas/farmacología , Piridonas/uso terapéutico , Humanos , Animales , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ratones , Fibrosis/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Gemcitabina , Proteína Glutamina Gamma Glutamiltransferasa 2 , Microambiente Tumoral/efectos de los fármacos , FN-kappa B/metabolismoRESUMEN
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 , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/mortalidad , Adulto , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Unión Esofagogástrica/patología , Imidazoles/administración & dosificación , Imidazoles/uso terapéutico , Imidazoles/efectos adversos , Anciano de 80 o más Años , Estudios de CohortesRESUMEN
BACKGROUND: Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. METHODS: This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). RESULTS: As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9). CONCLUSIONS: First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04228601.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Anciano , Adenocarcinoma/tratamiento farmacológico , Adulto , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Dosis Máxima Tolerada , Resultado del TratamientoRESUMEN
Ferroptosis is a form of regulated cell death initiated by oxidative perturbations that can be blocked by iron chelators and lipophilic antioxidants, and ferroptosis may be the silver bullet treatment for multiple cancers, including immunotherapy- and chemotherapy-insensitive cancers such as pancreatic ductal adenocarcinoma (PDAC). Numerous studies have noted that long non-coding RNAs (lncRNAs) regulate the biological behaviour of cancer cells by binding to DNA, RNA and protein. However, few studies have reported the role of lncRNAs in ferroptosis processes and the function of ferroptosis-associated lncRNAs. The primary objective of the present study was to identify ferroptosis-related lncRNAs using bioinformatic approaches combined with experimental validation. The second objective was to construct a prognostic model to predict the overall survival of patients with PDAC. The present study identified ferroptosis-related lncRNAs using a bioinformatic approach and validated them in an independent pancreatic cancer cohort from Fudan University Shanghai Cancer Center. The lncRNA SLCO4A1-AS1 was identified as a novel molecule mediating ferroptosis resistance in vitro. A novel algorithm was used to construct a '0 or 1' matrix-based prognosis model, which showed promising diagnostic accuracy for potential clinical translation (area under the curve = 0.89 for the 2-year survival rate). Notably, molecular subtypes classified by the risk scores of the model did not belong to any previously reported subtypes of PDAC. The immune microenvironment, metabolic activities, mutation landscape and ferroptosis sensitivity were significantly distinct between patients with different risk scores. Sensitivity (IC50) to 30 common anticancer drugs was analysed between patients with different risks, and imatinib and axitinib were found to be potential drugs for the treatment of patients with lower risk scores. Overall, we developed an accurate prognostic model based on the expression patterns of ferroptosis lncRNAs, which may contribute greatly to the evaluation of patient prognosis, molecular characteristics and treatment modalities and could be further translated into clinical applications.
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Carcinoma Ductal Pancreático , Ferroptosis , Neoplasias Pancreáticas , ARN Largo no Codificante , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , China , Ferroptosis/genética , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Microambiente TumoralRESUMEN
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 Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Carcinoma Ductal Pancreático/patología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/patología , Fosforilación , PronósticoRESUMEN
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 , Coinfección , Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Masculino , Adulto , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/aislamiento & purificación , Varicela/tratamiento farmacológico , Varicela/complicaciones , Varicela/virología , Varicela/diagnóstico , Coinfección/virología , Coinfección/tratamiento farmacológico , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Hemorragia/virología , Hemorragia/etiología , Herpesvirus Humano 3/aislamiento & purificación , Activación ViralRESUMEN
Severe acute pancreatitis (SAP) is a common critical disease of the digestive system, with high mortality and a lack of effective prevention and treatment measures. Despite mesenchymal stromal cell transplantation having the potential to treat SAP, its clinical application prospect is limited, and the mechanism is unclear. Here, we reveal the therapeutic role of exosomes from TNF-α-preconditioned human umbilical cord mesenchymal stromal cells (HUCMSCs) in attenuating SAP and show that it is partly dependent on exosomal metabolites. Bioactive metabolomics analysis showed that 48 metabolites be significantly differentially expressed between the two groups (Exo-Ctrl group versus Exo-TNF-α group). Then, the further functional experiments indicated that 3,4-dihydroxyphenylglycol could be a key molecule mediating the therapeutic effect of TNF-α-preconditioned HUCMSCs. The animal experiments showed that 3,4-dihydroxyphenylglycol reduced inflammation and oxidative stress in the pancreatic tissue and inhibited acinar cell autophagy in a rat model of SAP. Mechanistically, we revealed that 3,4-dihydroxyphenylglycol activated the mTOR pathway to inhibit acinar cell autophagy and alleviate SAP. In summary, our study demonstrated that exosomes from TNF-α-preconditioned HUMSCs inhibit the autophagy of acinar cells of SAP by shuttling 3,4-dihydroxyphenylglycol and inhibiting the mTOR pathway. This study revealed the vital role and therapeutic potential of metabolite-derived exosomes in SAP, providing a new promising method to prevent and therapy SAP.
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Exosomas , Células Madre Mesenquimatosas , Pancreatitis , Humanos , Animales , Ratas , Pancreatitis/terapia , Células Acinares , Factor de Necrosis Tumoral alfa , Enfermedad Aguda , Autofagia , Serina-Treonina Quinasas TOR , Cordón UmbilicalRESUMEN
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 , Bibliometría , Herpes Zóster , Moxibustión , Neuralgia Posherpética , Humanos , Terapia por Acupuntura/métodos , Terapia por Acupuntura/estadística & datos numéricos , Moxibustión/métodos , Neuralgia Posherpética/terapia , Herpes Zóster/terapiaRESUMEN
BACKGROUND: Small cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes. METHODS: The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. RESULTS: In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3ß/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. CONCLUSIONS: Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.
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Trióxido de Arsénico , Proliferación Celular , Sinergismo Farmacológico , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-akt , Piridinas , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas , Serina-Treonina Quinasas TOR , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Trióxido de Arsénico/uso terapéutico , Trióxido de Arsénico/farmacología , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proliferación Celular/efectos de los fármacos , Animales , Piridinas/farmacología , Piridinas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína Adaptadora GRB10/genética , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación hacia Abajo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.
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Carcinoma Ductal Pancreático , Células Supresoras de Origen Mieloide , Neoplasias Pancreáticas , Microambiente Tumoral , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/patología , Proteínas Portadoras , Proteínas con Dominio LIM/metabolismo , FN-kappa B/metabolismo , Neoplasias Pancreáticas/patología , Factor de Transcripción ReIA/metabolismo , Neoplasias PancreáticasRESUMEN
PURPOSE: Tumor deposits (TDs) are discrete tumor nodules within the lymphatic drainage area of the primary tumor without histological evidence of lymph node tissue or identifiable vascular or neural structure. This study aims to analyze the prognostic impact of TDs in patients with pancreatic ductal adenocarcinoma (PDAC) and explore their potential role in staging system. METHODS: The prospectively maintained database from the Fudan University Shanghai Cancer Center was queried for patients undergoing resection for PDAC. Patients with TDs were matched by propensity score with those without TDs. The cumulative prevalence of recurrence was estimated using the cumulative incidence function. Overall survival was estimated using Kaplan-Meier curves. RESULTS: A total of 123 patients (9.7%) had TDs, of whom 108 were matched at a 1:3 ratio with 324 patients without TDs. The cumulative incidence of recurrence was significantly higher for TD-positive patients than TD-negative patients (P = 0.04). The median overall survival was significantly shorter for patients with TDs than for those without TDs (15.9 versus 21.8 months, P < 0.001). The presence of TDs attenuated the effect of lymph node metastasis on survival, with no significance between node-negative and node-positive subpopulations (P = 0.165). Patients with TDs had comparable survival to N2 patients without TDs (15.9 versus 17.1 months, P = 0.383). CONCLUSIONS: TD is an important prognostic factor for recurrence and survival in patients undergoing resection for PDAC. We suggest that patients presenting TDs be classified into the stage III category in the next edition of the staging system.
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Extensión Extranodal , Neoplasias Pancreáticas , Humanos , Pronóstico , Estadificación de Neoplasias , Extensión Extranodal/patología , China , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Ganglios Linfáticos/patología , Neoplasias PancreáticasRESUMEN
OBJECTIVES: We aimed to compare the diagnostic and prognostic performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in pancreatic cancer. METHODS: This single-center retrospective study enrolled 51 patients who underwent [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT. The final diagnosis on PET/CT images was verified by histopathology or 1-year follow-up. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT were calculated to compare the diagnostic efficacy. Progression-free survival (PFS) was the endpoint for the survival analysis. Twenty-six patients were eligible for the Kaplan-Meier survival analysis using a log-rank test. And multivariate analysis including age, sex, stage, CA199 level, and SUVmax of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 was also performed. Two-tailed p < 0.05 was considered statistically significant. RESULTS: [68Ga]Ga-DOTA-FAPI-04 showed a higher sensitivity than [18F]FDG for detecting primary tumor (100% vs. 95.0%), metastatic lymph nodes (96.2% vs. 61.5%), and distant metastases (100% vs. 84.0%) (p < 0.0001, respectively). For [68Ga]Ga-DOTA-FAPI-04, the tumor-to-liver background ratio (TLBR) of liver metastases was higher (5.7 ± 3.2 vs. 3.2 ± 1.3, p < 0.0001). Furthermore, SUVmax > 14.9 on [68Ga]Ga-DOTA-FAPI-04 was significantly associated with PFS rates (chi-square = 12.05, p = 0.001). The Cox regression analysis showed that SUVmax of [68Ga]Ga-DOTA-FAPI-04 was an independent prognostic factor for PFS (p = 0.001; hazard ratio, 8.877). CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a higher sensitivity and accuracy than [18F]FDG PET/CT in diagnosing pancreatic cancer and might have an independent prognostic value for pancreatic cancer patients. KEY POINTS: ⢠[68Ga]Ga-DOTA-FAPI-04 PET/CT had a higher sensitivity and accuracy in detecting primary tumors, metastatic lymph nodes, and distant metastases than [18F]FDG PET/CT. ⢠SUVmax > 14.9 on [68Ga]Ga-DOTA-FAPI-04 PET/CT before chemotherapy was significantly associated with progress-free status rates (chi-square = 12.05, p = 0.001) in pancreatic cancer patients.
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Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radioisótopos de Galio , Estudios Retrospectivos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias PancreáticasRESUMEN
Septic arthritis induced by Staphylococcus aureus (S. aureus) causes irreversible cartilage degradation and subsequent permanent joint dysfunction. Recently, cartilage degradation in osteoarthritis is recognized to be associated with metabolic disorders. However, whether cholesterol metabolism is linked to septic arthritis pathology remains largely unknown. Here, we found that exposure to fermentation supernatant (FS) of S. aureus in chondrocytes resulted in a significant increase in expression of key modulators involved in cholesterol metabolism, including lectin-type oxidized low density lipoprotein receptor 1 (LOX1), cholesterol 25-hydroxylase (CH25H), 25- hydroxycholesterol 7α-hydroxylase (CYP7B1) as well as retinoic acid-related orphan receptor alpha (RORα), a binding receptor for cholesterol metabolites. We further demonstrated that enhancement of CH25H/CYP7B1/RORα axis resulted from FS exposure was mediated by activation of NF-κB signaling, along with upregulation in catabolic factors including matrix metallopeptidases (MMP3 and MMP13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2) in chondrocytes. Exogenous cholesterol acts synergistically with FS in activating NF-κB pathway and increases cholesterol metabolism. While, the addition of tauroursodeoxycholic acid (TUDCA) which promotes cholesterol efflux, resulted in remarkable reduction of intracellular cholesterol level and restoration of balance between anabolism and catabolism in FS treated chondrocytes. Collectively, our data indicated that, in response to FS of S. aureus, NF-κB signaling activation coupled with increased cholesterol metabolism to stimulate catabolic factors in chondrocytes, highlighting cholesterol metabolism as a potential therapeutic target for treating septic arthritis.
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Artritis Infecciosa/genética , Cartílago/crecimiento & desarrollo , Osteoartritis/genética , Staphylococcus aureus/patogenicidad , Proteína ADAMTS5/genética , Artritis Infecciosa/microbiología , Artritis Infecciosa/patología , Cartílago/metabolismo , Cartílago/microbiología , Cartílago/patología , Células Cultivadas , Colesterol/genética , Condrocitos/metabolismo , Condrocitos/microbiología , Condrocitos/patología , Familia 7 del Citocromo P450/genética , Regulación de la Expresión Génica/genética , Humanos , Metaloproteinasa 13 de la Matriz/genética , Metabolismo/genética , FN-kappa B/genética , Óxido Nítrico Sintasa de Tipo II/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Osteoartritis/microbiología , Osteoartritis/patología , Receptores Depuradores de Clase E/genética , Transducción de Señal/genética , Esteroide Hidroxilasas/genética , Ácido Tauroquenodesoxicólico/genética , Factor de Transcripción ReIA/genéticaRESUMEN
Pancreatic cancer is one of the most lethal malignancies. Desmoplastic stroma and metabolic reprogramming are two hallmarks of pancreatic cancer that support its malignant biological behaviors. However, the underlying mechanism by which the stroma maintain the redox balance remains unclear in pancreatic ductal adenocarcinoma (PDAC). Here, we demonstrated that the physical properties of the stroma could regulate the expression of PIN1 in pancreatic cancer cells. Moreover, we found that hard matrix-cultured pancreatic cancer cells induced the upregulation of PIN1 expression. Since PIN1 maintained redox balance via synergistic activation of NRF2 transcription, PIN1 promoted the expression of NRF2 to induce the expression of intracellular antioxidant response element (ARE)-driven genes. Consequently, the antioxidant stress ability of PDAC was increased, and the intracellular level of reactive oxygen species (ROS) was decreased. Thus, PIN1 is expected to be an important target for the treatment of PDAC, especially PDAC with an exuberant desmoplastic stroma.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Elementos de Respuesta Antioxidante , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Factor 2 Relacionado con NF-E2/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Oxidación-Reducción , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
OBJECTIVE: This study aimed to examine the expression profiles and prognostic value of multiple DDR proteins in resected PanNENs. BACKGROUND: DDR proteins play important roles in various cancers, including pancreatic ductal adenocarcinoma. However, the expression patterns and prognostic value of DDR proteins in PanNENs remain unclear. METHODS: This retrospective analysis included PanNEN patients who underwent resection at the Fudan University Shanghai Cancer Center from 2012 to 2018. Immunohistochemical staining was performed for 12 DDR proteins in tissue microarrays. The associations of DDR protein expression and clinicopathological features with recurrence-free survival (RFS) were examined via a Cox regression model and random survival forest. A recurrence signature was constructed using recursive partitioning analysis. RESULTS: In total, 131 PanNEN patients were included, with 32 (24.4%) cases of recurrence. Among the 12 DDR proteins, low checkpoint kinase 2 (CHK2) expression (P = 0.020) and loss of ataxia-telangiectasia-mutated (ATM) (P = 0.0007) significantly correlated with recurrence. Multivariable Cox regression analysis identified tumor size ≥3âcm, lymph node (LN) metastasis, high tumor grade, low CHK2 expression, and ATM loss as independent risk factors for recurrence. A recurrence signature was established based on the importance of recurrence-specific risk factors; patients with the LNnegTumorSize<3cm signature had a 5-year RFS rate of 96.8%, whereas patients with the LNposCHK2low signature had the worst 5-year RFS rate (0%). Discrimination (concordance index: 0.770) and calibration plots indicated that the recurrence signature had a good ability to identify patients at risk for recurrence. CONCLUSIONS: By analyzing large-scale tissue microarrays of PanNENs, we evaluated 12 DDR protein expression profiles. We developed a recurrence signature that can identify distinct subpopulations according to RFS, which may help refine individual follow-up.
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Carcinoma Neuroendocrino/genética , Daño del ADN , Reparación del ADN/fisiología , Neoplasias Pancreáticas/genética , Biosíntesis de Proteínas , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
New antiviral influenza treatments can effectively alleviate illness while reducing viral shedding. However, how such effects can translate into lower population infections of seasonal influenza in China remains unknown. To shed light on the public health impacts of novel antiviral agents for influenza, we constructed a dynamic transmission model to simulate the seasonal influenza epidemics in China. Two antivirus treatments, baloxavir and oseltamivir, were evaluated by estimating their impacts on the incidences of influenza infection in a single flu season. In the base-case analysis of a 10% antiviral treatment uptake rate, 2760 and 3420 per 10 000 persons contracted influenza under the treatment of baloxavir and oseltamivir, respectively. These incidence rates amounted to an 18.90% relative risk reduction (RRR) of infection associated with baloxavir in relation to oseltamivir. The corresponding RRR was 82.16% when the antiviral treatment uptake rate was increased to 35%. In addition, the peak of the prevalence of infected individuals per 10 000 persons under the baloxavir treatment was 177 (range: 93-274) fewer than that of oseltamivir. Our analyses suggest that the baloxavir treatment strategy reduces the incidence of influenza in China compared with oseltamivir in the setting of a seasonal flu epidemic. Also, increasing the uptake rate of antiviral treatment can potentially prevent millions of infections during a single flu season.
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Gripe Humana , Tiepinas , Antivirales/farmacología , Antivirales/uso terapéutico , Dibenzotiepinas , Humanos , Gripe Humana/tratamiento farmacológico , Gripe Humana/epidemiología , Morfolinas , Oseltamivir/uso terapéutico , Oxazinas/uso terapéutico , Piridinas/farmacología , Piridonas , Estaciones del Año , Tiepinas/farmacología , Tiepinas/uso terapéutico , TriazinasRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.
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Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Reprogramación Celular , Resistencia a Antineoplásicos , Metaboloma/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
BACKGROUND: So far, SARS-CoV-2 is the seventh coronavirus found to infect humans and cause disease with quite a strong infectivity. Patients diagnosed as severe or critical cases are prone to multiple organ dysfunction syndrome, acute respiratory distress syndrome and even death. Proinflammatory cytokine IL-6 has been reported to be associated with the severity of disease and mortality in patients with COVID-19. OBJECTIVE: This systematic review and meta-analysis were carried out to evaluate the association between IL-6 and severe disease and mortality in COVID-19 disease. METHODS: A systematic literature search using China National Knowledge Infrastructure, Wanfang databases, China Science and Technology Journal Database, Chinese Biomedical Literature, Embase, PubMed and Cochrane Central Register of Controlled Trials was performed from inception until 16 January 2021. RESULTS: 12 studies reported the value of IL-6 for predicting the severe disease in patients with COVID-19. The pooled area under the curve (AUC) was 0.85 (95% CI 0.821 to 0.931). 5 studies elaborated the predictive value of IL-6 on mortality. The pooled sensitivity, specificity and AUC were 0.15 (95% CI 0.13 to 0.17, I2=98.9%), 0.73 (95% CI 0.65 to 0.79, I2=91.8%) and 0.531 (95% CI 0.451 to 0.612), respectively. Meta-regression analysis showed that country, technique used, cut-off, sample, study design and detection time did not contribute to the heterogeneity of mortality. CONCLUSION: IL-6 is an adequate predictor of severe disease in patients infected with the COVID-19. The finding of current study may guide clinicians and healthcare providers in identifying potentially severe or critical patients with COVID-19 at the initial stage of the disease. Moreover, we found that only monitoring IL-6 levels does not seem to predict mortality and was not associated with COVID-19's mortality. PROSPERO REGISTRATION NUMBER: CRD42021233649.