In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. ...E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.
Background
Osteosarcoma is well‐established as the most common bone cancer in children and adolescents. Patients with localized disease have different prognoses and management than those with ...metastasis at the time of diagnosis. The purpose of this study was to explore potential risk factors for metastatic disease.
Methods
The Surveillance, Epidemiology, and End Results (SEER) Program database was used to identify patients diagnosed with osteosarcoma between 2004 and 2015. We developed prediction models for distant metastasis using six machine learning (ML) techniques, including logistic regression (LR), support vector machine (SVM), Gaussian Naive Bayes (GaussianNB), Extreme Gradient Boosting (XGBoost), random forest (RF), and k‐nearest neighbor algorithm (kNN). The adaptive synthetic (ADASYN) technique was used to deal with imbalanced data. The Shapley Additive Explanation (SHAP) analysis generated visualized explanations for each patient. Finally, the average precision (AP), sensitivity, specificity, accuracy, F1 score, precision‐recall curves, calibration plots, and decision curve analysis (DCA) were conducted to evaluate the models' effectiveness.
Results
The six machine learning algorithms achieved AP of 0.661–0.781 for predicting distant metastasis. The RF model yielded the best performance with an accuracy of 71.8 percent and an AP of 0.781 and was highly dependent on tumor size, primary surgery, and age. SHAP analysis provided model‐independent interpretation, highlighting significant clinical factors associated with the risk of metastasis in osteosarcoma patients.
Conclusions
An accurate machine learning‐based prediction model was established for metastasis in osteosarcoma patients to help clinicians during clinical decision‐making.
We developed a machine learning‐based model to predict the explore potential risk factors for metastatic disease in osteosarcoma patients according to the tumor features and the treatment duration in this study. As a result, the Random Forest model outperformed all other models in training and validation sets. To improve the interpretability of our machine learning model, we reported the SHAP values and a list of highly influential features.
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•A novel lectin-based sandwich aptasensor for carcinoembryonic antigen was developed.•The aptasensor is label- and antibody-free, with aptamer as the capture probe.•ConA serves as the ...tracing probe, and HRP is the labeling enzyme.•ConA and HRP were incorporated into the biosensor through lectin-sugar interactions.•The aptasensor is reproducible, accurate, specific, stable, simple and low-cost.
Carcinoembryonic antigen (CEA), a glycoprotein, is a wide-spectrum tumor marker for cancer diagnosis. Developing simple, stable, and low-cost methods for CEA detection is of great importance. In this work, a novel, label-free, and antibody-free electrochemical sandwich CEA biosensor was developed based on concanavalin A (ConA) and a DNA aptamer against CEA. Horse radish peroxidase (HRP) was labeled on the sandwich structure for signal production and amplification. Both the CEA and the HRP bind to ConA through sugar-lectin interactions. Under optimum conditions, the detection linear range was from 5 to 40 ng mL−1 CEA, with a detection limit of 3.4 ng mL−1, lower than the threshold level in human serum for cancer patients (∼10 ng mL−1). The biosensor is reproducible, accurate, specific, and stable, with RSD value of 3% for inter-biosensors, and relative error of <13% compared with those obtained by a commercial diagnostic kit. No obvious responses were observed toward interfering proteins. Storage did not cause obvious signal diminishment for the biosensor. The simple and low-cost aptasensor is promisingly applicable for CEA detection in cancer diagnosis, and could be able to serve as a general platform for detection of other interested glycoproteins.
Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect RAW 264.7 cells from ...inflammatory insults and explored mechanisms underlying inhibitory effects of resveratrol on RAW 264.7 cells.
Murine RAW 264.7 cells were treated with resveratrol (1, 5, and 10 µM) and/or LPS (5 µg/ml). Nitric oxide (NO) and prostaglandin E2 (PGE2) were measured by Griess reagent and ELISA. The mRNA and protein levels of proinflammatory proteins and cytokines were analysed by ELISA, RT-PCR and double immunofluorescence labeling, respectively. Phosphorylation levels of Akt, cyclic AMP-responsive element-binding protein (CREB), mitogen-activated protein kinases (MAPKs) cascades, AMP-activated protein kinase (AMPK) and expression of SIRT1(Silent information regulator T1) were measured by western blot. Wortmannin (1 µM), a specific phosphatidylinositol 3-kinase (PI3-K) inhibitor, was used to determine if PI3-K/Akt signaling pathway might be involved in resveratrol's action on RAW 264.7 cells. Resveratrol significantly attenuated the LPS-induced expression of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in RAW 264.7 cells. Resveratrol increased Akt phosphorylation in a time-dependent manner. Wortmannin, a specific phosphatidylinositol 3-kinase (PI3-K) inhibitor, blocked the effects of resveratrol on LPS-induced RAW 264.7 cells activation. In addition, PI3-K inhibition partially abolished the inhibitory effect of resveratrol on the phosphorylation of cyclic AMP-responsive element-binding protein (CREB) and mitogen-activated protein kinases (MAPKs) cascades. Meanwhile, PI3-K is essential for resveratrol-mediated phosphorylation of AMPK and expression of SIRT1.
This investigation demonstrates that PI3-K/Akt activation is an important signaling in resveratrol-mediated activation of AMPK phosphorylation and SIRT1 expression, and inhibition of phosphorylation of CREB and MAPKs activation, proinflammatory mediators and cytokines production in response to LPS in RAW 264.7 cells.
Graphene supported electrocatalysts have demonstrated remarkable catalytic performance for oxygen reduction reaction (ORR). However, their durability and cycling performance are greatly limited by ...Oswald ripening of platinum (Pt) and graphene support corrosion. Moreover, comprehensive studies on the mechanisms of catalysts degradation under 0.6-1.6 V versus RHE (Reversible Hydrogen Electrode) is still lacking. Herein, degradation mechanisms triggered by different defects on graphene supports are investigated by two cycling protocols. In the start-up/shutdown cycling (1.0-1.6 V vs. RHE), carbon oxidation reaction (COR) leads to shedding or swarm-like aggregation of Pt nanoparticles (NPs). Theoretical simulation results show that the expansion of vacancy defects promotes reaction kinetics of the decisive step in COR, reducing its reaction overpotential. While under the load cycling (0.6-1.0 V vs. RHE), oxygen containing defects lead to an elevated content of Pt in its oxidation state which intensifies Oswald ripening of Pt. The presence of vacancy defects can enhance the transfer of electrons from graphene to the Pt surface, reducing the d-band center of Pt and making it more difficult for the oxidation state of platinum to form in the cycling. This work will provide comprehensive understanding on Pt/Graphene catalysts degradation mechanisms.
The objective of this study was to investigate the effects of human parathyroid hormone (1–34) (PTH
1–34
; PTH) plus menaquinone-4 (vitamin K
2
; MK) on the osseous integration of hydroxyapatite ...(HA)-coated implants in osteoporotic rats. Ovariectomized female Sprague–Dawley rats were used for the study. Twelve weeks after bilateral ovariectomy, HA-coated titanium implants were inserted bilaterally in the femoral medullary canal of the remaining 40 ovariectomized rats. All animals were then randomly assigned to four groups: Control, MK, PTH and PTH + MK. The rats from groups MK, PTH and PTH + MK received vitamin K
2
(30 mg/kg/day), PTH
1–34
(60 μg/kg, three times a week), or both for 12 weeks. Thereafter, serum levels of γ-carboxylated osteocalcin (Gla-OC) were quantitated by ELISA and the bilateral femurs of rats were harvested for evaluation. The combination of PTH and MK clearly increased the serum levels of Gla-OC (a specific marker for bone formation) compared to PTH or MK alone. The results of our study indicated that all treated groups had increased new bone formation around the surface of implants and increased push-out force compared to Control. In addition, PTH + MK treatment showed the strongest effects in histological, micro-computed tomography and biomechanical tests. In summary, our results confirm that treatment with PTH
1–34
and MK together may have a therapeutic advantage over PTH or MK monotherapy on bone healing around HA-coated implants in osteoporotic rats.
Idiopathic pulmonary fibrosis (IPF) is a fatal parenchymal lung disease with limited effective therapies. Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory ...cytokine, which acts in both acquired and innate immunity. We have previously reported that IL-18 play an important role in lipopolysaccharide-induced acute lung injury in mice. Persistent inflammation often drives fibrotic progression in the bleomycin (BLM) injury model. However, the role of IL-18 in pulmonary fibrosis (PF) is still unknown. IL-18 binding protein (IL-18BP) is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to investigate the effects of IL-18BP on BLM-induced PF. In the present study, we found that IL-18 was upregulated in lungs of BLM-injured mice. Neutralization of IL-18 by IL-18BP improved the survival rate and ameliorated BLM-induced PF in mice, which was associated with attenuated pathological changes, reduced collagen deposition, and decreased content of transforming growth factor-β1 (TGF-β1). We further demonstrated that IL-18BP treatment suppressed the BLM-induced epithelial mesenchymal transition (EMT), characterized by decreased α-smooth muscle actin (α-SMA) and increased E-cadherin (E-cad) in vivo. In addition, we provided in vitro evidence demonstrating that IL-18 promoted EMT through upregulation of Snail-1 in A549 cells. In conclusion, our findings raise the possibility that the increase of IL-18 is involved in the development of BLM-induced PF through modulating EMT in a Snail-1-dependent manner. IL-18BP may be a worthwhile candidate option for PF therapy.
•IL-18 expression is increased in BLM-induced pulmonary fibrosis mice.•Neutralization of IL-18 by IL-18BP ameliorates pulmonary fibrosis via inhibition of EMT.•IL-18 promotes EMT in a Snial-1-dependent manner in A549 cells.
Background
The best choice between levodopa alone and levodopa sparing medications for early Parkinson’s disease (PD) remains controversial. We aimed to evaluate the effect and safety of levodopa ...alone and levodopa sparing therapy in symptom relief, neuroimage results and complications.
Methods
A systematic search was performed in PubMed, The Cochrane Library, EMBASE, and Web of Science for randomized controlled trials of early PD patients comparing levodopa-alone with levodopa-sparing therapy. The mean difference (MD) and the risk ratio (RR) were meta-analyzed.
Results
Twenty-three articles with 4913 patients were included. Significantly greater benefit was detected for the levodopa group in the changes of Unified Parkinson’s Disease Rating Scale part II (
p
< 0.00001), III (
p
< 0.00001), and total (
p
< 0.00001) scores, and the between-group MD in part III score increased over time. The loss of the radioligands uptake in levodopa-alone group was also increasingly greater over time. Patients treated with levodopa alone were at higher risk for wearing-off (
p
< 0.001) and dyskinesia (
p
< 0.001), but the RR for dyskinesia between the two groups decreased after 2 years of follow-up.
Conclusion
Levodopa-alone therapy might be superior in motor symptom relief than levodopa-sparing therapy for early PD patients, and the motor advantage of levodopa-alone might grow over time. Sparing therapy might be associated with less risk of wearing-off and dyskinesia, but the events between the two groups might not be different in the long run. Overall, levodopa alone therapy might bring more net benefit to early PD patients compared with levodopa sparing strategies. The clinical and imaging findings are conflicting, which requires further investigation.
SiC whiskers are bridged on rGO through SiC nuclei (C-Si covalent bonds). C-O groups in graphene promote the reaction possibility of SiC nucleation. Special defective configurations induce unpaired ...electrons of the surrounding carbon atoms, which is the prerequisite of the C-Si covalent bonds. With the construction of C-Si bonds, SiCw@rGO composites achieve good thermal conductivity and electrical insulation capability.
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•SiCw@rGO thermal conductive filler was synthesized, in which SiCw are bridged on rGO through SiC nuclei (C-Si covalent bonds).•C-O groups in graphene promote the reaction possibility of SiC nucleation.•Special defective graphene configurations induce the unpaired electrons, enhancing the formation of C-Si covalent bonds.•With the construction of C-Si covalent bonds, SiCw@rGO/EP achieves good thermal conductivity property.
SiC whisker (SiCw) anchoring on reduced graphene oxide (rGO) is a promising thermal conductive filler, which not only constructs the high-effective phonon transmission pathway but also resolves the agglomeration phenomenon of rGO. However, how to quantificationally anchor SiCw on rGO to build a phonon transmission pathway is incompletely understood. That is, the nucleation mechanism of SiCw requires a full investigation. Here, SiCw@rGO was synthesized by stacking bed method using rGO and rice husk ash as materials, in which SiCw is bridged on the rGO sheets through SiC crystal nucleus (C-Si covalent bonds). The experimental and density functional theoretical results reveal that the oxygen-containing defects (C-O groups) of rGO provide favorable sites for SiC nucleation and promote the yield of SiCw. Additionally, some specific defects of rGO induce the unpaired electrons of the surrounding carbon atoms, which is the prerequisite of the formation of C-Si covalent bonds. The construction of C-Si bonds between SiCw and rGO serves to enhance phonon accessibility, making SiCw@rGO composites achieve good thermal conductivity property and electrical insulation performance. The combination of experimental and theoretical research provides guides for the design of high-efficient thermal conductive materials.
•IL-18 induces primary lung fibroblast senescence by down-regulating Klotho expression.•Overexpression of Klotho protects lung fibroblast against senescence induced by IL-18.•Neutralization of IL-18 ...by IL-18BP ameliorates lung fibroblast senescence in bleomycin-induced pulmonary fibrosis mice.
Idiopathic pulmonary fibrosis (IPF) is a lethal disease of unknown aetiology that largely presents in the elderly. The mechanisms related to aging such as fibroblast senescence have been strongly implicated in pathology of IPF. We have previously demonstrated the protective effects of IL-18 binding protein (IL-18BP) against bleomycin (BLM)-induced pulmonary fibrosis (PF) via inhibition of epithelial-to-mesenchymal transition. However, the role of IL-18 in fibroblast senescence in PF is still unknown. The aim of this study was to investigate the effects of IL-18 on fibroblast senescence in the development of PF. We found that SA-β-gal positive cells, the proportion of cells in G1 phase, and expressions of p21 and p53 were increased in primary lung fibroblasts isolated from BLM-challenged mice, while the fibroblasts from IL-18BP-treated mice showed decreased senescence propensity. We further demonstrated that IL-18 was sufficient to trigger senescence of primary lung fibroblasts. The senescence-associated secretory phenotype (SASP) of fibroblasts treated with IL-18 robustly stimulated a fibrotic phenotype in pulmonary fibroblasts. Moreover, the expression of Klotho, an anti-senescence protein, was down-regulated after IL-18 treatment in primary lung fibroblasts. Overexpression of Klotho reversed the senescence and SASP induced by IL-18 in lung fibroblasts. In summary, we reported for the first time that IL-18 promoted the lung fibroblast senescence and SASP in PF through blocking Klotho pathway. Neutralize IL-18 by IL-18BP exhibited antifibrotic effects partly by suppressing lung fibroblast senescence in PF. It contributes to the growing evidence that IL-18 could be a therapeutic target for PF.
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