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Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor in East Asia. Hypoxia, a hallmark of solid tumors, significantly alters redox homeostasis inside tumor microenvironment. This alteration drives tumor proliferation, invasion, and metastasis, leading to poor prognostic outcomes. However, the role of hypoxia-related genes in ESCC remains poorly understood. We employed RNA sequencing to identify differentially expressed genes in ESCC. Clinical data, transcriptome profiles, and a hypoxia-related gene set were extracted from open-source databases. A prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression, which was then validated through Cox regression analysis. Within this prognostic model, we pinpointed and investigated a key hypoxia-related gene affecting prognosis. The gene's expression was validated using real-time PCR and immunohistochemistry in both esophageal carcinoma and normal tissues. Tumor proliferation was examined through in vitro and in vivo assays, including the Cell Counting Kit-8, EdU, colony formation, and subcutaneous tumor models. A robust four-gene prognostic model (VBP1, BGN, CDKN1A, and PPFIA1) was successfully constructed and validated. Among these, VBP1 emerged as a key gene, exhibiting high expression levels that correlated with poor prognosis in ESCC. Functional experiments confirmed that VBP1 significantly accelerated tumor proliferation both in vitro and in vivo. VBP1 is identified as a pivotal gene within the hypoxia-related prognostic signature, and it significantly promotes tumor proliferation in ESCC.
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Proliferación Celular , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Animales , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Hipoxia/genética , Pronóstico , Transcriptoma/genética , Hipoxia Tumoral/genéticaRESUMEN
Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.
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Claudinas , Neoplasias Ováricas , Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Femenino , Receptores Quiméricos de Antígenos/genética , Neoplasias Ováricas/terapia , Neoplasias Ováricas/metabolismo , Línea Celular Tumoral , Apoptosis , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Antígenos CD28/metabolismo , Células Asesinas Naturales , Inmunoterapia/métodos , Inmunoterapia Adoptiva/métodosRESUMEN
This study aimed to identify potential therapeutic targets of artesunate in an MRL/lpr lupus nephritis mouse model by quantitative proteomics. We detected serum autoimmune markers and proteinuria in 40 female mice that were divided into 4 groups (n = 10): normal C57BL/6 control group; untreated MRL/lpr lupus; 9 mg/kg/day prednisone positive control MRL/lpr lupus; and 15 mg/kg/day artesunate-treated MRL/lpr lupus groups. Renal pathology in the untreated MRL/lpr lupus and artesunate groups was examined by Periodic acid-Schiff (PAS) staining. Artesunate treatment in lupus mice decreased serum autoantibody levels and proteinuria while alleviating lupus nephritis pathology. Through tandem mass tag-tandem mass spectrometry (TMT-MS/MS) analyses, differentially expressed proteins were identified in the artesunate group, and subsequent functional prediction suggested associations with antigen presentation, apoptosis, and immune regulation. Data are available via ProteomeXchange with the identifier PXD046815. Parallel reaction monitoring (PRM) analysis of the top 19 selected proteins confirmed the TMT-MS/MS results. Immunohistochemistry, immunofluorescence, and Western blotting of an enriched protein from PRM analysis, cathepsin S, linked to antigen presentation, highlighted its upregulation in the untreated MRL/lpr lupus group and downregulation following artesunate treatment. This study suggests that artesunate holds potential as a therapeutic agent for lupus nephritis, with cathepsin S identified as a potential target.
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Nefritis Lúpica , Femenino , Animales , Ratones , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/patología , Artesunato/uso terapéutico , Ratones Endogámicos MRL lpr , Proteómica , Espectrometría de Masas en Tándem , Ratones Endogámicos C57BL , Riñón/metabolismo , Proteinuria/tratamiento farmacológico , Proteinuria/metabolismo , Proteinuria/patología , Catepsinas/uso terapéuticoRESUMEN
BACKGROUND: The progression of Type 2 Diabetes Mellitus (T2DM) can lead to various complications. Compounds derived from natural products have been found to be effective in combatting T2DM. This study aimed to investigate the effects of Astragaloside IV (AS-IV) on insulin resistance and the inflammatory response of adipocytes. The study also aimed to determine the downstream signaling pathways involved. MATERIALS AND METHODS: The glucose consumption of adipocytes was assessed using a glucose assay kit. qRT-PCR, Western blot, and ELISA assays were used to measure mRNA and protein levels. The interaction between miR-21 and PTEN was assessed using a Dual-luciferase reporter assay. RESULTS: The results showed that AS-IV increased glucose consumption and the expression of GLUT-4 in adipocytes with insulin resistance in a concentration-dependent manner. However, ASIV decreased the protein levels of TNF-α and IL-6 in these cells. Additionally, AS-IV up-regulated miR-21 expression in adipocytes with insulin resistance in a concentration-dependent manner. Furthermore, miR-21 overexpression increased glucose consumption and GLUT-4 expression but decreased TNF-α and IL-6 protein levels in adipocytes. Conversely, miR-21 inhibition attenuated the AS-IV-induced increase in glucose consumption and GLUT-4 expression and the decrease in TNF- α and IL-6 protein levels in adipocytes. MiR-21 also inversely regulated PTEN in adipocytes, and PTEN overexpression had effects similar to miR-21 inhibition in AS-IV-treated adipocytes. Finally, AS-IV up-regulated p-PI3K and p-AKT protein expression in adipocytes, which was attenuated by miR-21 inhibition. CONCLUSION: The study concluded that AS-IV attenuated insulin resistance and the inflammatory response in adipocytes. The mechanistic studies indicated that AS-IV modulated the miR- 21/PTEN/PI3K/AKT signaling in adipocytes to exert these effects.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , MicroARNs , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , MicroARNs/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Glucosa/metabolismo , Adipocitos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismoRESUMEN
Chronic stress can cause intestinal barrier damage. MAPK and NF-κB are closely related to it. Chlorogenic acid (CGA), a dietary polyphenol, has been shown to have intestinal protective effects, but whether by regulating MAPK and NF-κB is not known. Therefore, in this experiment, 24 Wistar rats were randomly divided into 4 groups (C group, CS group, CS + SB203580, and CS + CGA group). Rats in the CS group were restrained stress for 6 h per day for 21 days. Rats in the CS + SB203580 group were given SB203582 (0.5 mg/kg, intraperitoneal injection) 1 h before restraint stress every other day. Rats in the CS + CGA group were given CGA (100 mg/kg, gavage) 1 h before restraint stress. In chronic stress, intestinal barrier damage was evident, while being restored after CGA treatment. After chronic stress, the levels of p-P38 were increased (P < 0.01), while the levels of p-JNK and p-ERK were not changed. The levels of p-p38 were elevated after CGA treatment (P < 0.01). These results suggested that p38MAPK played an important role in chronic stress-induced intestinal injury, and CGA could inhibit p38MAPK activity. Therefore, we chose SB203582 (P38MAPK inhibitor) to elucidate the role of p38. After chronic stress, intestinal tight junction key proteins Occludin, ZO-1, and Claudin3 protein and gene expression were reduced (P < 0.01), while being elevated after CGA or SB203582 intervention (P < 0.05). After CGA treatment, the levels of p-IκB, p-p65, p-p38, and TNF-α were reduced (P < 0.01). SB203582 intervention reduced p-p65 and TNF-α levels significantly (P < 0.01). These results suggested that CGA could inhibit the NF-κB pathway by suppressing p38MAPK, thereby alleviating chronic stress-induced intestinal damage.
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Ácido Clorogénico , FN-kappa B , Ratas , Animales , FN-kappa B/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Factor de Necrosis Tumoral alfa , Ratas WistarRESUMEN
PURPOSE: The efficacy and safety of nimotuzumab (NTZ) added to concurrent chemoradiotherapy (CCRT) were investigated in patients with stage III-IVa nasopharyngeal carcinoma (NPC). METHODS: Patients with stage III-IVa NPC treated with CCRT, with or without NTZ, were screened between January 2015 and December 2017. We compared patients' overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) between different therapeutic regimens. Propensity score matching (PSM) was applied to reduce the selection bias. Nomogram models were developed to predict the survival of CCRT with or without NTZ. RESULTS: Four hundred and twenty-six patients were included after PSM, with 213 patients in each regimen. Compared with NPC patients receiving CCRT alone, patients who received NTZ plus CCRT treatment had significantly better OS (5 year OS, 76.1 vs. 72.3%, P = 0.004), PFS (5 year PFS, 73.2 vs. 69.0%, P = 0.002), and LRFS (5 year LRFS, 73.2 vs. 69.0%, P = 0.028). A multivariate Cox regression analysis demonstrated that, compared with receiving CCRT alone, NTZ plus CCRT was an independently positive factor for OS, PFS, and LRFS. No significant difference was observed in the major toxicities between the two treatments (all P > 0.05). In addition, the nomogram presented good accuracy for predicting the prognosis of NPC patients. CONCLUSION: CCRT combined with NTZ presented favorable clinical outcomes for stage III-IVa NPC patients with good tolerance and similar toxicity compared to CCRT alone. A prospective, randomized clinical trial is essential to validate the current findings.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Estudios Prospectivos , Quimioradioterapia/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de InducciónRESUMEN
INTRODUCTION: Emerging evidence showed that adipocytes are important regulators in controlling insulin resistance in type 2 diabetes mellitus (T2DM). So far, compounds isolated from natural plants have been widely studied for their roles in alleviating T2DM-associated complications. This work evaluated the actions of astragaloside IV (AS-IV) on insulin resistance and inflammatory biomarker expression in adipocytes and explored the potential mechanisms. METHODS: Glucose consumption of the adipocytes was determined by a glucose assay kit; the mRNA expression levels of glucose transporter type 4 (GLUT-4), interleukin-6 (IL-6), TNF-α and C1q tumor necrosis factor-related protein 3 (CTRP3) were measured by quantitative real-time PCR (qRT-PCR); the protein levels were determined by western blot assay and enzyme-linked immunosorbent assay. RESULTS: AS-IV concentration-dependently increased glucose consumption in the insulin resistance adipocytes. Further qRT-PCR results showed that AS-IV concentration-dependently reduced adipocyte IL-6 and TNF-α expression. Moreover, GLUT-4 expression in adipocytes was also significantly upregulated by AS-IV. Furthermore, we found that AS-IV concentration-dependently increased CTRP3 expression in adipocytes. CTRP3 silence decreased glucose consumption, upregulated IL-6 and TNF-α expression and downregulated GLUT-4 mRNA expression in 200 µM AS-IV-treated adipocytes. Moreover, AS-IV treatment enhanced the activity of phosphoinositide 3-kinase (PI3K)/AKT signaling in adipocytes, which was markedly attenuated by CTRP3 silencing. Importantly, inhibition of PI3K/AKT signaling also attenuated AS-IV induced an increase in glucose consumption and GLUT-4 expression and a decrease in IL-6 and TNF-α expression of adipocytes. CONCLUSIONS: Collectively, our data indicated that AS-IV attenuated insulin resistance and inflammation in adipocytes via targeting CTRP3/PI3K/Akt signaling.
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Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC50: 1.18-14.13 µM) than the lead compound 6. Further molecular docking studies showed that compounds 13, 26, 27 and 28 had multiple interactions with active sites. Among them, compound 13 exhibited dose-dependent increased antituberculosis activity in mouse macrophages. The results displayed that the strategy of modification utilizing biphenyl scaffold was efficient. Our study identifies biphenyls bearing thiobarbiturate fragment as new MptpB inhibitors and verifies the therapeutic potential of antimycobacterial agent targeting MptpB.
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Mycobacterium tuberculosis , Tuberculosis , Animales , Antituberculosos/química , Proteínas Bacterianas/metabolismo , Compuestos de Bifenilo , Inhibidores Enzimáticos/química , Ratones , Simulación del Acoplamiento Molecular , Mycobacterium tuberculosis/metabolismo , Proteínas Tirosina Fosfatasas , Tiobarbitúricos , Tuberculosis/microbiología , Factores de VirulenciaRESUMEN
Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8+ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8+ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Contaminación por Humo de Tabaco , Animales , Linfocitos T CD8-positivos/metabolismo , Carcinógenos/toxicidad , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Nicotiana/metabolismo , TriptófanoRESUMEN
BACKGROUND: Circular RNA (circRNA) has been recently identified as a critical regulator during carcinogenesis. However, the biological function and potential underlying mechanisms of circRNAs in lung cancer remain to be further elucidated. METHODS: Here, we first evaluated the differentially expressed circRNAs between tumor and the matched adjacent nontumor tissues (3 pairs) of lung cancer patients via circRNA microarray. The expression of top five dysregulated circRNAs were tested in lung cancer cell lines and the circSCAP with concordant alteration in microarray data and cell lines was selected for further investigation. Then we validated the expression level of circSCAP in tumor and corresponding adjacent tissues (161 pairs) from a lung cancer cohort by RT-PCR analysis followed by correlation and prognosis analysis between circSCAP and clinical characteristics. Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnosis (about 80% in the cohort used in this study). Therefore, we focused the role of circSCAP in NSCLC in the present study. In vitro and in vivo assays were performed to study the biological function of circSCAP in NSCLC. Biotin-labeled RNA pulldown and RNA immunoprecipitation (RIP) assays were carried out to identify the proteins directly interacting with circSCAP. The molecular mechanism of circSCAP-driven tumor suppression was demonstrated by immunoblotting, immunoprecipitation and luciferase reporter assays. In vitro and in vivo rescue experiments were conducted to verify the role of the circSCAP/SF3A3/p53 signaling axis in NSCLC. RESULTS: We screened the expression profiles of human circRNAs in lung cancer tissues and found that hsa_circ_0065214 (termed as circSCAP) was significantly decreased. Kaplan-Meier analysis showed that patients with low level of circSCAP had a significantly poor prognosis. Gain- and loss-of-function experiments suggested that circSCAP played an important role in NSCLC cell proliferation, cell migration and apoptosis. Mechanistically, circSCAP directly binds to the SF3A3 protein, facilitating the reduction of SF3A3 by promoting its ubiquitin-proteasome-mediated degradation, which enhances the expression of MDM4-S to finally activate its downstream p53 signaling. CONCLUSION: These findings illustrate a novel circSCAP/SF3A3/p53 signaling axis involved in suppressing the malignance of NSCLC and provide a promising target for NSCLC prognosis prediction and treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , ARN Circular/genética , Ribonucleoproteína Nuclear Pequeña U2/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/genética , Humanos , Neoplasias Pulmonares/patología , MicroARNs/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: The development of lung adenocarcinoma (LUAD) involves the interactions between cell proliferation and death. Autophagy-dependent ferroptosis, a distinctive cell death process, was implicated in a multitude of diseases, whereas no research revealing the relationship between autophagy-dependent ferroptosis and LUAD pathogenesis was reported. Thus, the primary objective was to explore the role and potential function of the autophagy-dependent ferroptosis-related genes in LUAD. METHODS: Clinical information and transcriptome profiling of patients with LUAD were retrieved and downloaded from open-source databases. Autophagy-dependent ferroptosis-related genes were screened by published articles. The critical gene was identified as the intersection between the differentially expressed genes and prognosis-related genes. Patients were divided into high- and low-risk groups using the expression level of the critical gene. The validity of the key gene prognosis model was verified by survival analysis. The correlation between the clinical characteristics of LUAD and the expression level of the key gene was analyzed to explore the clinical significance and prognosis value. And the roles of the key gene in response to chemotherapy, immune microenvironment, and tumor mutation burden were predicted. The validation of key gene expression levels was further performed by quantitative real-time PCR and immunohistochemistry staining. RESULTS: FANCD2, an essential autophagy-dependent ferroptosis-related gene by searching database, was confirmed as an independent prognostic factor for LUAD occurrence. The high expression level of FANCD2 was associated with an advantaged TNM stage, a less chemotherapy sensitivity, a low ImmuneScore, which indicated a deactivation status in an immune microenvironment, a high tumor mutation burden, and poor survival for LUAD patients. Pathway enrichment analysis showed that FANCD2 responded to oxidative stress and neutrophil-mediated immunity. Quantitative real-time PCR and immunohistochemistry staining showed that the expression level of FANCD2 is higher in LUAD patients than in normal tissue samples, which was in accordance with the database report. CONCLUSION: FANCD2, an essential gene related to autophagy-dependent ferroptosis, could work as a biomarker, predicting the survival, chemotherapy sensitivity, tumor immunity, and mutation burden of LUAD. Researching autophagy-dependent ferroptosis and targeting the FANCD2 may offer a new perspective for treating and improving prognosis in LUAD.
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Adenocarcinoma del Pulmón/genética , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genética , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , Autofagia/genética , Biomarcadores de Tumor/genética , Femenino , Ferroptosis/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis de SupervivenciaRESUMEN
BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is an uncommon, but serious complication in patients with continuous ambulatory peritoneal dialysis (PD) who have a considerable mortality rate. This study aimed to identify risk factors and outcomes of EPS in Chinese patients on PD. METHODS: Sixteen patients on PD who met the International Society for Peritoneal Dialysis criteria for diagnosis of EPS in the First Affiliated Hospital of Sun Yat-Sen University from 1997 to 2018 were included. Patients without EPS were matched for age, sex and the duration of PD and selected at a 1:3 ratio for the controls. A case-control study was conducted to analyse the clinical profile and risk factors associated with EPS in patients. RESULTS: The prevalence of EPS in patients on PD in our centre was 0.55%. The percentage of EPS significantly increased with the duration of PD. In univariate regression analysis, a history of peritonitis (odds ratios (OR): 2.83; 95% confidence interval (CI): 0.82-9.68; p = 0.08), peritoneal glucose exposure (OR: 1.12; 95% CI: 1.03-1.22; p < 0.01) and a high peritoneal transport status (OR: 14.70; 95% CI: 1.85-117.02; p < 0.01) were associated with EPS in patients on PD. However in the multivariate model, only a high peritoneal transport status (adjusted odds ratios (aOR): 13.65; 95% CI: 1.69-109.96; p = 0.01) was independently associated with EPS. CONCLUSION: The rate of EPS significantly increases with the duration of PD. Progressive peritoneal dysfunction, especially a high peritoneal transport status, is associated with a higher risk of EPS in this population.
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Diálisis Peritoneal , Fibrosis Peritoneal , Estudios de Casos y Controles , Humanos , Diálisis Peritoneal/efectos adversos , Fibrosis Peritoneal/diagnóstico , Fibrosis Peritoneal/epidemiología , Fibrosis Peritoneal/etiología , Peritoneo/patología , Factores de Riesgo , Esclerosis/etiologíaRESUMEN
BACKGROUND: The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases. METHODS: Adult patients diagnosed with locally advanced rectal adenocarcinoma with potentially resectable metastases, who received neoadjuvant chemotherapy and radiotherapy from July 2013 and September 2019 at Sun Yat-sen University cancer center, were included. Completion of the whole treatment schedule, pathological response, treatment-related toxicity and survival were evaluated. RESULTS: A total of 228 patients were analyzed with a median follow-up of 33 (range 3.3 to 93.4) months. Eventually, 112 (49.1%) patients finished the whole treatment schedule, of which complete response of all tumor sites and pathological downstaging of the rectal tumor were observed in three (2.7%) and 90 (80.4%) patients. The three-year overall survival (OS) and progression-free survival (PFS) of all patients were 56.6% (50.2 to 63.9%) and 38.6% (95% CI 32.5 to 45.8%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P < 0.001) and 3-year PFS (45.5% vs 30.5%, P = 0.004) were significantly improved compared those who did not finish the treatment. Grade 3-4 chem-radiotherapy treatment toxicities were observed in 51 (22.4%) of all patients and surgical complications occurred in 22 (9.6%) of 142 patients who underwent surgery, respectively. CONCLUSIONS: Neoadjuvant chemotherapy and radiotherapy followed by resection/ablation and subsequent adjuvant chemotherapy offered chances of long-term survival with tolerable toxicities for selected patients with potentially resectable stage IV rectal cancer, and could be considered as an option in clinical practice.
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Técnicas de Ablación/mortalidad , Adenocarcinoma/terapia , Terapia Neoadyuvante/mortalidad , Proctectomía/mortalidad , Neoplasias del Recto/terapia , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos Antineoplásicos , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/mortalidad , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Supervivencia sin Progresión , Radioterapia Adyuvante/métodos , Radioterapia Adyuvante/mortalidad , Neoplasias del Recto/mortalidad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Albumin-to-alkaline phosphatase ratio (AAPR) has been reported as a novel prognostic predictor for numerous solid tumors. We aimed to assess the prognostic role of preoperative AAPR in surgically resectable esophageal squamous cell carcinoma (ESCC) by a propensity score matching (PSM) analysis with predictive nomograms. METHODS: Our study was conducted in a single-center prospective database between June 2009 and December 2012. Kaplan-Meier analysis was used to distinguish the difference in survival outcomes between patients stratified by an AAPR threshold. Multivariable Cox proportional hazards regression model was finally generated to specify independent prognostic markers for the entire and PSM cohorts. RESULTS: A total of 497 patients with ESCC were included in this study. An AAPR of 0.50 was determined as the optimal cutoff point for prognostic outcome stratification. Patients with AAPR<0.50 had significantly worse overall survival (OS), and progression-free survival (PFS) compared to those with AAPR≥0.50 (Log-rank P<0.001). This significant difference remained stable in the PSM analysis. Multivariable analyses based on the entire and PSM cohorts consistently showed that AAPR<0.50 might be one of the most predominant prognostic factors resulting in unfavorable OS and PFS of ESCC patients undergoing esophagectomy (P<0.001). The nomograms consisting of AAPR and other independent prognostic factors further demonstrated a plausible predictive accuracy of postoperative OS and PFS. CONCLUSION: AAPR can be considered as a simple, convenient and noninvasive biomarker with a significant prognostic effect in surgically resected ESCC.
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Under guidance of 1H NMR, ten new polypropionate derivatives, decempyrones A-J (1-10) along with two known analogues (11 and 12), were isolated from the marine-derived fungusFusarium decemcellulare SYSU-MS6716. The planar structures were elucidated on the basis of extensive spectroscopic analyses (1D and 2D NMR, and HR-ESIMS). The absolute configuration of the chiral centers in the side chain is a major obstacle for the structure identification of natural polypropionate derivatives. Herein, the J-based configurational analysis (JBCA), chemical degradation, geminal proton rule, and the modified Mosher's method were adopted to fix their absolute configurations in the side chain. Compounds 3 and 10 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide with IC50values 22.4 ± 1.8 and 21.7 ± 1.1 µM. In addition, compounds 3 and 10 displayed MptpA inhibitory activity with an IC50 value of 19.2 ± 0.9 and 33.1 ± 2.9 µM. Structure-activity relationships of the polypropionate derivatives were discussed.
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Antiinflamatorios/química , Propionatos/química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Fusarium/química , Fusarium/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Espectroscopía de Resonancia Magnética , Ratones , Conformación Molecular , Óxido Nítrico/metabolismo , Propionatos/aislamiento & purificación , Propionatos/farmacología , Proteínas Tirosina Fosfatasas/metabolismo , Células RAW 264.7RESUMEN
BACKGROUND: Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive malignancy. It has a poor survival rate, and there is no consensus as to a standard therapeutic modality. In this study, we aimed to investigate the prognostic factors and evaluate the outcomes of patients with PSCCE who had been treated with different therapeutic methods. METHODS: We retrospectively evaluated 113 consecutive patients with PSCCE who received treatment at our center from 2003 to 2016. The primary endpoint was overall survival (OS). The Cox regression model was used to analyze the prognostic factors. The survival analysis was calculated using the Kaplan-Meier and log-rank methods. RESULTS: The 12- and 36-month OS rates of all 113 enrolled patients were 45% and 12%, respectively. A significantly prolonged OS rate was associated with lymph node stages N0-N1 (P=0.022), the Veterans' Administration Lung Study Group (VALSG) system limited-disease (LD) staging (P=0.040), and multimodality treatments (P=0.047). Patients with regional lymph node metastasis benefited more from surgery combined with chemotherapy than surgery or chemotherapy alone (P=0.046). Concerning chemotherapy, cisplatin plus etoposide was the regimen most commonly used to treat PSCCE patients (67.5%). CONCLUSIONS: An early lymph node stage, the VALSG LD staging, and multimodality treatments were identified as independent prognostic factors of PSCCE. Surgery combined with adjuvant chemotherapy was especially necessary for LD stage PSCCE patients with lymph node stages N1-3.
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INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common symptom, but prophylactic measures cannot still be carried out effectively. In addition, the efficacy of vitamin E in preventing peripheral neurotoxicity caused by chemotherapy is inconclusive. Therefore, we collected the relevant randomized controlled trials (RCTs) and performed a meta-analysis to examine whether the vitamin E has a positive effect in CIPN. METHODS: We searched PubMed, EMBASE, Cochrane, and other databases in December 2019 for eligible trials. Two reviewers conducted the analysis independently when studies were homogeneous enough. RESULTS: Eight RCTs, involving 488 patients, were identified. Upon pooling these RCTs, patients who received vitamin E supplementation of 600 mg/day had a lower incidence of CIPN (risk ratio [RR] 0.31; 95% confidence interval [CI] 0.14-0.65; p = 0.002) than the placebo group. Vitamin E played a key role in decreasing the incidence of peripheral neuropathy in the cisplatin chemotherapy group (RR 0.28; 95% CI 0.14-0.54; p = 0.0001). Moreover, vitamin E supplementation significantly decreased patients' sural amplitude after 3 rounds of chemotherapy (RR -2.66; 95% CI -5.09 to -0.24; p = 0.03) in contrast with that of placebo supplementation, while no significant difference was observed when patients were treated with vitamin E after 6 rounds of chemotherapy. In addition, the vitamin E-supplemented group had better improvement in the neurotoxicity score and lower incidence of reflexes and distal paraesthesias than the control group. CONCLUSION: Available data in this meta-analysis showed that vitamin E supplementation can confer modest improvement in the prevention of CIPN.
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Enfermedades del Sistema Nervioso Periférico , Antineoplásicos/efectos adversos , Cisplatino , Humanos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Vitamina E/uso terapéuticoRESUMEN
BACKGROUND: Although previous studies have discussed whether the minimally invasive esophagectomy (MIE) is superior to open surgery, the data concerning esophageal squamous cell carcinoma (ESCC) patients underwent neoadjuvant treatment followed by radical resection is limited. The purpose of our study was to compare the short- and long-term clinical outcomes of the two surgical approaches in treating ESCC patients. METHODS: Between January 2010 and December 2016, ESCC patients who had received neoadjuvant therapy and underwent Mckeown esophagectomy at our institute were eligible. The baseline characteristics, pathological data, short-and long-term outcomes of these patients were collected and compared based on the surgical approach. RESULTS: A total of 195 patients was included in the current study. Compared to patients underwent open surgery, patients underwent MIE had shorter operative time and less intraoperative bleeding (390 min vs 330 min, P = 0.001; 204 ml vs 167 ml, P = 0.021). In addition, the risk of anastomotic leakage was decreased in MIE group (20.0% vs 3.3%, P < 0.001), while the occurrence of other complications did not have statistical significance between two groups. Overall survival (OS) and disease-free survival (DFS) was no difference in patients received neoadjuvant chemotherapy between the two approaches. For the patients underwent neoadjuvant chemoradiotherapy, OS was significantly better in the MIE group (log rank = 6.197; P = 0.013). CONCLUSION: Minimally invasive Mckeown esophagectomy is safe and feasible for ESCC patients who underwent neoadjuvant therapy. MIE approach presented better perioperative results than open esophagectomy. The effect of surgical approaches on survival was depending on the scheme of neoadjuvant treatment.
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Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía/mortalidad , Procedimientos Quirúrgicos Mínimamente Invasivos/mortalidad , Terapia Neoadyuvante/mortalidad , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Long non-coding RNAs (lncRNAs) play vital roles in the development and progression of non-small-cell lung cancer (NSCLC); however, the role of most lncRNAs in NSCLC remains unknown. This study explored the clinical significance, biological function and underlying mechanism of lnc-GAN1 in NSCLC. METHODS: With a custom lncRNA microarray we found that lnc-GAN1 is markedly downregulated in NSCLC tissues. Then lnc-GAN1 expression level was measured using qRT-PCR in NSCLC tissues and cell lines. Survival was assessed using the Kaplan-Meier method. The biological functions of lnc-GAN1 in lung cancer cells were evaluated in vitro and in vivo. RNA fluorescence in situ hybridization and subcellular localization assays revealed the subcellular distribution of lnc-GAN1 in cells. Bioinformatic analysis was adopted to predict miRNAs and signaling pathways regulated by lnc-GAN1. RNA immunoprecipitation and Dual-luciferase reporter assays were used to assess the interaction between lnc-GAN1 and miR-26a-5p in lung cancer cells. RESULTS: lnc-GAN1 is downregulated in HCC tissues and associated with larger tumor size and poor overall survival and disease-free survival; its ectopic expression suppresses cell proliferation, colony formation, and cell cycle progression and induces apoptosis in NSCLC cells; it also inhibits tumor growth in the NSCLC xenograft model. We further proved that lnc-GAN1 is localized in cytoplasm and transcribed independently from its parental gene GAN. Mechanistically, lnc-GAN1 acts as a sponge for miR-26a-5p by two seed sequences, and the two non-coding RNAs have a negative relationship in NSCLC tissues; we further prove that PTEN is a direct target of miR-26a-5p and lnc-GAN1 inhibits cell cycle signaling pathway by activating PTEN, whose expression level correlated negatively with miR-26a-5p level but positively with lnc-GAN1 level in NSCLC samples. CONCLUSIONS: Lnc-GAN1 is downregulated and associated with poor survival of NSCLC patients, and mechanistically acts as a tumor suppressor via sponging and inhibiting miR-26a-5p to upregulate PTEN. This study provides a potential prognostic biomarker and treatment target for NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Transducción de Señal , Análisis de Supervivencia , TransfecciónRESUMEN
BACKGROUND: Lung adenocarcinoma (LUAD) is a heterogeneous disease with high mortality. Close attention has been paid to immunotherapy in LUAD treatment. However, immunotherapy has produced different therapeutic effects because of immune heterogeneity. Long noncoding RNAs (lncRNAs) are survival prognostic indicators with functions in the immune process. The present study was designed to examine the predictive power of immune-related lncRNAs in LUAD prognosis and investigated potential molecular mechanisms. METHODS: Transcriptome profiling and LUAD sample clinical information were retrieved from online database. The immune-related lncRNAs signature was identified by Cox regression. Survival analysis was used to verify the validity of the prognosis model. Then, possible biological functions were predicted and the abundance of infiltrating immune cells in LUAD samples were further analyzed. RESULTS: An immune-associated lncRNAs signature was established by combining six lncRNAs. Patients with LUAD were stratified into high- and low-risk groups using the six lncRNAs signature. Patients in different risk levels had significantly different prognoses (P<0.001), and the immune-associated lncRNAs signature was identified as an independent prognostic factor for LUAD. The functions of the lncRNA signature were confirmed as ubiquitin mediated proteolysis and signal sequence binding. The lncRNA signature negatively correlates with B-cell immune infiltration. CONCLUSION: A reliable immune-related lncRNAs prognosis model for LUAD was identified. lncRNAs played a vital role in the tumor immune process and were associated with the LUAD prognosis. Research of lncRNAs in B-cell immune infiltration could provide new insight into the immunotherapy of LUAD.