Adipocyte differentiation of bone marrow mesenchymal stem/stromal cells (BMSCs) instead of osteoblast formation contributes to age- and menopause-related marrow adiposity and osteoporosis. Vascular ...calcification often occurs with osteoporosis, a contradictory association called "calcification paradox". Here we show that extracellular vesicles derived from aged bone matrix (AB-EVs) during bone resorption favor BMSC adipogenesis rather than osteogenesis and augment calcification of vascular smooth muscle cells. Intravenous or intramedullary injection of AB-EVs promotes bone-fat imbalance and exacerbates Vitamin D3 (VD3)-induced vascular calcification in young or old mice. Alendronate (ALE), a bone resorption inhibitor, down-regulates AB-EVs release and attenuates aging- and ovariectomy-induced bone-fat imbalance. In the VD3-treated aged mice, ALE suppresses the ovariectomy-induced aggravation of vascular calcification. MiR-483-5p and miR-2861 are enriched in AB-EVs and essential for the AB-EVs-induced bone-fat imbalance and exacerbation of vascular calcification. Our study uncovers the role of AB-EVs as a messenger for calcification paradox by transferring miR-483-5p and miR-2861.
Cancer incidence is rising, and the efficacy of current available anticancer agents is limited by severe dose‐limiting toxicities and drug resistance problems. Nanoparticles are heralded as the next ...frontier in cancer treatment. Here, a pure physical method is used to efficiently fabricate very small silver particles even approaching the Ångstrom (Ång) dimension. Fructose is used as a dispersant and stabilizer to coat the Ång‐scale silver particles (AgÅPs). Functional and mechanistic studies demonstrate that fructose‐coated AgÅPs (F‐AgÅPs) can enter and accumulate in multiple cultured cancer cell lines to induce apoptotic death, whereas most normal cells are resistant to the efficacious dose of F‐AgÅPs; in vivo, intravenous administration of F‐AgÅPs potently inhibits the growth of pancreatic and lung cancer xenografts in nude mice, without inducing notable toxic effects on the healthy tissues. The results suggest the promising potential of F‐AgÅPs as a potent, safe, and broad‐spectrum agent for the cancer treatment.
Physical method‐fabricated fructose‐coated Ångstrom‐scale silver particles (F‐AgÅPs) have the ability to enter multiple cancer cells to induce apoptosis. Intravenous injection of F‐AgÅPs potently inhibits the growth of cancer xenograft models, without inducing notable toxic effects on healthy tissues. These results suggest that F‐AgÅPs have a great potential to be used as a potent, safe, and broad‐spectrum agent for cancer treatment.
Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we ...demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8
T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.
The radial conjugated π‐system of cycloparaphenylenes (CPPs) makes them intriguing fluorophores and unique supramolecular hosts. However, the bright photoluminescence (PL) of CPPs was limited to the ...blue light and the supramolecular assembly behavior of large CPPs was rarely investigated. Here we present the synthesis of tetra‐benzothiadiazole‐based 12cycloparaphenylene (TB12CPP), which exhibits a lime to orange PL with an excellent quantum yield up to 82 % in solution. The PL quantum yield of TB12CPP can be further improved to 98 % in polymer matrix. Benefiting from its enlarged size, TB12CPP can accommodate a fullerene derivative or concave–convex complexes of fullerene and buckybowl through the combined π–π and C−H⋅⋅⋅π interactions. The latter demonstrates the first case of a ternary supramolecule of CPPs.
A benzothiadiazole‐based 12cycloparaphenylene (TB12CPP) is obtained and characterized. TB12CPP exhibits a lime to orange emission with a quantum yield up to 98 %, ranking it as one of the brightest CPPs. As a supramolecular host, TB12CPP is bright as well, showing adaptable ring structure. A ternary assembly between TB12CPP, fullerene, and buckybowl is realized.
It remains a challenge to exploit dual-functional metal–organic frameworks (MOFs) for applications, including luminescence detection and proton conduction. With the deliberate selection of the ...bifunctional organic ligand 5-sulfoisophthalic acid monosodium salt (NaH2bts), and the phosphonic acid ligand N,N′-piperazine (bismethylenephosphonic acid; H4L), a robust three-dimensional (3D) noninterpenetrating dual-functional MOF, Tb(H2L)(H2bts)(H2O)·H2O (1), has been synthesized hydrothermally. On the basis of the excellent thermal and chemical as well as superior luminescence stabilities in water and solutions with different pHs, 1 can serve as the simple, rapid, and highly selective and sensitive luminescence detection of the carcinoid biomarkers 5-hydroxytryptamine (HT) and its metabolite 5-hydroxyindole-3-acetic acid (HIAA) with detection limits of nanomolar magnitude in water and in simulated blood plasma and urine systems. Due to the change in the signals that could be readily differentiated by the naked eye under a UV lamp, a portable test paper has been developed. The probable quenching mechanisms are discussed in detail. In addition, a great number of hydrogen-bonding networks are formed among the uncoordinated carboxylic oxygen atoms, sulfonate oxygen atoms, protonated nitrogen atoms, and water molecules, which provide potential proton-hopping sites for proton conduction, leading to a maximum proton conductivity of 2.3 × 10–4 S cm–1 at 368 K and 95% relative humidity. The above results suggest that rationally designed dual-functional MOFs can open an avenue for the development of occupational diagnostic tools and alternative energy technology.
Objective
Osteosarcoma is a primary malignancy originating from mesenchymal tissue characterized by rapid growth, early metastasis and poor prognosis. Ginsenoside Rg5 (G‐Rg5) is a minor ginsenoside ...extracted from Panax ginseng C.A. Meyer which has been discovered to possess anti‐tumor properties. The objective of current study was to explore the mechanism of G‐Rg5 in the treatment of osteosarcoma by network pharmacology and molecular docking technology.
Methods
Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases were used to obtain the pharmacological targets of G‐Rg5. Related genes of osteosarcoma were searched for in the GeneCards, OMIM and DrugBank databases. The targets of G‐Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G‐Rg5 in the treatment of osteosarccoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein–protein interaction (PPI) network, and the Database for Annotation, Visualization and Integrated Discovery (DAVID) platform was used to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. AutoDock vina software was used to perform molecular docking between G‐Rg5 and hub targets. The hub genes were imported into the Kaplan–Meier Plotter online database for survival analysis.
Results
A total of 61 overlapping targets were obtained. The related signaling pathways mainly included PI3K‐Akt signaling pathway, Proteoglycans in cancer, Lipid and atherosclerosis and Kaposi sarcoma‐associated herpesvirus infection. Six hub targets including PIK3CA, SRC, TP53, MAPK1, EGFR, and VEGFA were obtained through PPI network and targets‐pathways network analyses. The results of molecular docking showed that the binding energies were all less than –7 kcal/mol. And the results of survival analysis showed TP53 and VEGFA affect the prognosis of sarcoma patients.
Conclusion
This study explored the possible mechanism of G‐Rg5 in the treatment of osteosarcoma using network pharmacology method, suggesting that G‐Rg5 has the characteristics of multi‐targets and multi‐pathways in the treatment of osteosarcoma, which lays a foundation for the follow‐up experimental and clinical researches on the therapeutic effects of G‐Rg5 on osteosarcoma.
The pharmacological targets of Rg5 were selected from the Pharmmapper, SwissTargetPrediction and similarity ensemble approach databases. The osteosarcoma genes were found from the GeneCards, OMIM, and drugbank databases.The targets of G‐Rg5 and the related genes of osteosarcoma were intersected to obtain the potential target genes of G‐Rg5 against osteosarcoma. The STRING database and Cytoscape 3.8.2 software were used to construct the protein–protein interaction (PPI) network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were identified by the DAVID database. Hub genes were obtained through PPI network and targets‐pathways network analyses. AutoDock vina software was used to perform molecular docking between G‐Rg5 and hub targets. The hub genes were then imported into the Kaplan–Meier Plotter online database for survival analysis.
Daytime sleepiness is associated with poor daytime functioning and adverse cognitive and emotional consequences, such as impaired decision-making and increased impulsivity. Little is known about the ...association between daytime sleepiness and suicidal behaviors. This study examined the prospective relationship between daytime sleepiness and suicidal behaviors, including suicidal thought (ST), suicide plan (SP), and suicide attempt (SA), in a large sample of adolescents.
A prospective longitudinal study of 7072 adolescents (mean age = 14.6 years) was conducted in Shandong province, China. Participants completed a self-administered questionnaire to assess suicidal behaviors, daytime sleepiness, nighttime sleep duration, insomnia, snoring, hopelessness, impulsivity, anxiety/depression, and family demographics. Participants were first surveyed in November-December 2015 and resurveyed 1 year later. Of the 7072 participants, 77.1% (n = 5451) who did not report suicidal behaviors at baseline were included for primary analysis.
The incidence rates of ST, SP, and SA at 1 year follow-up were 6.0%, 2.1%, and 1.6%, respectively. The incidence rates of ST and SP significantly increased with elevated daytime sleepiness score at baseline. After adjusting for adolescent and family covariates including sleep-related variables (i.e. insomnia, nighttime sleep duration, and snoring), a daytime sleepiness score ≥ median at baseline was significantly associated with increased risk of ST (OR = 1.55, 95%CI = 1.02-2.35) and SP (OR = 2.60, 95%CI = 1.22-5.53).
Daytime sleepiness appears to be a significant predictor of subsequent suicidal behaviors in adolescents. These findings emphasize the importance of assessing and intervening daytime sleepiness for preventing suicide in adolescents.
Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on ...single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier.
In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival.
Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve AUC at 5 years: 0·749 95% CI 0·660–0·826 in region 1, 0·734 0·651–0·814 in region 2, and 0·736 0·649–0·824 in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio HR 5·32 95% CI 2·81–10·07 in the internal testing set, 5·39 3·38–8·59 in the independent validation set, and 4·62 2·48–8·61 in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 95% CI 0·756–0·861).
Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence.
National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.
•Stressful life events were associated with overall suicidality, suicidal ideation and suicide plan.•Insomnia was an independent risk factor of suicidality in adolescents.•Insomnia had a mediating ...effect on the association between stressful life events and suicidality.
This study aimed to examine the associations between stressful life events, insomnia, and suicidality including suicidal ideation (SI), suicide plan (SP) and suicide attempt (SA) in a large sample of Chinese adolescents.
A total of 11,831 adolescents who participated in the baseline survey of Shandong Adolescent Behavior and Health Cohort were included for the analysis. Participants were sampled from 8 middle/high schools in 3 counties of Shandong, China. Participants completed a structured behavior and health questionnaire, including suicidality, demographics, depression/anxiety, stressful life events (SLEs), and insomnia in November-December 2015. A series of logistic regression models and mediation analyses were performed to examine the associations between SLEs, insomnia and suicidality.
The prevalence rates of overall suicidality, SI, SP and SA in the last year were 13.1%, 12.5%, 3.3%, and 1.5%, respectively. SLEs were significantly associated with overall suicidality, SI, and SP. Insomnia was an independent risk factor of suicidality and a mediator of the association between SLEs and suicidality. The total effect of SLEs on overall suicidality was 0.597 (95%CI: 0.534–0.661), including 0.457 (95%CI: 0.391–0.523) for direct effect and 0.158 (95%CI: 0.138–0.178) for indirect effect. Insomnia also mediated the associations of SLEs with SI, SP and SA, respectively.
Causal relationship could not be concluded because this study is cross-sectional.
Stressful life events and insomnia are directly associated with suicidality in adolescents. The association between SLEs and suicidality is partially mediated by insomnia.
The seasonal human coronaviruses (HCoVs) have zoonotic origins, repeated infections, and global transmission. The objectives of this study are to elaborate the epidemiological and evolutionary ...characteristics of HCoVs from patients with acute respiratory illness. We conducted a multicenter surveillance at 36 sentinel hospitals of Beijing Metropolis, China, during 2016–2019. Patients with influenza‐like illness (ILI) and severe acute respiratory infection (SARI) were included, and submitted respiratory samples for screening HCoVs by multiplex real‐time reverse transcription‐polymerase chain reaction assays. All the positive samples were used for metatranscriptomic sequencing to get whole genomes of HCoVs for genetical and evolutionary analyses. Totally, 321 of 15 677 patients with ILI or SARI were found to be positive for HCoVs, with an infection rate of 2.0% (95% confidence interval, 1.8%–2.3%). HCoV‐229E, HCoV‐NL63, HCoV‐OC43, and HCoV‐HKU1 infections accounted for 18.7%, 38.3%, 40.5%, and 2.5%, respectively. In comparison to ILI cases, SARI cases were significantly older, more likely caused by HCoV‐229E and HCoV‐OC43, and more often co‐infected with other respiratory pathogens. A total of 179 full genome sequences of HCoVs were obtained from 321 positive patients. The phylogenetical analyses revealed that HCoV‐229E, HCoV‐NL63 and HCoV‐OC43 continuously yielded novel lineages, respectively. The nonsynonymous to synonymous ratio of all key genes in each HCoV was less than one, indicating that all four HCoVs were under negative selection pressure. Multiple substitution modes were observed in spike glycoprotein among the four HCoVs. Our findings highlight the importance of enhancing surveillance on HCoVs, and imply that more variants might occur in the future.
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