RESUMO
The dysregulation of long non-coding RNAs (lncRNAs) are involved in regulating tumor progression in multiple manner. However, little is known about whether lncRNA is involved in the translation regulation of proteins. Here, we identified that the suppressor of inflammatory macrophage apoptosis lncRNA (SIMALR) was highly expressed in nasopharyngeal carcinoma (NPC) tissues by analyzing the lncRNA microarray. Clinically, the high expression of SIMALR served as an independent predictor for inferior prognosis in NPC patients. SIMALR functioned as an oncogenic lncRNA that promoted the proliferation and metastasis of NPC cells in vitro and in vivo. Mechanistically, SIMALR served as a critical accelerator of protein synthesis by binding to eEF1A2 (eukaryotic translation elongation factor 1 alpha 2), one of the most crucial regulators in the translation machinery of the eukaryotic cells, and enhancing its endogenous GTPase activity. Furthermore, SIMALR mediated the activation of eEF1A2 phosphorylation to accelerate the translation of ITGB4/ITGA6, ultimately promoting the malignant phenotype of NPC cells. In addition, N-acetyltransferase 10 (NAT10) enhanced the stability of SIMALR and caused its overexpression in NPC through the N4-acetylcytidine (ac4C) modification. In sum, our results illustrate SIMALR functions as an accelerator for protein translation and highlight the oncogenic role of NAT10-SIMALR-eEF1A2-ITGB4/6 axis in NPC.
RESUMO
BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Assuntos
Anticorpos Monoclonais Humanizados , Quimiorradioterapia , Quimioterapia de Indução , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/tratamento farmacológico , Adulto , China/epidemiologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/terapia , Quimiorradioterapia/métodos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Idoso , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Adulto Jovem , Adolescente , Intervalo Livre de ProgressãoRESUMO
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
Assuntos
Docetaxel , Resistencia a Medicamentos Antineoplásicos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Piroptose , Ubiquitina-Proteína Ligases , Ubiquitinação , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dinaminas/metabolismo , Dinaminas/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Gasderminas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosforilação/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Piroptose/genética , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Metastasis has emerged as the major reason of treatment failure and mortality in patients with nasopharyngeal carcinoma (NPC). Growing evidence links abnormal DNA methylation to the initiation and progression of NPC. However, the precise regulatory mechanism behind these processes remains poorly understood. METHODS: Bisulfite pyrosequencing, RT-qPCR, western blot, and immunohistochemistry were used to test the methylation and expression level of NEURL3 and its clinical significance. The biological function of NEURL3 was examined both in vitro and in vivo. Mass spectrometry, co-immunohistochemistry, immunofluorescence staining, and ubiquitin assays were performed to explore the regulatory mechanism of NEURL3. RESULTS: The promoter region of NEURL3, encoding an E3 ubiquitin ligase, was obviously hypermethylated, leading to its downregulated expression in NPC. Clinically, NPC patients with a low NEURL3 expression indicated an unfavorable prognosis and were prone to develop distant metastasis. Overexpression of NEURL3 could suppress the epithelial mesenchymal transition and metastasis of NPC cells in vitro and in vivo. Mechanistically, NEURL3 promoted Vimentin degradation by increasing its K48-linked polyubiquitination at lysine 97. Specifically, the restoration of Vimentin expression could fully reverse the tumor suppressive effect of NEURL3 overexpression in NPC cells. CONCLUSIONS: Collectively, our study uncovers a novel mechanism by which NEURL3 inhibits NPC metastasis, thereby providing a promising therapeutic target for NPC treatment.
Assuntos
Neoplasias Nasofaríngeas , Ubiquitina-Proteína Ligases , Humanos , Carcinoma Nasofaríngeo/genética , Ubiquitina-Proteína Ligases/genética , Vimentina/genética , Transição Epitelial-Mesenquimal , Neoplasias Nasofaríngeas/genéticaRESUMO
Emerging evidence indicates that DNA methylation plays an important role in the initiation and progression of nasopharyngeal carcinoma (NPC). DNAJA4 is hypermethylated in NPC, while its role in regulating NPC progression remains unclear. Here, we revealed that the promoter of DNAJA4 was hypermethylated and its expression was downregulated in NPC tissues and cells. Overexpression of DNAJA4 significantly suppressed NPC cell migration, invasion, and EMT in vitro, and markedly inhibited the inguinal lymph node metastasis and lung metastatic colonization in vivo, while it did not affect NPC cell viability and proliferation capability. Mechanistically, DNAJA4 facilitated MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2. Furthermore, the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT were reversed by overexpression of MYH9 in NPC cells. Clinically, a low level of DNAJA4 indicated poor prognosis and an increased probability of distant metastasis in NPC patients. Collectively, DNAJA4 serves as a crucial driver for NPC invasion and metastasis, and the DNAJA4-PSMD2-MYH9 axis might contain potential targets for NPC treatments.
Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Transição Epitelial-Mesenquimal/genética , Transdução de Sinais , Movimento Celular/genética , Neoplasias Nasofaríngeas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Fator 2 Associado a Receptor de TNF/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Proteínas de Choque Térmico HSP40/metabolismoRESUMO
BACKGROUND: The placenta serves as the sole maternal organ responsible for transmitting nutrients to the fetus, playing a crucial role in supporting standard fetal growth and development. To date, only a small number of studies have investigated the impact of maternal gestational weight gain and lipid concentrations on placental development. This study aimed to explore the influence of weight gain during pregnancy and lipid levels in the second trimester on placental weight, volume, and the placental weight ratio. METHODS: This birth cohort study encompassed 1,358 mother-child pairs. Placental data for each participant was gathered immediately post-delivery, and the study incorporated data on gestational weight gain throughout pregnancy and lipid profiles from the mid-trimester. A linear regression model was employed to assess the correlations between gestational weight gain, mid-trimester lipid levels, and metrics such as placental weight, placental volume, and the placental-to-birth weight ratio (PFR). RESULTS: In the study groups of pre-pregnancy underweight, normal weight, and overweight, the placental weight increased by 4.93 g (95% CI: 1.04-8.81), 2.52 g (95% CI: 1.04-3.99), and 3.30 g (95% CI: 0.38-6.22) per 1 kg of gestational weight gain, respectively. Within the pre-pregnancy underweight and normal weight groups, the placental volume increased by 6.79 cm^3 (95% CI: 3.43-10.15) and 2.85 cm^3 (95% CI: 1.31-4.39) per 1 kg of gestational weight gain, respectively. Additionally, placental weight exhibited a positive correlation with triglyceride (TG) levels (ß = 9.81, 95% CI: 3.28-16.34) and a negative correlation with high-density lipoprotein (HDL-C) levels (ß = - 46.30, 95% CI: - 69.49 to - 23.11). Placental volume also showed a positive association with TG levels (ß = 14.54, 95% CI: 7.69-21.39). Conversely, PFR demonstrated a negative correlation with increasing HDL-C levels (ß = - 0.89, 95% CI: - 1.50 to - 0.27). CONCLUSIONS: Gestational weight gain was significantly correlated with both placental weight and volume. This association was especially pronounced in women who, prior to pregnancy, were underweight or of normal weight. Additionally, TG and HDL-C levels during the mid-trimester were linked to placental development.
Assuntos
Ganho de Peso na Gestação , Placenta , Feminino , Humanos , Gravidez , Peso ao Nascer , Estudos de Coortes , População do Leste Asiático , Lipídeos , Placenta/embriologia , Magreza , Tamanho do ÓrgãoRESUMO
BACKGROUND: It has been suggested that gestational diabetes mellitus (GDM) alters the growth trajectory of a fetus and increases the risk of abnormal birth weight. In spite of this, there is still a significant debate regarding the mode and optimal timing of diagnosing this condition. Our aim was to determine fetal growth velocity and birth biometry in pregnant women with GDM at varying risk levels. METHODS: We conducted a cohort study involving 1023 pregnant women at a maternity hospital in Ma'anshan, China. All women completed an oral glucose tolerance test at 24-28 weeks' gestation. We measured fetal head circumference (HC), femoral length (FL), abdominal circumference (AC), biparietal diameter (BPD), and estimate fetal weight (EFW) by ultrasound at 17, 24, 31, and 35 weeks' gestation, respectively. RESULTS: Overall, 5115 ultrasound scans were performed. Among both low-risk and medium-high-risk pregnant women at 17-24 weeks' gestation, GDM exposure was associated with an increase in fetal growth velocity. Neonates born to women with GDM at medium-high risk had significantly larger birth weights than those born to women without GDM, while this was not observed in women at low risk. CONCLUSION: In medium-high-risk pregnant women, exposure to GDM has a greater effect on the fetus, leading to abnormal fetal growth velocity that lasts beyond week 24. It is evident from our results that the effects of GDM on fetal growth differ between medium-high-risk pregnant women and low-risk pregnant women, and therefore a different screening program based on the risk factor for GDM is warranted.
RESUMO
Environmental hazards are an increasing concern due to the rapid pace of industrialization. Among these hazards, noise and carbon monoxide (CO) are common risk factors and have been shown to cause serious health problems. However, existing studies focused on the individual effects of noise and CO exposure and the combined effects of these two factors remain poorly understood. Our study aimed to examine the combined effects of noise and CO exposure on testicular function by constructing individual and combined exposure models. Our findings indicated that combined exposure to noise and CO was associated with a higher risk of testicular damage and male reproductive damage when compared to exposure alone. This was evidenced by poorer semen quality and more severe pathological damage to the testis. This combined exposure led to higher levels of oxidative stress and apoptosis in the testes, with bioinformatics analyses suggesting the signaling pathways involved in these responses. Specifically, activation of the P53 signaling pathway was found to contribute to the testicular damage caused by the combined exposure. Encouragingly, pterostilbene (PTE), a novel phytochemical, alleviated combined exposure-induced testicular damage by reducing oxidative stress and germ cell apoptosis. Overall, we identified joint reproductive toxicity resulting from the exposure to noise and CO, and found that PTE is a promising potential treatment for injuries caused by these factors. The cover image is based on the Research Article Effects and possible mechanisms of combined exposure to noise and carbon monoxide on male reproductive system in rats by Yingqing Li et al., https://doi.org/10.1002/tox.23927.
Assuntos
Monóxido de Carbono , Análise do Sêmen , Ratos , Masculino , Animais , Monóxido de Carbono/toxicidade , Testículo , Células Germinativas , Reprodução , Estresse OxidativoRESUMO
We aimed to characterize the association between air pollutants exposure and periodontal diseases outpatient visits and to explore the interactions between ambient air pollutants and meteorological factors. The outpatient visits data of several large stomatological and general hospitals in Hefei during 2015-2020 were collected to explore the relationship between daily air pollutants exposure and periodontal diseases by combining Poisson's generalized linear model (GLMs) and distributed lag nonlinear model (DLNMs). Subgroup analysis was performed to identify the vulnerability of different populations to air pollutants exposure. The interaction between air pollutants and meteorological factors was verified in both multiplicative and additive interaction models. An interquartile range (IQR) increased in nitrogen dioxide (NO2) concentration was associated with the greatest lag-specific relative risk (RR) of gingivitis at lag 3 days (RR = 1.087, 95% CI 1.008-1.173). Fine particulate matter (PM2.5) exposure also increased the risk of periodontitis at the day of exposure (RR = 1.049, 95% CI 1.004-1.096). Elderly patients with gingivitis and periodontitis were both vulnerable to PM2.5 exposure. The interaction analyses showed that exposure to high levels of NO2 at low temperatures was related to an increased risk of gingivitis, while exposure to high levels of NO2 and PM2.5 may also increase the risk of gingivitis and periodontitis in the high-humidity environment, respectively. This study supported that NO2 and PM2.5 exposure increased the risk of gingivitis and periodontitis outpatient visits, respectively. Besides, the adverse effects of air pollutants exposure on periodontal diseases may vary depending on ambient temperature and humidity.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Gengivite , Doenças Periodontais , Periodontite , Humanos , Idoso , Dióxido de Nitrogênio/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Poluentes Atmosféricos/toxicidade , Poluentes Atmosféricos/análise , Material Particulado/análise , Conceitos Meteorológicos , Doenças Periodontais/etiologia , Doenças Periodontais/induzido quimicamente , Periodontite/induzido quimicamente , Gengivite/induzido quimicamente , Gengivite/epidemiologia , China , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análiseRESUMO
This study aims to explore the male reproductive toxicity of Benzo[b]fluoranthene (BbF) and related mechanisms. The results of computational toxicology analysis indicated male reproductive toxicity of BbF was related to apoptosis of Leydig cells and that Akt/p53 pathway might play a key role. In experiments, BbF induced testosterone decline, decreased concentration and motility of sperm and aggravated testicular pathological injury in mice. Besides, BbF led to apoptosis in Leydig cells, and decreased expressions of p-Akt and Bcl2, while improving the expressions of p53, Bax and Cleaved Caspase-3 in vivo and in vitro. Further, compared with BbF group, Akt activator SC79 significantly reduced cell apoptosis rate, improved cell viability, promoted the expressions of p-Akt and p-Mdm2, and reversed the above molecular expressions. Similarly, p53 inhibitor Pifithrin-α also significantly enhanced the cell vitality, alleviated the apoptosis of TM3 cells induced by BbF, and decreased the expressions of Bax and Cleaved Caspase-3, with the up-regulation of Bcl2. To sum up, by inhibiting Akt-Mdm2 signaling, BbF activated the p53-mediated mitochondrial apoptosis pathway, further inducing the apoptosis of Leydig cells, therefore resulting in testosterone decline and male reproductive damage. Besides, this study provided a valid mode integrating computational toxicology and experimental approaches in toxicity testing.
Assuntos
Células Intersticiais do Testículo , Proteínas Proto-Oncogênicas c-akt , Masculino , Camundongos , Animais , Células Intersticiais do Testículo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Caspase 3/metabolismo , Proteína X Associada a bcl-2/metabolismo , Sêmen/metabolismo , Testosterona/metabolismo , ApoptoseRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that exhibits elevated glycolytic capacity. Lactate, as a byproduct of glycolysis, is considered a major oncometabolite that plays an important role in oncogenesis and remodeling of the tumor microenvironment. However, the potential roles of lactate in TNBC are not yet fully understood. In this study, our goal was to identify prognosis-related lactate genes (PLGs) and construct a lactate-related prognostic model (LRPM) for TNBC. METHODS: First, we applied lactate-related genes to classify TNBC samples using a hierarchical clustering algorithm. Then, we performed the log-rank analysis and the least absolute shrinkage and selection operator analysis to screen PLGs and construct the LRPM. The biological functions of the identified PLGs in TNBC were investigated using CCK8 assay and clone formation assay. Finally, we constructed a nomogram based on the lactate-risk score and tumor clinical stage. We used the operating characteristic curve and decision curve analysis to evaluate the predictive capability of the nomogram. RESULTS: Our results showed that the TNBC samples could be classified into two subgroups with different survival probabilities. Three genes (NDUFAF3, CARS2 and FH), which can suppress TNBC cell proliferation, were identified as PLGs. Moreover, the LRPM and nomogram exhibited excellent predictive performance for TNBC patient prognosis. CONCLUSION: We have developed a novel LRPM that enables risk stratification and identification of poor molecular subtypes in TNBC patients, showing great potential in clinical practice.
RESUMO
BACKGROUND: Studies on male reproductive toxicity of microplastics are still scarce and the precise mechanism is not distinct. METHODS: C57BL/6 male mice were given oral gavage treatments treated with 5 µm (MPs) and 80 nm (NPs) polystyrene microplastics every day for 60 consecutive days in a row at dosages of 0, 10 and 40 mg/kg/d. The major damage of MPs and NPs were assessed by the assays in vivo and in vitro. Transcriptome sequencing was applied to screen the key involved pathways. RESULTS: In the 10 mg/kg/d NPs group, there was an increase in testicular organ coefficient, and in the 40 mg/kg/d MPs group, an increase in epididymal weight was observed. Vacuolization of spermatogenic cell layer, interstitial congestion, and germ cell apoptosis were found in the testes of MPs and NPs treatment mice at different dose groups. Higher apoptosis rate was observed in GC-2 cells after MPs and NPs treatment at different concentrations. Transcriptome analysis suggested that p53 pathway might be the key signal pathway of the cell apoptosis, and the expressions of p53 and other markers of cell apoptosis were indeed altered after exposure to MPs and NPs. CONCLUSIONS: MPs and NPs can cause reproductive toxicity in male mice through inducing apoptosis of spermatogenic cells via p53 signaling pathway, indicating MPs and NPs exposure be an unnegligible risk factor for reproductive health in male mice.
Assuntos
Microplásticos , Plásticos , Camundongos , Masculino , Animais , Microplásticos/toxicidade , Proteína Supressora de Tumor p53 , Camundongos Endogâmicos C57BL , Transdução de Sinais , Células Germinativas , ApoptoseRESUMO
BACKGROUND: Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunotherapy of NB. METHODS: Immunohistochemistry integrated with digital pathology was used to determine the expression levels of 9 immune checkpoints in 212 tumor tissues used as the discovery set. The GSE85047 dataset (n=272) was used as a validation set in this study. In the discovery set, the ICS was constructed using a random forest algorithm and confirmed in the validation set to predict overall survival (OS) and event-free survival (EFS). Kaplan-Meier curves with a log-rank test were drawn to compare the survival differences. A receiver operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC). RESULTS: Seven immune checkpoints, including PD-L1, B7-H3, IDO1, VISTA, T-cell immunoglobulin and mucin domain containing-3 (TIM-3), inducible costimulatory molecule (ICOS) and costimulatory molecule 40 (OX40), were identified as abnormally expressed in NB in the discovery set. OX40, B7-H3, ICOS and TIM-3 were eventually selected for the ICS model in the discovery set, and 89 patients with high risk had an inferior OS (HR 15.91, 95% CI 8.87 to 28.55, p<0.001) and EFS (HR 4.30, 95% CI 2.80 to 6.62, p<0.001). Furthermore, the prognostic value of the ICS was confirmed in the validation set (p<0.001). Multivariate Cox regression analysis demonstrated that age and the ICS were independent risk factors for OS in the discovery set (HR 6.17, 95% CI 1.78 to 21.29 and HR 1.18, 95% CI 1.12 to 1.25, respectively). Furthermore, nomogram A combining the ICS and age demonstrated significantly better prognostic value than age alone in predicting the patients' 1-year, 3-year and 5-year OS in the discovery set (1 year: AUC, 0.891 (95% CI 0.797 to 0.985) vs 0.675 (95% CI 0.592 to 0.758); 3 years: 0.875 (95% CI 0.817 to 0.933) vs 0.701 (95% CI 0.645 to 0.758); 5 years: 0.898 (95% CI 0.851 to 0.940) vs 0.724 (95% CI 0.673 to 0.775), respectively), which was confirmed in the validation set. CONCLUSIONS: We propose an ICS that significantly differentiates between low-risk and high-risk patients, which might add prognostic value to age and provide clues for immunotherapy in NB.
Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Neuroblastoma , Humanos , Neuroblastoma/tratamento farmacológico , Área Sob a Curva , Imunoterapia , Análise MultivariadaRESUMO
Background: There is growing evidence that the COVID-19 pandemic has had a dramatic impact on public mental health. However, less attention has been paid to left-behind experience college students (LBEs). This online study aimed to investigate the relationship between psychological capital (PsyCap) and anxiety among LBEs during COVID-19 pandemic, and further analyze the mediation role of self-esteem between them. Methods: A total of 9990 students were chosen using the stratified cluster sampling method. Three self-reported questionnaires were used to assess the PsyCap, self-esteem, and anxiety, respectively. All the statistical analyses were conducted using SPSS 23.0 and R, and to further investigate the mediation effect of self-esteem in the association of PsyCap with anxiety, AMOS 23.0 was used to build a structural equation model. Results: PsyCap, self-esteem, and anxiety were significantly correlated among LBEs during the COVID-19 pandemic. PsyCap affects anxiety directly (ß = -0.22, SE = 0.051, 95% CI: -0.27, -0.17, P < 0.05). In addition, self-esteem partially mediated the relationship between PsyCap and anxiety (mediating effect value = -0.16, 95% CI: -0.20, -0.13, P < 0.05). Conclusion: During the pandemic of COVID-19, left-behind experience had a negative influence on the PsyCap and self-esteem of college students. In addition, for LBEs, self-esteem plays an important mediating role between PsyCap and anxiety. Therefore, from the perspective of PsyCap and self-esteem, schools should translate them into practical educational strategies to enhance the mental health and mitigate the anxiety levels of LBEs.
RESUMO
Fine particulate matter (PM2.5) has been reported to cause various types of damage to male reproductive system, but the research on the underlying mechanisms is still insufficient. This study attempted to explore the underlying mechanisms of this widely concerning environmental health problem through in vivo and in vitro exposure models. Significant pathological damage and abnormal mitochondria in spermatocytes were observed in the real-time PM2.5 exposure animal model. In addition, significant alterations in key biomarkers of iron metabolism and ferroptosis were found in testis tissues. Notably decreased cell viability was found in vitro. Moreover, the ferroptosis pathway was significantly enriched in the transcriptome enrichment analysis. Subsequent experiments showed that the two core events of ferroptosis, iron overload and lipid peroxidation, occurred in spermatocytes after PM2.5 treatment. Moreover, lipid metabolic genes (Acsl4 and Aloxe3) and the antioxidant gene Gpx4 were found to be key target genes of ferroptosis caused by PM2.5 in spermatocytes. Importantly, further studies showed that the damaging effect could be reversed by the iron chelator deferoxamine mesylate (DFOM) and the lipid peroxidation inhibitor ferrostatin-1 (Fer-1), which further confirmed the role of ferroptosis in PM2.5 toxicity. Our study revealed the vital role of ferroptosis in PM2.5-induced male reproductive damage, providing novel insights into the air pollution-induced decrease in male fertility.
Assuntos
Ferroptose , Ferro , Animais , Masculino , Ferro/metabolismo , Ferroptose/genética , Espermatócitos/metabolismo , Oxirredução , Peroxidação de Lipídeos , Homeostase , Material Particulado/toxicidade , Material Particulado/metabolismoRESUMO
An increasing number of studies have found that long non-coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non-protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras-related protein Rab-1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation-associated 2G4 (PA2G4) and stromal cell-derived factor 4 (SDF4; also known as 45-kDa calcium-binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173-knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173-RAB1B-PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients.
Assuntos
Neoplasias Nasofaríngeas , RNA Longo não Codificante , Proteínas de Ligação a RNA , Proteínas rab1 de Ligação ao GTP , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/genética , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas rab1 de Ligação ao GTP/genética , Proteínas rab1 de Ligação ao GTP/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismoRESUMO
Green space and 25-hydroxyvitamin D (25(OH)D) can affect maternal and infant health, but limited studies have examined their effects on disorders of maternal glucolipid metabolism. We aimed to explore the interaction between green space, maternal serum 25(OH)D, and disorders of glucolipid metabolism in early pregnancy. A total of 2551 pregnant women were recruited from the Maanshan Maternal and Child Health Hospital birth cohort in China between 2020 and 2022. We calculated average residential greenness during early pregnancy using 250 m normalized difference vegetation index (NDVI) from satellites. Serum biomarkers (25(OH)D, total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol(HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1(ApoA1), and apolipoprotein B(ApoB)) were measured. Associations between the factors were analyzed using multiple linear regression, mediation analysis, and stratified analysis. After adjusting for potential confounders, green space exposure associated with decreased TG (- 7.8%; 95% confidence interval (CI): - 12.8, - 2.9), TC (- 7.0%; 95% CI: - 11.4, - 2.7), and LDL-C (- 8.4%; 95% CI: - 12.9, - 3.9), ApoB (- 2.0%; 95% CI: - 3.0, - 1.0) and increased HDL-C (2.7%; 95% CI: 1.5, 3.8) and ApoA1 (5.1%; 95% CI: 3.9, 6.3) for each IQR increase in NDVI. A comparable link was found between maternal serum 25(OH)D and indicators of glucolipid metabolism (P < 0.05). In addition, mediation analysis showed that the association between green space exposure and maternal glucolipid metabolic index was mediated by serum 25(OH)D at 6.37%. In stratified analyses, a considerable association between 25(OH)D and glucolipid metabolic index (except TG) was observed only at higher green space exposures. This study confirms that high levels of green space exposure in early pregnancy and vitamin D are associated with a reduced risk of glucolipid metabolism disorders and suggests that green space may favor glucolipid metabolism by increasing vitamin D levels, particularly at high NDVI values.
Assuntos
Exposição Ambiental , Transtornos do Metabolismo dos Lipídeos , Vitamina D , Criança , Feminino , Humanos , Gravidez , Apolipoproteínas B , LDL-Colesterol , Exposição Ambiental/estatística & dados numéricos , Metabolismo dos Lipídeos , Exposição Materna/estatística & dados numéricos , Parques Recreativos , Triglicerídeos , Vitamina D/sangueRESUMO
An important form of human learning and cognition is imitation. In environments where uncertainty is more incremental, imitation of peers is a natural response to uncertainty. While there are substantial literature documenting peer effects in other settings, the study of peer effects in working capital management is novel; little research exists on peer effects in working capital management and their impact mechanism. Using data of China's listed firms from 2010 to 2021, we empirically demonstrate significant peer effects due to working capital management. Firstly, we find that the behavior of working capital management of firms in the same industry is positively related to a firm's working capital management. We used peer firms' target debt ratio as an instrumental variable to address potential endogeneity problem. Secondly, the moderating effects test shows that the positive relationship between the behavior of working capital management of firms in the same industry and a firm's working capital management behavior is moderated by knowledge flow. Meanwhile, the peer effects in the high group of knowledge flow are greater than that of in the low group of knowledge flow. The study is based on the Active Intermodal Matching theory of psychology. It enriches the research findings on the moderating effect of peer effects and has important implications for policymaking to stimulate the economy.
RESUMO
The effects of ambient fine particles on male reproductive health have raised widespread concern. The particular underlying mechanisms of the damage remain largely unclear and demand more research in new directions. Previous research has revealed that DNA methylation plays an important role in male reproductive development and is also vulnerable to environmental influences. However, there hasn't been enough investigation into the involvement of DNA methylation in PM2.5-induced male reproductive toxicity. Here, we establish a real-time PM2.5 exposure model and revealed that PM2.5 exposure could lead to testicular dysfunction including spermatogenesis impairment and steroid hormone dysfunction. In particular, the decrease in the testicular global level of 5-methylcytosine (5mC) indicated a possible association of DNA methylation with testicular injury induced by PM2.5 exposure. Further genome-wide methylation analysis revealed genomic hypomethylation of testicular DNA and identified more than 1000 differentially methylated regions in both CAP and UA versus FA, indicating that PM2.5 exposure, even low-dose, could modulate the testicular methylome. Furthermore, integrated analysis of methylome and transcriptome identified some key methylated genes and networks, which may be involved in spermatogenesis and synthesis of steroid hormone. The testicular methylation levels of key genes especially Cyp11a1 and Pax8 raised, and their consequent reduced expression may impair the testosterone and sperm production process. Our research provides fundamental knowledge as well as novel insights into the possible involvement of DNA methylation in PM2.5-induced male reproductive harm.
Assuntos
Metilação de DNA , Material Particulado , 5-Metilcitosina/farmacologia , Enzima de Clivagem da Cadeia Lateral do Colesterol , Humanos , Masculino , Material Particulado/análise , Material Particulado/toxicidade , Sêmen/química , Espermatogênese , Testosterona/farmacologiaRESUMO
Background and Objective: Immune checkpoint inhibitor (ICI)-associated myocarditis is a fatal immune-related adverse events (irAEs), which is prone to affecting multiple organ systems. Multi-organ irAEs have not been fully studied in ICI-associated myocarditis. Therefore, we aimed to explore the impact of multi-organ irAEs on ICI myocarditis in terms of clinical features, treatment, and prognosis. Methods: This was a retrospective study. The clinical data of ICI myocarditis patients were collected from 6 hospitals in China. The risk factors and characteristics of pure myocarditis and multi-organ irAEs were analyzed. The overall survival (OS) after myocarditis was analyzed and univariate and multivariate regression analysis were performed. Results: A total of 46 patients were analyzed in this study. Multi-organ irAEs were common (30/46, 65.2%) and prone to severe heart failure. The severe myocarditis was observed in 32 patients (69.6%). When myocarditis occurred, neutrophil to lymphocyte ratio, C-reactive protein, lactate dehydrogenase, interleukin (IL)-6, IL-10, creatine kinase, MB isoenzyme of creatine kinase, and brain natriuretic peptide increased from baseline, but absolute lymphocyte count decreased. Thymoma (B2/B3) was a risk factor for multi-organ irAEs. Heart failure and myocarditis were more severe in patients with multi-organ irAEs and require early corticosteroid therapy (<24 hours). Univariate analysis showed that age ≥ 60 years, myocarditis (grade 3-4), heart failure (grade 3-4), multi-organ irAEs, and severe myocarditis were associated with OS after myocarditis. After adjusting for other factors, heart failure (grade 3-4) was an independent risk factor for immune-related myocarditis (HR: 6.655, 95% CI: 1.539-28.770, p=0.011). Conclusion: Patients with ICI-associated myocarditis had multi-organ irAEs with a high incidence of severe myocarditis, mortality, and poor prognosis. Thymoma was prone to those patients with multiple organs involvement. Patients could benefit from early corticosteroid intervention. Heart failure (grade 3-4) was an independent risk factor for OS after myocarditis.