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Epithelial ovarian cancer (EOC) is an often-fatal malignancy marked by the development of resistance to platinum-based chemotherapy. Thus, accurate prediction of platinum drug efficacy is crucial for strategically selecting postoperative interventions to mitigate the risks associated with suboptimal therapeutic outcomes and adverse effects. Tissue-derived extracellular vesicles (tsEVs), in contrast to their plasma counterparts, have emerged as a powerful tool for examining distinctive attributes of EOC tissues. In this study, 4D data-independent acquisition (DIA) proteomic sequencing was performed on tsEVs obtained from 58 platinum-sensitive and 30 platinum-resistant patients with EOC. The analysis revealed a notable enrichment of differentially expressed proteins that were predominantly associated with immune-related pathways. Moreover, pivotal immune-related proteins (IRPs) were identified by LASSO regression. These factors, combined with clinical parameters selected through univariate logistic regression, were used for the construction of a model employing multivariate logistic regression. This model integrated three tsEV IRPs, CCR1, IGHV_35 and CD72, with one clinical parameter, the presence of postoperative residual lesions. Thus, this model could predict the efficacy of initial platinum-based chemotherapy in patients with EOC post-surgery, providing prognostic insights even before the initiation of chemotherapy.
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Carcinoma Epitelial do Ovário , Vesículas Extracelulares , Neoplasias Ovarianas , Humanos , Feminino , Vesículas Extracelulares/metabolismo , Carcinoma Epitelial do Ovário/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Idoso , Resistencia a Medicamentos Antineoplásicos , Platina/uso terapêutico , Platina/farmacologia , Adulto , Proteômica/métodos , Prognóstico , Biomarcadores Tumorais/metabolismoRESUMO
The expanding impact of algal blooms on marine areas poses a severe threat to the sustainable development of aquaculture, human health, and the ecological safety of coastal areas. To address this issue, the exploration of natural algicidal compounds with high efficiency, selectivity, and environmental friendliness has gained attention as potential substances for algae removal. However, the integration of related work still needs to be improved. Therefore, an in-depth study of algicidal strategies and applications of algicidal compounds for biodiversity has become crucial. Here, we aim to consolidate the current advancements in research on the sources and types of algicidal compounds. We also delve into various algicidal strategies, including the damage inflicted on algal structures, inhibition of photosynthesis, effects on oxidative damage, and impacts on gene expression. Additionally, we highlight practical applications of algicidal compounds, taking into account their specificities and limitations. This review contributes to the protection of marine biodiversity and the promotion of sustainable environmental development. Furthermore, we provide recommendations for future research on algicidal compounds to overcome existing barriers. By doing so, we hope to offer valuable references for researchers engaged in further studies on managing algal outbreaks.
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BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated. METHODS: In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology. RESULTS: GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect. CONCLUSION: Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.
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Introduction: Ovarian cancer (OV) is a highly lethal gynecological malignancy with a poor prognosis. Lactate metabolism is crucial for tumor cell survival, proliferation, and immune evasion. Our study aims to investigate the role of lactate metabolism-related genes (LMRGs) in OV and their potential as biomarkers for prognosis, immune microenvironment, and immunotherapy response. Methods: Ovarian samples were collected from the TCGA cohort. And 12 lactate-related pathways were identified from the MsigDB database. Differentially expressed genes within these pathways were designated as LMRGs, which undergo unsupervised clustering to identify distinct clusters based on LMRGs. Subsequently, we assessed survival outcomes, immune cell infiltration levels, Hallmaker pathway activation patterns, and chemotaxis among different subtypes. After conducting additional unsupervised clustering based on differentially expressed genes (DEGs), significant differences in the expression of LMRGs between the two clusters were observed. The differentially expressed genes were subjected to subsequent functional enrichment analysis. Furthermore, we construct a model incorporating LMRGs. Subsequently, the lactate score for each tumor sample was calculated based on this model, facilitating the classification of samples into high and low groups according to their respective lactate scores. Distinct groups examined disparities in survival prognosis, copy number variation (CNV), single nucleotide variation (SNV), and immune infiltration. The lactate score served as a quantitative measure of OV's lactate metabolism pattern and an independent prognostic factor. Results: This study investigated the potential role of LMRGs in tumor microenvironment diversity and prognosis in OV, suggesting that LMRGs play a crucial role in OV progression and the tumor microenvironment, thus serving as novel indicators for prognosis, immune microenvironment status, and response to immunotherapy.
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Variações do Número de Cópias de DNA , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Prognóstico , Ácido Láctico , Microambiente Tumoral/genéticaRESUMO
OBJECTIVE: Fear of falling (FOF) is common among older adults. Currently, physical exercise, cognitive intervention, and combined physical and cognitive intervention have been proven to be effective interventions. However, whether combined interventions can provide additional benefits than single interventions remains unclear. Thus, the systematic and meta-analysis was conducted to explore the immediate and retention effects of combined physical and cognitive interventions, in comparison with a single intervention. MATERIALS AND METHODS: Randomized controlled trials of combined interventions on FOF in older adults were searched using Web of Science, PubMed, Cochrane Library, EMBASE, SCOPUS, CINAHL, and PsycINFO from inception to March 20, 2023. The risk of bias in included studies was evaluated using the Cochrane Collaboration Risk of Bias tool. Two independent researchers extracted the data using predetermined criteria. RESULTS: 31 studies were included in the systematic review and meta-analysis. For the immediate post-intervention effect, the combined intervention was more effective than the blank/placebo/conventional intervention and the single cognitive intervention, while no additional effect was observed compared with the single physical intervention. Moreover, no additional follow-up retention effects were found when comparing the combined intervention with the single intervention. CONCLUSIONS: Combined interventions had positive immediate effects on FOF in older adults, compared with single cognitive intervention, while combined interventions had a similar effect as a single physical intervention. More well-designed studies are required to explore the additional benefits of combined interventions compared with a single intervention and to investigate the follow-up effects of combined interventions.
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Exercício Físico , Medo , Humanos , Idoso , Cognição , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
N6-methyladenosine (m6A) RNA methylation, a dynamic regulator of transcript expression, plays a pivotal role in cancer by influencing diverse mRNA processes, including nuclear export, splicing, translation and decay. It intersects with cancer biology, impacting progression, treatment sensitivity and prognosis. Platinum-based compounds are essential in cancer treatment, while intrinsic or acquired resistance poses a formidable challenge, limiting therapeutic efficacy. Recent breakthroughs have established a direct association between m6A RNA methylation and platinum resistance in various cancer types. This review summarized related studies, aiming to provide profound insights into the interplay between m6A-associated regulation and platinum-resistance mechanisms in cancer. It explores therapeutic approaches, including personalized treatments based on m6A profiles, guiding future research to enhance clinical strategies for oncological prognostic outcomes.
Cancer poses a global health challenge, with platinum-based drugs as a cornerstone of treatment. Regrettably, cancer cells can develop resistance to these drugs, diminishing their effectiveness. Recent research suggests that a subtle modification known as N6-methyladenosine (m6A) on RNA molecules may contribute to this resistance. m6A acts as a minuscule tag on RNA molecules within the cells, akin to a genetic switch. When altered, it can render cancer cells less responsive to platinum-based drugs. Scientists have found that m6A changes in various cancer types can bolster resistance to platinum-based drugs. This reduced drug efficacy presents a significant concern, as platinum-based drugs are vital in treating diverse cancer types, including ovarian, lung and colorectal cancer. Understanding the impact of m6A on platinum resistance is pivotal. It may enable doctors to identify patients less likely to respond to treatment. Researchers are also investigating methods to target m6A alterations in cancer cells, potentially rendering them more receptive to platinum-based drugs. Ongoing research into m6A and its role in platinum resistance holds promise for enhancing cancer treatments, ultimately increasing the chances of success for patients requiring platinum-based drugs.
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Adenosina , Metilação de RNA , Humanos , Splicing de RNA , RNA Mensageiro , RNARESUMO
PURPOSE: This study sought to examine grouped and right-censored (GRC) counts of adolescent marijuana use and estimate its temporal trajectories and sociodemographic disparities over almost half a century. METHODS: After compiling 46 waves of nationally representative data from the Monitoring the Future (MTF) study from 1976 to 2021 (sample size = 491,348), we utilized an innovative modified Poisson (mixture) approach to analyze past-year marijuana use quantified by GRC counts. RESULTS: The overall reduction in incidence rates of marijuana use was attributable to an almost 40% reduction in the risk of marijuana use (with the proportion of at-risk adolescents at 51.36% in 1979 and 31.53% in 2021). Despite substantial changes over the study period, the recent incidence rates for at-risk individuals were similar to those in the early 1980s. Living in an intact family was a protective factor against adolescent marijuana use over time. CONCLUSIONS: The incidence rates of marijuana use among at-risk students, especially those from disadvantaged families, remained high over the study period. The modified Poisson (mixture) approach serves as the preferred tool for modeling GRC responses. It is essential to distinguish among risk, at-risk incidence, and overall incidence when assessing substance use and other risky behaviors.
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Comportamento do Adolescente , Abuso de Maconha , Fumar Maconha , Uso da Maconha , Transtornos Relacionados ao Uso de Substâncias , Adolescente , Humanos , Estados Unidos/epidemiologia , Uso da Maconha/epidemiologia , Fumar Maconha/epidemiologia , Abuso de Maconha/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
We demonstrate a chip-based octave-spanning soliton microcomb in a whispering gallery mode microresonator platform. By fabricating a silica microdisk resonator and optimizing its dispersion with dry etching, we achieve an octave-spanning single-soliton microcomb with a repetition rate of â¼670â GHz at an optical pump power of 162.6â mW. Also, two dispersive waves at the end of the spectrum are observed to extend the comb spectral range and improve the comb power.
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OBJECTIVE: The aim was to assess the expression levels of SLC7A11 and GPX4 in relation to platinum resistance and prognosis in patients with epithelial ovarian cancer (EOC). DESIGN: A retrospective cohort study. SETTING: Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China. POPULATION OR SAMPLE: We included 192 eligible patients from hospital between January 2002 and December 2018. METHODS: We retrospectively analysed the medical records of patients with EOC. Surgical specimens of EOC were stained for SLC7A11 and GPX4. Survival analysis was performed using the Kaplan-Meier and Cox regression methods. MAIN OUTCOME MEASURES: Clinical end points include platinum-free interval (PFI), progression-free survival (PFS) and overall survival (OS). RESULTS: Patients with high co-expression levels of SLC7A11 and GPX4 had a 60-fold higher risk of platinum resistance compared with those with low co-expression (risk ratio, 60.46; 95% confidence interval [CI] 22.76-160.58; p < 0.001). Moreover, high co-expression level of SLC7A11 and GPX4 was an independent prognostic factor for poor OS (p < 0.001, hazard ratio [HR] 4.44, 95% CI, 2.77-7.14) and poor PFS (p < 0.001, HR = 5.73, 95% CI, 3.86-8.73). For in vitro experiments, SLC7A11 and GPX4 expression were both upregulated in platinum-resistant cells compared with their parental ovarian cancer cells, and siRNA-induced SLC7A11 and GPX4 inhibition decreased platinum resistance. CONCLUSIONS: High expression levels of SLC7A11 and GPX4 are associated with platinum resistance in EOC patients. High co-expression of SLC7A11 and GPX4 may be a significant independent prognostic factor and a potential therapeutic target for platinum resistance in EOC patients.
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Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Neoplasias Ovarianas , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Feminino , Humanos , Sistema y+ de Transporte de Aminoácidos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Epiteliais e Glandulares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Platina/metabolismo , Platina/uso terapêutico , Prognóstico , Estudos Retrospectivos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismoRESUMO
Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.
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Alphapapillomavirus , Infecções por Papillomavirus , Humanos , Alphapapillomavirus/metabolismo , Carcinogênese , Proteínas de Choque Térmico , Resposta ao Choque Térmico , Papillomaviridae , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Complexo de Endopeptidases do Proteassoma , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , Ubiquitina , Proteínas de Ligação a RNARESUMO
Two-dimensional MXene materials with high electrotonic conductivity, good chemical stability, and unique laminar structure show great potential in the field of electrochemistry. In contrast to the widely concerned electrical properties, studies on the thermal properties of MXene materials are very limited. This paper presents a comprehensive analysis of the thermal properties of Ti3C2TxMXene thin film. Thermal diffusivity and thermal conductivity of Ti3C2Txfilms are characterized by the transient electro-thermal technique. The experimental results show a 16% enhancement in thermal conductivity when the temperature is increased from 307 K to 352 K. The phonon transport contributes substantially to thermal conductivity compared with electron transport. Molecular dynamic simulation is employed to further investigate the role of phonon thermal transport of Ti3C2layer. It is found that the combined effect of specific heat capacity, stacking structure and internal stress states is responsible for the thermal transport performance of Ti3C2TxMXene thin film.
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AIMS AND OBJECTIVES: To evaluate the effectiveness of family-based intervention for adults with diabetes on glycosylated haemoglobin and other health-related outcomes. BACKGROUND: The impact of family-based intervention on adults with diabetes has been evaluated in various studies, but there is uncertainty about their effect on health-related outcomes for adults with diabetes. DESIGN: A systematic review and meta-analysis of randomised controlled trials. METHODS: A review was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Six relevant databases were searched from inception to 5 March 2021. Heterogeneity between studies was quantified by using Higgins' I2 test. Sensibility and subgroup analyses were used to explore potential heterogeneity. RESULTS: The review included 23 studies (3,114 participants). Family-based intervention had a significant effect on improving glycosylated haemoglobin levels, body mass index, blood pressure, fasting glucose, diabetes self-care, diabetes self-efficacy, diabetes distress and positive family support. Non-significant results were obtained for blood lipid, body weight, depression and negative family support. In particular, subgroup analyses indicated that family-based intervention in Asian regions was more effective in improving glycosylated haemoglobin levels than in other areas. CONCLUSION: Family-based intervention may improve diabetes control, diabetes self-care, psychological well-being and positive family support in adults with diabetes and is especially effective in Asian regions. Given the limitations in current studies, further studies are recommended to combine family theory with family-based intervention, and to examine the effectiveness of such intervention for family members. RELEVANCE TO CLINICAL PRACTICE: This review and meta-analysis provides evidence that family-based intervention can improve positive family support, which has a good effect on diabetes control and psychological well-being in adults with diabetes, and it is especially effective in Asian regions. Findings suggested that unreinforced participation by family members and integrating flexible strategies into family-based intervention may be equally effective.
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Diabetes Mellitus Tipo 2 , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/psicologia , Hemoglobinas Glicadas , Humanos , Autocuidado , AutoeficáciaRESUMO
Non-nutritive sweeteners are the most widely used food additives designed to provide sweetness and reduce caloric intake. Studies have confirmed a link between sweeteners and colitis, yet supporting scientific data remain exiguous and controversial. In this study, three common sweeteners (Saccharin sodium, Stevioside, and Sucralose) in acceptable daily intake dosage were added to water in order to determine their effects on dextran sodium sulfate-induced colitis in mice. Our results show that the three sweeteners meliorate colitis to varying degreesâSaccharin exerts the most pronounced effect, followed by Stevioside and Sucralose. Intake of sweeteners alleviates colitis symptoms, alters gut microbiota, reshapes the TH17/Treg balance, protects the intestinal barrier, and reduces inflammation. Most significantly, sweeteners can enhance the abundance of Mucispirillum and Alistipes, which are conducive to colitis recovery, and upregulate the expression of E-cadherin through the miR-15b/RECK/MMP-9 axis to improve intestinal barrier integrity. Moreover, by inhibiting the MMP-9/AKT/NF-κB pathway, inflammation is relieved, as reflected in the restoration of the Th17/Treg balance. Our results link the consumption of sweeteners to the remission of colitis, which provides new scientific evidence for the safe use of sweeteners.
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Colite , MicroRNAs , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Colo , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Homeostase , Metaloproteinase 9 da Matriz , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Sulfatos , EdulcorantesRESUMO
Cerium (IV)-based metal-organic frameworks (MOFs) are highly desirable due to their unique potential in fields such as redox catalysis and photocatalysis. However, due to the high reduction potential of CeIV species in solution, it is still a great challenge to synthesize CeIV -MOFs with novel structures, which are extremely dominated by the hexanuclear Ce-O cluster inorganic building units (IBUs). Herein, a Ce-O IBU chain containing CeIV -MOF, CSUST-3 (CSUST: Changsha University of Science and Technology), was successfully prepared using the kinetic stabilization study of UiO-66(Ce)-NDC (H2 NDC=2,6-naphthalenedicarboxylic acid). Furthermore, owing to the superior redox activity, Lewis acidity and semiconductor-like behavior owing to Ce4+ , activated CSUST-3 was demonstrated to be an excellent catalyst for CO2 chemical fixation. One-pot synthesis of styrene carbonate from styrene and CO2 was achieved under mild conditions (1â atm CO2 , 80 °C, and solvent free). Moreover, activated CSUST-3 was shown to be a remarkable co-catalyst-free photocatalyst for overall water splitting (OWS), rendering 59â µmol g-1 h-1 of H2 and 22â µmol g-1 h-1 of O2 under simulated sunlight irradiation (Na2 S-Na2 SO3 as sacrificial agent).
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Optical frequency combs (OFCs) are essential in precision metrology, spectroscopy, distance measurement, and optical communications. Significant advances have been made recently in achieving micro-OFC devices based on parametric frequency conversion or electro-optic phase modulation. Here, we demonstrate a new kind of microcomb using a cavity optomechanical system with giant oscillation amplitude. We observe both optical and microwave frequency combs in a microtoroid resonator, which feature a flat OFC with 938 comb lines and a repetition rate as low as 50.22 MHz, as well as a flat microwave frequency comb with 867 comb lines. To generate such giant oscillation amplitude, we excite an overcoupled optical mode with a large blue detuning that is assisted with the thermo-optic nonlinearity. A new type of nonlinear oscillation, induced by competition between the optomechanical oscillation and thermo-optic nonlinearity, is also observed.
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This study was conducted to investigate the connection between social support and the treatment burden among older patients with chronic obstructive pulmonary disease (COPD), and to examine the mediating role of psychological capital within that connection. Although treatment burden is common, the current data on social support associated with it is limited, and the theoretical mechanisms underlying the relationship between the two variables have not yet been clarified. A total of 245 older outpatients with COPD were recruited. Descriptive and Structural Equation Modelling was employed to test the hypothesised model using SPSS 26 and IBM SPSS AMOS 26. The modified model yielded an adequate fit to the data. The variation in the treatment burden explained by the hypothetical model was 57.2%. The study provides a new perspective for medical professionals to manage the treatment burden by developing efficient social support and psychological capital measures.
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Doença Pulmonar Obstrutiva Crônica , Apoio Social , Humanos , Análise de Classes Latentes , Doença Pulmonar Obstrutiva Crônica/terapiaRESUMO
AIM: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the autoimmune encephalitis, which often occurs in children and young adults, especially in young women. In addition to viral infection, teratoma is an important causative factor. Anti-NMDAR encephalitis is well known to neurologist. However, this is less well known to gynecologists, who may have a decisive role in etiological management. Therefore, from the perspective of gynecologists, we provide an overview of the relationship between the encephalitis and ovarian teratoma, the clinical features and treatment of this disease, and prognosis of pregnant women with this encephalitis. METHODS: We searched the PubMed database using the search terms in various combinations "teratoma," "dermoid cyst," "ovary," "ovarian," "anti-NMDAR encephalitis," and "N-methyl-D-aspartate receptor." RESULTS: According to the current literature, the mechanism of anti-NMDAR encephalitis is probably due to the ectopic expression of the NMDAR in the teratomas tissue. The disease has a high mortality rate if not treated promptly and effectively. An important way to improve patients' outcome is to remove the ovarian tumor in time. Pregnant women are also at risk of developing anti-NMDAR encephalitis during pregnancy. The fetal outcome is usually better in patients with mid- to late-pregnancy onset than in early pregnancy, and patients are often able to maintain their pregnancies into late pregnancy. CONCLUSION: Young women with sudden onset of abnormal psychiatric behavior should be actively screened for ovarian tumors and, if confirmed to be teratoma-associated anti-NMDAR encephalitis, should undergo gynecologic surgery as early as possible, which can help improve their prognosis.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Neoplasias Ovarianas , Teratoma , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Criança , Feminino , Humanos , Gravidez , Prognóstico , Receptores de N-Metil-D-Aspartato , Adulto JovemRESUMO
Tea polyphenol of epigallocatechin-3-gallate (EGCG) has been verified to possess multiple biological activities. Interleukin-23 (IL-23) is a heterodimeric cytokine consisting of two subunits of IL-23p19 and IL-12p40, with the functionality in regulating the production of cytokines under physiological or pathological conditions. By serendipity, the raised expression of IL-23 was observed after treating cells with EGCG, whereas the detailed mechanism remains poorly understood. This study was proposed to investigate the signaling related to EGCG-induced IL-23. The raised expression of IL-23 was confirmed primarily by intraperitoneally injecting with different concentrations of EGCG (0, 20, 50, 80 mg/kg) into BALB/c mice, and the raised expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Results from enzyme-linked immunosorbent assay (ELISA) revealed the increase of IL-23 in serum from 116.09 to 153.90 pg/mL after treating with EGCG. The same results were also observed in RAW264.7 and peritoneal macrophages after treating with EGCG (0, 1, 5, 10, 25 µM) with the increased tendency of IL-23 in cultural medium (7.98 to 25.38 pg/mL for RAW264.7; 3.64 to 260.93 pg/mL for peritoneal macrophages). After preliminary exploration of the signaling related to the increased IL-23, the classical signaling pathways and key transcription factors, such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) signaling pathways, and interferon regulatory factor 5 (IRF5), were demonstrated with no relevant contribution. A further study revealed the involvement of the key transcription factor of BATF2, which could antagonistically modulate the transcription and translation of IL-23. The signaling of STAT3-BATF2-c-JUN/ATF2-IL-23 has been further verified in RAW264.7 macrophages using the STAT3 inhibitor of AG490 and the activator of Colivelin TFA. The results indicated that EGCG inhibits the phosphorylation of STAT3 to facilitate the decreased level of BATF2, which contributed to the increased level of IL-23 by the enhancing heterodimerization of c-JUN and ATF2.
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Catequina , Interleucina-23 , Fator 2 Ativador da Transcrição , Animais , Fatores de Transcrição de Zíper de Leucina Básica , Catequina/análogos & derivados , Fatores Reguladores de Interferon , Interleucina-23/genética , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-jun , Fator de Transcrição STAT3RESUMO
Macadamia nut contains important food allergens that potentially cause allergic reactions with severe adverse effects in infants and adults. Reliable and accurate detection of macadamia is critical to avoid allergic reactions. However, knowledge on macadamia allergen is scarce and a reliable detection method has not been reported, yet. In this study, an unbiased immunization and selection strategy was employed to select nanobodies (Nbs) recognizing specifically macadamia allergen, as well as to establish a detection method to unveil a macadamia protein contamination. An alpaca was immunized with a crude protein extract of macadamia followed by construction of a Nb library from its lymphocytes. The panning and screening of this immune Nb repertoire resulted in the selection of six target-specific Nbs. Nb-mediated immuno-capturing combined with mass spectrometry allowed us to identify the target as the macadamia vicilin-like antimicrobial peptides 2-3 (MiAMP2), a novel food allergenic protein abbreviated as Mac i 1. Later on, an immunoassay of a heterologous sandwich ELISA method based on the selected Nb-pairs was established, providing a linear response in the range of 0.442-2,800 µg/mL and with a limit of detection of 27.1 ng/mL. The dedicated immunoassay has been verified by detecting the antigen spiked in food samples. Our study provided evidence for the successful application of the unprejudiced strategy to retrieve Nbs against a priori undefined macadamia allergen. These target-specific Nbs were used to design a highly reliable and effective immunoassay.