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Radium-223 (223 Ra) is the first-in-class alpha-emitter to mediate tumor eradication, which is commonly thought to kill tumor cells by directly cleaving double-strand DNA. However, the immunogenic characteristics and cell death modalities triggered by 223 Ra remain unclear. Here, it is reported that the 223 Ra irradiation induces the pro-inflammatory damage-associated molecular patterns including calreticulin, HMGB1, and HSP70, hallmarks of tumor immunogenicity. Moreover, therapeutic 223 Ra retards tumor progression by triggering pyroptosis, an immunogenic cell death. Mechanically, 223 Ra-induced DNA damage leads to the activation of stimulator of interferon genes (STING)-mediated DNA sensing pathway, which is critical for NLRP3 inflammasome-dependent pyroptosis and subsequent DCs maturation as well as T cell activation. These findings establish an essential role of STING in mediating alpha-emitter 223 Ra-induced antitumor immunity, which provides the basis for the development of novel cancer therapeutic strategies and combinatory therapy.
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Piroptose , Rádio (Elemento) , Rádio (Elemento)/farmacologia , Rádio (Elemento)/uso terapêutico , Morte Celular , DNARESUMO
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell-intrinsic cGAS-STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T-cell priming. Targeting the cGAS-STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS-STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS-STING pathway and analyse the dichotomous roles of the cGAS-STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS-STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS-STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS-STING in RT are explored.
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Interferons , Neoplasias , Humanos , Proteínas de Membrana/genética , Nucleotidiltransferases/genética , Transdução de Sinais , Imunidade Inata , Microambiente TumoralRESUMO
Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We have found, however, that intravenously administered octreotide (Oct) armed with astatine-211 ([211At]SAB-Oct) is effective against a somatostatin receptor 2 (SSTR2)-positive SCLC tumor in SCLC tumor-bearing BALB/c nude mice. In biodistribution analysis, [211At]SAB-Oct achieved the highest concentration in the SCLC tumors up to 3 h after injection as time proceeded. A single intravenous injection of [211At]SAB-Oct (370 kBq) was sufficient to suppress SSTR2-positive SCLC tumor growth in treated mice by inducing DNA double-strand breaks. Additionally, a multitreatment course (370 kBq followed by twice doses of 370 kBq for a total of 1110 kBq) inhibited the growth of the tumor compared to the untreated control group without significant off-target toxicity. Surprisingly, we found that [211At]SAB-Oct could up-regulate the expressions of calreticulin and major histocompatibility complex I (MHC-I) on the tumor cell membrane surface, suggesting that α-particle internal irradiation may activate an endogenous antitumor immune response through the regulation of immune cells in the tumor microenvironment, which could synergically enhance the efficacy of immunotherapy. We conclude that [211At]SAB-Oct is a potential new therapeutic option for SSTR2-positive SCLC.
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Antineoplásicos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Animais , Camundongos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Distribuição Tecidual , Receptores de Somatostatina/metabolismo , Antineoplásicos/uso terapêutico , Octreotida/uso terapêutico , Octreotida/metabolismo , Imunidade , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
BACKGROUND: Angiography derived fractional flow reserve (angio-FFR) has been proposed. This study aimed to assess its diagnostic performance with cadmium-zinc-telluride single emission computed tomography (CZT-SPECT) as reference. METHODS AND RESULTS: Patients underwent CZT-SPECT within 3 months of coronary angiography were included. Angio-FFR computation was performed using computational fluid dynamics. Percent diameter (%DS) and area stenosis (%AS) were measured by quantitative coronary angiography. Myocardial ischemia was defined as a summed difference score ≥ 2 in a vascular territory. Angio-FFR ≤ 0.80 was considered abnormal. 282 coronary arteries in 131 patients were analyzed. Overall accuracy of angio-FFR to detect ischemia on CZT-SPECT was 90.43%, with a sensitivity of 62.50% and a specificity of 98.62%. The diagnostic performance (= area under ROC = AUC) of angio-FFR [AUC = 0.91, 95% confidence intervals (CI) 0.86-0.95] was similar as those of %DS (AUC = 0.88, 95% CI 0.84-0.93, p = 0.326) and %AS (AUC = 0.88, 95% CI 0.84-0.93 p = 0.241) by 3D-QCA, but significantly higher than those of %DS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) and %AS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) by 2D-QCA. However, in vessels with 50-70% stenoses, AUC of angio-FFR was significantly higher than those of %DS (0.80 vs. 0.47, p < 0.001) and %AS (0.80 vs. 0.46, p < 0.001) by 3D-QCA and %DS (0.80 vs. 0.66, p = 0.036) and %AS (0.80 vs. 0.66, p = 0.034) by 2D-QCA. CONCLUSION: Angio-FFR had a high accuracy in predicting myocardial ischemia assessed by CZT-SPECT, which is similar as 3D-QCA but significantly higher than 2D-QCA. While in intermediate lesions, angio-FFR is better than 3D-QCA and 2D-QCA in assessing myocardial ischemia.
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Doença da Artéria Coronariana , Estenose Coronária , Reserva Fracionada de Fluxo Miocárdico , Isquemia Miocárdica , Humanos , Angiografia Coronária/métodos , Estenose Coronária/diagnóstico por imagem , Doença da Artéria Coronariana/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Constrição Patológica , Índice de Gravidade de Doença , Valor Preditivo dos TestesRESUMO
In this paper, we investigate the effectiveness of COVID-19 vaccination in controlling the infectivity and mortality of the SARS-CoV-2. Two major variants Delta and Omicron are investigated respectively. The main method used in the research is the multifractal detrended fluctuation analysis (MF-DFA). We use Δ α as the evaluation of control effectiveness. In the transmission stages of Delta and Omicron, we observe whether Δ α shows a downward trend by gradually expanding the length of time series. Vaccine effectiveness is evaluated using a time series of newly diagnosed patients and newly reported deaths. Data samples are taken from 9 different countries. According to the obtained results, the vaccine controls infectivity and mortality of the virus in the Delta transmission stage, but infectivity control is less effective than mortality. In the Omicron transmission stage, the immune effect of the vaccine is not obvious, which may be related to the high infectivity of Omicron. However, the vaccine is still effective in controlling mortality. We also find that the immune effect of vaccine on Omicron was lower than that of Delta. Finally, we observe that the immune effect of the vaccine in 'Poland' was abnormal. By analyzing the vaccination curve, we conclude that in 'Poland', when the growth rate of vaccination rate slowed down, the immune effect of the vaccine was very poor in terms of pathogenicity and lethality. Therefore, we suggest that all countries should continue to strengthen the vaccination rate. A higher or faster growth rate of vaccination rate will help control the infectivity and mortality rate, especially in the effectiveness of controlling mortality. Our research can be used to evaluate the effectiveness of vaccines for epidemic prevention and control, the formulation of epidemic prevention measures and vaccination policies for different countries with respect to their current pandemic situation accordingly.
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BACKGROUND: Auricularia auricula (A. auricula) is one of the most abundant sources of plant protein in edible fungi. Problems of low protein yield exist in traditional methods of protein extraction such as alkali extraction and ultrasonic-assisted alkali after pretreatment with enzymes. Thus, the protein extraction process was investigated and optimized using a definitive screening design from A. auricula to improve the protein yield under practical operating conditions of temperature, the concentration of NaCl, meal/water ratio, extraction time and pH. RESULTS: The yield of protein isolates of the isoelectric-ammonium sulfate precipitation (9.34% w/w) was obtained almost three times and the protein content (55.23% w/w) was approximately 1.6 times that of the traditional extraction method of isoelectric precipitation. Next, the optimized method was successfully applied to the analysis of the functional properties of the protein. A. auricula protein isolate (AAPI) had better solubility, emulsification and foaming capacity than soy protein isolate (SPI) and pea protein isolate (PPI), and the oil holding capacity of AAPI exhibited extremely well, which was approximately five times that of SPI and six times that of PPI. The texture properties of AAPI gel were similar to those of PPI gels. CONCLUSION: AAPI extracted by the optimized method had a satisfactory yield and had the potential to substitute plant-originated proteins in food processing. © 2022 Society of Chemical Industry.
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Proteínas de Plantas , Proteínas de Soja , Proteínas de Plantas/química , Solubilidade , Proteínas de Soja/químicaRESUMO
BACKGROUND: Similar to other local therapeutic methods, local interstitial radiotherapy (IRT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis. RESULTS: Mn-based IRT radiosensitizers consisting of 131I, MnO2 and bovine serum albumin (BSA) (131I-MnO2-BSA) were engineered. Such Mn-based IRT radiosensitizers successfully unlocked radiogenetics to magnify systematic immune responses of local IRT via remodeling hypoxic and immunosuppressive microenvironments and resist tumor metastasis. The MnO2 in 131I-MnO2-BSA caused decomposition of H2O2 enriched in tumors to generate O2 for alleviating hypoxic microenvironment and removing tumor resistances to IRT. Concurrently, hypoxia mitigation by such radiosensitizers-unlocked radiogenetics can effectively remodel immunosuppressive microenvironment associated with regulatory T (Treg) cells and tumor-associated macrophages (TAMs) infiltration inhibition to induce immunogenic cell death (ICD), which, along with hypoxia mitigation, activates systematic immune responses. More intriguingly, 131I-MnO2-BSA-enabled radiogenetics can upregulate PD-L1 expression, which allows anti-PD-L1-combined therapy to exert a robust antitumor effect on primary tumors and elicit memory effects to suppress metastatic tumors in both tumor models (4T1 and CT26). CONCLUSIONS: IRT radiosensitizer-unlocked radiogenetics and the corresponding design principle provide a general pathway to address the insufficient systematic immune responses of local IRT.
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Braquiterapia , Microambiente Tumoral , Biomimética , Linhagem Celular Tumoral , Peróxido de Hidrogênio/metabolismo , Imunidade , Compostos de Manganês/farmacologia , Óxidos/farmacologiaRESUMO
In this paper, we analyzed the difference of nonlinear dynamic characteristics of SARS-CoV-2 transmission caused by 'Delta Variant'. We selected the daily new diagnostic data of SARS-CoV-2 from 15 countries. Four different kinds of complexity metrics such as Kolmogorov complexity, Higuchi's Hurst exponent, Shannon entropy, and multifractal degrees were selected to explore the features of information content, persistence, randomness, multifractal complexity. Afterwards, Student's t-tests were performed to assess the presence of differences of these nonlinear dynamic characteristics for periods before and after "Delta Variant" appearance. The results of two-tailed Student's t-test showed that for all the nonlinear dynamic characteristics, the null hypothesis of equality of mean values were strongly rejected for the two periods. In addition, by one-tailed Student's t-test, we concluded that time series in "Delta period" exhibit higher value of Kolmogorov complexity and Shannon entropy, indicating a higher level of information content and randomness. On the other hand, the Higuchi's Hurst exponent in "Delta period" was lower, which showed the weaker persistent in this period. Moreover, the multifractal specturm width after "Delta" emergence were reduced, representing a more stable multifractality. The sources for the formation of multifractal features are also investigated.
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The limitations in discriminating preablation disease-active status of differentiated thyroid carcinoma (DTC) still represent a major challenge to radioiodine dose management. Cytokines, the small protein signaling molecules that constitute the thyroid tumor microenvironment, play significant roles in the facilitation of intercellular communication and the control of tumorigenesis. Also, more attention should be paid to the molecular events within the innate and adaptive immune systems that occur after the organism being exposed to ionizing radiation. Therefore, we implemented a study of 260 patients with DTC in thyroid hormone withdrawal status who were treated with total thyroidectomy to explore the relationship between cytokines and recurrence/active disease status. Besides, we made a cross-sectional study to analyze pre- and post-ablation serum concentration of cytokines of 86 patients with DTC. There was a relationship between clinicohistopathological characteristics of patients with DTC and the presence of cytokines. It is noteworthy that patients with recurrence/active disease were at a higher serum interleukin-2 receptor (IL-2R) level than the disease-free patients (213.59 ± 75.43 pg/ml vs. 186.80 ± 77.40 pg/ml, P = 0.005). Positive correlation was observed between serum IL-2R and thyroglobulin (Tg) (P = 0.003). We also found significant changes in the cytokine profile after radioiodine ablation, including the decrease of tumor necrosis factor-α and IL-8 (P < 0.001, P < 0.001, respectively), and increase of IL-2R (P < 0.001). Thus, we suggest that serum IL-2R may assist in evaluating the disease status during the post-thyroidectomy follow-up and radioiodine therapy has an immunoregulatory effect on serum cytokines.
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Biomarcadores Tumorais/sangue , Citocinas/sangue , Radioisótopos do Iodo/uso terapêutico , Recidiva Local de Neoplasia/patologia , Receptores de Interleucina-2/sangue , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodos , Estudos Transversais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/terapiaRESUMO
Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-ß1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-ß1 (p < 0.05), and increased the expression of E-cadherin (p < 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (p < 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.
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Movimento Celular/efeitos dos fármacos , Cisplatino/farmacologia , Resveratrol/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fuzheng huayu formula (FZHY), an antifibrotic traditional Chinese medicine, is frequently used for the treatment of liver fibrosis. In this study, network analysis, transcriptomic analysis, assays of cell apoptosis, viability and protein expression were used for investigating the effects and mechanisms of compounds derived from FZHY on hepatic parenchymal cell (HPC) protection and hepatic stellate cell activation. Network pharmacology analysis found that 6 major compounds and 39 potential targets were important network nodes. Our analysis predicted that the active compounds of FZHY, including hederagenin, luteolin and tanshinone IIA inhibited cell apoptosis (p < 0.05), increased PI3K expression and reduced cleaved caspase 3 expression and the Bax/Bcl-w ratio (p < 0.05) in L02 cells that had apoptosis induced by TNF-α. Few significant changes caused by FZHY, hederagenin, luteolin and tanshinone IIA were observed in hepatic stellate Lx2 cells upon TGF-ß1 induction. These data suggest that FZHY is active against liver fibrosis, protects hepatic parenchymal cells from apoptosis, and recovers liver function, possibly through the effects of its active compounds hederagenin, luteolin and tanshinone IIA and is involved in the inhibition of apoptosis in HPCs, possibly through regulating the PI3K, ERK, cleaved caspase 3 and Bax/Bcl-w levels.
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Apoptose/efeitos dos fármacos , Apoptose/genética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Transcriptoma , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacocinética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Based on the anticancer mechanism of biological alkylating agent, we designed and synthesized two alpha pinene derivatives:(1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl benzenesulfonate and (1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl 4-methylbenzenesulfonate, of which structures were confirmed by ¹H-NMR, HPLC and MS date. These two compounds showed a good inhibition of tumor cells' proliferation. Further, the computer siuulation of molecular docking and metabolic kinetics indicated that these two copounds may have stable molecular complexation with protein CDK2, which closely related to the cell cycle.
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Antineoplásicos/síntese química , Desenho de Fármacos , Monoterpenos/síntese química , Antineoplásicos/farmacologia , Monoterpenos Bicíclicos , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Simulação de Acoplamento Molecular , Monoterpenos/farmacologia , Relação Estrutura-AtividadeRESUMO
To investigate the anti-hepatoma mechanism of α-pinene, HepG2 cell was treated with α-pinene and the change of cell cycle was examined by flow cytometry. The expression of miR-221, which was related the regulation of G2/M phase, was detected by quantitative Real-time PCR. Meanwhile, TargetScan and other online bioinformatics methods were used to analyze and predict the target genes of miR-221, then the expression level of related target genes were detected by quantitative Real-time PCR. The results showed that α-pinene inhibited the proliferation of HepG2 cells in dose-dependent manner. It was also proved that HepG2 cells were arrested at G2/M phase by α-pinene (P<0.05). The expression of miR-221 was down-regulated in α-pinene treated HepG2 cell. The bioinformatics analysis showed that CDKN1B/P27 and CDKN1C/P57 may be the protential targets of miR-221 and both of them were significantly up-regulatedï¼P<0.001,P<0.05ï¼by α-pinene treatment. According to these results, it was believed that α-pinene may inhibit the proliferation of hepatocellular carcinoma cells through arrest the cell at G2/M phase, which may be associated with the down-regulate of the miR-221 expression and up-regulate of the CDKN1B/P27 and CDKN1C/P57 expression.
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MicroRNAs/genética , Monoterpenos/farmacologia , Pinus/química , Apoptose/efeitos dos fármacos , Monoterpenos Bicíclicos , Carcinoma Hepatocelular , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas , Folhas de Planta/químicaRESUMO
BACKGROUND: Insomnia has become a common health problem in modern society, especially among college students. The purpose of this study was to analyze the research status, research hotspots and frontier trends of insomnia among college students over the past 20 years. METHODS: VOSviewer 1.6.19 and CiteSpace 6.2 were used. R4: This study conducts a bibliometric and visualization analysis of the annual publications, authors, countries/regions, institutions, categories, journal/literature cocitations and keywords related to insomnia among college students in the Web of Science (WoS) core collection from 2003 to 2022. RESULTS: A total of 590 studies were included, and the number of studies on insomnia among college students has steadily increased over the last 20 years. The authors of high yield are represented by Taylor DJ and Miller MB. The countries/regions with high yields were the USA and China. The institutions of high yield were King Saud University and Southern Medical University. Its research fields were mainly Clinical Neurology, Psychiatry and Neurosciences. Mental health and insomnia, sleep quality and the impact of coronavirus disease 2019 (COVID-19) on insomnia are current research hotspots. Future research could focus on predicting the chronotype and physical activity of insomnia students. CONCLUSION: Through bibliometric and visualization analysis, this study investigated insomnia among college students over the past 20 years and preliminarily revealed the findings of coauthors and institutions. This study provides a general understanding of the research hotspots and frontier trends of insomnia among college students and provides some references for future research.
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Bibliometria , Distúrbios do Início e da Manutenção do Sono , Estudantes , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Humanos , Estudantes/estatística & dados numéricos , Universidades/estatística & dados numéricos , COVID-19/epidemiologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Cardiovascular disease is a leading cause of mortality and premature death. Early intervention in asymptomatic individuals through risk assessment can reduce the incidence of disease. Atherosclerosis is a major cause of cardiovascular disease and early detection can effectively prevent and treat it. In this study, we used real patient data to evaluate the risk of atherosclerosis, assisting doctors in diagnosis and reducing the incidence of cardiovascular disease. METHODS: We proposed a multi-stage atherosclerosis risk assessment model that includes three main stages: (i) SMOTE and decorrelation weighting algorithm technology were added to the causal stability middle layer to address class imbalance in the dataset and reduce the impact of feature-induced dataset distribution shifts on model differences. (ii) The feature interaction layer considered possible feature interactions and classified features by different categories. By adding more effective feature information, the accuracy and generalizability of the model were improved. (iii) In the integrated model layer, we chose LightGBM as the decision tree integration model for risk assessment because it has higher accuracy and robustness compared to other machine learning algorithms. RESULTS: The final model used a dataset containing 21 original features and 17 interaction features, achieving excellent performance under a 10-fold cross-validation strategy. The macro accuracy reached 93.86%, macro precision was 94.82%, macro recall was 93.52%, and macro F1 score was as high as 93.37%. These indicators demonstrate the accuracy and robustness of the model in atherosclerosis risk assessment. CONCLUSION: The model provides strong support for the prevention and diagnosis of cardiovascular disease. Through atherosclerosis risk assessment, the model can help doctors develop personalized prevention and treatment plans, which is of great significance for the prevention and treatment of cardiovascular disease.
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Aterosclerose , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Algoritmos , Aterosclerose/diagnóstico , Aprendizado de Máquina , Medição de RiscoRESUMO
Purpose: This study aims to evaluate the diagnostic value of texture analysis for lymph node metastasis after thyroid cancer surgery. Methods: We retrospectively analyzed patients who underwent positron emission tomography/computed tomography (PET/CT) examination before 131I treatment at Shanghai Tenth People's Hospital between 2017 and 2020. Clinical follow-up results were used as the criterion for determining the presence of lymph node metastasis. The study included 119 patients, who were then randomly divided into training and test groups in a 7:3 ratio. Regions of interest were identified, and radiomics features were extracted using LIFEx 7.3.0. Mann-Whitney U test and LASSO regression were employed to screen radiomics parameters for modeling. Subsequently, a nomogram model was built by combining radscore and clinical features. SPSS 26.0 software was utilized for statistical analysis, and p < 0.05 was considered statistically significant. Results: Follow-up confirmed 54 patients with thyroid cancer lymph node metastasis and 65 patients in the non-metastasis group. A total of 119 lymph nodes were delineated. For each lesion, 164 CT texture features and 164 PET texture features were extracted, and 107 significant parameters were identified, including 16 CT texture parameters and 91 PET texture parameters. After screening, 3 CT parameters, 4 PET parameters and 12 PET/CT parameters were selected to establish three radiomic models. The AUC values were as follows: AUC (CT) = 0.730, AUC (PET) = 0.759 and AUC (PET/CT) = 0.864. We then combined clinical features and radscore to construct a nomogram, resulting in a C-index of 0.915 in the training group. In the test group, the C-index was confirmed to be 0.868. Conclusions: Radiomics may enhance the diagnostic efficiency of lymph node metastases after thyroid cancer surgery and could potentially assist clinicians in future diagnoses. The developed nomogram, which combines radiomics and clinical features, offers relatively high accuracy in helping clinicians assess the risk of metastasis in thyroid patients after surgery.
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The abnormal fear memory will lead to the onset of stress disorders, such as post-traumatic stress disorder (PTSD) and so on. Therefore, the intervention in the formation of abnormal fear memory will provide a new strategy for the prevention and treatment of PTSD. In our previous studies, we found that blockade of dopamine D3 receptor (DRD3) with highly selective antagonist YQA14 or knockout of DRD3 was able to attenuate the expression or retrieval of fear memory in PTSD animal models. However, the neurobiological mechanism of regulation of DRD3 in fear is unclear. In the present research, we clarified that DRD3 was expressed in the dopaminergic (DAergic) neurons in the ventral tegmental area (VTA). Then, we identified that microinjection of YQA14 (1 µg/0.2 µl/side) in VTA before the aversive stimuli in the training session or during days subsequent to the shock significantly meliorated the freezing behaviors in the inescapable electric foot-shock model. At last, using fiber photometry system, we found that microinjection of YQA14 in VTA promoted the dopamine neurotransmitter release in the basolateral amygdala (BLA), and pre-training YQA14 infusion in VTA lowered the increase of dopamine (DA) in BLA induced by shock during the training session or by context during the retrieval session. All above the results demonstrated that YQA14 attenuated the fear learning through the blockade of DRD3 in VTA decreasing the excitability of the projection to BLA. This study may provide new mechanisms and potential intervention targets for stress disorders with abnormal fear memory.
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Receptores de Dopamina D3 , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/metabolismo , Receptores de Dopamina D3/metabolismo , Dopamina/metabolismo , Tonsila do Cerebelo , MedoRESUMO
Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor (D3R) have effects on addiction in different animal models. We have previously reported that YQA14, a D3R antagonist, exhibits very high affinity and selectivity for D3Rs over D2Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D3R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
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Analgésicos Opioides , Comportamento Aditivo , Ratos , Camundongos , Animais , Dopamina , Heroína/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/metabolismo , Morfina/farmacologia , Comportamento Aditivo/tratamento farmacológico , AutoadministraçãoRESUMO
Organic room-temperature phosphorescence (RTP) materials are currently the focus of research in the field of bioimaging. In comparison with the conventional imaging modalities based on organic fluorescent dyes, RTP materials with long lifetime enable time-resolved imaging to improve the imaging resolution by avoiding autofluorescence. In this review, we will start with summarizing strategies for achieving high performance RTP materials for bioimaging, including the development of RTP-compounds, host-guest doping materials, and supramolecular assemblies. We then discuss the optimization of nanonization processes to obtain RTP nanoparticles with controllable size, high dispersibility, and improved stability. The differences between top-down and bottom-up approaches are further described. Finally, we briefly introduce the emerging methods for preparing RTP materials for bioimaging.
Assuntos
Corantes Fluorescentes , Nanopartículas , TemperaturaRESUMO
PURPOSE: Nanobodies have become promising carriers due to excellent in vivo properties. Radiopharmaceutical therapy targeting programmed cell death ligand 1 (PD-L1) is an effective therapeutic strategy. Our study aimed to explore therapeutic efficacy of 131I labeled PD-L1 nanobody (Nb109) in non-small cell lung cancers (NSCLCs) in vitro and in vivo. METHODS: 131I-Nb109 was synthesized by chloramine-T method. We implemented stability analysis, SDS-PAGE and lipid-water partition coefficient test to assess its quality. Cell uptake assay and SPECT/CT scan were applied to evaluate its ability to target NSCLCs (H460 and A549). CCK8 assay and in vivo efficacy assay were conducted to estimate its therapeutic effect in H460 tumors. Damage-associated molecular patterns (DAMPs) release in H460 cells incubated with 131I-Nb109 was investigated by western blot and ATP test kit. RESULTS: 131I-Nb109 was hydrophilic with high labeling rate (69.51-98.06%), radiochemical purity (99.17% ± 0.76%) and stability. Cell uptake experiments showed that H460 cells (PD-L1 positive) compared with A549 cells (PD-L1 negative) had higher 131I-Nb109 uptake. SPECT/CT imaging revealed the accumulation of 131I-Nb109 in H460 tumor within 48 h. 131I-Nb109 inhibited H460 tumor growth without toxic side effects in contrast with control group. It also induced H460 cells to release DAMPs (adenosine triphosphate, high mobility group box 1, and heat shock protein 70). CONCLUSION: 131I-Nb109 had high stability, excellent ability to target and treatment PD-L1 positive tumors, and can improve tumor immunogenicity. The results of our study were expected to inspire the development of more novel radiopharmaceuticals to treat NSCLCs.