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BACKGROUND & AIMS: Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. METHODS: We employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. RESULTS: Pathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. CONCLUSION: Our findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy.
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BACKGROUND: Accumulating evidence has shown that circular RNAs (circRNAs) are involved in gastric cancer (GC) tumorigenesis. However, specific functional circRNAs in GC remain to be discovered, and their underlying mechanisms remain to be elucidated. METHODS: CircRNAs that were differentially expressed between GC tissues and controls were analyzed using a circRNA microarray dataset. The expression of circVDAC3 in GC was determined using quantitative real-time PCR (qRT-PCR), and the structural features of circVDAC3 were validated. Cell function assays and animal experiments were conducted to explore the effects of circVDAC3 on GC. Finally, bioinformatics analysis, fluorescent in situ hybridization, and dual luciferase assays were used to analyze the downstream mechanisms of circVDAC3. RESULTS: Our results showed that circVDAC3 was downregulated in GC and inhibited the proliferation and metastasis of GC cells. Mechanistically, circVDAC3 acts as a competing endogenous RNA (ceRNA) of miR-592 and deregulates the repression of EIF4E3 by miR-592. EIF4E3 is downregulated in GC and overexpression of miR-592 or knockdown of EIF4E3 in circVDAC3-overexpressing cells weakens the anticancer effect of circVDAC3. CONCLUSION: Our study provides evidence that circVDAC3 affects the growth and metastasis of GC cells via the circVDAC3/miR-592/EIF4E3 axis. Our findings offer valuable insights into the mechanisms underlying GC tumorigenesis and suggest novel therapeutic strategies.
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Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic targeting of gene mutations in governing tumor progression. TP53 is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that TP53 is able to mediate tumor immune escape. Herein, we summarized the relationship between TP53 gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.
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Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Genes p53 , Neoplasias/genética , Cognição , Instabilidade Genômica , Microambiente Tumoral/genéticaRESUMO
BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.
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Lesões Encefálicas , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/patologia , Estudos Retrospectivos , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Estudo de Associação Genômica Ampla , Lesões Encefálicas/etiologia , Radioterapia de Intensidade Modulada/efeitos adversos , Medição de RiscoRESUMO
Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Seguimentos , Predisposição Genética para Doença , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Homeodomínio/genéticaRESUMO
Chemoradiation-induced hearing loss (CRIHL) is one of the most devasting side effects for nasopharyngeal carcinoma (NPC) patients, which seriously affects survivors' long-term quality of life. However, few studies have comprehensively characterized the risk factors for CRIHL. In this study, we found that age at diagnosis, tumor stage, and concurrent cisplatin dose were positively associated with chemoradiation-induced hearing loss. We performed a genome-wide association study (GWAS) in 777 NPC patients and identified rs1050851 (within the exon 2 of NFKBIA), a variant with a high deleteriousness score, to be significantly associated with hearing loss risk (HR = 5.46, 95% CI 2.93-10.18, P = 9.51 × 10-08). The risk genotype of rs1050851 was associated with higher NFKBIA expression, which was correlated with lower cellular tolerance to cisplatin. According to permutation-based enrichment analysis, the variants mapping to 149 hereditary deafness genes were significantly enriched among GWAS top signals, which indicated the genetic similarity between hereditary deafness and CRIHL. Pathway analysis suggested that synaptic signaling was involved in the development of CRIHL. Additionally, the risk score integrating genetic and clinical factors can predict the risk of hearing loss with a relatively good performance in the test set. Collectively, this study shed new light on the etiology of chemoradiation-induced hearing loss, which facilitates high-risk individuals' identification for personalized prevention and treatment.
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Surdez , Perda Auditiva , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Cisplatino/efeitos adversos , Estudo de Associação Genômica Ampla , Qualidade de Vida , Perda Auditiva/induzido quimicamente , Perda Auditiva/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/induzido quimicamenteRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. METHODS: Whole-exome sequencing was performed in 13 NPC pedigrees with multiple cases. Mutations co-segregated with disease status were further validated in a cohort composed of 563 probands from independent families, 2,953 sporadic cases, and 3,175 healthy controls. Experimental studies were used to explore the functions of susceptibility genes and their disease-related mutations. FINDINGS: The three rare missense mutations in POLN (DNA polymerase nu) gene, P577L, R303Q, and F545C, were associated with familial NPC risk (5/576 [0·87%] in cases vs. 2/3374 [0·059%] in healthy controls with an adjusted OR of 44·84 [95% CI:3·91-514·34, p = 2·25 × 10-3]). POLN was involved in Epstein-Barr virus (EBV) lytic replication in NPC cells in vitro. POLN promoted viral DNA replication, immediate-early and late lytic gene expression, and progeny viral particle production, ultimately affecting the proliferation of host cells. The three mutations were located in two pivotal functional domains and were predicted to alter the protein stability of POLN in silico. Further assays demonstrated that POLN carrying any of the three mutations displayed reduced protein stability and decreased expression levels, thereby impairing its ability to promote complete EBV lytic replication and facilitate cell survival. INTERPRETATION: We identified a susceptibility gene POLN for familial NPC and elucidated its function. FUNDING: This study was funded by the National Key Research and Development Program of China (2021YFC2500400); the National Key Research and Development Program of China (2020YFC1316902); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the National Natural Science Foundation of China (81973131); the National Natural Science Foundation of China (82003520); the National Natural Science Foundation of China (81903395).
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DNA Polimerase Dirigida por DNA , Infecções por Vírus Epstein-Barr , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Replicação do DNA , DNA Viral/genética , DNA Viral/metabolismo , DNA Polimerase Dirigida por DNA/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Mutação , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Replicação ViralRESUMO
BACKGROUND: Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. METHODS: We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218). RESULTS: Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%). CONCLUSIONS: This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Masculino , Humanos , Carcinoma Nasofaríngeo/genética , Sequenciamento do Exoma , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/genética , Predisposição Genética para Doença , Herpesvirus Humano 4/genética , Estudos de Casos e Controles , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
BACKGROUND: Ewing's sarcoma of the adrenal gland with inferior vena cava (IVC) and right atrium thrombus is extremely rare. Here, we report a case of giant adrenal Ewing's sarcoma with IVC and right atrium tumor thrombus and summarize the anesthesia and perioperative management. CASE SUMMARY: A young female was admitted to the Department of Urology with intermittent pain under the right costal arch for four months. Enhanced abdominal computed tomography revealed a large retroperitoneal mass (22 cm in diameter), which may have originated from the right adrenal gland and was closely related to the liver. Transthoracic echocardiography showed a strong echogenic filling measuring 70 mm extended from the IVC into the right atrium and ventricle. After preoperative preparation with cardiopulmonary bypass, sufficient blood products, transesophageal echocardiography and multiple monitoring, tumor and thrombus resection by IVC exploration and right atriotomy were successfully performed by a multidisciplinary team. Intraoperative hemodynamic stability was the major concern of anesthesiologists and the status of tumor thrombus and pulmonary embolism were monitored continuously. During transfer of the patient to the intensive care unit (ICU), cardiac arrest occurred without external stimulus. Cardiopulmonary resuscitation was performed immediately and cardiac function was restored after 1 min. In the ICU, extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) were provided to maintain cardiac, liver and kidney function. Histopathologic examination confirmed the diagnosis of Ewing's sarcoma. After postoperative treatments and rehabilitation, the patient was discharged from the urology ward. CONCLUSION: An adrenal Ewing's sarcoma with IVC and right atrium thrombus is extremely rare, and its anesthesia and perioperative management have not been reported. Thus, this report provides significant insights in the perioperative management of patients with adrenal Ewing's sarcoma and IVC tumor thrombus. Intraoperative circulation fluctuations and sudden cardiovascular events are the major challenges during surgery. In addition, postoperative treatments including ECMO and CRRT provide essential support in critically ill patients. Moreover, this case report also highlights the importance of multidisciplinary cooperation during treatment of the disease.
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As a unique organofluorine fragment, gem-difluoromethylated motifs have received widespread attention. Here, a convenient and efficient synthesis of aryldifluoromethyl aryl ethers (ArCF2OAr') was established via Nickel-catalyzed aryloxydifluoromethylation with arylboronic acids. This approach features easily accessible starting materials, good tolerance of functionalities, and mild reaction conditions. Diverse late-stage difluoromethylation of many pharmaceuticals and natural products were readily realized. Notably, a new difluoromethylated PD-1/PD-L1 immune checkpoint inhibitor was conveniently synthesized and showed both improved metabolic stability and enhanced antitumor efficacy. Preliminary mechanistic studies suggested the involvement of a Ni(I/III) catalytic cycle.
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Epstein-Barr virus (EBV) infection is associated with multiple malignancies, including pulmonary lymphoepithelioma-like carcinoma (pLELC), a particular subtype of primary lung cancer. However, the genomic characteristics of EBV related to pLELC remain unclear. Here, we obtained the whole-genome data set of EBV isolated from 78 pLELC patients and 37 healthy controls using EBV-captured sequencing. Compared with the reference genome (NC_007605), a total of 3,995 variations were detected across pLELC-derived EBV sequences, with the mutational hot spots located in latent genes. Combined with 180 published EBV sequences derived from healthy people in Southern China, we performed a genome-wide association study and identified 32 variations significantly related to pLELC (P < 2.56 × 10-05, Bonferroni correction), with the top signal of single nucleotide polymorphism (SNP) coordinate T7327C (OR = 1.22, P = 2.39 × 10-15) locating in the origin of plasmid replication (OriP). The results of population structure analysis of EBV isolates in East Asian showed the EBV strains derived from pLELC were more similar to those from nasopharyngeal carcinoma (NPC) than other EBV-associated diseases. In addition, typical latency type-II infection were recognized for EBV of pLELC at both transcription and methylation levels. Taken together, we defined the global view of EBV genomic profiles in pLELC patients for the first time, providing new insights to deepening our understanding of this rare EBV-associated primary lung carcinoma. IMPORTANCE Pulmonary lymphoepithelioma-like carcinoma (pLELC) is a rare, distinctive subtype of primary lung cancer closely associated with Epstein-Barr virus (EBV) infection. Here, we gave the first overview of pLELC-derived EBV at the level of genome, methylation and transcription. We obtained the EBV sequences data set from 78 primary pLELC patients, and revealed the sequences diversity across EBV genome and detected variability in known immune epitopes. Genome-wide association analysis combining 217 healthy controls identifies significant variations related to the risk of pLELC. Meanwhile, we characterized the integration landscapes of EBV at the genome-wide level. These results provided new insight for understanding EBV's role in pLELC tumorigenesis.
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Carcinoma Pulmonar de Células não Pequenas/virologia , Infecções por Vírus Epstein-Barr/virologia , Genoma Viral/genética , Herpesvirus Humano 4/genética , Neoplasias Pulmonares/virologia , Povo Asiático , China , Metilação de DNA , Epitopos de Linfócito T/genética , Genes Virais/genética , Variação Genética , Estudo de Associação Genômica Ampla , Herpesvirus Humano 4/isolamento & purificação , Humanos , Integração Viral , Latência Viral/genéticaRESUMO
BACKGROUND: MicroRNAs, as small non-coding RNAs, play an important role in tumorigenesis. MiR-483-5p was found to have a significant increase as a diagnostic biomarker of nasopharyngeal carcinoma (NPC), not only in plasma from NPC patients but also in tumor cell lines and biopsy tissues in our previous study. However, its function and mechanism in NPC are still unclear. METHODS: Tissue microarray including 178 primary NPC and 35 adjacent non-cancerous nasopharyngeal mucosal tissues was used to further validate the overexpression of miR-483-5p. Wound healing and invasion assays were conducted to verify its biological function. RNA sequencing (RNA-seq) and dual-luciferase reporter assay was performed to explore its target, and it was verified in fresh biopsy tissues from 23 NPC patients and 9 patients with chronic nasopharyngitis. RESULTS: MiR-483-5p was highly expressed in NPC tissues than in adjacent non-cancerous tissues. It was found to have a significant correlation with poor overall survival (OS) [hazard ratio (HR) = 2.89, 95% confidence interval (CI) = 1.00-8.35, p = 0.041] and progression-free survival (PFS) (HR = 1.95, 95%CI = 1.06-3.60, p = 0.029) of NPC patients. Silencing of its expression inhibited the migratory and invasive capacities of NPC cells in vitro. EGR3 (early growth response 3) was identified as a direct target, and inhibiting miR-483-5p expression markedly enhanced the expression of EGR3 at both the mRNA and protein levels. Besides, a significant decrease of EGR3 expression was found in fresh biopsy tissues from NPC patients, in contrast to miR-483-5p expression. Furthermore, directly decreasing the expression of EGR3 could enhance the migration and invasion of NPC cells. CONCLUSION: The newly identified miR-483-5p/EGR3 pathway provides further insights into the development and metastasis of NPC and may provide a potential therapeutic target for NPC treatment in order to improve survival of NPC patients.
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BACKGROUND: Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta-IgA, in healthy males from NPC endemic area. METHODS: HLA alleles of 1078 healthy males in southern China from the 21-RCCP study were imputed using genome-wide single nucleotide polymorphism data. EBV Zta-IgA in blood samples were measured using an enzyme-linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta-IgA serological status and its potential joint association with smoking. The binding affinity for Zta-peptide was predicted using NetMHCIIpan 4.0. RESULTS: HLA-DRB1*09:01 was found to be associated with a higher risk of Zta-IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32-2.45; p = 1.82 × 10-4 ). Compared with non-smokers without HLA-DRB1*09:01, the effect size increased to 2.19- and 3.70-fold for the light and heavy smokers carrying HLA-DRB1*09:01, respectively. Furthermore, HLA-DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA-DRB1 alleles. CONCLUSIONS: Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA-DRB1*09:01 have a significantly higher risk of being Zta-IgA seropositive, which indicates the necessity of smoking cessation in certain high-risk populations and also provide clues for further research on the etiology of NPC.
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Infecções por Vírus Epstein-Barr/imunologia , Antígenos HLA/genética , Herpesvirus Humano 4/imunologia , Imunoglobulina A/imunologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Transativadores/imunologia , Adulto , Alelos , Anticorpos Antivirais/imunologia , Povo Asiático/genética , Infecções por Vírus Epstein-Barr/virologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Voluntários Saudáveis , Humanos , Imunoglobulina A/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/imunologia , Fumar/efeitos adversos , Proteínas Virais/imunologiaRESUMO
PURPOSE: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. EXPERIMENTAL DESIGN: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. RESULTS: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. CONCLUSIONS: Our immune risk score complements current AML prediction models.
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Leucemia Mieloide Aguda/mortalidade , Microambiente Tumoral/imunologia , Conjuntos de Dados como Assunto , Feminino , Citometria de Fluxo , Regulação Leucêmica da Expressão Gênica/imunologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , RNA-Seq , Curva ROC , Medição de Risco/métodos , Fatores de Risco , Taxa de Sobrevida , Linfócitos T/imunologia , Microambiente Tumoral/genéticaRESUMO
[This corrects the article DOI: 10.21037/atm.2019.12.150.].
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Optimal acetabular cup orientation is of substantial importance to good long-term function and low complication rates after total hip arthroplasty (THA). The radiographic anteversion (RA) and inclination (RI) angles of the cup are typically studied due to the practicability, simplicity, and ease of interpretation of their measurements. A great number of methods have been developed to date, most of which have been performed on pelvic or hip anteroposterior radiographs. However, there are primarily two influencing factors for these methods: X-ray offset and pelvic rotation. In addition, there are three types of pelvic rotations about the transverse, longitudinal, and anteroposterior axes of the body. Their effects on the RA and RI angles of the cup are interactively correlated with the position and true orientation of the cup. To date, various fitted or analytical models have been established to disclose the correlations between the X-ray offset and pelvic rotation and the RA and RI angles of the cup. Most of these models do not incorporate all the potential influencing parameters. Advanced methods for performing X-ray offset and pelvic rotation corrections are mainly performed on a single pelvic AP radiograph, two synchronized radiographs, or a two-dimensional/three-dimensional (2D-3D) registration system. Some measurement systems, originally developed for evaluating implant migration or wear, could also be used for correcting the X-ray offset and pelvic rotation simultaneously, but some drawbacks still exist with these systems. Above all, the 2D-3D registration technique might be an alternative and powerful tool for accurately measuring cup orientation. In addition to the current methods used for postoperative assessment, navigation systems and augmented reality are also used for the preoperative planning and intraoperative guidance of cup placement. With the continuing development of artificial intelligence and machine learning, these techniques could be incorporated into robot-assisted orthopaedic surgery in the future.
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With the growing attention on ecological environment problems and gradual realization of ecological environment value, environmental damage has jumped from administrative penalty to a new stage, judicial penalty, and environmental damage appraisal has provided a legal weapon to safeguard ecological security. As a new forensic category of China with high comprehensiveness and technical difficulty, environmental damage appraisal involves diversified and complex subjects, fields and appraisal objects, and is still in an early stage in terms of theory and practice. This study aims to provide an important reference for the improvement of the Chinese environmental damage appraisal system of environmental damage by summarizing advanced international experience in areas such as laws and regulations, working mechanism and technical system, and putting forward targeted countermeasures and suggestions based on the problems existing in the development and practice of environmental damage appraisal in China.
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Humanos , China , Meio Ambiente , Poluição Ambiental/análise , Medicina LegalRESUMO
The objective of this study is to investigate the synergetic effect of the pelvic rotation and X-ray offset on the radiographic anteversion/inclination (RA/RI) angles of the acetabular cup using a mathematical model. A cone model for establishing the spatial relationship between a three-dimensional (3D) circle and its two-dimensional (2D) elliptical projection is utilized to quantify the relationship between the 3D RA/RI angles of the cup and their 2D counterparts with different types of pelvic rotations in pelvic/hip anteroposterior radiographs. The results reveal that the effect of inlet/outlet views on the 2D RA angle is similar to that of iliac/obturator views. The permissible ranges of pelvic rotation for the 2D RA angle with an acceptable bias are the 3D space formed by the limits of triple axial rotations. For a specified acceptable bias of the 2D RA angle, these ranges are almost equal between pelvic and hip radiographs. The combined inlet/obturator or outlet/iliac views can maintain the 2D RA angle of a pelvic radiograph within the same range of acceptable bias as that of a hip radiograph. For a 2D RA angle with an acceptable bias, the permissible range of pelvic rotation needs to be evaluated with equal attention in both radiographs. Graphical abstract The traditional methods for calculating the radiographic angles of the acetabular cup are based on the ellipse projection of the opening circle of the cup on radiographs. However, with varying locations of the X-ray source and pelvis rotations about different axes, the outline of this ellipse projection will change, and accordingly, the traditional method and calculating results will be inaccurate. In this study, a cone model for three-dimensional circle-to-two-dimensional ellipse projection is utilized to incorporate the effect of X-ray offset and quantify the relationships of the radiographic angles of the cup with the true orientation of the cup and pelvic rotations in either pelvic or hip anteroposterior radiographic situation.