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BACKGROUND: Low muscle mass (LMM) can be a frequent complication in Crohn's disease (CD). We attempted to explore the effect of LMM on the efficacy of biologics in patients with CD. METHODS: The retrospective cohort study included moderate-to-severe CD patients treated with infliximab or ustekinumab, and appendicitis patients as control. The skeletal muscle area (SMA) of L3 was assessed to evaluate the patients' muscle mass. After propensity score matching, the impact of LMM on drug efficacy was assessed in CD patients. RESULTS: A total of 269 patients with CD and 172 appendicitis patients were included. The CD group had lower skeletal muscle density and BMI, and a higher risk of developing LMM than the control group. BMI (OR = 0.48, p < 0.001) and previous use of biologics (OR = 2.94, p = 0.019) were found to be independently associated with LMM. LMM was found to be associated with a decrease in clinical response (at weeks 8-14), clinical remission (at weeks 8-14, 24-30 and 52) and biochemical remission (at week 52). At weeks 24-30 and 52, LMM was independently associated with loss of response (LOR). We found LMM could be a predictor of lower clinical remission at week 30, lower clinical remission at week 52 and a higher LOR rate at week 30 in infliximab. While in ustekinumab, LMM was associated with lower endoscopic remission at week 24, biochemical remission at week 52 and a higher LOR rate at weeks 24 and 52. CONCLUSIONS: The prevalence of LMM was higher in the CD group compared to the control group. For CD patients with LMM, the efficacy of infliximab and ustekinumab was relatively poor in both the short-term and long-term.

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Recycling spent lithium-ion batteries (LIBs) to efficient water-splitting electrocatalysts is a promising and sustainable technology route for green hydrogen production by renewables. In this work, a fluorinated ternary metal oxide (F-TMO) derived from spent LIBs was successfully converted to a robust water oxidation catalyst for pure water electrolysis by utilizing an anion-exchange membrane. The optimized catalyst delivered a high current density of 3.0 A cm-2 at only 2.56 V and a durability of >300 h at 0.5 A cm-2, surpassing the noble-metal IrO2 catalyst. Such excellent performance benefits from an artificially endowed interface layer on the F-TMO, which renders the exposure of active metal (oxy)hydroxide sites with a stabilized configuration during pure water operation. Compared to other metal oxides (i.e., NiO, Co3O4, MnO2), F-TMO possesses a higher stability number of 2.4 × 106, indicating its strong potential for industrial applications. This work provides a feasible way of recycling waste LIBs to valuable electrocatalysts.

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The peracetic acid (PAA)-based water purification process is often controlled by the solution pH. Herein, we explored the usage of biochar (BC) supported zero-valent iron/cobalt nanoparticles (Fe/Co@BC) for triggering PAA oxidation of sulfamethazine (SMT), and discovered the PAA activation mechanisms at different pHs. Fe/Co@BC exhibited extraordinary PAA activation efficiency over the pH range of 3.0-8.2, effectively broadening the working pH of the zero-valent iron nanoparticles (NZVI)-PAA process. Specifically, the SMT removal efficiency increased by 8.3 times in Fe/Co@BC-PAA system compared to the NZVI-PAA system at pH 8.2. Besides, the leaching and recycling experiments indicated the improved stability and reusability of the materials. For the mechanism study, the main reactive species was •OH under acidic conditions and R-O•/Fe(IV) under neutral/alkaline conditions. More interestingly, the reactive sites on Fe/Co@BC shifted from Fe species to Co species as pH increased, and the role of H2O2 in this reaction system also shifted from a radical precursor to a radical scavenger with increasing pH. This study highlights the distinct mechanism of PAA activation by bimetallic composites under different pH conditions and provides a new efficient approach for PAA activation to degrade organic contaminants.

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Objective To identify nivolumab resistance-related genes in patients with head and neck squamous cell carcinoma (HNSCC) using single-cell and bulk RNA-sequencing data. Methods The single-cell and bulk RNA-sequencing data downloaded from the Gene Expression Omnibus database were analyzed to screen out differentially expressed genes (DEGs) between nivolumab resistant and nivolumab sensitive patients using R software. The Least Absolute Shrinkage Selection Operator (LASSO) regression and Recursive Feature Elimination (RFE) algorithm were performed to identify key genes associated with nivolumab resistance. Functional enrichment of DEGs was analyzed with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. The relationships of key genes with immune cell infiltration, differentation trajectory, dynamic gene expression profiles, and ligand-receptor interaction were explored. Results We found 83 DEGs. They were mainly enriched in T-cell differentiation, PD-1 and PD-L1 checkpoint, and T-cell receptor pathways. Among six key genes identified using machine learning algorithms, only PPP1R14A gene was differentially expressed between the nivolumab resistant and nivolumab sensitive groups both before and after immunotherapy (P < 0.05). The high PPP1R14A gene expression group had lower immune score (P < 0.01), higher expression of immunosuppressive factors (such as PDCD1, CTLA4, and PDCD1LG2) (r > 0, P < 0.05), lower differentiation of infiltrated immune cells (P < 0.05), and a higher degree of interaction between HLA and CD4 (P < 0.05). Conclusions PPP1R14A gene is closely associated with resistance to nivolumab in HNSCC patients. Therefore, PPP1R14A may be a target to ameliorate nivolumab resistance of HNSCC patients.

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Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.

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[This corrects the article DOI: 10.3389/fsurg.2022.939591.].

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OBJECTIVE: The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME. METHODS: We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages. RESULTS: Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages. CONCLUSIONS: DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.

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Objective Machine learning was used to screen the key characteristic genes of nasopharyngeal carcinoma (NPC) and analyze their correlation with immune cells. Methods Download the NPC training datasets (GSE12452 and GSE13597) and the validation dataset (GSE53819) from the Gene Expression Omnibus (GEO). Firstly, the training data sets were merged and screened for differentially expressed genes (DEGs); Secondly, the DEGs were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Next, the least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM) algorithms were used to identify NPC-related genes in the training datasets and examined in the validation dataset, to further identify key genes using the area under curve (AUC) of receiver operating characteristic curve (ROC); Finally, the correlation between the key genes and immune cells was analyzed. Results A total of 55 DEGs were obtained, including 43 down-regulated genes and 12 up-regulated genes. The GO functions were enriched in humoral immune response, cell differentiation, neutrophil activation and chemokine receptor binding. The KEGG were mainly enriched in the IL-17 signaling pathway. The GSEA was enriched in cell cycle, extracellular matrix receptor interactions, cancer pathways and DNA replication. Immune infiltration analysis showed that the expression of naive B cells, memory B cells, and resting memory CD4+ T cells was significantly lower in NPC, while CD8+ T cells, naive CD4+ T cells, activated memory CD4+ T cells, follicular helper T cells, M0 macrophages and M1 macrophages were highly expressed in NPC. Among the feature genes screened by LASSO and SVM, only CCDC19, LAMB1, SPAG6 and RAD51AP1 genes' AUC were greater than 0.9 in both the training and validation datasets and were closely associated with immune cell infiltration. Conclusion The key genes CCDC19, LAMB1, SPAG6 and RAD51AP1 in NPC development are screened by machine learning algorithms, and are closely associated with immune cell infiltration.

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The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.

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Purpose: The repair and treatment of infected bone defects (IBD) is a common challenge faced by orthopedic clinics, medical materials science, and tissue engineering. Methods: Based on the treatment requirements of IBD, we utilized multidisciplinary knowledge from clinical medicine, medical materials science, and tissue engineering to construct a high-efficiency vancomycin sustained-release system with nanodiamond (ND) and prepare a composite scaffold. Its effect on IBD treatment was assessed from materials, cytology, bacteriology, and zoology perspectives. Results: The results demonstrated that the Van-ND-45S5 scaffold exhibited an excellent antibacterial effect, biocompatibility, and osteogenesis in vitro. Moreover, an efficient animal model of IBD was established, and a Van-ND-45S5 scaffold was implanted into the IBD. Radiographic and histological analyses and bone repair-related protein expression, confirmed that the Van-ND-45S5 scaffold had good biocompatibility and osteogenic and anti-infective activities in vivo. Conclusion: Collectively, our findings support that the Van-ND-45S5 scaffold is a promising new material and approach for treating IBD with good antibacterial effects, biocompatibility, and osteogenesis.

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Background: Heart Failure (HF) is the end-stage cardiovascular syndrome with poor prognosis. Proteomics holds great promise in the discovery of novel biomarkers and therapeutic targets for HF. The aim of this study is to investigate the causal effects of genetically predicted plasma proteome on HF using the Mendelian randomization (MR) approach. Methods: Summary-level data for the plasma proteome (3,301 healthy individuals) and HF (47,309 cases; 930,014 controls) were extracted from genome-wide association studies (GWASs) of European descent. MR associations were obtained using the inverse variance-weighted (IVW) method, sensitivity analyses, and multivariable MR analyses. Results: Using single-nucleotide polymorphisms as instrumental variables, 1-SD increase in MET level was associated with an approximately 10% decreased risk of HF (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.89 to 0.95; p = 1.42 × 10-6), whereas increases in the levels of CD209 (OR: 1.04; 95% CI: 1.02-1.06; p = 6.67 × 10-6) and USP25 (OR: 1.06; 95% CI: 1.03-1.08; p = 7.83 × 10-6) were associated with an increased risk of HF. The causal associations were robust in sensitivity analyses, and no evidence of pleiotropy was observed. Conclusion: The study findings suggest that the hepatocyte growth factor/c-MET signaling pathway, dendritic cells-mediated immune processes, and ubiquitin-proteasome system pathway are involved in the pathogenesis of HF. Moreover, the identified proteins have potential to uncover novel therapies for cardiovascular diseases.

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Too high or too low thyroid-stimulating hormone (TSH) has been associated with the progress and prognosis of coronary artery disease (CAD). However, whether TSH within its normal reference range plays a role in the severity of CAD remains unclear. In this observational study, we explored the potential relationship of hypersensitive TSH (hs-TSH) with the severity of CAD in euthyroid patients with or without diabetes mellitus. A total of 7357 CAD patients with euthyroidism were enrolled in this study. Of those, 1997 had diabetes mellitus. The severity of CAD was evaluated through the presence of myocardial infarction (MI) and the severity of coronary lesions, which was calculated using the Gensini score (GS). Logistic regression models treating hs-TSH as a categorical variable and restricted cubic spline analyses treating it as a continuous variable were used to evaluate the associations of hs-TSH with the severity of CAD. The propensity score matching method was used to further validate the differences between diabetic and nondiabetic patients. CAD patients with diabetes mellitus had lower levels of hs-TSH (1.6 (0.97-2.53) vs 1.67 (1.00-2.64)) in serum compared with CAD patients without diabetes mellitus. Meanwhile, hs-TSH was independently related to the severity of CAD. In CAD patients with vs without diabetes mellitus, the U-shaped relationship between hs-TSH and MI was more prominent in patients without diabetes mellitus, and the significant U-shaped association between higher GS and hs-TSH remained only in nondiabetes. Therefore, hs-TSH within the normal reference range has a U-shaped association with the severity of CAD in nondiabetic patients, which is markedly diluted in diabetic patients.

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Percarbonate (SPC) has drawn considerable attention due to its merits in the safety of handling and transport, stability, and price as well as environmental friendliness, which has been extensively applied in advanced oxidation processes (AOPs) for water decontamination. Nevertheless, comprehensive information on the application of SPC-AOPs for the treatment of organic compounds in aquatic media is scarce. Hence, the focus of this review is to shed light on the mechanisms of reactive oxygen species (ROS) evolution in typical SPC-AOPs (i.e., Fenton-like oxidation, photo-assisted oxidation, and discharge plasma-involved oxidation processes). These SPC-AOPs enable the formation of multiple reactive species like hydroxyl radical (•OH), superoxide radical (O2•-), singlet oxygen (1O2), carbonate radicals (CO3•-), and peroxymonocarbonate (HCO4-), which together or solely contribute to the degradation of target pollutants. Simultaneously, the potential challenges in practical applications of SPC-AOPs are systematically discussed, which include the influence of water quality parameters, cost-effectiveness, available active sites, feasible activation approaches, and ecotoxicity. Subsequently, enhancing strategies to improve the feasibility of SPC-AOPs in the practical implementation are tentatively proposed, which can be achieved by introducing reducing and chelating agents, developing novel activation approaches, designing multiple integrated oxidation processes, as well as alleviating the toxicity after SPC-AOPs treatment. Accordingly, future perspectives and research gaps in SPC-AOPs are elucidated. This review will hopefully offer valuable viewpoints and promote the future development of SPC-AOPs for actual water purification.

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The bacteria toxicity of nanoscale zero-valent iron (nZVI) can be changed during its application in water treatment but the toxicity mechanism is still not well understood, particularly under anaerobic conditions. Here, the toxicity of nZVI and its aging products towards Escherichia coli (E. coli) and the mechanisms of extracellular and intracellular reactive oxygen species (ROS) damage were deeply probed in the presence and absence of oxygen in ultrapure water. Under aerobic conditions, the ROS damage primarily caused by the generation of extracellular free •OH can be a major contributor to the toxicity of nZVI to E. coli. By contrast, in anaerobic nZVI treatment system, the intracellular •OH can be quenched by benzoic acid which is a cell permeable quencher and the electron spin resonance (ESR) signals of 5,5-dimethy-1-pyrroline (DMPO)- •OH were evidently observed in system with the addition of F- which could desorb the surface •OH into solution. It indicated that the intracellular •OH adsorbed on the particle surface can also play an indispensable role in inactivating cells under anaerobic conditions. Moreover, nZVI can steeply decline the membrane potential, causing severe membrane disruption and therefore resulting in the stronger toxicity in anaerobic conditions. Furthermore, the chemical composition transformation of nZVI and generation of benign iron corrosion products (e.g., Fe3O4, γ-Fe2O3, γ-FeOOH) are mainly responsible for the reduced toxicity with the increasing aging time. These results provide insights into the extracellular and intracellular ROS damage occurred in aerobic and anaerobic nZVI treatment systems, offering more perspective to the risk assessment of nZVI application.

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Background: Acute myocardial infarction (AMI), as well as its long-term and short-term complications, is known to present with high morbidity and mortality. Cardiac function deterioration and ventricular remodelling after AMI are known to be correlated to worse long-term outcomes. However, the underlying mechanism remains elusive and there is a shortage of serum prediction markers. This study investigates the relationship between in-hospital Cystatin C (CysC) and cardiac function and subsequent prognosis among AMI patients. Research Design and Methods. We measured admission CysC and cardiac function parameters, including ejection fraction (EF) and pro-BNP value in 5956 patients diagnosed with AMI. Simple and multiregression analyses were performed to investigate the correlation between CysC and cardiac function in AMI patients. Major adverse cardiovascular events (MACE), cardiovascular, and all-cause mortality were documented, and 351 participants with high cystatin (≥1.09 mg/L) and 714 low cystatin (<1.09 mg/L) were investigated for survival analysis during a 48-month follow-up. Results: 5956 patients with AMI were enrolled in the initial observational analysis, and 1065 patients of the whole cohort were included in the follow-up survival analysis. The admission CysC level was found to be significantly positively correlated to the pro-BNP level (R square = 0.2142, 95% CI 4758 to 5265, p < 0.0001) and negatively correlated to the EF value (R square = 0.0095, 95% CI -3.503 to -1.605, p < 0.0001). Kaplan-Meier survival analysis revealed significantly increased MACE incidence (HR = 2.293, 95% CI 1.400 to 3.755, p < 0.0001), cardiovascular mortality (HR = 3.016, 95% CI 1.694 to 5.371, p = 0.0002), and all-cause mortality (HR = 3.424, 95% CI 2.010 to 5.835, p < 0.0001) in high-admission CysC cohort with AMI at the end of 4-year follow-up. Conclusions: Admission CysC is negatively correlated with cardiac function in AMI patients and acts as a novel predictor for MACE incidence in the whole population. Further studies are needed to investigate the specific mechanism of CysC in the cardiac function deterioration among AMI patients.

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Unlike genomes, which are static throughout the lifespan of an organism, DNA methylomes are dynamic. To study these dynamics, we developed quantitative models that measure the effect of multiple factors on DNA methylomes including, age, sex, weight, and genetics. We conducted our study in canids, which prove to be an ideal species to assess epigenetic moderators due to their extreme variability in size and well-characterized genetic structure. We collected buccal swabs from 217 canids (207 domestic dogs and 10 grey wolves) and used targeted bisulphite sequencing to measure methylomes. We also measured genotypes at over one thousand single nucleotide polymorphisms (SNPs). As expected, we found that DNA methylomes are strongly associated with age, enabling the construction of epigenetic clocks. However, we also identify novel associations between methylomes and sex, weight, and sterilization status, leading to accurate models that predict these factors. Methylomes are also affected by genetics, and we observe multiple associations between SNP loci and methylated CpGs. Finally, we show that several factors moderate the relationship between epigenetic ages and real ages, such as body weight, which increases epigenetic ageing. In conclusion, we demonstrate that the plasticity of DNA methylomes is impacted by myriad genetics and physiological factors, and that DNA methylation biomarkers are accurate predictors of age, sex and sterilization status.

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We here address the question of the extent to which judgments of mathematical beauty (which we categorize as biological beauty) are resistant to revision through external opinion. A total of 100 mathematicians of different national and ethnic origins were asked to rate 60 mathematical equations for their beauty; after being presented a fictitious "expert rating," they were asked to re-rate the same equations. Results showed that the judgments of mathematical beauty had a high level of resistance to external opinion. This is in line with the resistance to revision of a judgments for other categories of biological beauty.

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Nasopharyngeal carcinoma (NPC) is a clinically multiple malignant tumor. At present, with the increase in the infection rate of Epstein-Barr virus, the incidence of nasopharyngeal carcinoma is also increasing day by day. To explore the effect of body size change on off-center cervical point and face doses in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy, in total, 100 patients with NPC from January 2019 to May 2020 in our hospital were selected for retrospective analysis, and they all received intensity-modulated radiation therapy. Bodyweight, horizontal longitudinal diameter of the odontoid process, longitudinal diameter of the third cervical spine, maximum radiation dose, and average radiation dose of normal organs in the first and last treatments were assessed, and the correlation between normal organ irradiation dose and body size was analyzed. Bodyweight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine in the last treatment were lower than those in the first treatment, with a statistically significant difference. There was no statistically significant difference in the maximum normal organ irradiation dose to the left eyeball, right eyeball, left crystalline lens, right crystalline lens, and maximum irradiation dose to optic nerve between the last treatment and the first treatment. In the last treatment, the maximum dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was higher than that in the first treatment. The average irradiation dose to the left eye bulb, right eye bulb, left lens, right lens, optic nerve in the last treatment, and that in the first treatment showed no significant difference. The average dose to the left parotid gland, right parotid gland, spinal cord, and brain stem in the last treatment was higher than that in the first treatment. The irradiation dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was significantly negatively correlated with body weight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine. After NPC radiotherapy, the body size of patients can change, which can have different effects on irradiation doses. Therefore, the target area and dose should be corrected during treatment to ensure the efficacy and safety of the treatment.

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