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1.
Int J Biol Macromol ; : 132177, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38729484

RESUMO

Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.

2.
J Cell Mol Med ; 28(9): e18286, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38742843

RESUMO

Osteosarcoma, the primary bone cancer in adolescents and young adults, is notorious for its aggressive growth and metastatic potential. Our study delved into the prognostic impact of inflammasome-related gene signatures in osteosarcoma patients, employing comprehensive genetic profiling to uncover signatures linked with patient outcomes. We identified three patient subgroups through consensus clustering, with one showing worse survival rates correlated with high FGFR3 and RARB expressions. Immune profiling revealed significant immune cell infiltration differences among these subgroups, affecting survival. Utilising advanced machine learning, including StepCox and gradient boosting machine algorithms, we developed a prognostic model with a notable c-index of 0.706, highlighting CD36 and MYD88 as key genes. Higher inflammasome risk scores from our model were associated with poorer survival, corroborated across datasets. In vitro experiments validated CD36 and MYD88's roles in promoting osteosarcoma cell proliferation, invasion and migration, emphasising their therapeutic potential. This research offers new insights into inflammasomes' role in osteosarcoma, introducing novel biomarkers for risk assessment and potential therapeutic targets. Our findings suggest a pathway towards personalised treatment strategies, potentially improving patient outcomes in osteosarcoma.


Assuntos
Biomarcadores Tumorais , Neoplasias Ósseas , Regulação Neoplásica da Expressão Gênica , Inflamassomos , Osteossarcoma , Humanos , Osteossarcoma/genética , Osteossarcoma/patologia , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Inflamassomos/metabolismo , Inflamassomos/genética , Biomarcadores Tumorais/genética , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/diagnóstico , Perfilação da Expressão Gênica , Feminino , Masculino , Transcriptoma/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Adolescente , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo
3.
J Appl Clin Med Phys ; 25(5): e14357, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38620027

RESUMO

PURPOSE: To investigate and characterize the performance of a novel orthogonal dual-layer alpha multileaf collimator (αMLC) mounted on the LinaTech VenusX linac. METHODS: We evaluated leaf positioning accuracy and reproducibility using an electronic portal imaging device through the picket fence test. The average, interleaf, intraleaf, and leaf tip transmissions of the single and dual layers were measured using an ionization chamber. Square and rhombus fields were used to evaluate the leaf penumbra of αMLC. To investigate the advantages of the orthogonal dual-layer multileaf collimator (MLC) in field shaping, right triangular and circular pattern fields were formed using both the dual layers and single layers of the αMLC. RESULTS: The average maximum positioning deviations of the upper and lower αMLC over 1 year were 0.76 ± 0.09 mm and 0.62 ± 0.07 mm, respectively. The average transmissions were 1.87%, 1.83%, and 0.03% for the upper-, lower- and dual-layer αMLC, respectively. The maximum interleaf transmissions of the lower- and dual-layer were 2.43% and 0.17%, respectively. The leaf tip transmissions were 9.34% and 0.25%, respectively. The penumbra of the square field was 6.2 mm in the X direction and 8.0 mm in the Y direction. The average penumbras of the rhombus fields with side lengths of 5 and 10 cm were 3.6 and 4.9 mm, respectively. For the right triangular and circular fields, the fields shaped by the dual-layer leaves were much closer to the set field than those shaped by single-layer leaves. The dose undulation amplitude of the 50% isodose lines and leaf stepping angle change of the dual-layer leaves were smaller than those of the single-layer leaves. CONCLUSIONS: The αMLC benefits from its orthogonal dual-layer design. Leaf transmission, dose undulations at the field edge, and MLC field dependence of the leaf stepping angle of the dual-layer αMLC were remarkably reduced.


Assuntos
Aceleradores de Partículas , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Humanos , Aceleradores de Partículas/instrumentação , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias/radioterapia , Imagens de Fantasmas
4.
J Med Chem ; 67(5): 4194-4224, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38442261

RESUMO

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.


Assuntos
Corantes Fluorescentes , Células Th17 , Corantes Fluorescentes/farmacologia , Fatores de Transcrição , Regulação da Expressão Gênica , Polarização de Fluorescência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo
5.
J Med Chem ; 67(6): 4346-4375, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38484122

RESUMO

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.


Assuntos
Neoplasias Pulmonares , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas c-ret/genética , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Neoplasias Pulmonares/tratamento farmacológico
7.
Hum Reprod ; 39(4): 658-673, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38335261

RESUMO

STUDY QUESTION: What is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions? SUMMARY ANSWER: EV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV. WHAT IS KNOWN ALREADY: EVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear. STUDY DESIGN, SIZE, DURATION: EV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits. MAIN RESULTS AND THE ROLE OF CHANCE: EV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.


Assuntos
Astenozoospermia , Canais de Cálcio , Vesículas Extracelulares , Sêmen , Motilidade dos Espermatozoides , Humanos , Masculino , Astenozoospermia/metabolismo , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio , Peptídeos/metabolismo , Peptídeos/farmacologia , Sêmen/química , Sêmen/metabolismo , Motilidade dos Espermatozoides/fisiologia , Espermatozoides/metabolismo , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo
8.
Phys Med Biol ; 68(24)2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37976548

RESUMO

Objective.Deep learning has shown promise in generating synthetic CT (sCT) from magnetic resonance imaging (MRI). However, the misalignment between MRIs and CTs has not been adequately addressed, leading to reduced prediction accuracy and potential harm to patients due to the generative adversarial network (GAN)hallucination phenomenon. This work proposes a novel approach to mitigate misalignment and improve sCT generation.Approach.Our approach has two stages: iterative refinement and knowledge distillation. First, we iteratively refine registration and synthesis by leveraging their complementary nature. In each iteration, we register CT to the sCT from the previous iteration, generating a more aligned deformed CT (dCT). We train a new model on the refined 〈dCT, MRI〉 pairs to enhance synthesis. Second, we distill knowledge by creating a target CT (tCT) that combines sCT and dCT images from the previous iterations. This further improves alignment beyond the individual sCT and dCT images. We train a new model with the 〈tCT, MRI〉 pairs to transfer insights from multiple models into this final knowledgeable model.Main results.Our method outperformed conditional GANs on 48 head and neck cancer patients. It reduced hallucinations and improved accuracy in geometry (3% ↑ Dice), intensity (16.7% ↓ MAE), and dosimetry (1% ↑γ3%3mm). It also achieved <1% relative dose difference for specific dose volume histogram points.Significance.This pioneering approach for addressing misalignment shows promising performance in MRI-to-CT synthesis for MRI-only planning. It could be applied to other modalities like cone beam computed tomography and tasks such as organ contouring.


Assuntos
Neoplasias de Cabeça e Pescoço , Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada de Feixe Cônico , Processamento de Imagem Assistida por Computador/métodos , Dosagem Radioterapêutica
9.
Biomed Pharmacother ; 169: 115905, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38000356

RESUMO

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Animais , Camundongos , Peixe-Zebra , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mutação
10.
J Phys Chem Lett ; 14(40): 9082-9089, 2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37788256

RESUMO

The Fe-N-C catalyst represents one of the most promising candidates for replacing platinum-based catalysts toward the oxygen reduction reaction. The pivotal factor in the successful integration of Fe-N-C catalysts within applications is the attainment of a large-scale production capability. Microwave-assisted pyrolysis offers various advantages, including enhanced energy and time efficiency, uniform heating, and high yield in single-batch processes. These characteristics render it exceptionally suitable for the mass production of catalysts. Through a synergistic approach involving machine learning techniques and microscopic characterization, we discerned performance trends and underlying mechanisms within batch-synthesized Fe-N-C catalysts under microwave-assisted preparation conditions. Machine learning analysis revealed that the precursor mass exerts the most substantial influence on product performance. Furthermore, microscopic characterization unveiled that these influencing factors impact catalyst performance by modulating the degree of agglomeration. Our research introduces an efficacious machine learning model for prognosticating performance and dissecting the influencing factors pertinent to Fe-N-C catalyst synthesis within a microwave system.

11.
Sci Data ; 10(1): 694, 2023 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-37828063

RESUMO

Human papillomavirus (HPV) status strongly predicts positive clinical outcomes in patients with head and neck squamous cell cancer (HNSCC); however, the potential reasons have not been fully elucidated. Here, we characterized the immune context in HPV+ and HPV- HNSCC by integrating scRNA-seq and bulk RNA-seq data. In scRNA-seq data, HPV + HNSCC displayed increased B cells, plasma cells, CD4+ effector T cells, and decreased macrophages and mast cells. This finding was validated using bulk-cell data. Plasma cells predicted improved survival, and macrophages were associated with survival disadvantage. 1403 upregulated and 1877 downregulated differential expressed genes (DEGs) were obtained. Gene Ontology and KEGG enrichment analysis showed these DEGs focused on cytokine-related activity. Transcriptional analysis of B and plasma cells revealed associations between B-cell surface marker FCER2 and improved survival. In vitro assays confirmed the ability of FCER2 to suppress cellular proliferation and migration of HPV + tumors. In conclusion, our analysis revealed a heterogeneous tumor immune environment (TME) for HPV+ and HPV- HNSCC. Further, FCER2+ B cells contribute to antitumor immunity.


Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Infecções por Papillomavirus/complicações , Transdução de Sinais , Linfócitos B , Microambiente Tumoral
12.
Bioresour Technol ; 387: 129697, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37598801

RESUMO

Waste molasses, the abundant byproducts of the sugar industry, is a cost-efficient carbon source for advanced denitrification. However, the efficiency of waste molasses-driven denitrification is limited by its complex carbon content, hindering its practical application. Weak magnetic field (WMF) is reported to enhance biological nitrogen removal, but its effects on molasses-driven denitrification remains unknown. This study investigated whether the WMF can enhance waste molasses-driven nitrogen removal and explore the underlying mechanisms. It was found that WMF significantly facilitated waste molasses-driven denitrification, with total nitrogen removal efficiency increased by 1.25 times (from 77% to 96%). WMF stimulated the nitrate reductase's activity by 7-18%, and the enhancement was improved as WMF intensified. Quantitative qPCR analysis indicated that the abundances of denitrifying enzymes increased under WMF, which was consistent with the proliferation of denitrifying bacteria Denitratisoma and Devosia. This study has demonstrated that WMF is promising for enhancing complex carbon-driven denitrification processes.


Assuntos
Desnitrificação , Purificação da Água , Melaço , Carbono , Campos Magnéticos , Nitrogênio
13.
Eur J Med Chem ; 260: 115726, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37597436

RESUMO

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.


Assuntos
Produtos Biológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Antivirais/farmacologia , Produtos Biológicos/farmacologia , Movimento Celular
14.
Clinics (Sao Paulo) ; 78: 100261, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37515928

RESUMO

BACKGROUND: Infertility is caused by heterogeneous risks, but most of them are unexplained. The sperm DNA Fragmentation Index (DFI) was increasingly acknowledged as a parameter for the evaluation of male infertility. This study aimed to investigate the association between sperm DFI and laboratory and clinical outcomes in a population with unexplained infertility. METHODS: The clinical data of an infertile population was collected for the selection of reproductive patients with unexplained infertility. The authors classified the patients with normal sperm parameters in a control group (DFI < 25%) and an observation group (DFI ≥ 25%) and compared the difference in basal characteristics, laboratory, and clinical outcomes between the two groups. The authors conducted a correlation analysis to examine the relationship between DFI and the number of D3 good-quality embryos, as well as the clinical pregnancy rate and live birth rate. A total of 176 cases were enrolled in the retrospective study. RESULTS: The observation group (n = 88) showed advanced male age, lower sperm concentration, progressive motility, and morphology assessment than the control group. In addition, lower No. of D3 good-quality embryos, clinical pregnancy rate, and the live birth rate were shown in the observation group. A negative correlation between the DFI and No. of D3 good-quality embryos (rs = -0.347, p < 0.001) or live birth rate (rs = -0.185, p = 0.028) was shown. CONCLUSIONS: Sperm DFI was a good indicator for the prediction of D3 good-quality embryos in unexplained infertility couples, but it did not provide sufficient information regarding clinical pregnancy outcome but live pregnancy outcome.


Assuntos
Infertilidade Masculina , Sêmen , Feminino , Humanos , Masculino , Gravidez , Fragmentação do DNA , Estudos Retrospectivos , Fertilização in vitro , Espermatozoides , Infertilidade Masculina/genética , Resultado da Gravidez
15.
Eur J Med Chem ; 257: 115464, 2023 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-37235998

RESUMO

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Isocitratos , Ligantes , Isocitrato Desidrogenase/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Mutação
16.
Aging Dis ; 14(2): 529-547, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37008055

RESUMO

Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.

17.
Front Public Health ; 11: 1096330, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37113174

RESUMO

Purpose: To predict the need for cycloplegic assessment, as well as refractive state under cycloplegia, based on non-cycloplegic ocular parameters in school-age children. Design: Random cluster sampling. Methods: The cross-sectional study was conducted from December 2018 to January 2019. Random cluster sampling was used to select 2,467 students aged 6-18 years. All participants were from primary school, middle school and high school. Visual acuity, optical biometry, intraocular pressure, accommodation lag, gaze deviation in primary position, non-cycloplegic and cycloplegic autorefraction were conducted. A binary classification model and a three-way classification model were established to predict the necessity of cycloplegia and the refractive status, respectively. A regression model was also developed to predict the refractive error using machine learning algorithms. Results: The accuracy of the model recognizing requirement of cycloplegia was 68.5-77.0% and the AUC was 0.762-0.833. The model for prediction of SE had performances of R^2 0.889-0.927, MSE 0.250-0.380, MAE 0.372-0.436 and r 0.943-0.963. As the prediction of refractive error status, the accuracy and F1 score was 80.3-81.7% and 0.757-0.775, respectively. There was no statistical difference between the distribution of refractive status predicted by the machine learning models and the one obtained under cycloplegic conditions in school-age students. Conclusion: Based on big data acquisition and machine learning techniques, the difference before and after cycloplegia can be effectively predicted in school-age children. This study provides a theoretical basis and supporting evidence for the epidemiological study of myopia and the accurate analysis of vision screening data and optometry services.


Assuntos
Refração Ocular , Erros de Refração , Humanos , Criança , Estudos Transversais , Erros de Refração/diagnóstico , Acuidade Visual , Testes Visuais , Midriáticos
18.
Front Cell Dev Biol ; 11: 971091, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36910156

RESUMO

Lipid metabolism disorder is the basis of atherosclerotic lesions, in which cholesterol and low-density lipoprotein (LDL) is the main factor involved with the atherosclerotic development. A high-fat and high-cholesterol diet can lead to this disorder in the human body, thus accelerating the process of disease. The development of single-cell RNA sequencing in recent years has opened the possibility to unbiasedly map cellular heterogeneity with high throughput and high resolution; alterations mediated by a high-fat and high-cholesterol diet at the single-cell transcriptomic level can be explored with this mean afterward. We assessed the aortic arch of 16-week old Apoe-/- mice of two control groups (12 weeks of chow diet) and two HFD groups (12 weeks of high fat, high cholesterol diet) to process single-cell suspension and use single-cell RNA sequencing to anatomize the transcripts of 5,416 cells from the control group and 2,739 from the HFD group. Through unsupervised clustering, 14 cell types were divided and defined. Among these cells, the cellular heterogeneity exhibited in endothelial cells and immune cells is the most prominent. Subsequent screening delineated ten endothelial cell subsets with various function based on gene expression profiling. The distribution of endothelial cells and immune cells differs significantly between the control group versus the HFD one. The existence of pathways that inhibit atherosclerosis was found in both dysfunctional endothelial cells and foam cells. Our data provide a comprehensive transcriptional landscape of aortic arch cells and unravel the cellular heterogeneity brought by a high-fat and high-cholesterol diet. All these findings open new perspectives at the transcriptomic level to studying the pathology of atherosclerosis.

19.
Polymers (Basel) ; 15(3)2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36771905

RESUMO

To enhance the damping properties of nitrile butadiene rubber (NBR), the elastomer used was blended with chlorinated paraffin 52 (CP52) to prepare NBR/CP52 composites. The results showed that CP52 could significantly enhance the damping properties of NBR and shift the glass transition temperature (Tg) to lower temperatures. Molecular dynamics models of the CP52/NBR system were established, and the damping properties of the CP52-reinforced NBR were investigated using molecular dynamics (MD) simulations. Through the combination of MD simulations and the experimental results, the essential mechanism of the enhanced damping properties of the NBR was methodically expatiated and was ascribed to the Cl-CP-H····NC-NBR (type I) and CP-Cl····H-NBR-CN (type II) analogous hydrogen bonds formed between NBR and CP52. The higher the CP52 content, the higher the analogous hydrogen bond concentration, and the better the damping properties of the CP52/NBR composites. The experimental results were very consistent with the MD simulation results, meaning that the combination method can provide a new means to optimize the design of damping materials and broaden the application range of small polar molecules in the damping modification of polar rubber materials.

20.
Environ Int ; 173: 107841, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36842385

RESUMO

The Medium Resolution Spectral Imager-II (MERSI-II) onboard the recently launched Chinese Fengyun-3D (FY-3D) satellite has great capability in detecting global aerosols as it includes aerosol bands similar to Moderate Resolution Imaging Spectroradiometer (MODIS). However, to date, aerosol retrieval based on MERSI-II is still limited to dark target regions and there is no official aerosol products for the MERSI-II. This study focuses on developing a high-precision algorithm to retrieve aerosol optical depth (AOD) suitable for entire land areas (except snow/ice and inland waters) based on MERSI-II measurements. Considering both the accuracy and retrieval efficiency, a new cost function is constructed based on (1) the fact that the AOD (550 nm) retrieved independently from different bands should be the same with the correct aerosol model, and (2) the assumption that the aerosol types are the same in the 5 × 5 km spatial range. The retrieval method based on the new cost function is nearly 50 times faster than most current methods using iterative calculations. To extend the application adaption of the FY-3D MERSI-II AOD retrieval and avoid the errors caused by the surface Lambertian hypothesis, a bidirectional reflectance distribution function (BRDF) database is built using MODIS products. Eight candidate aerosol models in different natural zones of China are constructed based on AERONET aerosol products from 2010 - 2021. The new method is applied to MERSI-II images over China and validated against ground-based measurements at 14 stations from 2020 to 2021. MODIS aerosol products from three operational algorithms are also used for comparison purposes. The results show that MERSI-II AOD retrievals agree well with the ground-based measurements with correlation coefficient (R), root mean square error (RMSE), and relative mean bias (RMB) of 0.913, 0.123, and 0.955, respectively. In addition, 72.19 % of AOD matchups fall within the expected error (EE) envelopes. The MERSI-II retrievals show higher accuracy than that of MODIS dark target (DT) and deep blue (DB) products and comparable accuracy of the MODIS Multi-Angle Implementation of Atmospheric Correction (MAIAC) product. MERSI-II AOD also shows higher stability in terms of spatial and temporal and better performance under heavy aerosol loading conditions than MODIS products. A good AOD agreement with R from 0.777 to 0.863 between MERSI-II and MODIS products is found over the land of China. The new method showing high retrieval efficiency and accuracy has great potential to be operationally applied on AOD retrieval for MERSI-II.


Assuntos
Poluentes Atmosféricos , Poluentes Atmosféricos/análise , Material Particulado/análise , Monitoramento Ambiental/métodos , Aerossóis/análise , Algoritmos
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