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Chronic diabetic wounds represent a significant clinical challenge because of impaired healing processes, which require innovative therapeutic strategies. This study explores the therapeutic efficacy of insulin-induced gene 1-induced bone marrow mesenchymal stem cell exosomes (Insig1-exos) in promoting wound healing in diabetic mice. We demonstrated that Insig1 enhanced the secretion of bone marrow mesenchymal stem cell-derived exosomes, which are enriched with miR-132-3p. Through a series of in vitro and in vivo experiments, these exosomes significantly promoted the proliferation, migration, and angiogenesis of dermal fibroblasts under high-glucose conditions. They also regulated key wound-healing factors, including matrix metalloproteinase-9, platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-ß1, and platelet endothelial cell adhesion molecule-1, thereby accelerating wound closure in diabetic mice. Histological analysis showed that Insig1-exos were more effective in promoting epithelialization, enhancing collagen deposition, and reducing inflammation. Additionally, inhibition of miR-132-3p notably diminished these therapeutic effects, underscoring its pivotal role in the wound-healing mechanism facilitated by Insig1-exos. This study elucidates the molecular mechanisms through which Insig1-exos promotes diabetic wound healing, highlighting miR-132-3p as a key mediator. These findings provide new strategies and theoretical foundations for treating diabetes-related skin injuries.
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OBJECTIVE: It is always difficult to obtain a comfortable surgical margin for patients with recurrent malignant or invasive benign spinal tumors. Tumor intraspinal invasion and dural adhesion are the essential reasons. There are always residual tumor cells maintained at the edge of dura. Dural resection is a key point to obtain a comfortable surgical margin for such cases. Whether such patients benefit from this risky surgical procedure is unknown. This study aims to understand better the oncological results, associated risks, and neurological function of this risky surgical procedure. METHODS: We retrospectively reviewed clinical data from six consecutive patients who registered spinal tumors in our institute and underwent dural resection during en bloc spinal resection from June 2013 to May 2020. The demographic and perioperative data, oncological outcomes, complications, and neurological status were collected and analyzed. RESULTS: All six patients were followed up for 24 to 46 months (mean follow-up time: 32.8 months). Local recurrence was detected in one patient (1/6, 16.7%) at 36 months postoperatively and in five patients with no evidence of disease at the last follow up (survival rate 83.3%). Eleven complications occurred in four patients (66.7%), and the dural resection-related complications included only four cases of cerebrospinal fluid leakage (CSFL), which accounted for 36.4% (4/11) of all complications. Neurologic status evaluated by the Frankel grade showed improvement of one grade in one case and deterioration of one to two grades in five patients immediately after surgery. All deterioration cases recovered to the preoperative level 6 months after the operation. CONCLUSION: Dural resection is significant for patients with dura matter invaded by recurrent primary malignant or invasive benign spinal tumors with the purpose of clinical cure. This study demonstrated that in strictly selected cases, intentional dural resection could provide satisfying local control and long-term disease-free survival with acceptable complications and satisfying neurological function.
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Dura-Máter , Margens de Excisão , Recidiva Local de Neoplasia , Neoplasias da Coluna Vertebral , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Retrospectivos , Dura-Máter/cirurgia , Adulto , Neoplasias da Coluna Vertebral/cirurgia , Idoso , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Systemic immune-inflammation index (SII) provides convincing evaluation of systemic immune and inflammatory condition in human body. Its correlation with prostate cancer (PCa) risk remains uncharted. The principal objective of this investigation was to elucidate the association between SII and the risk for PCa in middle-aged and elderly males. MATERIALS AND METHODS: Analysis entailed multivariate linear and logistic regression, generalized additive model, and smoothing curve fitting using resource from 2007 to 2010 National Health and Nutrition Examination Survey (NHANES). To ascertain robustness and consistency of this association across different demographic strata, we conducted rigorous subgroup analyses and interaction tests. RESULTS: Among 3359 participants, those with elevated SII displayed higher total prostate-specific antigen (tPSA) levels, higher risk for PCa, and lower free/total PSA (f/t PSA) ratio. Specifically, each unit increase of log2 (SII) was associated with a 0.22 ng/mL increase in tPSA (ß: 0.22, 95% confidence intervals [CI] 0.05-0.38), a 2.22% decline in f/t PSA ratio (ß: -2.22, 95% CI -3.20 to -1.23), and a 52% increased odds of being at high risk for PCa (odds ratio [OR]: 1.52, 95% CI 1.13-2.04). People in the top quartile of log2 (SII) exhibited 0.55 ng/mL increased tPSA (ß: 0.55, 95% CI 0.19-0.90), 4.39% reduced f/t PSA ratio (ß: -4.39, 95% CI -6.50 to -2.27), and 168% increased odds of being at high risk for PCa (OR: 2.68, 95% CI 1.32-5.46) compared to those in the bottom quartile. CONCLUSION: Systemic immune and inflammatory condition, as represented by SII, is independently and positively associated with tPSA levels and the risk for PCa, as well as independently and negatively associated with f/t PSA ratio among middle-aged and older US males. These findings may enhance the effectiveness of PCa screening in predicting positive biopsy results.
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Inflamação , Inquéritos Nutricionais , Antígeno Prostático Específico , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Pessoa de Meia-Idade , Idoso , Inflamação/sangue , Inflamação/imunologia , Inflamação/epidemiologia , Estados Unidos/epidemiologia , Antígeno Prostático Específico/sangue , Fatores de RiscoRESUMO
Cholestane-3ß,5α,6ß-triol (CT) and its analogues are abundant in natural sources and are reported to demonstrate cytotoxicity toward different kinds of tumor cells without a deep probe into their mechanism of action. CT is also one of the major metabolic oxysterols of cholesterol in mammals and is found to accumulate in various diseases. An extensive exploration of the biological roles of CT over the past few decades has established its identity as an apoptosis inducer. In this study, the effects of CT on A549 cell death were investigated through cell viability assays. RNA-sequencing analysis and western blot of CT-treated A549 cells revealed the role of CT in inducing endoplasmic reticulum (ER) stress response and enhancing autophagy flux, suggesting a putative mechanism of CT-induced cell-death activation involving reactive oxygen species (ROS)-mediated ER stress and autophagy. It is reported for the first time that the upregulation of autophagy induced by CT can serve as a cellular cytotoxicity response in accelerating CT-induced cell death in A549 cells. This research provides evidence for the effect of CT as an oxysterol in cell response to oxidative damage and allows for a deep understanding of cholesterol in its response in an oxidative stress environment that commonly occurs in the progression of various diseases.
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Autofagia , Sobrevivência Celular , Colestanóis , Estresse do Retículo Endoplasmático , Espécies Reativas de Oxigênio , Humanos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Células A549 , Espécies Reativas de Oxigênio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Colesterol/metabolismo , Colestanos/farmacologia , Morte Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Tumour necrosis factor (TNF) is a pleiotropic inflammatory cytokine that not only directly induces inflammatory gene expression but also triggers apoptotic and necroptotic cell death, which leads to tissue damage and indirectly exacerbates inflammation. Thus, identification of inhibitors for TNF-induced cell death has broad therapeutic relevance for TNF-related inflammatory diseases. In the present study, we isolated and identified a marine fungus-derived sesquiterpenoid, 9α,14-dihydroxy-6ß-p-nitrobenzoylcinnamolide (named as Cpd-8), that inhibits TNF receptor superfamily-induced cell death by preventing the formation of cytosolic death complex II. EXPERIMENTAL APPROACH: Marine sponge-associated fungi were cultured and the secondary metabolites were extracted to yield pure compounds. Cell viability was measured by ATP-Glo cell viability assay. The effects of Cpd-8 on TNF signalling pathway were investigated by western blotting, immunoprecipitation, and immunofluorescence assays. A mouse model of acute liver injury (ALI) was employed to explore the protection effect of Cpd-8, in vivo. KEY RESULTS: Cpd-8 selectively inhibits TNF receptor superfamily-induced apoptosis and necroptosis. Cpd-8 prevents the formation of cytosolic death complex II and subsequent RIPK1-RIPK3 necrosome, while it has no effect on TNF receptor I (TNFR1) internalization and the formation of complex I in TNF signalling pathway. In vivo, Cpd-8 protects mice against TNF-α/D-GalN-induced ALI. CONCLUSION AND IMPLICATIONS: A marine fungus-derived sesquiterpenoid, Cpd-8, inhibits TNF receptor superfamily-induced cell death, both in vitro and in vivo. This study not only provides a useful research tool to investigate the regulatory mechanisms of TNF-induced cell death but also identifies a promising lead compound for future drug development.
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Morte Celular , Sesquiterpenos , Animais , Camundongos , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/química , Humanos , Morte Celular/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Poríferos/química , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Necroptosis is a type of programmed cell death that is morphologically similar to necrosis. This type of cell death is involved in various pathophysiological disorders, including inflammatory, neurodegenerative, infectious, and malignant diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) pseudokinase constitute the core components of the necroptosis signaling pathway and are considered the most promising targets for therapeutic intervention. The discovery and characterization of necroptosis inhibitors not only accelerate our understanding of the necroptosis signaling pathway but also provide important drug candidates for the treatment of necroptosis-related diseases. Here, we will review recent research progress on necroptosis inhibitors, mechanisms of action and their potential applications for disease treatment.
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Apoptose , Proteínas Quinases , Humanos , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Necroptose/genética , Morte Celular , Necrose/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Head and neck cancer (HNC) is the seventh most prevalent cancer globally, often characterized by chemo-resistance and immunosuppression, which significantly hampers treatment efficacy. Cold atmospheric plasma (CAP) has recently emerged as a promising adjuvant oncotherapy with substantial potential and advantages. In this study, Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. We aimed to investigate the effects of CAPPZ2 on various types of HNC cells and elucidate the underlying mechanisms. In addition, we endeavored to examine the efficacy of combining CAPPZ2 with chemotherapy drugs (i.e., cisplatin) or immune checkpoint blockade (ICB, i.e., PD1 antibody) in HNC treatment. Firstly, the results demonstrated that CAPPZ2 exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promoting apoptosis and autophagy. Secondly, using transcriptomic sequencing, Western blotting, and quantitative real-time PCR, the mechanisms underlying CAPPZ2 treatment in vitro was presumed to be a multitargeted blockade of major cancer survival pathways, such as redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling. Lastly, combinatorial thearpy containing CAPPZ2 and cisplatin or PD-1 antibody significantly suppressed tumor growth and prolonged recipient survival in vivo. Collectively, the synergistic effects of CAPPZ2 and cisplatin or PD-1 antibody could serve as a promising solution to enhance head and neck tumor elimination.
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Neoplasias de Cabeça e Pescoço , Gases em Plasma , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Gases em Plasma/farmacologia , Gases em Plasma/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Receptor de Morte Celular Programada 1 , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológicoRESUMO
The aim of the current study was to investigate the feasibility of three-dimensional ultrashort echo time quantitative susceptibility mapping (3D UTE-QSM) for the assessment of gadolinium (Gd) deposition in cortical bone. To this end, 40 tibial bovine cortical bone specimens were divided into five groups then soaked in phosphate-buffered saline (PBS) solutions with five different Gd concentrations of 0, 0.4, 0.8, 1.2, and 1.6 mmol/L for 48 h. Additionally, eight rabbits were randomly allocated into three groups, consisting of a normal-dose macrocyclic gadolinium-based contrast agent (GBCA) group (n = 3), a high-dose macrocyclic GBCA group (n = 3), and a control group (n = 2). All bovine and rabbit tibial bone samples underwent magnetic resonance imaging (MRI) on a 3-T clinical MR system. A 3D UTE-Cones sequence was utilized to acquire images with five different echo times (i.e., 0.032, 0.2, 0.4, 0.8, and 1.2 ms). The UTE images were subsequently processed with the morphology-enabled dipole inversion algorithm to yield a susceptibility map. The average susceptibility was calculated in three regions of interest in the middle of each specimen, and the Pearson's correlation between the estimated susceptibility and Gd concentration was calculated. The bone samples soaked in PBS with higher Gd concentrations exhibited elevated susceptibility values. A mean susceptibility value of -2.47 ± 0.23 ppm was observed for bovine bone soaked in regular PBS, while the mean QSM value increased to -1.75 ± 0.24 ppm for bone soaked in PBS with the highest Gd concentration of 1.6 mmol/L. A strong positive correlation was observed between Gd concentrations and QSM values. The mean susceptibility values of rabbit tibial specimens in the control group, normal-dose GBCA group, and high-dose GBCA group were -4.11 ± 1.52, -3.85 ± 1.33, and -3.39 ± 1.35 ppm, respectively. In conclusion, a significant linear correlation between Gd in cortical bone and QSM values was observed. The preliminary results suggest that 3D UTE-QSM may provide sensitive noninvasive assessment of Gd deposition in cortical bone.
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Gadolínio , Imageamento Tridimensional , Animais , Bovinos , Coelhos , Osso e Ossos/diagnóstico por imagem , Meios de Contraste , Osso Cortical/diagnóstico por imagem , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
Cerebral ischemia, also known as ischemic stroke, accounts for nearly 85% of all strokes and is the leading cause of disability worldwide. Due to disrupted blood supply to the brain, cerebral ischemic injury is trigged by a series of complex pathophysiological events including excitotoxicity, oxidative stress, inflammation, and cell death. Currently, there are few treatments for cerebral ischemia owing to an incomplete understanding of the molecular and cellular mechanisms. Accumulated evidence indicates that various types of programmed cell death contribute to cerebral ischemic injury, including apoptosis, ferroptosis, pyroptosis and necroptosis. Among these, necroptosis is morphologically similar to necrosis and is mediated by receptor-interacting serine/threonine protein kinase-1 and -3 and mixed lineage kinase domain-like protein. Necroptosis inhibitors have been shown to exert inhibitory effects on cerebral ischemic injury and neuroinflammation. In this review, we will discuss the current research progress regarding necroptosis in cerebral ischemia as well as the application of necroptosis inhibitors for potential therapeutic intervention in ischemic stroke.
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INTRODUCTION: Tricuspid regurgitation (TR) is one of the most prevalent types of valvular heart disease linked to poor prognosis in patients with heart failure and is usually ignored. TR has received considerable attention due to the progressive advancements in transcatheter therapies in recent years. AREAS COVERED: With relatively solid data and rapid technological advancements, tricuspid transcatheter edge-to-edge repair (T-TEER) is the most frequently employed in a series of tricuspid transcatheter interventional treatments for TR. However, the efficacy and technical benefits of T-TEER are limited because of the unique anatomical characteristics and pathological mechanisms of the tricuspid valve. The aim of this review is to summarize reported data on current status of T-TEER and to provide an expert opinion regarding the challenges it is now experiencing and future development direction and approach. EXPERT OPINION: T-TEER is a significant treatment for TR, but its effectiveness and technical promotion are limited due to the tricuspid valve unique anatomical characteristics and pathological mechanisms. The selection criteria for suitable patients, the choice of when to intervene, device innovation, the advancement of ultrasound technology, and the volume of evidence in evidence-based medicine all indicate that the disorder of TR will eventually be better treated and understood.
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Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Tricúspide , Humanos , Resultado do Tratamento , Cateterismo Cardíaco , Valva Tricúspide/cirurgia , Insuficiência da Valva Tricúspide/cirurgiaRESUMO
Introduction: Diastasis recti abdominis (DRA) is a common condition in postpartum women. Measuring the distance between separated rectus abdominis (RA) in ultrasound images is a reliable method for the diagnosis of this disease. In clinical practice, the RA distance in multiple ultrasound images of a patient is measured by experienced sonographers, which is time-consuming, labor-intensive, and highly dependent on experience of operators. Therefore, an objective and fully automatic technique is highly desired to improve the DRA diagnostic efficiency. This study aimed to demonstrate the deep learning-based methods on the performance of RA segmentation and distance measurement in ultrasound images. Methods: A total of 675 RA ultrasound images were collected from 94 postpartum women, and were split into training (448 images), validation (86 images), and test (141 images) datasets. Three segmentation models including U-Net, UNet++ and Res-UNet were evaluated on their performance of RA segmentation and distance measurement. Results: Res-UNet model outperformed the other two models with the highest Dice score (85.93% ± 0.26%), the highest MIoU score (76.00% ± 0.39%) and the lowest Hausdorff distance (21.80 ± 0.76 mm). The average physical distance between RAs measured from the segmentation masks generated by Res-UNet and that measured by experienced sonographers was only 3.44 ± 0.16 mm. In addition, these two measurements were highly correlated with each other (r = 0.944), with no systematic difference. Conclusion: Deep learning model Res-UNet has good reliability in RA segmentation and distance measurement in ultrasound images, with great potential in the clinical diagnosis of DRA.
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With increasingly serious environmental problems caused by the greenhouse effect, it has also become essential to reduce the concentration of CO2 in the atmosphere. In this paper, CaCO3 -supported Fe-based catalysts doped with Mn, Al, and K are prepared by a straightforward method and used for CO2 hydrogenation. The fresh and spent catalysts were characterized by SEM-EDS, BET, TG, CO2 -TPD, XRD, and XPS. The experimental results show that the highest CO2 conversion rate of Fe10Mn2Al10Ca is 35.99 %, the maximum FTY value is 293.98â µmolCO2 â g Fe - 1 ${{\rm{g}}_{{\rm{Fe}}}^{ - 1} }$ â s-1 , the maximum O/P value is 6.61, and the lowest CO selectivity is 32.21 %. At the same time, according to the characterization results, the doping of Mn and Al increased the Fe3 O4 /FeCx ratio. As the Fe3 O4 /FeCx ratio increases, the proportion of short-chain hydrocarbons (CH4 , C2-4 ) in the products increases, and the proportion of long-chain hydrocarbons (C5+ ) decrease. Therefore, the co-doping of Mn and Al promotes the conversion of CO and reduces its selectivity, and promotes the formation of light olefins. Finally, it is hoped that this study can provide a reference for further research on CaCO3 -supported Fe catalysts.
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Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer-related death worldwide. Advanced or metastatic HCC is currently managed using systemic drug therapy with unsatisfactory patient survival. Cold atmospheric plasma has emerged as a promising, physicochemical, and broad-spectrum oncotherapy. In this preclinical study, we investigated the anti-neoplastic functions and mechanism of piezoelectric direct discharge technology-based CAP, Piezo-CAP, on HCC in vitro and in vivo. Various HCC cells lines, such as SMMC7721, HepG2 and LM3, were used as in vitro cancer model for the phenotypic and mechanistic studies. Specifically, the cell counting Kit-8 and colony formation assay, flow cytometry, Transwell assay, Western blot, reactive oxygen species (ROS) assay, and glutathione to oxidized glutathione ratio (GSH/GSSG) assay were used to demonstrate plasma-induced changes in HCC cell proliferation, cell cycle progression, migration and invasion, epithelial-to-mesenchymal transition, intracellular ROS, and antioxidant capacity, respectively. In addition, the Acridine orange and ethidium bromide (AO/EB) staining and transmission electron microscopy were performed for cellular and subcellular assessment of HCC cell apoptosis. The Ad-mCherry-RFP-LC3B fluorescent double-labeled lentiviral system was used to detect autophagic flux. On the other hand, RNA-sequencing, quantitative real-time PCR, and Western blot were used to demonstrate plasma-induced metabolic and molecular disruption of tumor glycolysis and oncogenic proliferation, respectively. In vivo experiments using a human cell-line-derived xenograft model and immunohistochemistry (IHC) were utilized to investigate the mechanism. Piezo-CAP exerted anti-neoplastic functions through inhibiting cell proliferation, migration and invasion, and promote cell apoptosis and autophagy. Treatment of Piezo-CAP could suppress proliferation and induce autophagy of HCC cells through simultaneously disrupts cancer survival pathways of redox deregulation, glycolytic pathway, and PI3K/AKT/mTOR/HIF1α pathway signaling. Moreover, upon translation of these in vitro results into the tissue level, Piezo-CAP significantly suppressed in situ tumor growth. These findings collectively suggest that Piezo-CAP-induced apoptosis and autophagy of HCC cells though a multitargeted blockade of major cancer survival pathways of deregulated redox balance, glycolysis, and PI3K/AKT/mTOR/HIF-1α signaling.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Espécies Reativas de Oxigênio , Linhagem Celular Tumoral , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Apoptose , Proliferação de Células , Autofagia , GlicóliseRESUMO
Amino acid metabolism has been implicated in tumorigenesis and tumor progression. Alterations in intracellular and extracellular metabolites associated with metabolic reprogramming in cancer have profound effects on gene expression, cell differentiation, and tumor immune microenvironment. However, the prognostic significance of amino acid metabolism in head and neck cancer remains to be further investigated. In this study, we identified 98 differentially expressed genes related to amino acid metabolism in head and neck cancer in The Cancer Genome Atlas. Using batch univariate Cox regression and Lasso regression, we extracted nine amino acid metabolism-related genes. Based on that, we developed the amino acid metabolism index. The prognostic value of this index was validated in two Gene Expression Omnibus cohorts. The results show that this model can help predict tumor recurrence and prognosis. The infiltration of immune cells in the tumor microenvironment was analyzed, and it was discovered that the high index is associated with an immunosuppressive microenvironment. In addition, this study demonstrated the impact of the amino acid metabolism index on clinical indicators, survival of patients with head and neck cancer, and the prediction of treatment response to immune checkpoint inhibitors. We conducted several cell experiments and demonstrated that epigenetic drugs could affect the index and enhance tumor immunity. In conclusion, our study demonstrates that the index not only has important prognostic value in head and neck cancer patients but also facilitates patient stratification for immunotherapy.
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Neoplasias de Cabeça e Pescoço , Recidiva Local de Neoplasia , Humanos , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Carcinogênese , Imunossupressores , Aminoácidos , Microambiente Tumoral/genéticaRESUMO
Background: Osteosarcoma initially metastasing to bone only shows distinct biological features compared to osteosarcoma that firstly metastasizes to the lung, which suggests us underlying different genomic pathogenetic mechanism. Methods: We analyzed whole-exome sequencing (WES) data for 38 osteosarcoma with paired samples in different relapse patterns. We also sought to redefine disease subclassifications for osteosarcoma based on genetic alterations and correlate these genetic profiles with clinical treatment courses to elucidate potential evolving cladograms. Results: We investigated WES of 12/38 patients with high-grade osteosarcoma (31.6%) with initial bone metastasis (group A) and 26/38 (68.4%) with initial pulmonary metastasis (group B), of whom 15/38 (39.5%) had paired samples of primary lesions and metastatic lesions. We found that osteosarcoma in group A mainly carries single-nucleotide variations displaying higher tumor mutation burden and neoantigen load and more tertiary lymphoid structures, while those in group B mainly exhibits structural variants. High conservation of reported genetic sequencing over time in their evolving cladograms. Conclusions: Osteosarcoma with mainly single-nucleotide variations other than structural variants might exhibit biological behavior predisposing toward bone metastases as well as better immunogenicity in tumor microenvironment.
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In this paper, CaxZn10-xFe20 catalysts were prepared by the co-precipitation method and applied to CO2 hydrogenation. The experimental results show that the CO2 conversion of the catalyst Ca1Zn9Fe20 at a Ca doping amount of 1â mmol can reach 57.91 %, which is 13.5 % more than the CO2 conversion of the catalyst Zn10Fe20. Moreover, the catalyst Ca1Zn9Fe20 has the lowest selectivity for both CO and CH4, with 7.40 % and 6.99 %, respectively. The catalysts were characterized by XRD, N2 adsorption-desorption, CO2 -TPD, H2 -TPR, and XPS. The results demonstrate that the doping of Ca increases the basic sites on the catalyst surface and thus allows the catalyst to adsorb more CO2 to promote the reaction. Besides, the Ca doping amount of 1â mmol can suppress the formation of graphitic carbon on the catalyst surface and prevent the excess graphitic carbon from covering the active site Fe5 C2 .
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Background: Kidney renal clear cell carcinoma (KIRC) is a representative histologic subtype of renal cell carcinoma (RCC). RCC exhibits a strong immunogenicity with a prominent dysfunctional immune infiltration. Complement C1q C chain (C1QC) is a polypeptide in serum complement system and is involved in tumorigenesis and the modulation of tumor microenvironment (TME). However, researches have not explored the effect of C1QC expression on prognosis and tumor immunity of KIRC. Methods: The difference in a wide variety of tumor tissues and normal tissues in terms of the C1QC expression was detected using TIMER and TCGA portal databases, and further validation of protein expression of C1QC was conducted via Human Protein Atlas. Then, the associations of C1QC expression with clinicopathological data and other genes were studied with the use of UALCAN database. Subsequently, the association of C1QC expression with prognosis was predicted by searching the Kaplan-Meier plotter database. A protein-protein interaction (PPI) network with the Metascape database was built using STRING software, such that the mechanism underlying the C1QC function can be studied in depth. The TISCH database assisted in the evaluation of C1QC expression in different cell types in KIRC at the single-cell level. Moreover, the association of C1QC and the infiltration level of tumor immune cell was assessed using TIMER platform. The TISIDB website was selected to deeply investigate the Spearman correlation between C1QC and immune-modulator expression. Lastly, how C1QC affected the cell proliferation, migration, and invasion in vitro was assessed using knockdown strategies. Results: KIRC tissues had notably upregulated C1QC level in comparison with adjacent normal tissues, with showed a positive relevance to clinicopathological features including tumor stage, grade, and nodal metastasis, and a negative relevance to clinical prognosis in KIRC. C1QC knockdown inhibited KIRC cell proliferation, migration, and invasion, as indicated by the results of the in vitro experiment. Furthermore, functional and pathway enrichment analysis demonstrated that C1QC was involved in immune system-related biological processes. According to single-cell RNA analysis, C1QC exhibited a specific upregulation in macrophages cluster. Additionally, there was an obvious association of C1QC and a wide variety of tumor-infiltrating immune cells in KIRC. Also, high C1QC expression presented inconsistent prognosis in different enriched immune cells subgroups in KIRC. Immune factors might contribute to C1QC function in KIRC. Conclusion: C1QC is qualified to predict KIRC prognosis and immune infiltration biologically. Targeting C1QC may bring new hope for the treatment of KIRC.
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Due to its potential to address low achievement, high dropout rates, and misbehavior among students, school engagement has become an important topic in contemporary developmental psychology and educational research. Although there is a wealth of literature on the causes and effects of student engagement, the current understanding of how student engagement varies in response to different teaching styles is limited. This study examined the engagement and burnout profiles of elementary school pupils (N = 798; 51% females; Mage = 11.54, SDage = 0.72) and the interactions between those profiles, students' characteristics and their perceptions of instructional behaviors (e.g., supporting criticism, suppressing criticism & independent viewpoints, intruding). Latent profile analysis revealed five types of profiles: moderately burned out, slightly burned out, moderately engaged, highly engaged, and highly burned out. Follow-up logistic regression analysis found that students clustered into engagement groups were likely to report higher autonomy support from teachers, especially when teachers permit criticism and independent thinking from students. In contrast, students clustered into burned out profiles were more likely to rate teacher strategies as autonomy suppressive. This became more obvious when instructors imposed meaningless and uninteresting activities. Taken together, this study indicated that autonomy-supportive teaching behaviors are pivotal in understanding student engagement and school burnout. The significance of the findings was addressed, along with implications and limitations.
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Esgotamento Profissional , Pessoal de Educação , Feminino , Humanos , Criança , Lactente , Masculino , Estudantes/psicologia , Instituições AcadêmicasRESUMO
Intelligent Tutoring Systems (ITSs) have a great potential to effectively transform teaching and learning. As more efforts have been put on designing and developing ITSs and integrating them within learning and instruction, mixed types of results about the effectiveness of ITS have been reported. Therefore, it is necessary to investigate how ITSs work in real and natural educational contexts and the associated challenges of ITS application and evaluation. Through a systematic literature review method, this study analyzed 40 qualified studies that applied social experiment methods to examine the effectiveness of ITS during 2011-2022. The obtained results highlighted a complicated landscape regarding the effectiveness of ITS in real educational contexts. Specifically, there was an "intelligent" regional gap regarding the distribution of countries where ITS studies using social experiment methods were conducted. Compared to learning performance, relatively less attention was paid to investigating the impact of ITS on non-cognitive factors, process-oriented factors, and social outcomes, calling for more research in this regard. Considering the complexities and challenges existing in real educational fields, there was a lack of scientific rigor in terms of experimental design and data analysis in some of the studies. Based on these findings, suggestions for future study and implications were proposed.
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PURPOSE: The optimal dose schedule of vincristine, irinotecan, and temozolomide (VIT) in relapsed or refractory patients with Ewing sarcoma requires clarification. PATIENTS AND METHODS: Patients with relapsed or refractory Ewing sarcoma were randomly assigned (1:1) to either a shorter d × 5 schedule (irinotecan 50 mg/m2/d D1-5, vincristine 1.4 mg/m2 D1) or protracted d × 5×2 schedule (irinotecan 20 mg/m2/d D1-5,8-12, vincristine 1.4 mg/m2 D1,8) together with temozolomide (100 mg/m2/d D1-5). Patients were treated every 3 weeks for up to eight cycles until progression or unacceptable toxic effects occurred. The primary endpoint was objective response rate at 12 weeks (ORR12w). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULT: A total of 46 patients presenting with relapsed or refractory Ewing sarcoma were randomly assigned to the d × 5 (n = 24) or d × 5×2 (n = 22) schedules. Median follow-up was 10.7 months in the d × 5 group and 8.3 months in the d × 5×2 group. ORR12w was lower for d × 5 (5/24; 20.8%) patients than for d × 5×2 (12/22; 54.5%; P = 0.019), but no significant difference was found in PFS (median PFS, 2.3 months for d × 5 vs. 4.3 months for d × 5×2) or OS (median OS, 14.8 months for d × 5 and 12.8 months for d × 5×2). Patients receiving the d × 5 schedule reported more grade 3 and 4 adverse events (AE) than those receiving d × 5×2, including diarrhea/abdominal pain and vomiting/nausea. CONCLUSIONS: The protracted d × 5×2 VIT schedule showed superior efficacy and favorable tolerability compared with the shorter d × 5 VIT schedule in patients with relapsed or refractory Ewing sarcoma.