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RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.
Assuntos
Progressão da Doença , Neoplasias de Próstata Resistentes à Castração , Proteínas de Ligação a RNA , Masculino , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Humanos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Animais , Linhagem Celular Tumoral , Adenosina/análogos & derivados , Adenosina/metabolismo , Proliferação de Células/genética , Camundongos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Melatonina/metabolismo , Camundongos NusRESUMO
Acute myeloid leukemia (AML) is the most common hematopoietic malignancy with abnormal lipid metabolism. However, currently available information on the involvement of the alterations in lipid metabolism in AML development is limited. In this study, we demonstrate that FABP5 expression facilitates AML cell viability, protects AML cells from apoptosis, and maintains triglyceride production. Our bioinformatics analysis revealed that FABP5 expression was upregulated and correlated with unfavorable overall survival of AML patients. FABP5 expression may be used to distinguish normal and AML with high accuracy. FABP5-based risk score was an independent risk factor for AML patients. AML patients with highly expressed FABP5 predicted resistance to drugs. In vitro study showed that FABP5 expression was remarkably elevated in primary AML blasts and an AML cell line. Silencing FABP5 expression attenuated AML cell viability, reduced triglyceride production and lipid droplet accumulation, and induced apoptosis. We utilized AutoDock online tool to identify lycorine as an FABP5 inhibitor by binding FABP5 at amino acid residues Ile54, Thr56, Thr63, and Arg109. Lycorine treatment downregulated the expression levels of FABP5 and its target PPARγ, impaired AML cell viability, triggered apoptosis, and reduced triglyceride production in AML cells. These results demonstrate that FABP5 is critical for AML cell survival and highlight a novel metabolic vulnerability for AML.
Assuntos
Alcaloides de Amaryllidaceae , Leucemia Mieloide Aguda , Humanos , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Apoptose , Proliferação de Células , Proteínas de Ligação a Ácido Graxo/genéticaRESUMO
PURPOSE: Studies show that patients with obstructive sleep apnea (OSA) are more likely than the general population to have psychological disorders such as depression. However, it is less clear how OSA treatment affects this association. This meta-analysis aimed to assess whether or not continuous positive airway pressure (CPAP) and mandibular advancement devices (MADs) reduce depression symptoms in patients with OSA. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane Library from creating the databases until November 2022. Our analysis included RCTs that examined CPAP and MAD treatment effectiveness for depression in patients with OSA. RESULTS: We identified 17 CPAP studies comprising 1,931 patients for inclusion in the meta-analysis. The results of the meta-analysis using a fixed effects model found that CPAP improved depressed mood in patients with OSA relative to controls (SMD = 0.27;95% CI:0.18,0.36), with small heterogeneity among trials (I2 = 8.1% < 50%, P = 0.359). We performed subgroup analyses on three factors: the length of trial follow-up, patient adherence data, and depression assessment scales. The meta-analysis also identified six MAD studies involving 315 patients. According to this analysis, there was no heterogeneity between studies (I2 = 0%, P = 0.748). MADs did not significantly improve depression symptoms compared to controls, indicating a combined effect of SMD = 0.07 (95% CI: - 0.15,0.29), P > 0.05. CONCLUSION: The present findings confirm that CPAP may improve depressive symptoms in patients with OSA. However, the review results suggest that MADs have no significant effect on depressive symptoms in patients with OSA, a finding that is different from the results of previous meta-analyses.
Assuntos
Avanço Mandibular , Apneia Obstrutiva do Sono , Humanos , Depressão/terapia , Placas Oclusais , Avanço Mandibular/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Apneia Obstrutiva do Sono/terapiaRESUMO
Acute myeloid leukaemia (AML) is very common haematopoietic malignancies with poor prognosis. Chemotherapy is still a mainstay therapy for AML patients. AML microenvironment plays critical roles in therapy response. However, the role of chemotherapy in AML microenvironment is poorly understood. In this study, we report that cytarabine (AraC)-triggered TNFα from AML cells expanded myeloid-derived suppressor cells (MDSCs) and enhanced MDSC functions and survival through activating IL-6/STAT3 and NFκB pathways. Blockade of TNFα in conditioned medium-derived AraC-treated AML cells (AraC_CM) impaired MDSC expansion and functions, reduced IL-6 secretion and the level of activated STAT3. Inhibiting IL6 or STAT3 abrogated AraC_CM-mediated MDSC suppressive function. Additionally, inhibiting TNFα also impaired AraC_CM-mediated NFκB activation. Blocking NFκB activation reduced MDSC viability induced by AraC_CM. Together, these results provided a role of AraC-induced TNFα in MDSC expansion and functions and suggest that targeting TNFα may benefit AML patients to current anticancer strategies by blocking MDSC-mediated immunosuppression.
Assuntos
Leucemia Mieloide Aguda , Células Supressoras Mieloides , Citarabina/metabolismo , Citarabina/farmacologia , Citarabina/uso terapêutico , Humanos , Interleucina-6/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Células Supressoras Mieloides/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Segmenting peripancreatic vessels in CT, including the superior mesenteric artery (SMA), the coeliac artery (CA), and the partial portal venous system (PPVS), is crucial for preoperative resectability analysis in pancreatic cancer. However, the clinical applicability of vessel segmentation methods is impeded by the low generalizability on multi-center data, mainly attributed to the wide variations in image appearance, namely the spurious correlation factor. Therefore, we propose a causal-invariance-driven generalizable segmentation model for peripancreatic vessels. It incorporates interventions at both image and feature levels to guide the model to capture causal information by enforcing consistency across datasets, thus enhancing the generalization performance. Specifically, firstly, a contrast-driven image intervention strategy is proposed to construct image-level interventions by generating images with various contrast-related appearances and seeking invariant causal features. Secondly, the feature intervention strategy is designed, where various patterns of feature bias across different centers are simulated to pursue invariant prediction. The proposed model achieved high DSC scores (79.69%, 82.62%, and 83.10%) for the three vessels on a cross-validation set containing 134 cases. Its generalizability was further confirmed on three independent test sets of 233 cases. Overall, the proposed method provides an accurate and generalizable segmentation model for peripancreatic vessels and offers a promising paradigm for increasing the generalizability of segmentation models from a causality perspective. Our source codes will be released at https://github.com/SJTUBME-QianLab/PC_VesselSeg.
RESUMO
OBJECTIVES: Preoperative lymph node (LN) status is essential in formulating the treatment strategy among pancreatic cancer patients. However, it is still challenging to evaluate the preoperative LN status precisely now. METHODS: A multivariate model was established based on the multiview-guided two-stream convolution network (MTCN) radiomics algorithms, which focused on primary tumor and peri-tumor features. Regarding discriminative ability, survival fitting, and model accuracy, different models were compared. RESULTS: Three hundred and sixty-three pancreatic cancer patients were divided in to train and test cohorts by 7:3. The modified MTCN (MTCN+) model was established based on age, CA125, MTCN scores, and radiologist judgement. The MTCN+ model outperformed the MTCN model and the artificial model in discriminative ability and model accuracy. [Train cohort area under curve (AUC): 0.823 vs. 0.793 vs. 0.592; train cohort accuracy (ACC): 76.1 vs. 74.4 vs. 56.7%; test cohort AUC: 0.815 vs. 0.749 vs. 0.640; test cohort ACC: 76.1 vs. 70.6 vs. 63.3%; external validation AUC: 0.854 vs. 0.792 vs. 0.542; external validation ACC: 71.4 vs. 67.9 vs. 53.5%]. The survivorship curves fitted well between actual LN status and predicted LN status regarding disease free survival and overall survival. Nevertheless, the MTCN+ model performed poorly in assessing the LN metastatic burden among the LN positive population. Notably, among the patients with small primary tumors, the MTCN+ model performed steadily as well (AUC: 0.823, ACC: 79.5%). CONCLUSIONS: A novel MTCN+ preoperative LN status predictive model was established and outperformed the artificial judgement and deep-learning radiomics judgement. Around 40% misdiagnosed patients judged by radiologists could be corrected. And the model could help precisely predict the survival prognosis.
Assuntos
Aprendizado Profundo , Neoplasias Pancreáticas , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Estudos Retrospectivos , Prognóstico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Linfonodos/patologia , Neoplasias PancreáticasRESUMO
Although AgIn5S8 as one kind of ternary chalcogenides has been extensively investigated due to its band-edge positions meeting the thermodynamic requirement for water photosplitting, very little attention has been focused on the crystallinity and facet effects of AgIn5S8 on its photocatalytic activity. Herein, a facile hydrothermal route was developed to fabricate regular single-crystalline AgIn5S8 octahedrons with only {111} facets exposed. Also, the effects of the hydrothermal reaction conditions on the composition, crystal phase, crystallinity, and morphology of the obtained AgxInyS(x+3y/2) products (hereafter denoted as AIS-x, where x represents the pH value of the reaction solution) were investigated, and it was found that the accurately released S2- ions from the thermal decomposition of thioacetamide (TAA) is the central factor for the nucleation and growth of the AgIn5S8 octahedrons. The experimental results indicate that the resultant regular AgIn5S8 octahedrons (AIS-10.6) exhibit the best photocatalytic activity for H2 production among those AgxInyS(x+3y/2) products, and the higher crystallinity and fewer defects of the AgIn5S8 octahedrons compared to the other AgxInyS(x+3y/2) products can retard the photogenerated charge recombination, while those indium atoms with higher density in the exposed {111} facets might be beneficial for the photocatalytic H2 production reaction by acting as active sites to promote the charge separation and transfer processes. The results presented here provide new insights into the significance of crystallinity and exposed facets in the visible-light-responsive activity of AgIn5S8, thus paving new ways into the design and synthesis of high-performance, cost-effective AgIn5S8 photocatalysts for H2 production.
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·AIM: To observe the application of optical coherence tomography ( OCT ) in the diseases of traumatic macular hole.·METHODS: Twenty - five eyes of 23 patients with traumatic macular hole from January 2015 to January 2017 were enrolled in this study, including 9 eyes treated without surgeries, 16 eyes with surgeries. The image features were analyzed using OCT from ZEISS.·RESULTS: The OCT characteristics in patients with traumatic macular hole were partial or full - thickness disappearance of the neuro-epithelium. Posterior vitreous detachment was not seen in the traumatic macular hole. OCT examination revealed that 4 eyes had partial detachment of macular hole and 21 eyes had full thickness detachment. Of the twenty-one eyes, 4 eyes had simple macular hole, 10 eyes had macular full-layer division with peripheral nerve epithelium edema, 7 eyes had the macular full - layer hole with the neuro - epithelium localized detachment. In the 25 eyes, 9 eyes did not undergo the surgery, of which 7 eyes were self-healing;16 eyes were surgically treated. Postoperative OCT showed the macular structure were normal in 12 eyes with the visual acuity improved 3 lines; retinal nerve epithelium were thinning in 4 eyes, visual acuities were not significant improved after surgery.·CONCLUSION: OCT examination is necessary for the diagnosis and treatment of traumatic macular hole.