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To effectively manage water constraints (WCs) within a basin, it is crucial to first scientifically delineate their spatial distribution and thoroughly understand the interactions between WCs. Investigating the complex driving mechanisms at multiple scales is also essential. In this study, a basin WC evaluation framework is constructed using a conflict risk assessment model. The spatiotemporal variations of four types of WCs across three spatial scales in the Taihu Lake Basin (TLB) are thoroughly investigated. Furthermore, the study quantifies the trade-offs, synergy effects, and bundle patterns of these water constraints. The study employs the Optimal Parameters-based Geographic Detector (OPGD) and multivariate linear regression to identify the key socio-ecological drivers of WCs. Our findings indicate that between 2010 and 2020, water resource constraint (WREC), water environment constraint (WENC), water safety constraint (WSAC), water ecology constraint (WECC), and the comprehensive WC (CWC) displayed varying degrees of heterogeneity. Particularly, the mean values of WSAC, WECC, and CWC witnessed an increase over the decade. Additionally, all WCs exhibited a strong positive spatial autocorrelation. Synergistic interactions among WCs were predominantly observed in pairs such as WREC-WSAC, WREC-WECC, and WSAC-WECC, while a weaker trade-off effect was noted in the WENC-WECC pair. At multiple scales, we identified eight types of WC bundles capable of undergoing mutual transformations, especially at the basin scale. The primary drivers of WCs varied across different stages and scales, with most factors collectively exerting a more significant impact than individually. Notably, factors like secondary and tertiary industry GDP (X2), population density (X3), precipitation (X6), and elevation (X7) were identified as core drivers influencing the evolution of WCs in the TLB. Integrating these spatiotemporal characteristics and driving mechanisms of WC interactions into basin planning and management can significantly support the alleviation of multidimensional water constraints in territorial spaces.
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OBJECTIVES: To investigate the epidemiological trend for nasopharyngeal carcinoma among children and young adults and the disease burden they caused. MATERIALS AND METHODS: Data were collected from the Global Burden of Disease (GBD) study 2019. A comprehensive analysis was performed, with age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), disability-adjusted life-years (DALYs) and estimated annual percentage changes (EAPC). And decomposition and frontier analyses were done. Future trends were predicted using Bayesian age-period-cohort model. RESULTS: Globally, there were decreases in the ASIR (EAPC -0.175, 95 % confidence interval [CI]: -0.352 to 0.002), ASMR (EAPC -2.681, 95 % CI: -2.937 to -2.424), and age-standardized DALYs rates (EAPC -2.643, 95 % CI: -2.895 to -2.391). However, the ASIR for males in global (EAPC 0.454, 95 % CI: 0.302 to 0.606), Asia (EAPC 0.782, 95 % CI: 0.610 to 0.954) and America (EAPC 0.448, 95 % CI: 0.379 to 0.517), as well as females in European (EAPC 0.595, 95 % CI: 0.479 to 0.712) and American (EAPC 0.369, 95 % CI: 0.324 to 0.415), showed an increasing trend. The future ASIR per 100,000 will likely show a slight upward trend in 2020 to 2040 (increased from 0.254 to 0.284), particularly among females (increased from 0.177 to 0.206), and a continued decline in ASMR for both sexes (decreased from 0.070 to 0.061). CONCLUSIONS: Globally, NPC in children and young adults remains a major public health issue, with the global distribution and magnitude of the burden varies markedly, highlighting the need to formulate regional and population-based policies for primary prevention.
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Carga Global da Doença , Carcinoma Nasofaríngeo , Humanos , Masculino , Feminino , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/mortalidade , Criança , Adolescente , Adulto Jovem , Carga Global da Doença/tendências , Adulto , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/mortalidade , Incidência , Pré-Escolar , Saúde Global/estatística & dados numéricos , Teorema de Bayes , Lactente , Anos de Vida Ajustados por Deficiência/tendênciasRESUMO
Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.
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BACKGROUND: [18 F]-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has the ability to detect local and/or regional recurrence as well as distant metastasis. We aimed to evaluate the prognosis value of PET/CT in locoregional recurrent nasopharyngeal (lrNPC). METHODS: A total of 451 eligible patients diagnosed with recurrent I-IVA (rI-IVA) NPC between April 2009 and December 2015 were retrospectively included in this study. The differences in overall survival (OS) of lrNPC patients with and without PET/CT were compared in the I-II, III-IVA, r0-II, and rIII-IVA cohorts, which were grouped by initial staging and recurrent staging (according to MRI). RESULTS: In the III-IVA and rIII-IVA NPC patients, with PET/CT exhibited significantly higher OS rates in the univariate analysis (P = 0.045; P = 0.009; respectively). Multivariate analysis revealed that with PET/CT was an independent predictor of OS in the rIII-IVA cohort (hazard ratio [HR] = 0.476; 95% confidence interval [CI]: 0.267 to 0.847; P = 0.012). In the rIII-IVA NPC, patients receiving PET/CT sacns before salvage surgery had a better prognosis compared with MRI alone (P = 0.036). The recurrent stage (based on PET/CT) was an independent predictor of OS. (r0-II versus [vs]. rIII-IVA; HR = 0.376; 95% CI: 0.150 to 0.938; P = 0.036). CONCLUSION: The present study showed that with PET/CT could improve overall survival for rIII-IVA NPC patients. PET/CT appears to be an effective method for assessing rTNM staging.
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Neoplasias Nasofaríngeas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18 , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patologia , Prognóstico , Estudos Retrospectivos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patologia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Estadiamento de NeoplasiasRESUMO
Kirsten rat sarcoma virus protein (KRAS) is a protein that plays a central role in signal transduction using extracellular signal regulated kinase (ERK) and mitogen activated protein kinase (MAPK) cellular signaling pathway. KRAS is a frequently mutated oncogene and plays a pivotal role in tumor initiation and progression. Hotspot mutations on codon 12, 13 and 61 in KRAS are well-known for their role in drug resistance and non-hotspot mutations also play a significant part in contributing to resistance mechanisms. The understanding of how these non-hotspot mutations might affect the signal transduction of KRAS and their contribution towards drug resistance is understudied. Here we provide structural insights into the interaction of non-hotspot KRAS mutants with GTP (the native ligand) using a molecular docking and molecular dynamics simulation approach. Extensive molecular docking and simulation studies suggest that non-hotspot mutations (E31D and E63K) show stable interaction with native ligand using all five trajectories, as evidenced by root mean square of distance (RMSD), root mean square of fluctuation (RMSF), radius of gyration (RoG), coulomb short-range energy and MMGBSA analysis. These results suggest that non-hotspot mutations do not undermine the oncogenic nature of KRAS. This observation is consistent with previous findings where overexpressing E31D and E63K mutations share phenotypic features with G12D and G13D transfected cells, including increased proliferative capacity, actin cytoskeleton organization, and migration rates. We further test whether FDA-approved KRAS inhibitors sotorasib and adagrasib successfully inhibit the E31D and E63K mutants. Results suggest that these two non-hotspot mutants can be inhibited by both drugs with following trend of structural stability (E31D > E63K > wild-KRAS > Q61H > G12C). Based on sharp coherence in trajectories between wild KRAS and non-hotspot mutants, it is suggested that these novel mutants do not contribute to drug resistance mechanism. Overall, we provide a comprehensive understanding of the impact of non-hotspot mutations on KRAS and their potential as targets for effective cancer therapies.Communicated by Ramaswamy H. Sarma.
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BACKGROUND: Non-anatomical factors significantly affect treatment guidance and prognostic prediction in nasopharyngeal carcinoma (NPC) patients. Here, we developed a novel survival model by combining conventional TNM staging and serological indicators. METHODS: We retrospectively enrolled 10,914 eligible patients with nonmetastatic NPC over 2009-2017 and randomly divided them into training (n = 7672) and validation (n = 3242) cohorts. The new staging system was constructed based on T category, N category, and pretreatment serological markers by using recursive partitioning analysis (RPA). RESULTS: In multivariate Cox analysis, pretreatment cell-free Epstein-Barr virus (cfEBV) DNA levels of >2000 copies/mL [HROS (95 % CI) = 1.78 (1.57-2.02)], elevated lactate dehydrogenase (LDH) levels [HROS (95 % CI) = 1.64 (1.41-1.92)], and C-reactive protein-to-albumin ratio (CAR) of >0.04 [HROS (95 % CI) = 1.20 (1.07-1.34)] were associated with negative prognosis (all P < 0.05). Through RPA, we stratified patients into four risk groups: RPA I (n = 3209), RPA II (n = 2063), RPA III (n = 1263), and RPA IV (n = 1137), with 5-year overall survival (OS) rates of 93.2 %, 86.0 %, 80.6 %, and 71.9 % (all P < 0.001), respectively. Compared with the TNM staging system (eighth edition), RPA risk grouping demonstrated higher prognostic prediction efficacy in the training [area under the curve (AUC) = 0.661 vs. 0.631, P < 0.001] and validation (AUC = 0.687 vs. 0.654, P = 0.001) cohorts. Furthermore, our model could distinguish sensitive patients suitable for induction chemotherapy well. CONCLUSION: Our novel RPA staging model outperformed the current TNM staging system in prognostic prediction and clinical decision-making. We recommend incorporating cfEBV DNA, LDH, and CAR into the TNM staging system.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Estadiamento de Neoplasias , Carcinoma Nasofaríngeo/patologia , Estudos Retrospectivos , Herpesvirus Humano 4/genética , Prognóstico , Neoplasias Nasofaríngeas/patologia , DNARESUMO
BACKGROUND AND PURPOSE: Whether concurrent chemoradiotherapy would provide survival benefits in patients with stage II and T3N0 NPC with adverse factors remains unclear in IMRT era. We aimed to assess the value of concurrent chemotherapy compared to IMRT alone in stage II and T3N0 NPC with adverse features. MATERIALS AND METHODS: 287 patients with stage II and T3N0 NPC with adverse factors were retrospectively analyzed, including 98 patients who received IMRT alone (IMRT alone group) and 189 patients who received cisplatin-based concurrent chemotherapy (CCRT group). The possible prognostic factors were balanced using propensity score matching (PSM). Kaplan-Meier analysis was used to evaluate the survival rates, and log-rank tests were employed to compare differences between groups. RESULTS: The median follow-up duration was 90.8 months (interquartile range = 75.6-114.7 months). The IMRT alone and the CCRT group were well matched; however, for all survival-related endpoints, there were no significant differences between them (5-year failure-free survival: 84.3% vs. 82.7%, P value = 0.68; 5-year overall survival: 87.3% vs. 90.6%, P value = 0.11; 5-year distant metastasis-free survival: 92.8% vs. 92.5%, P value = 0.97; 5-year locoregional relapse-free survival: 93.4% vs. 89.9%, P value = 0.30). The incidence of acute toxicities in the IMRT alone group was significantly lower than that in the CCRT group. CONCLUSION: For patients with stage II and T3N0 NPC with adverse features treated using IMRT, no improvement in survival was gained by adding concurrent chemotherapy; however, the occurrence of acute toxicities increased significantly. For those combined with non-single adverse factors, the comprehensive treatment strategy needs further exploration.
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Quimiorradioterapia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Estadiamento de Neoplasias , Pontuação de Propensão , Radioterapia de Intensidade Modulada , Humanos , Masculino , Feminino , Quimiorradioterapia/efeitos adversos , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/mortalidade , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Estudos Retrospectivos , Adulto , Radioterapia de Intensidade Modulada/efeitos adversos , Cisplatino/uso terapêutico , Cisplatino/administração & dosagem , Estudos de Coortes , Taxa de Sobrevida , Carcinoma/terapia , Carcinoma/patologia , Carcinoma/mortalidade , IdosoRESUMO
The AJCC/UICC TNM classification describes anatomic extent of tumor progression and guides treatment decisions. Our comprehensive analysis of 8,834 newly diagnosed patients with non-metastatic Epstein-Barr virus related nasopharyngeal carcinoma (NPC) from six Chinese centers indicates certain limitations in the current staging system. The 8th edition of the AJCC/UICC TNM classification inadequately differentiates patient outcomes, particularly between T2 and T3 categories and within the N classification. We propose reclassifying cases of T3 NPC with early skull-base invasion as T2, and elevating N1-N2 cases with grade 3 image-identified extranodal extension (ENE) to N3. Additionally, we suggest combining T2N0 with T1N0 into a single stage IA. For de novo metastatic (M1) NPC, we propose subdivisions of M1a, defined by 1-3 metastatic lesions without liver involvement, and M1b, characterized by >3 metastatic lesions or liver involvement. This proposal better reflects responses of NPC patients to the up-to-date treatments and their evolving risk profiles.
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Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Estadiamento de Neoplasias , Herpesvirus Humano 4 , Prognóstico , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/patologia , Infecções por Vírus Epstein-Barr/patologia , Carcinoma/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Treating nasopharyngeal carcinoma (NPC) with radiotherapy frequently causes hearing impairment (HI). HI risk data haven't been evaluated quantitatively. This study aimed to analyze the probability of HI and sever HI (SHI), develop a nomogram to quantify individual prediction, and provide dose limitation suggestions. METHODS AND MATERIALS: This single-center, retrospective study was conducted based on 588 adolescents and young adults with non-metastatic NPC treated using intensity modulated radiation therapy (IMRT) at Sun Yat-sen University Cancer Center between 2010 and 2016. A least absolute shrinkage and selection operator (LASSO) logistic regression model and univariate analysis were used to screen potential risk factors. The concordance index and a calibration curve evaluated the nomogram models' predictive ability, with bootstrap resampling validation. RESULTS: We analyzed 588 patients with NPC, with a median follow-up of 103.4 months. HI occurred in 39.5 % of patients, with 29.7 % experiencing SHI. Two factors were classified as precursors for HI (volume 45 Gy of the inner ear (IEV45) and volume 50 Gy of the internal auditory canal (IACV50)), and IACmin and IACV60 for SHI, respectively. Prognostic nomograms were developed to predict HI and SHI probabilities, showing excellent discriminative abilities (c-index values = 0.806 and 0.793, respectively). We also suggested IEV45 < 50 % and/or IACV50 < 40 % as rational dose limitations for HI, and IACmin < 44 Gy and/or the IACV60 < 40 % for SHI. CONCLUSION: Comprehensive analysis could predict the risk of HI and SHI in NPC after IMRT, proposing rational dose limitations and improving long-term quality of life.
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Perda Auditiva , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Adolescente , Adulto Jovem , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Neoplasias Nasofaríngeas/patologia , Qualidade de Vida , Nomogramas , Perda Auditiva/etiologia , Fatores de RiscoRESUMO
AIM: Despite the high risk of tumor recurrence, patients with nasopharyngeal carcinoma (NPC) with persistently (at least twice) detected circulating cell-free Epstein-Barr virus (EBV) DNA levels during follow-up are routinely recommended to keep observation. For these patients, whether administering more aggressive treatment could improve survival outcomes remains unknown. MATERIALS AND METHODS: We retrospectively included 431 patients with nonmetastatic NPC with persistently detected EBV DNA during follow-up, who do not have clinical or imaging evidence of recurrence. Among these patients, 79 were administered oral chemotherapy, and the remaining 352 underwent observation alone. Baseline characteristics were balanced with propensity score matching (PSM) analysis. The primary endpoint was modified disease-free survival (mDFS), defined as time from detectable EBV DNA result to tumor recurrence or death. The secondary endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS: One-to-three PSM resulted in 251 eligible patients (oral chemotherapy group, 73; observation group, 178). In the matched cohort, the oral chemotherapy group had higher median mDFS (12.9 months [95 % confidence interval [CI] 9.6-16.3] vs. 6.8 months [95 % CI 5.8-7.8], p = 0.009) and DFS (24.1 months [95 % CI 18.5-29.7] vs. 16.7 months [95 % CI 14.4-19.1], p = 0.035) than the observation group. The median OS was numerically higher in the oral chemotherapy group than in the observation group (57.9 months [95 % CI 42.5-73.3] vs. 50.8 months [95 % CI 39.7-61.9], p = 0.71). A consistent benefit favoring oral chemotherapy was observed for mDFS in all subgroups analyses for male, <45 years, stage III-IVa disease, pretreatment EBV DNA load ≥ 4,000 copies/mL, no induction chemotherapy, or a detectable EBV DNA load ≥ 1,200 copies/mL. After adjusting for other confounders in the multivariate analysis, oral chemotherapy remained a significantly favorable factor for both mDFS (hazard ratio [HR] 0.67, 95 % CI 0.50-0.89; p = 0.006) and DFS (HR 0.68, 95 % CI 0.51-0.91; p = 0.01), but not a significant factor for OS (HR 0.89, 95 % CI 0.62-1.27; p = 0.52). CONCLUSIONS: In patients with NPC having persistently detected EBV DNA levels but without clinical or imaging evidence of recurrence during follow-up, oral chemotherapy significantly prolongs mDFS and DFS. Employing oral chemotherapy as a more aggressive treatment option, as opposed to mere observation, could potentially benefit these patients, although further prospective validation is necessitated.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Masculino , Carcinoma Nasofaríngeo/tratamento farmacológico , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/complicações , Estudos Retrospectivos , Seguimentos , Recidiva Local de Neoplasia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , PrognósticoRESUMO
BACKGROUND: Thyroid dysfunction is associated with abnormal glucose-insulin homeostasis, and the triglyceride-glucose (TyG) index has been recommended as a convenient surrogate of insulin resistance (IR). This study aimed to investigate the relationship between TyG and thyroid function in the US population. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2012 in a cross-sectional manner. Aside from conventional thyroid parameters, our study evaluated the central sensitivity to thyroid hormones (THs) using the thyroid feedback quantile-based index (TFQI), thyrotropin resistance index (TT4RI), and thyrotropin index (TSHI). To evaluate peripheral sensitivity to THs, we calculated the ratio of free triiodothyronine (FT3) to free thyroxine (FT4) and the sum activity of peripheral deiodinases (SPINA-GD). In the 1848 adults, multivariable linear regression, subgroup, and interaction analyses were employed to estimate the association between TyG and thyroid parameters. The nonlinear relationship was addressed by smooth curve fittings and generalized additive models. RESULTS: After adjusting covariates, we demonstrated a significant negative association between TyG and FT4 (ß = - 0.57, p < 0.001), and a positive relationship between TyG and thyroid-stimulating hormone (ß = 0.34, p = 0.037), as well as TgAb (ß = 17.06, p = 0.005). Subgroup analysis indicated that the association between TyG and TgAb was more pronounced in the female subjects (ß = 32.39, p < 0.001, p for interaction = 0.021). We also confirmed an inverse correlation between TyG and central sensitivity to THs, as assessed by TSHI and TT4RI (ßTSHI = 0.12, p < 0.001; ßTT4RI = 2.54, p = 0.023). In terms of peripheral sensitivity to THs, we found a significant positive correlation between TyG and FT3/FT4 (ß = 0.03, p = 0.004), and SPINA-GD (ß = 2.93, p = 0.004). CONCLUSION: The present study established a noteworthy association between TyG and thyroid parameters, indicating a strong link between IR and thyroid dysfunction. Further investigations are warranted to validate these results.
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Resistência à Insulina , Glândula Tireoide , Adulto , Humanos , Feminino , Inquéritos Nutricionais , Estudos Transversais , Tireotropina , GlucoseRESUMO
OBJECTIVES: To investigate the value of integrating primary gross tumor volume (GTVp) and gross tumor volume of nodes (GTVn) after induction chemotherapy (IC) and dynamic changes in plasma cell-free Epstein-Barr virus DNA (cfEBV DNA) during sequential chemoradiotherapy (CRT) in high-risk locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIALS AND METHODS: We retrospectively reviewed 988 patients with LA-NPC undergoing IC plus concurrent chemoradiotherapy (CCRT) between 2014 and 2018. The entire cohort was divided into four subgroups according to tumor volume and the cfEBV DNA load. Using a supervised statistical clustering approach, we stratified the subgroups into three clusters. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and locoregional relapse-free survival (LRRFS) were calculated using Kaplan-Meier analysis and inter-group differences were compared using the log-rank test. RESULTS: We observed that GTVp & GTVn and cfEBV DNApostIC & cfEBV DNApostCRT were powerful prognostic factors for OS (p = 0.004, p < 0.001, p < 0.001, and p < 0.001, respectively). The survival curves of the three clusters were significantly different. The 5-year OS for the low-risk, intermediate-risk and high-risk clusters were 97.0%, 86.2% and 77.1% (all P values < 0.001), respectively. The risk stratification system showed better predictive performance than the current tumor-node-metastasis (TNM) classification for OS (area under curve [AUC]: 0.653 versus 0.560, p < 0.001), DFS (AUC: 0.639 versus 0.540, p < 0.001), DMFS (AUC: 0.628 versus 0.535, p < 0.001) and LRRFS (AUC: 0.616 versus 0.513, p < 0.001). CONCLUSION: Both tumor volume and the cfEBV DNA level during sequential CRT are effective prognostic indicators for patients with high-risk LA-NPC. The developed risk stratification system incorporating above factors improved survival prediction and demonstrated potential value in decision-making.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patologia , Prognóstico , Herpesvirus Humano 4/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudos Retrospectivos , Carga Tumoral , Recidiva Local de Neoplasia/etiologia , DNA , Quimiorradioterapia/efeitos adversos , Quimioterapia de InduçãoRESUMO
Background: Nonresolving inflammation is a major driver of disease and needs to be taken seriously. Hypoxia-inducible factor (HIF) is closely associated with inflammation. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), as stabilizers of HIF, have recently been reported to have the ability to block inflammation. We used MK8617, a novel HIF-PHI, to study its effect on macrophage inflammation and to explore its possible mechanisms. Methods: Cell viability after MK8617 and lipopolysaccharide (LPS) addition was assessed by Cell Counting Kit-8 (CCK8) to find the appropriate drug concentration. MK8617 pretreated or unpretreated cells were then stimulated with LPS to induce macrophage polarization and inflammation. Inflammatory indicators in cells were assessed by real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), western blot (WB) and immunofluorescence (IF). The level of uridine diphosphate glucose (UDPG) in the cell supernatant was measured by ELISA. Purinergic G protein-coupled receptor P2Y14, as well as hypoxia-inducible factor-1α (HIF-1α) and glycogen synthase 1 (GYS1) were detected by qRT-PCR and WB. After UDPG inhibition with glycogen phosphorylase inhibitor (GPI) or knockdown of HIF-1α and GYS1 with lentivirus, P2Y14 and inflammatory indexes of macrophages were detected by qRT-PCR and WB. Results: MK8617 reduced LPS-induced release of pro-inflammatory factors as well as UDPG secretion and P2Y14 expression. UDPG upregulated P2Y14 and inflammatory indicators, while inhibition of UDPG suppressed LPS-induced inflammation. In addition, HIF-1α directly regulated GYS1, which encoded glycogen synthase, an enzyme that mediated the synthesis of glycogen by UDPG, thereby affecting UDPG secretion. Knockdown of HIF-1α and GYS1 disrupted the anti-inflammatory effect of MK8617. Conclusions: Our study demonstrated the role of MK8617 in macrophage inflammation and revealed that its mechanism of action may be related to the HIF-1α/GYS1/UDPG/P2Y14 pathway, providing new therapeutic ideas for the study of inflammation.
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Glicogênio Sintase , Uridina Difosfato Glucose , Humanos , Uridina Difosfato Glucose/metabolismo , Glicogênio Sintase/metabolismo , Lipopolissacarídeos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/induzido quimicamente , Macrófagos , Hipóxia/metabolismoRESUMO
This study aims to explore the mechanism of Yanghe Decoction(YHD) against subcutaneous tumor in pulmonary metastasis from breast cancer, which is expected to lay a basis for the treatment of breast carcinoma with YHD. The chemical components of medicinals in YHD, and the targets of the components were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and SwissTargetPrediction. The disease-related targets were searched from GeneCards and Online Mendelian Inheritance in Man(OMIM). Excel was employed to screen the common targets and plot the Venn diagram. The protein-protein interaction network was constructed. R language was used for Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. A total of 53 female SPF Bablc/6 mice were randomized into normal group(same volume of normal saline, ig), model group(same volume of normal saline, ig), and low-dose and high-dose YHD groups(YHD, ig, 30 days), with 8 mice in normal group and 15 mice in each of the other groups. Body weight and tumor size was measured every day. Curves for body weight variation and growth of tumor in situ were plotted. In the end, the subcutaneous tumor sample was collected and observed based on hematoxylin and eosin(HE) staining. The mRNA and protein levels of hypoxia inducible factor-1α(HIF-1α), pyruvate kinase M2(PKM2), lactate dehydrogenase A(LDHA), and glucose transporter type 1(GLUT1) were detected by PCR and Western blot. A total of 213 active components of YHD and 185 targets against the disease were screened out. The hypothesis that YHD may regulate glycolysis through HIF-1α signaling pathway to intervene in breast cancer was proposed. Animal experiment confirmed that the mRNA and protein levels of HIF-1α, PKM2, LDHA, and GLUT1 in the high-and low-dose YHD groups were lower than those in the model group. YHD has certain inhibitory effect on subcutaneous tumor in pulmonary metastasis from breast cancer in the early stage, which may intervene pulmonary metastasis from breast cancer by regulating glycolysis through HIF-1α signaling pathway.
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Experimentação Animal , Medicamentos de Ervas Chinesas , Neoplasias , Feminino , Camundongos , Animais , Transportador de Glucose Tipo 1/genética , Farmacologia em Rede , Solução Salina , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa , Transdução de Sinais , Glicólise , RNA Mensageiro , Neoplasias/tratamento farmacológico , Simulação de Acoplamento MolecularRESUMO
BACKGROUND AND AIMS: Leisure sedentary behavior (LSB) is associated with the risk of cancer, but the causal relationship between them has not been clarified. The aim of this study was to assess the potential causal association between LSB and risk of 15 site-specific cancers. METHODS: The causal association between LSB and cancer were assessed with univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR). 194 SNPs associated with LSB (from the UK Biobank 408,815 individuals) were adopted as the instrument variables. Sensitivity analyses were performed to ensure the robustness of the results. RESULTS: UVMR analysis revealed that television watching significantly increased the risk of endometrial cancer (OR = 1.29, 95% CI = 1.02-1.64, p = 0.04) (mainly the endometrioid histology [OR = 1.28, 95% CI = 1.02-1.60, p = 0.031])ï¼breast cancer (OR = 1.16, 95% CI = 1.04-1.30, p = 0.007) (both ER+ breast cancer [OR = 1.17, 95% CI = 1.03-1.33, p = 0.015], and ER- breast cancer [OR = 1.55, 95% CI = 1.26-1.89, p = 2.23 × 10-5 ]). Although causal association was not found between television watching and ovarian cancer, it was seen in low grade and low malignant potential serous ovarian cancer (OR = 1.49, 95% CI = 1.07-2.08, p = 0.018). However, significant results were not obtained in the UVMR analysis between driving, computer use and the 15 types of cancer. Further MVMR analysis indicated that the above results are independent from most metabolic factors and dietary habits, but mediated by educational attainment. CONCLUSION: LSB in form of television watching has independent causal association with the risk of endometrial cancer, breast cancer, and ovarian cancer.
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Neoplasias da Mama , Neoplasias do Endométrio , Neoplasias Ovarianas , Feminino , Humanos , Fatores de Risco , Comportamento Sedentário , Análise da Randomização Mendeliana/métodos , Neoplasias Ovarianas/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Neoplasias do Endométrio/etiologia , Neoplasias do Endométrio/genética , Polimorfismo de Nucleotídeo Único , Atividades de Lazer , Estudo de Associação Genômica AmplaRESUMO
Introduction: To explore the role of PINK1/Parkin-mediated mitochondrial autophagy in H2O2-induced abnormal proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). Methods: Firstly, we isolated fibroblast like synoviocytes (RA-FLS) from RA patients. H2O2-induced oxidative stress, and NAC (a ROS inhibitor) or FCCP (a mitochondrial autophagy activator) treatment inhibited ROS level or activate mitochondrial autophagy in RA-FLS. MitoSOX Red, JC-1 kit, DCFH-DA kit and CCK8 kit were used to evaluate mitochondrial redox status, mitochondrial membrane potential, intracellular ROS level and cell activity, respectively. Western blot was used to detect the protein expression. The rat model of Freund's complete adjuvant arthritis (AA) was established and treated with NAC and FCCP, respectively. The pathological changes of synovium and the percentage of apoptotic cells in synovium were detected by H&E and TUNEL staining, respectively. Results: We have successfully isolated synovial cells from RA patients. Using 5µM H2O2 to stimulate RA-FLS could induce mitochondrial abnormalities of RA-FLS and inhibit RA-FLS autophagy. FCCP could reverse the effect of H2O2 on RA-FLS cell proliferation and apoptosis. NAC could reverse the effect of H2O2 on PINK1/Parkin. Overexpression of PINK1 or Parkin reversed the effect of H2O2 on RA-FLS mitochondrial autophagy, proliferation and apoptosis. The in vivo experiment results showed that both NAC and FCCP could prevent the pathogenesis of RA, reduce RA-FLS cell viability and increase RA-FLS cell apoptosis. Conclusion: The PINK1/Parkin-mediated mitochondrial autophagy participates in H2O2-induced abnormal proliferation of RA-FLS, and targeting of PINK1/Parkin-mediated mitochondrial autophagy may be the key mechanism in the treatment of RA.
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PURPOSE: Upper-neck irradiation (UNI) at the uninvolved neck has shown similar regional relapse-free survival as standard whole-neck irradiation (WNI) in patients with N0-1 nasopharyngeal carcinoma. However, whether UNI at the contralateral uninvolved neck is feasible in unilateral N3 disease, defined as >6 cm and/or below the caudal border of the cricoid cartilage, remains unclear. METHODS AND MATERIALS: Data for 291 patients with nasopharyngeal carcinoma with unilateral N3 disease who were treated with intensity modulated radiation therapy from 2009 to 2015 were retrospectively analyzed. Among them, 190 received bilateral WNI (WNI group); the remaining 101 received WNI at the involved neck and UNI at the contralateral uninvolved neck (UNI group). Survival rates were estimated using the Kaplan-Meier method, and differences between groups were compared using the log rank tests. RESULTS: The median follow-up was 79.4 months (interquartile range, 56.0-89.3). Twenty-five patients had regional lymph node relapses (UNI: 10.9%, 11/101 vs WNI: 7.4%, 14/190; P = .31). Of these, 23 patients relapsed within the previously involved neck regions, while only 2 patients had relapses in the contralateral uninvolved neck (1 each in the UNI and WNI groups). Five-year regional relapse-free survival rates were similar between groups (89.7% vs 92.7%, P = .29). Similar between-group findings were also observed for 5-year overall survival (76.1% vs 80.4%, P = .40), distant metastasis-free survival (74.9% vs 79.2%, P = .44), and local relapse-free survival (95.6% vs 94.7%, P = .64). Furthermore, oncologic outcomes in subgroup and multivariable analyses were similar between groups. CONCLUSIONS: Regional control and survival outcomes were comparable in UNI at the contralateral uninvolved neck and standard WNI in patients with nasopharyngeal carcinoma with unilateral N3 disease. Our findings provide evidence for future radiation therapy guidelines of nasopharyngeal carcinoma.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia/patologia , Pescoço/efeitos da radiação , Estadiamento de NeoplasiasRESUMO
AIM: Level Ib lymph nodes metastasis is rare in nasopharyngeal carcinoma (NPC). We aimed to evaluate the feasibility of sparing level Ib-irradiation in NPC patients with high-risk factors. MATERIALS AND METHODS: Four hundred forty-three NPC patients with radiologic extranodal extension (rENE) or level II lymph node maximal axial diameter (MAD) ≥ 20 mm treated by intensity-modulated radiotherapy (IMRT) between 2009 and 2012 were included in this study. Propensity score matching (PSM) was applied to balance potential prognostic factors (including age, sex, T and N stage, pretreatment EBV DNA level, and level II rENE and MAD) between patients who received and omitted level Ib irradiation. Kaplan-Meier analysis and the log-rank test were used to compare regional survival outcomes. RESULTS: PSM resulted in 169 matched pairs of eligible patients. The median follow-up period was 119 months in the matched cohort. The number of level Ib failure in the level Ib-sparing and level-Ib irradiation groups were 3/169 (1.8 %) vs 2/169 (1.2 %), P > 0.999. And the 5-year regional relapse-free survival (RRFS) rates of the two groups were 88.4 % vs 92.6 %, respectively. After PSM, RRFS (hazard ratio [HR]: 1.508, 95 % confidence interval [CI]: 0.762-2.986, P = 0.239), OS (HR: 1.219, 95 % CI: 0.754-1.972, P = 0.418), distant metastasis-free survival (DMFS) (HR: 1.605, 95 % CI: 0.900-2.863, P = 0.109), and local relapse-free (LRFS) (HR: 0.956, 95 % CI: 0.436-2.095, P = 0.910) were similar in the two arms. The incidence of grade ≥ 1 dry mouth after 5 years was higher in the level Ib-irradiation group (27.5 % vs 16.5 %, P = 0.029). However, the incidences of grade 3-4 late toxicities were similar between the two groups. CONCLUSION: Neck level Ib-sparing appears to be safe and feasible in NPC patients with rENE or level II MAD ≥ 20 mm and negative level Ib lymph nodes. Compared with cervical level Ib-irradiation, omission of irradiation to level Ib provides less dry mouth symptom.