RESUMEN
PURPOSE: To evaluate the clinical implication of magnetic resonance imaging (MRI)-derived skeletal muscle index (SMI) in locoregionally advanced nasopharyngeal carcinoma (LANPC) patients undergoing induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) and further to develop a nomogram for predicting survival prognosis. METHODS: SMI was determined through baseline MRI at the third cervical level. The nomogram was based on a training cohort involving 409 LANPC patients. We validated the prognostic accuracy of this prognostic model in an internal validation cohort (n = 204) and an external independent cohort (n = 272). RESULTS: SMI was an independent risk factor for OS. A prognostic model comprising age, TNM stage and SMI for individual survival prediction was developed and graphically represented as a nomogram. The model showed favorable discrimination (C-index: 0.686), predictive accuracy [time dependent area under the curve (tAUC) at 5 years: 0.70], and calibration, and was further validated in the internal and external validation datasets. A risk stratification derived from the model stratified these patients into three prognostic subgroups with significantly different survival. CONCLUSIONS: Low SMI accessed by MRI was significantly associated with poor overall survival in LANPC patients undergoing IC + CCRT. Moreover, we established and validated a novel nomogram involving age, TNM stage and SMI that could provide accurate prognostic stratification among this population.
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Imagen por Resonancia Magnética , Músculo Esquelético , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Estadificación de Neoplasias , Nomogramas , Humanos , Masculino , Imagen por Resonancia Magnética/métodos , Femenino , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/mortalidad , Persona de Mediana Edad , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Adulto , Pronóstico , Músculo Esquelético/patología , Músculo Esquelético/diagnóstico por imagen , Quimioradioterapia , Anciano , Quimioterapia de Inducción , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.
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Hipertermia Inducida , Neoplasias Nasofaríngeas , Humanos , Animales , Ratones , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Chaperón BiP del Retículo Endoplásmico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/metabolismo , Complemento C3/genética , Complemento C3/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Antígenos CD55 , Regulación Neoplásica de la Expresión Génica , Microambiente TumoralRESUMEN
PURPOSE: The goal of this study was to establish a nomogram that included pre-treatment tumor size and lymph node (LN) size to assess personalized overall survival (OS) of patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results dataset was used to extract statistics for 1083 individuals with NPC (training cohort). In the validation cohort, 266 patients were included from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University. Age, tumor-node-metastasis (TNM) stage, pre-treatment tumor size, and LN size were chosen in both the training and validation sets to build a nomogram to forecast the 3-year and 5-year OS probability using the multivariate Cox regression model. Using the C-index, calibration plot, and receiver operating characteristic (ROC) curve, the predictive model's predictive value and discriminative capacity were determined. RESULTS: Pre-treatment tumor size, LN size, age, and TNM stage were all independent prognostic factors in the multivariate analysis. After combining these characteristics, a nomogram with a C-index of 0.7367 in the training cohort and 0.795 in the validation cohort was created, suggesting strong predictive capacity. Analysis of the ROC curve revealed that the constructed nomogram was clinically applicable. CONCLUSIONS: In patients with NPC, the developed nomogram, which includes pre-treatment tumor size, LN size, age, and TNM stage, is a reliable predictive predictor of OS.
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Neoplasias Nasofaríngeas , Nomogramas , Humanos , Pronóstico , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/patología , Ganglios Linfáticos/patología , Estadificación de NeoplasiasRESUMEN
Cytokines interact closely with each other and play a crucial role in the progression of sepsis. We focused on the associations of a cytokine network with IL-35 in sepsis. First, the retrospective study included 42 patients with sepsis and 23 healthy controls. Blood samples were collected from patients on days 1, 2, 4. Levels of IL-35, IL-1ß, IL-4, IL-6, IL-10, IL-17A, TNF-α and IFN-γ were measured. They all increased to various extend on days 1, 2, 4, and strongly associated with markers of disease severity. Network analysis revealed a network formed by IL-35, with IL-6, IL-10, IL-17A, TNF-α and IFN-γ throughout the acute phase of sepsis(days 1, 2 and4). Then, the CLP-induced septic rats were used. The recombinant human IL-35(rIL-35) upregulated the levels of IL-10, but downregulated IL-4, IL-6, IL-17A, TNF-α and IFN-γ, while it had no significant effect on IL-1ß, and upregulated the percentages of CD4+CD25+Tregs, and iTR35, but downregulated Teff cells in the peripheral blood. The rIL-35 reduced inflammation damage and improved prognosis of the septic rats. IL-35 forms a network with other cytokines and plays a major role in the immunopathogenesis of sepsis.
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Citocinas/metabolismo , Inflamación/metabolismo , Interleucinas/metabolismo , Interleucinas/farmacología , Sepsis/inmunología , Linfocitos T/fisiología , Anciano , Animales , Citocinas/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Estudios Retrospectivos , Organismos Libres de Patógenos EspecíficosRESUMEN
Microplastics (MPs), due to their impacts on the ecosystem and their integration into the food web either through trophic transfer or ingestion directly from the ambient environment, are an emerging class of environmental contaminants posing a great threat to marine organisms. Most reports on the toxic effects of MPs exclusively focus on bioaccumulation, oxidative stress, pathological damage, and metabolic disturbance in fish. However, the collected information on ï¬sh immunity in response to MPs is poorly deï¬ned. In particular, little is known regarding mucosal immunity and the role of mucins. In this study, marine medaka (Oryzias melastigma) larvae were exposed to 6.0 µm beads of polystyrene microplastics (PS-MPs) at three environmentally relevant concentrations (102 particles/L, 104 particles/L, and 106 particles/L) for 14 days. The experiment was carried out to explore the developmental and behavioural indices, the transcriptional profiles of mucins, pro-inflammatory, immune, metabolism and antioxidant responses related genes, as well as the accumulation of PS-MPs in larvae. The results revealed that PS-MPs were observed in the gastrointestinal tract, with a concentration- and exposure time-dependent manner. No significant difference in the larval mortality was found between the treatment groups and the control, whereas the body length of larvae demonstrated a significant reduction at 106 particles/L on 14 days post-hatching. The swimming behaviour of the larvae became hyperactive under exposure to 104 and 106 particles/L PS-MPs. In addition, PS-MP exposure significantly up-regulated the mucin gene transcriptional levels of muc7-like and muc13-like, however down-regulated the mucin gene expression levels of heg1, muc2, muc5AC-like and muc13. The immune- and inflammation and metabolism-relevant genes (jak, stat-3, il-6, il-1ß, tnf-а, ccl-11, nf-κb, and sod) were significantly induced by PS-MPs at 104 and 106 particles/L compared to the control. Taken together, this study suggests that PS-MPs induced inflammation response and might obstruct the immune functions and retarded the growth of the marine medaka larvae even at environmentally relevant concentrations.
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Oryzias , Contaminantes Químicos del Agua , Animales , Ecosistema , Inmunidad , Inflamación , Larva , Microplásticos/toxicidad , Mucinas/genética , Mucinas/metabolismo , Oryzias/metabolismo , Plásticos/toxicidad , Poliestirenos/metabolismo , Poliestirenos/toxicidad , Natación , Contaminantes Químicos del Agua/análisisRESUMEN
A novel peptide containing antimicrobial sequence and gelatinase cleavage sites was designed for Staphylococcus aureus detection. Since Staphylococcus aureus could secrete gelatinase, the fluorescein labeled peptide GKRWWKWWRRPLGVRGC could be recognized and cleaved. The obtained products were able to be analyzed by capillary electrophoresis with fluorescence detection. To explore the effect of Staphylococcus aureus concentration on enzyme digestion ability of peptide, Staphylococcus aureus with different concentrations were incubated with the peptide. Results indicated that capillary electrophoretic method was efficient for determining Staphylococcus aureus content. Compared with traditional approaches for Staphylococcus aureus detection, capillary electrophoresis possessed higher efficiency, enhanced sensitivity, and low sample consumption. Moreover, the proposed peptide also presented desirable antimicrobial activity. It suggested that the novel antimicrobial peptide used in this research opens a new path of detecting Staphylococcus aureus by capillary electrophoretic method.
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Péptidos Antimicrobianos , Staphylococcus aureus , Secuencia de Aminoácidos , Electroforesis Capilar , Fluoresceína , Gelatinasas , Staphylococcus aureus/aislamiento & purificaciónRESUMEN
DNA possesses various chemical and physical properties which make it important in biological analysis. The opportunity for DNA to 'meet' capillary-based microsystems is rapidly increasing owing to the expanding development of miniaturization. Novel capillary-based methods can provide favourable platforms for DNA-ligand interaction assay, DNA translocation study, DNA separation, DNA aptamer selection, DNA amplification assay, and DNA digestion. Meanwhile, DNA exhibits great potential in the fabrication of new capillary-based biosensors and enzymatic bioreactors. Moreover, DNA has received significant research interest in improving capillary electrophoresis (CE) performance. We focus on highlighting the advantages of combining DNA and capillary-based microsystems. The general trend presented in this review suggests that the 'meeting' has offered a stepping stone for the application of DNA and capillary-based microsystems in the field of analytical chemistry.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , ADN/genética , Electroforesis Capilar , MiniaturizaciónRESUMEN
Microplastics (MPs) in the Arctic have raised increasing concern, but knowledge on MP contamination in benthic organisms from Arctic shelf regions, e.g., the Chukchi Sea is still limited. Therefore, the present study investigated the occurrence, characteristics, sources, and environmental implications of MPs in the three most common benthic species, namely sea anemone (Actiniidae und.), deposit-feeding starfish (Ctenodiscus crispatus), and snow crab (Chionoecetes opilio), from the Chukchi Sea. The abundances of MPs in the three benthic species were significantly greater than those from the Bering Sea, but lower than those from other regions globally. The top three compositions of MPs in the three species were polyester, nylon, and polyethylene terephthalate. The detection limit for MP size in the present study was 0.03 mm and the mean size of MP in the three species was 0.89 ± 0.06 mm. The surfaces of MPs found in the starfish and crabs were covered with many attachments, cracks, and hollows, while the surfaces of MPs found in the sea anemones were smooth, which was likely a consequence of different feeding behaviors. There was a significantly positive correlation between the abundances of MPs and other anthropogenic substances. The mean MP abundances in the sea anemones ranged from 0.2 items/individual to 1.7 items/individual, which was significantly higher than that in the deposit-feeding starfish (0.1-1.4 items/individual) and snow crabs (0.0-0.6 items/individual). Sea anemones inhabiting lower latitudes ingested relatively higher levels of MPs than those inhabiting higher latitudes. The MP abundances in the sea anemones are significantly and positively correlated with the seasonal reduced ratio of sea ice coverage from August to September. Our findings indicate that sea anemones could function as a bioindicator of MP pollution, and that the MPs in the benthos from the Chukchi Sea might originate from the melting sea ice, fishery activities and ocean currents.
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Microplásticos , Contaminantes Químicos del Agua , Animales , Regiones Árticas , Monitoreo del Ambiente , Plásticos , Contaminantes Químicos del Agua/análisisRESUMEN
Cancer stem cells (CSCs) are a source of tumour recurrence in patients with nasopharyngeal carcinoma (NPC); however, the function of microRNA-124 (miR-124) in NPC CSCs has not been clearly defined. In this study, we investigated the role of miR-124 in NPC CSCs. qRT-PCR was performed to measure miR-124 expression in NPC tissues and cell lines and the effects of miR-124 on stem-like properties and radiosensitivity of NPC cells measured. Luciferase reporter assays and rescue experiments were used to investigate the interaction of miR-124 with the 3'UTR of junctional adhesion molecule A (JAMA). Finally, we examined the effects of miR-124 in an animal model and clinical samples. Down-regulation of miR-124 was detected in cancer tissues and was inversely associated with tumour stage and lymph node metastasis. Overexpression of miR-124 inhibited stemness properties and enhanced radiosensitivity of NPC cells in vitro and in vivo via targeting JAMA. Up-regulation of miR-124 was correlated with superior overall survival of patients with NPC. Our study demonstrates that miR-124 can inhibit stem-like properties and enhance radiosensitivity by directly targeting JAMA in NPC. These findings provide novel insights into the molecular mechanisms underlying therapy failure in NPC.
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Molécula A de Adhesión de Unión/genética , MicroARNs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Tolerancia a Radiación/genética , Regiones no Traducidas 3'/genética , Animales , Línea Celular Tumoral , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metástasis Linfática/genética , Ratones , Ratones Endogámicos BALB C , Recurrencia Local de Neoplasia/genética , Células Madre Neoplásicas/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: Microglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized. METHODS: We used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia. RESULTS: We found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR. CONCLUSIONS: Our findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.
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Senescencia Celular/efectos de la radiación , Microglía/metabolismo , ARN Largo no Codificante/metabolismo , Transducción de Señal/efectos de la radiación , Animales , Línea Celular , Ratones , Microglía/efectos de la radiación , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , ARN Largo no Codificante/genética , Radiación IonizanteRESUMEN
BACKGROUND: Despite improvements in nasopharyngeal carcinoma (NPC) treatment, patients with recurrence and metastasis still have a poor prognosis. Thus, the identification of novel biomarkers is urgently needed to predict outcomes and tailor treatment for NPC. METHODS: Four data sets were downloaded from Gene Expression Omnibus, and one data set GSE68799 of which was applied to filtrate key modules and hub genes by construction of a co-expression network. Other data sets (GSE12452 and GSE53819) were used to verify hub genes. The data set GSE102349 was devoted to identify prognostic hub genes by survival analysis. To explored whether prognostic hub genes are related to hypoxia signatures in NPC, correlation analysis was carried out, and followed by functional verification experiments of those genes in vitro. RESULTS: By co-expression network analysis, blue module was regarded as a key module in the benign and malignant group, and IGSF9 of the blue module was identified as a prognostic hub gene. Moreover, IGSF9 is expected to be a innovative hypoxia-related gene in NPC based on the strong associativity between expression of IGSF9 and hypoxia scores of three signatures (99-gene, 26-gene and 15-gene). Further functional studies verified that down-regulated expression of IGSF9 could reduce the proliferation, migration and invasion ability of NPC cells, and hypoxia could induce the expression of IGSF9. CONCLUSION: IGSF9 was identified to be relevant to prognosis and involved in hypoxia in NPC. IGSF9 might serve as one novel prognostic indicator of NPC in the future.
RESUMEN
Pollution with total petroleum hydrocarbons (TPHs) is a global concern and particularly in coastal environments. Polycyclic aromatic hydrocarbons (PAHs) are regarded as the most toxic components of TPHs and they can also be derived from other sources. Fangcheng Port is considered as a representative emerging coastal city in China, but the status, sources, and hazards to organisms and humans with respect to contamination with PAHs and TPHs are unknown in the coastal regions of this area. Therefore, in this study, we cloned cytochrome P450 family genes (CYP1A1, CYP3A, and CYP4) and heat shock protein 70 gene (HSP70) in the clam Meretrix meretrix as well as optimizing the method for measuring the 7-ethoxyresorufin O-deethylase activity. These molecular indicators and four specific physiological indexes were found to be appropriate biomarkers for indicating the harmful effects of PAHs and TPHs on clams after exposure to the crude oil water-soluble fraction. In field monitoring surveys, we found that the 2- and 3-ring PAHs were dominant in the clams whereas the 4- to 6-ring PAHs were dominant in the sediments at each site. The PAH levels (3.63-12.77 ng/g wet weight) in wild clams were lower, whereas the TPH levels (13.25-70.50 µg/g wet weight) were higher compared with those determined previous in China and elsewhere. The concentrations of PAHs and TPHs in the sediments (19.20-4215.76 ng/g and 3.65-866.40 µg/g dry weight) were moderate compared with those in other global regions. Diagnostic ratio analysis demonstrated that the PAHs were derived mainly from pyrogenic sources. The TPHs may have come primarily from industrial effluents, land and maritime transportation, or fishing activities. The Integrated Biomarker Response version 2 indexes indicated that the clams collected from site S5 exhibited the most harmful effects due to contamination by PAHs and TPHs. Human health risk assessments demonstrated that the risks due to PAHs and TPHs following the consumption of clams can be considered acceptable. Our results suggest that continuous monitoring of contamination by PAHs and TPHs is recommended in this emerging coastal city as well as assessing their human health risks.
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Monitoreo Biológico/métodos , Bivalvos/efectos de los fármacos , Biomarcadores Ambientales/efectos de los fármacos , Sedimentos Geológicos/química , Hidrocarburos Policíclicos Aromáticos/análisis , Contaminantes Químicos del Agua/análisis , Animales , Bivalvos/metabolismo , China , Ciudades , Humanos , Hidrocarburos Policíclicos Aromáticos/metabolismo , Urbanización , Contaminantes Químicos del Agua/metabolismoRESUMEN
Recurrence or metastasis resulting from radioresistance are the main challenges for the treatment of nasopharyngeal carcinoma (NPC). A great deal of evidence supports the role of abnormal expression of miRNAs in radioresistance and malignancy. In some cancers, miR-483-5p is associated with inferior disease-specific survival. Therefore, we investigated the role of miR-483-5p in NPC radiosensitivity and the mechanism by which the miR-483-5p affects the radiosensitivity of NPC cells. In this study, we show that the overexpression of miR-483-5p decreases the radiosensitivity of NPC cells in vitro and in vivo. Mechanistically, miR-483-5p exerts these functions by decreasing radiation-induced apoptosis and DNA damage, and by increasing NPC cell colony formation, via targeting death-associated protein kinase 1 (DAPK1). Finally, our results confirm that the upregulation of miR-483-5p is correlated with advanced clinical stage and inferior overall survival of patients with NPC. These findings provide novel insights into our understanding of the molecular mechanisms underlying therapy failure in NPC. Modulation of miR-483-5p and DAPK1 levels may provide a new approach for increasing the radiosensitivity of these tumors.
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Proteínas Quinasas Asociadas a Muerte Celular/genética , MicroARNs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Tolerancia a Radiación/genética , Regiones no Traducidas 3'/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Quimioradioterapia/métodos , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/terapia , Interferencia de ARN , Análisis de Supervivencia , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Pathogenic disease is a major factor affecting the aquaculture of the rockfish Sebastiscus marmoratus, an important commercial species inhabiting the nearshore waters of the Western Pacific Ocean. Antimicrobial peptides (AMPs), as critical components of innate immunity, have been considered as promising antibiotic substitutes. The aims of this study were 1) to identify major AMPs in the rockfish, 2) to assess their antimicrobial activity and 3) to evaluate their potential therapeutic application. Six AMPs were identified, Hepcidin 1, liver-expressed antimicrobial peptide 2 (LEAP-2), Piscidin, Moronecidin, NK-lysin and ß-defensin through analysis of the liver transcriptome of S. marmoratus. The transcriptional expression profiles of these AMPs were investigated by real-time quantitative PCR (RT-qPCR). These AMPs showed tissue-specific distribution patterns, and S. marmoratus displays a time-, dose- and tissue-dependent expression of AMPs in response to lipopolysaccharide (LPS) challenge. While the synthetic peptides of LEAP-2 and Moronecidin exerted broad-spectrum antimicrobial activity against important aquatic pathogens in vitro by directly disrupting microbial membrane, and no cytotoxicity against murine hepatic cells was observed at the effective concentrations from 5⯵M to 40⯵M. The existence of multiple AMPs and their distinct tissue distribution patterns and inducible expression patterns suggests a sophisticated, highly redundant, and multilevel network of antimicrobial defensive mechanisms of S. marmoratus. Therefore, S. marmoratus-derived AMPs appear to be potential therapeutic applications against pathogen infections in aquaculture.
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Péptidos Catiónicos Antimicrobianos/genética , Péptidos Catiónicos Antimicrobianos/inmunología , Perciformes/genética , Perciformes/inmunología , Animales , Antiinfecciosos/inmunología , Péptidos Catiónicos Antimicrobianos/metabolismo , Línea Celular , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Proteínas de Peces/metabolismo , Perfilación de la Expresión Génica/veterinaria , Humanos , Lipopolisacáridos/farmacología , Ratones , Perciformes/metabolismoRESUMEN
Agents targeting epidermal growth factor receptor (EGFR) are used to treat head and neck squamous cell carcinoma (HNSCC); however, their efficacy and safety is poorly understood. Here we evaluated the efficacy and safety of anti-EGFR agents administered concurrently with standard therapies for HNSCC. Randomized controlled trials that evaluated addition of EGFR targeted therapy versus standard therapy alone were included. The primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate (ORR), locoregional control, and severe adverse events (SAEs, grade ≥ 3). Sixteen eligible trials with 4031 patients were included. Addition of anti-EGFR regimens to standard therapy significantly improved OS of patients with HNSCC (HR = 0.89; 95% CI, 0.82-0.96), with a moderately elevated rate of SAEs (RR = 1.08; 95% CI, 1.03-1.13). Subgroup analysis indicated that the survival benefit was observed when cetuximab was administered concurrently with radiotherapy (RT) for stage III/IV patients (HR = 0.76; 95% CI, 0.61-0.94; p = 0.01), or with chemotherapy for recurrent or metastatic (R/M) HNSCC (HR = 0.86; 95% CI, 0.78-0.95; p = 0.005). Significantly increased ORR (RR = 1.51; 95% CI 1.05-2.18) and PFS (HR = 0.72; 95% CI, 0.59-0.88) were found in R/M HNSCC patients treated with anti-EGFR plus chemotherapy, while no significant improvements were found in stage III/IV patients treated with anti-EGFR plus standard therapy. In conclusion, addition of cetuximab to standard therapy may improve outcomes for R/M HNSCC patients, while causing a moderate increase in SAEs. For stage III/IV patients, anti-EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Femenino , Estudios de Seguimiento , Humanos , Masculino , Terapia Molecular Dirigida , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The aim of this study was to characterize dose- and time-dependent responses of gill 7-ethoxyresorufin O-deethylase (EROD) activity from Juvenile marbled rockfish (Sebastiscus marmoratus) exposed to the water-accommodated fraction (WAF) of crude oil and heavy metal Cd(â ¡) or Pb(â ¡) alone or in mixture. Compared to the control group, gill filament EROD activity in S. marmoratus was significantly induced after exposure to the WAF from 80 to 320µg/L for 5 days in dose response experiment and after exposure to 40µg/L WAF for 6-10 days in time course experiment, respectively. In the other hand, gill filament EROD activity were not significantly affected compared to the control group or related WAF groups no matter in the dose response experiment or in the time course experiment of Cd(â ¡), Pb(â ¡) or its mixture with WAF. The results suggest the use of gill filament EROD activity as a biomarker of exposure to waterborne AhR agonists in marine ecosystems while simultaneously being exposed to environmental concentrations of Cd(â ¡) or Pb(â ¡).
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Lubina , Cadmio/toxicidad , Citocromo P-450 CYP1A1/metabolismo , Branquias/efectos de los fármacos , Plomo/toxicidad , Petróleo/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Biomarcadores/metabolismo , Proteínas de Peces/metabolismo , Branquias/enzimologíaRESUMEN
Legionella pneumophila (L. pneumophila) is a prevalent pathogenic bacterium responsible for significant global health concerns. Nonetheless, the precise pathogenic mechanisms of L. pneumophila have still remained elusive. Autophagy, a direct cellular response to L. pneumophila infection and other pathogens, involves the recognition and degradation of these invaders in lysosomes. Histone deacetylase 6 (HDAC6), a distinctive member of the histone deacetylase family, plays a multifaceted role in autophagy regulation. This study aimed to investigate the role of HDAC6 in macrophage autophagy via the autophagolysosomal pathway, leading to alleviate L. pneumophila-induced pneumonia. The results revealed a substantial upregulation of HDAC6 expression level in murine lung tissues infected by L. pneumophila. Notably, mice lacking HDAC6 exhibited a protective response against L. pneumophila-induced pulmonary tissue inflammation, which was characterized by the reduced bacterial load and diminished release of pro-inflammatory cytokines. Transcriptomic analysis has shed light on the regulatory role of HDAC6 in L. pneumophila infection in mice, particularly through the autophagy pathway of macrophages. Validation using L. pneumophila-induced macrophages from mice with HDAC6 gene knockout demonstrated a decrease in cellular bacterial load, activation of the autophagolysosomal pathway, and enhancement of cellular autophagic flux. In summary, the findings indicated that HDAC6 knockout could lead to the upregulation of p-ULK1 expression level, promoting the autophagy-lysosomal pathway, increasing autophagic flux, and ultimately strengthening the bactericidal capacity of macrophages. This contributes to the alleviation of L. pneumophila-induced pneumonia.
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Legionella pneumophila , Legionella , Enfermedad de los Legionarios , Neumonía , Animales , Ratones , Autofagia , Histona Desacetilasa 6/genética , Legionella pneumophila/genética , Enfermedad de los Legionarios/genética , MacrófagosRESUMEN
PURPOSE: Carotid artery invasion (CAI) has been demonstrated to be an important prognosticator in some head and neck cancers. This study aimed to examine the prognostic value of radiologic CAI (rCAI) by cervical lymphadenopathy in nasopharyngeal carcinoma (NPC). METHODS: NPC patients treated between January 2013 and December 2016 were included. Pre-treatment MRIs were reviewed for cervical rCAI according to the radiologic criteria. Univariate and multivariate models were constructed to assess the association between cervical rCAI and clinical outcomes. A new N classification system was proposed and compared to the 8th AJCC system. RESULTS: The percentage of patients with MRI-positive lymph nodes was 84.7% (494/583), of whom cervical rCAI cases accounted for 42.3% (209/494). Cervical rCAI was associated with significantly poorer OS, DFS, DFFS and RFFS compared to non-rCAI (P < 0.05). Multivariate analyses confirmed that cervical rCAI was an independent prognosticator for DFS and DFFS, surpassing other nodal features, such as laterality, size, cervical node necrosis (CNN) and radiologic extranodal extension (rENE), while location of positive LNs remained independently associated with OS, DFS and DFFS. We propose a refined N classification: New_N1: upper neck LNs only without cervical rCAI; New_N2: upper neck LNs only with cervical rCAI; New_N3: upper and lower LNs. The proposed classification broadened the differences in OS, DFS and DFFS between N1 and N2 disease, and achieved a higher c-index for DFS and DFFS. CONCLUSIONS: Cervical rCAI was an independent unfavorable indicator of NPC. Compared to the AJCC system, the proposed N category showed satisfactory stratification between N1 and N2 disease, and better prediction of distant metastasis and disease failure.
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Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo , Pronóstico , Neoplasias Nasofaríngeas/diagnóstico por imagen , Neoplasias Nasofaríngeas/tratamiento farmacológico , Estadificación de Neoplasias , Metástasis Linfática/patología , Estudios Retrospectivos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Imagen por Resonancia Magnética/métodos , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patologíaRESUMEN
BACKGROUND: Epigenetic mechanismshave been reported to involve in shaping tumor immune microenvironment (TME). However, the role of RNA N6-methyladenosine (m6A) modification in breast cancerhas not been fully explored. METHODS: Based on m6A modification and TME infiltration characteristics of 2249 breast cancer patients, we comprehensively correlated m6A modification with immune landscapeby screeningcandidate genes, function analysis and constructing m6Asignatures. Principal component analysis was used to establish the m6Ascore. Both LASSO and Cox regression analyses were used to evaluate its prognostic value.Functional assays and immunohistochemistry were used to evaluate the expression of m6A regulators and immune cell infiltration. RESULTS: Based on the dysregulated expression of m6A, three distinct clusters were identified that displayed diverse types of tumour-associated TME cell infiltration in breast cancer.Gene signatures, stromal activity, and clinical prognosis were assessed by the m6Ascore. m6Ascore could function as a biomarker for predicting the therapeutic response to targeted therapy and immunotherapy.The dysregulated expression of m6Aregulators mediated the immune cell infiltration in the TME. CONCLUSION: Basedonthestudy,weidentified the signature and potential mechanism of m6AmodificationsthatmodifyTME cell infiltration. Thus, targeting m6A regulators may provide a promisingmethodoftreatingBRCA.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Mama , Adenosina/genética , Epigenómica , Microambiente Tumoral/genéticaRESUMEN
Although evidence suggests the ubiquity of meso- and microplastics (MMPs) in mangrove forests, our knowledge of their bioavailability and risk on mangrove leaves is scarce. Here, we investigated MMP contamination concerning submerged mangrove leaves and herbivorous snails that mainly feed on them from the four mangrove forests located in Beibu Gulf, Guangxi Province, China. Results showed that the MMP abundance on the mangrove leaves ranged from 0.01 ± 0.00 to 0.42 ± 0.15 items cm-2, while it ranged from 0.33 ± 0.21 to 6.20 ± 2.91 items individual-1 in the snails. There were significant positive correlations between snails and leaves regarding the abundance of total MMPs and the proportions of MMPs with the same characteristics. Expanded polystyrene (EPS) that mainly derived from aquaculture rafts, accounted for a major component both on the leaves and in the snails in Shi Jiao (SJ). Both the detection frequency and percentage of larger EPS (2.00-17.50 mm) on the leaves in SJ were higher than other sites. Meanwhile, the detection frequency, abundance and percentage of larger EPS on the leaves had significant positive correlations with those of micro-EPS in the snails. These findings suggested that mangrove leaves may represent a viable pathway for MMPs to enter the herbivorous snails. Larger EPS with higher frequency of occurrence on mangrove leaves were more likely to be encountered and ingested by snail considering its opportunistic feeding behavior. In addition, 11 sensitive genes involved in the processes of metabolism, intestinal mucosal immune systems, and cellular transduction in the snails were significantly suppressed by MMP exposure, which may be potentially used as early biomarkers to indicate the biological effects of MMPs under realistic environmental conditions. Overall, this study provides novel insights into the fate, sources, and biological effects of MMPs on mangrove leaves.