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To investigate the association of computed tomography-assessed body composition with survival outcomes of metastatic renal cell carcinoma (mRCC) received immunotherapy.In this multicenter, retrospective study, we reviewed 251 mRCC patients who received anti-PD1 from five centers. We analyzed the relationship between BMI, skeletal muscle area (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and subcutaneous adipose percentage (SAT%) with progression-free survival (PFS) and overall survival (OS). The spatial localization T cells was investigated by multiplex immunofluorescence.Among 224 evaluable patients, 23 (10.3%) patients were underweight, 118 (52.7%) had normal weight, 65 (29%) were overweight, and 18 patients (8%) were obese. The median age was 55 years and most patients were male (71%). No significant improvement in PFS (HR, 0.61; 95% CI, 0.27-1.42) or OS (HR, 1.09; 95% CI, 0.38-3.13) was observed for the obese patients. Besides, SM, VAT, and SAT were not associated with survival outcomes (all p0.05). Interestingly, SAT% independently predicted PFS (as continuous variable, HR: 0.02; 95% CI, 0.01-0.11) and OS (HR:0.05; 95% CI, 0.01-0.39), which remained significant in multivariate modeling (as continuous variable, adjusted HR for PFS, 0.01; 95% CI, 0.00-0.04; adjusted HR for OS, 0.08; 95% CI, 0.01-0.72). These associations were consistent in subgroup analysis of different gender, BMI, PD-L1 positive, and sarcopenia group. Tumor of high SAT% patients had a higher intratumoral PD1High SAT% predicts better outcomes in mRCC patients treated with anti-PD1 and T cell location may account for the better response.• CT-based subcutaneous adipose percentage independently predicted progression-free survival and overall survival. • Patients with a higher subcutaneous adipose percentage had a higher intratumoral PD1

To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will. (EEOD) on a three-dimensional (3D) human malignant glioma (MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will. (OD).The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology, and the action mechanism of Chinese medicine (CM) on human MG cells was investigated through network pharmacology analysis. First, the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Then, cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments, and two-dimensional (2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays. The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach.Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS. EEOD suppressed the viability of MG cells, promoted their apoptosis, and inhibited their migratory and invasive potentials (all P0.05). Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK, EGFR, MYC, GSK3B, and other targets. The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization.]EEOD could inhibit the invasion of human MG cells, and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization.

A high malignancy rate and poor prognosis are common problems with triple-negative breast cancer (TNBC). There is increasing evidence that glycolysis plays vital roles in tumorigenesis, tumor invasion, immune evasion, chemoresistance, and metastasis. However, a comprehensive analysis of the diagnostic and prognostic significance of glycolysis in TNBC is lacking.Transcriptomic and clinical data of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, respectively. Glycolysis-related genes (GRGs) were collected from the Molecular Signatures Database (MSigDB). Differential comparative analysis was performed to obtain the differentially expressed (DE)-GRGs associated with TNBC. Based on the DE-GRGs, a glycolysis-related risk signature was established using Least Absolute Shrinkage and Selector Operation (LASSO) and multivariable Cox regression analyses. The prognostic value, tumor microenvironment, mutation status, and chemotherapy response of different risk groups were analyzed. An independent cohort from the METABRIC database was used for external validation. Furthermore, the expression patterns of five genes derived from the prognostic model were validated by quantitative real-time polymerase chain reaction (RT-qPCR).The glycolysis-related prognostic signature included five genes (IFNG, ACSS2, IRS2, GFUS, and GAL3ST1) and predicted the prognosis of TNBC patients independent of clinical factors (p 0.05). Patients were divided into high- and low-risk groups based on the median risk score. Compared to low-risk TNBC patients, high-risk patients had significantly decreased overall survival (HR = 2.718, p 0.001). Receiver operating characteristic and calibration curves demonstrated that the model had high performance in terms of predicting survival and risk stratification. The results remained consistent after external verification. Additionally, the tumor immune microenvironment significantly differed between the risk groups. Low-risk TNBC patients had a better immunotherapy response than high-risk patients. High-risk TNBC patients with a poor prognosis may benefit from targeted therapy.This study developed a novel glycolysis and prognosis-related (GRP) signature based on GRGs to predict the prognosis of TNBC patients, and may aid clinical decision-making for these patients.

Background Urinary bladder cancer (UBC) is a common malignancy of the urinary tract; however, the mechanism underlying its high recurrence and responses to immunotherapy remains unclear, making clinical outcome predictions difficult. Epigenetic alterations, especially DNA methylation, play important roles in bladder cancer development and are increasingly being investigated as biomarkers for diagnostic or prognostic predictions. However, little is known about hydroxymethylation since previous studies based on bisulfite-sequencing approaches could not differentiate between 5mC and 5hmC signals, resulting in entangled methylation results. Methods Tissue samples of bladder cancer patients who underwent laparoscopic radical cystectomy (LRC), partial cystectomy (PC), or transurethral resection of bladder tumor (TURBT) were collected. We utilized a multi-omics approach to analyze both primary and recurrent bladder cancer samples. By integrating various techniques including RNA sequencing, oxidative reduced-representation bisulfite sequencing (oxRRBS), reduced-representation bisulfite sequencing (RRBS), and whole exome sequencing, a comprehensive analysis of the genome, transcriptome, methylome, and hydroxymethylome landscape of these cancers was possible. Results By whole exome sequencing, we identified driver mutations involved in the development of UBC, including those in FGFR3, KDMTA, and KDMT2C. However, few of these driver mutations were associated with the down-regulation of programmed death-ligand 1 (PD-L1) or recurrence in UBC. By integrating RRBS and oxRRBS data, we identified fatty acid oxidation-related genes significantly enriched in 5hmC-associated transcription alterations in recurrent bladder cancers. We also observed a series of 5mC hypo differentially methylated regions (DMRs) in the gene body of NFATC1, which is highly involved in T-cell immune responses in bladder cancer samples with high expression of PD-L1. Since 5mC and 5hmC alternations are globally anti-correlated, RRBS-seq-based markers that combine the 5mC and 5hmC signals, attenuate cancer-related signals, and therefore, are not optimal as clinical biomarkers. Conclusions By multi-omics profiling of UBC samples, we showed that epigenetic alternations are more involved compared to genetic mutations in the PD-L1 regulation and recurrence of UBC. As proof of principle, we demonstrated that the combined measurement of 5mC and 5hmC levels by the bisulfite-based method compromises the prediction accuracy of epigenetic biomarkers.

Metastasis is the main cause of mortality in renal cell carcinoma (RCC). Circular RNAs (circRNAs) involvement in RCC metastasis has been described, although the underlying mechanisms remain unknown. We evaluated recurring lung-metastasis cases using patient-derived xenograft models and isolated a highly metastatic clone. CircSPIRE1 was identified as a metastasis-inhibiting circRNA in clinical cohort and xenograft models. Mechanistically, circSPIRE1 suppressed mesenchymal state through regulating ELAV like RNA binding protein 1-mRNA binding, and upregulating polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and KH domain RNA binding protein (QKI) expression. GALNT3 promoted glycosylation and cytomembrane localization of E-cadherin. QKI formed a positive feedback loop to enhance circSPIRE1 expression. Meanwhile, exosomal circSPIRE1 suppressed angiogenesis and vessel permeability. Our work reveals a non-canonical route for circRNAs in RCC to suppress metastasis. Furthermore, a nanomedicine consisting of circSPIRE1 plasmid suppressed metastasis formation. In conclusion, circSPIRE1 may be a predictor of metastasis and a potential therapeutic target of metastatic RCC.

Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer’s disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.

In this paper, the pore structure characteristics of shales and its controlling factors were analyzed by means of total organic carbon (TOC) analysis, X-ray diffraction (XRD) analysis, field emission scanning electron microscopy (FE-SEM) and low-pressure N2 adsorption (LPNA) analysis. Based on the grey relational analysis, the controlling factors of pore structure parameters were discussed. The results showed that the TOC contents range from 2.98 to 4.97%, the main minerals of shales are quartz and clay minerals with an average of 41.62 and 30.98%, respectively. The organic matter pores, the interparticle pores, the intraparticle pores, and the micro-fractures are the main pore types determined by the FE-SEM observation. The pore volume of shales is between 0.0637 and 0.1053 cm3/g, the specific surface area ranges from 16.44 to 37.61 m2/g, the average pore size is between 11.20 and 15.50 nm. The organic matter and the quartz have a positive influence on the specific surface area and total pore volume, whereas the clay minerals have a negative impact. The shales have a wide range of pore size, and the mesopores and macropores are the dominant contributor to the total pore volume while the mesoporous contribute the main specific surface area. The TOC contents and quartz contents have the most significant effect on the total pore volume and specific surface area, and the average pore size is mainly controlled by the quartz contents.

As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.

The use of acellular dermal matrices (ADMs) and mesh reopened the possibility for the prepectoral single-stage breast reconstruction (PBR). The complications of single-stage breast reconstruction after PRB are controversial. We conducted a systematic review and meta-analysis of the impact of implant plane on single-stage breast reconstruction. Our aim was to evaluate the different postoperative complications between patients receiving prepectoral breast reconstruction and subpectoral breast reconstruction (SBR) on single-stage breast reconstruction.A comprehensive research on databases including PubMed, Embase, and Cochrane libraries was performed to retrieve literature evaluating the effect of implant plane on single-stage breast reconstruction from 2010 to 2020. All included studies were evaluated the complications after single-stage breast reconstruction. Only studies comparing patients who underwent prepectoral reconstruction with a control group who underwent subpectoral reconstruction were included.A total of 13 studies were included in the meta-analysis, with a total of 1724 patients. In general, compared with SBR group, the PBR significantly reduced the risk of total complications (including seroma, hematoma, necrosis, wound dehiscence, infection, capsular contraction, implant loss/remove, and rippling) after single-stage breast reconstruction (OR: 0.54, 95% CI: 0.44-0.67, p 0.001). Compared with the SBR group, the PBR had remarkably decreased capsular contracture (OR: 0.40, 95% CI: 0.27-0.58, p 0.001) and postoperative infection (OR: 0.58, 95% CI: 0.36-0.95, p = 0.03).The PBR is a safe single-stage breast reconstruction with fewer postoperative complications. It is an alternative surgical method for SBR.

Background The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer’s disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD. Methods Aβ1–42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively. Results Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells. Conclusion Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 mice.

Seroclearance of hepatitis B surface antigen (HBsAg) is regarded as the functional cure for chronic hepatitis B (CHB). The relationship between human leukocyte antigen (HLA) variants, hepatitis B virus genotype, and longitudinal HBsAg serodecline remains to be explored. A total of 1735 HBeAg-seronegative CHB patients with genotype B or C infection of the community-based REVEAL-HBV cohort were genotyped for rs1710 (HLA-G) and rs2770 (HLA-B) using TaqMan assay. Cox proportional hazard regression and generalized linear mixed models were used to analyze the association of HLA genetic variants with the rate of HBsAg seroclearance and longitudinal HBsAg serodecline. Rs1710 G allele was differentially associated with the HBsAg seroclearance in genotype B [aRR (95% CI) = 0.74 (0.56–0.98)] and genotype C [aRR (95%CI) = 1.43 (1.08–1.88)] infection. Rs2770 G allele was associated with HBsAg seroclearance only in genotype B infection [aRR (95% CI) = 0.69 (0.52–0.91)]. The alleles associated with HBsAg seroclearance were significant predictors for the serodecline of HBsAg levels in an HBV genotype-dependent manner (genotype B infection: rs1710, P = 0.013; rs2770, P = 0.0081; genotype C infection: rs1710, P = 0.0452). Our results suggest both spontaneous HBsAg seroclearance and serodecline are modified by the interaction between HLA variants and HBV genotype.

Mulberry leaf (Mori Folium) extract (MLE) is known to have anti-obesity effects. In this study, the enhanced effects of MLE after bioconversion treatment using Pectinex (BMLE) on obesity were explored, and the underlying mechanisms were investigated using the active components, neochlorogenic acid (5-CQA) and cryptochlorogenic acid (4-CQA), whose amounts were increased by bioconversion of MLE. Both MLE and BMLE inhibited lipid accumulation in 3T3-L1 adipocytes without cytotoxicity and suppressed the expression of CCAAT/enhancer-binding protein alpha (C/EBPα). In addition, MLE and BMLE decreased high-fat diet-induced adipose tissue mass expansion. Notably, BMLE significantly increased antiadipogenic and anti-obesity effects compared to MLE in vitro and in vivo. The active ingredients increased by bioconversion, 5-CQA and 4-CQA, inhibited the protein levels of C/EBPα and the mRNA levels of stearoyl-CoA desaturase 1 (Scd1). These findings provide new insights into the therapeutic possibility of using bioconversion of MLE, by which upregulation of 5-CQA and 4-CQA potently inhibits adipogenesis.

Background In recent years, silver nanoparticles (AgNPs) have gradually been widely used, especially in the field of anticancer medicine. Ovarian cancer (OC) is the gynaecological malignancy with the highest mortality rate, and the current treatment is still based on surgery, chemotherapy and postoperative targeted therapy. Therefore, the development of safe and effective nanoparticles for targeted therapy of OC is very important. This study aimed to prepare a new type of triangular silver nanoparticles (tAgNPs) and evaluate the anticancer properties for OC in vitro and in vivo. Methods The tAgNPs were chemically synthesized and characterized using scanning electron microscopy (SEM), ultraviolet (UV) spectrophotometry and other techniques. By performing cell-based tests, such as cell counting kit-8 (CCK-8), plate colony formation, cell apoptosis, reactive oxygen species (ROS), and western blot (WB) assays, the inhibitory effects and related mechanisms of tAgNPs on OC cells were analysed.The anticancer effect of tAgNPs in vivo was verified by a SKOV3 tumor-bearing mouse model. Results Five types of tAgNPs with different colours were successfully synthesized, with a particle size of 25–50 nm and a good dispersion. The results of in vitro experiments showed that tAgNPs treatment reduced the viability and proliferation of SKOV3 cells, arrested the cell cycle in G0/G1 phase, inhibited the expression levels of proliferation-related factors and cyclins, and promoted cell apoptosis by producing ROS and increasing caspase-3 activity. Consistent with the results of in vitro experiments, in vivo animal experiments also showed that tAgNPs significantly inhibited the proliferation of ovarian cancer. More importantly, no obvious toxic and side effects were observed. Conclusions In this study, a novel triangular AgNPs was successfully prepared. tAgNPs are very stable, significantly inhibit the proliferation of OC cells and tumour growth in tumour-bearing mice, providing a promising nanotargeted therapy for OC.

Background Massive hemorrhage is the main cause of preventable death after trauma. This study aimed to establish prediction models for early diagnosis of massive hemorrhage in trauma. Methods Using the trauma database of Chinese PLA General Hospital, two logistic regression (LR) models were fit to predict the risk of massive hemorrhage in trauma. Sixty-two potential predictive variables, including clinical symptoms, vital signs, laboratory tests, and imaging results, were included in this study. Variable selection was done using the least absolute shrinkage and selection operator (LASSO) method. The first model was constructed based on LASSO feature selection results. The second model was constructed based on the first vital sign recordings of trauma patients after admission. Finally, a web calculator was developed for clinical use. Results A total of 2353 patients were included in this study. There were 377 (16.02%) patients with massive hemorrhage. The selected predictive variables were heart rate (OR: 1.01; 95% CI: 1.01–1.02; PP = 0.004), base excess (OR: 0.90; 95% CI: 0.87–0.93; PPPP = 0.001). Model 1, which was developed based on LASSO feature selection results and LR, displayed excellent discrimination (AUC: 0.894; 95% CI: 0.875–0.912), good calibration (P = 0.405), and clinical utility. In addition, the predictive power of model 1 was better than that of model 2 (AUC: 0.718; 95% CI: 0.679–0.757). Model 1 was deployed as a public web tool (http://82.156.217.249:8080/). Conclusions Our study developed and validated prediction models to assist medical staff in the early diagnosis of massive hemorrhage in trauma. An open web calculator was developed to facilitate the practical application of the research results.

In response to infection or sterile insults, inflammatory programmed cell death is an essential component of the innate immune response to remove infected or damaged cells. PANoptosis is a unique innate immune inflammatory cell death pathway regulated by multifaceted macromolecular complexes called PANoptosomes, which integrate components from other cell death pathways. Growing evidence shows that PANoptosis can be triggered in many physiological conditions, including viral and bacterial infections, cytokine storms, and cancers. However, PANoptosomes at the single cell level have not yet been fully characterized. Initial investigations have suggested that key pyroptotic, apoptotic, and necroptotic molecules including the inflammasome adaptor protein ASC, apoptotic caspase-8 (CASP8), and necroptotic RIPK3 are conserved components of PANoptosomes. Here, we optimized an immunofluorescence procedure to probe the highly dynamic multiprotein PANoptosome complexes across various innate immune cell death-inducing conditions. We first identified and validated antibodies to stain endogenous mouse ASC, CASP8, and RIPK3, without residual staining in the respective knockout cells. We then assessed the formation of PANoptosomes across innate immune cell death-inducing conditions by monitoring the colocalization of ASC with CASP8 and/or RIPK3. Finally, we established an expansion microscopy procedure using these validated antibodies to image the organization of ASC, CASP8, and RIPK3 within the PANoptosome. This optimized protocol, which can be easily adapted to study other multiprotein complexes and other cell death triggers, provides confirmation of PANoptosome assembly in individual cells and forms the foundation for a deeper molecular understanding of the PANoptosome complex and PANoptosis to facilitate therapeutic targeting.

Background Neuroblastoma (NBL) is the most common extra-cranial solid tumour in childhood, with prognosis ranging from spontaneous remission to high risk for rapid and fatal progression. Despite existing therapy approaches, the 5-year event-free survival (EFS) for patients with advanced NBL remains below 30%, emphasizing urgent necessary for novel therapeutic strategies. Studies have shown that epigenetic disorders play an essential role in the pathogenesis of NBL. However, the function and mechanism of N7-methylguanosine (m7G) methyltransferase in NBL remains unknown. Methods The expression levels of m7G tRNA methyltransferase Methyltransferase-like 1 (METTL1) were analyzed by querying the Gene Expression Omnibus (GEO) database and further confirmed by immunohistochemistry (IHC) assay. Kaplan-Meier, univariate and multivariate cox hazard analysis were performed to reveal the prognostic role of METTL1. Cell function assays were performed to evaluate how METTL1 works in proliferation, apoptosis and migration in cell lines and xenograft mouse models. The role of METTL1 on mRNA translation activity of NBL cells was measured using puromycin intake assay and polysome profiling assay. The m7G modified tRNAs were identified by tRNA reduction and cleavage sequencing (TRAC-seq). Ribosome nascent-chain complex-bound mRNA sequencing (RNC-seq) was utilized to identify the variation of gene translation efficiency (TE). Analyzed the codon frequency decoded by m7G tRNA to clarify the translation regulation and mechanism of m7G modification in NBL. Results This study found that METTL1 were significantly up-regulated in advanced NBL, which acted as an independent risk factor and predicted poor prognosis. Further in NBL cell lines and BALB/c-nu female mice, we found METTL1 played a crucial role in promoting NBL progression. Furthermore, m7G profiling and translation analysis revealed downregulation of METTL1 would inhibit puromycin intake efficiency of NBL cells, indicating that METTL1 did count crucially in regulation of NBL cell translation. With all tRNAs with m7G modification identified in NBL cells, knockdown of METTL1 would significantly reduce the levels of both m7G modification and m7G tRNAs expressions. Result of RNC-seq shew there were 339 overlapped genes with impaired translation in NBL cells upon METTL1 knockdown. Further analysis revealed these genes contained higher frequency of codons decoded by m7G-modified tRNAs and were enriched in oncogenic pathways. Conclusion This study revealed the critical role and mechanism of METTL1-mediated tRNA m7G modification in regulating NBL progression, providing new insights for developing therapeutic approaches for NBL patients.

To investigate whether amide proton transfer-weighted imaging (APTWI) and diffusion kurtosis imaging (DKI) can be used to evaluate endometrial carcinoma (EC) in terms of clinical type, histological grade, subtype, and Ki-67 index. Eighty-eight patients with EC underwent pelvic DKI and APTWI. The non-Gaussian diffusion coefficient (Dapp), apparent kurtosis coefficient (Kapp), and magnetization transfer ratio asymmetry (MTRasym (3.5 ppm)) were calculated and compared based on the clinical type (type I, II), histological grade (high- and low-grade), and subtype (endometrioid adenocarcinoma (EA) and non-EA). Correlation coefficients were calculated for each parameter with histological grades and the Ki-67 index. The MTRasym (3.5 ppm) and Kapp values were higher in the type II group and high-grade group than in the type I and low-grade groups, respectively, while the Dapp values were lower in the type I and low-grade groups, respectively (all p < 0.05). The Kapp value was higher in the EA group than in the non-EA group (p = 0.022). The Kapp value was the only independent predictor for the histological grade of EA and the clinical type of EC. The AUC (DKI) was higher than the AUC (APTWI) in the identification of type I and II EC and high- and low-grade EA (Z = 2.042, 2.013, p = 0.041, 0.044), while in the identification of EA and non-EA, only the difference in Kapp was statistically significant. Moreover, the Kapp and MTRasym (3.5 ppm) values and Dapp values correlated positively and negatively, respectively, with histological grade (r = 0.759, 0.555, 0.624, and 0.462, all p < 0.05) and Ki-67 index (r = −0.704, −0.507, all p < 0.05). Both DKI- and APTWI-related parameters have potential as imaging markers in estimating the histological features of EC, while DKI shows better performance than APTWI in this study. • DKI and APTWI can be used to preliminarily evaluate the histological characteristics of endometrial carcinoma (EC). • The Kapp was the only independent predictor for the histological grade of EA and the clinical type of EC. • The Kapp, MTRasym (3.5 ppm), and Dapp correlated positively and negatively, respectively, with histological grade and Ki-67 index.

The studied slope is located in the middle reach of the Yalong River in the eastern margin of Qinghai-Tibet Plateau in Southwest China. A large hydropower station is planning to be built near the slope. Understanding the stability mechanism of the slope is important for dam site design. Under a combination of tectonic activity, unloading and weathering, the bedrock mass was fractured. On the basis of field investigation, the GSI classification system and Barton criterion were introduced to determine the strength of the rock mass. The kinematic, limit equilibrium and discontinuum modeling methods were carried out to comprehensively understand the stability of the slope. The kinematic analyses show that only wedge mode is possible for large rock mass failure. However, limit equilibrium analyses show that both wedge failure and circular slip are not expected for rock mass. The slope rock mass is now in the surface rebalance stage. The potentially unstable part is the covering deposit. The 40 million m3 surface deposit is now nearly in a limit equilibrium state. The possibility of failure reaches 41%. Mitigation measures must be put into effect on the deposit to assure the stability of the slope. The results indicated that the failure mechanism of the slope was not controlled by the discontinuities in the rock mass at present but depended on the stability of the surface deposit.

To evaluate ocular surface changes among patients with psoriasis in Malaysia, a developing country in Southeast Asia. An interdisciplinary case–control study (60 psoriasis patients and 40 control subjects) to look at the differences in ocular surface manifestations between patients with psoriasis and a group of age-, gender- and ethnicity-matched healthy controls. One hundred and twenty eyes of 60 patients with psoriasis and 80 eyes of 40 healthy controls without psoriasis were included in the study. Mild-to-moderate psoriasis was found in 42 patients (70%), while 18 patients (30%) had severe psoriasis. Psoriatic arthritis was found in 19 patients (32%). Of the 60 psoriatic patients, the prevalence of ocular involvement was 65% (39/60), in which 32% (19/60) had dry eyes, 27% (16/60) had lid margin abnormalities, 33% (20/60) had cataract, and one had history of anterior uveitis. Compared to controls, ocular surface of psoriatic patients showed more eyelid margin abnormalities, higher meibomian gland loss and lower tear film break-up time. The estimated odds ratio for dry eyes in the psoriasis group was 2.2 (95% CI: 0.8–6.9). Ocular surface disorders encompassing eyelid margin abnormalities, meibomian gland loss and tear dysfunction occur at an earlier and higher rate among psoriatic patients.

Polypharmacy is an important strategy for managing high blood pressure (BP). Combination treatment with a Ca2+ channel blocker (CCB) and an angiotensin II type 1 receptor blocker (ARB) can be used for this purpose. If combination therapy had additional beneficial effects such as protection against cardiovascular injury and regulation of blood glucose, it would be an effective tool for managing metabolic syndrome. Thus, this study investigated the effects of combination treatment with the CCB cilnidipine and the ARB telmisartan on hypertension, cardiovascular injury, and hyperglycemia. A telemetry system was used to measure BP and heart rate (HR) in spontaneous hypertensive rats (SHRs). The effectiveness of combination therapy in protecting against cardiovascular injury was examined using a myocardial ischemia/reperfusion (MI/R) system in SHRs and a cuff-placement-induced neointima hyperplasia model in C57BL/6 mice. An oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were also performed in obese diabetic mice. Combination treatment with a fixed (human equivalent) dose of cilnidipine and telmisartan can effectively lower BP without reflex tachycardia. This combination therapy may also induce cardioprotective effects by increasing the expression of endothelial nitric oxide synthase (eNOS) and vasoprotective effects by inhibiting DNA synthesis in cuff-induced vascular injury. In addition, it may also attenuate high blood glucose levels. The results of this study suggest that combination treatment with cilnidipine and telmisartan can be used as an effective strategy for the treatment of hypertension and related complications.

Nitrate leaching is severe in greenhouse where excessive nitrogen is often applied to maintain high crop productivities. In this study, we investigated the effects of carbon amendment in the subsoil on nitrate leaching and the emission of greenhouse gases (CH4 and N2O) using a soil column experiment. Carbon amendment resulted in over 39% reduction in nitrate leaching and 25.3% to 60.6% increase of total N content in the subsoil zone as compared to non-amended control. Strikingly, the abundance of nirS, nosZ, and 16S rRNA were higher in the treatment than the corresponding controls while no significant effect was detected for nirK. Carbon amendment explained 14%, 10%, and 4% of the variation in the community of nosZ, nirS, and nirK, respectively. It also considerably (more than 7 times) enriched genera such as Anaerovorax, Pseudobacteroides, Magnetospirillum, Prolixibacter, Sporobacter, Ignavibacterium, Syntrophobacter, Oxobacter, Hydrogenispora, Desulfosporomusa, Mangrovibacterium, and Sporomusa, as revealed by the analysis of 16S rRNA amplicon. Network analysis further uncovered that carbon amendment enriched three microbial hubs which mainly consists of positively correlated nirS, nosZ, and anaerobic bacterial populations. In summary, carbon amendment in the subsoil mitigated nitrate leaching and increased the nitrogen pool by possible activation of denitrifying and anaerobic bacterial populations. KEY POINTS: • Carbon amendment in subsoil reduced NO3- leaching by over 39% under high N input. • Carbon amendment increased the total N in subsoil from 25.3% to 60.6%. • Carbon amendment enriched nirS- and nosZ-type denitrifying bacteria in subsoil.

Here we noted significantly downregulated miR-1-3p in gastric cancer (GC) tissue compared with adjacent normal tissue through qRT-PCR. Lowly expressed miR-1-3p correlated GC progression. Overexpressing miR-1-3p could restrain tumor-relevant cell behaviors in GC, while miR-1-3p inhibitor treatment triggered the opposite results. Moreover, dual-luciferase reporter gene detection identified specific binding sites of miR-1-3p in CENPF 3’untranslated region. Upregulating miR-1-3p constrained cell progression of GC via CENPF downregulation. Western blot, qRT-PCR and dual-luciferase detections manifested that miR-1-3p negatively mediated CENPF expression in GC cells. Thus, we demonstrated that miR-1-3p negatively mediated CENPF to hamper GC progression. CENPF may be an underlying target for GC therapy.

Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.

Despite exceptional morphological and physicochemical attributes, mesoporous silica nanoparticles (MSNs) are often employed as carriers or vectors. Moreover, these conventional MSNs often suffer from various limitations in biomedicine, such as reduced drug encapsulation efficacy, deprived compatibility, and poor degradability, resulting in poor therapeutic outcomes. To address these limitations, several modifications have been corroborated to fabricating hierarchically-engineered MSNs in terms of tuning the pore sizes, modifying the surfaces, and engineering of siliceous networks. Interestingly, the further advancements of engineered MSNs lead to the generation of highly complex and nature-mimicking structures, such as Janus-type, multi-podal, and flower-like architectures, as well as streamlined tadpole-like nanomotors. In this review, we present explicit discussions relevant to these advanced hierarchical architectures in different fields of biomedicine, including drug delivery, bioimaging, tissue engineering, and miscellaneous applications, such as photoluminescence, artificial enzymes, peptide enrichment, DNA detection, and biosensing, among others. Initially, we give a brief overview of diverse, innovative stimuli-responsive (pH, light, ultrasound, and thermos)- and targeted drug delivery strategies, along with discussions on recent advancements in cancer immune therapy and applicability of advanced MSNs in other ailments related to cardiac, vascular, and nervous systems, as well as diabetes. Then, we provide initiatives taken so far in clinical translation of various silica-based materials and their scope towards clinical translation. Finally, we summarize the review with interesting perspectives on lessons learned in exploring the biomedical applications of advanced MSNs and further requirements to be explored.Graphical Abstract

Hydrothermally reaction of Cd(NO3)2·4H2O, pimelic acid (H2Pim) mixed with two N-containing ligands of 1,2-bis(2-methyl-imidazol-1-ylmethyl)benzene (1,2-mbix) or 1,3-bis(2-methyl-imidazol-1-ylmethyl)benzene (1,3-mbix) gave rise to two new Cd(II) MOFs, [Cd(Pim)(1,2-mbix)] (1) and [Cd(Pim)(1,3-mbix)]·H2O (2). Both MOFs were structurally characterized by IR and UV–Vis spectra, single-crystal and powder X-ray diffraction, thermogravimetric analyses. MOF 1 shows a fourfold interpenetrating dia network. Differently, MOF 2 shows a 2D → 3D interdigitated architecture base on the 63 hcb layer when 1,2-mbix was replaced by 1,3-mbix. The luminescent properties of 1 and 2 have been investigated. Furthermore, the luminescent quenching experiments suggest both MOFs exhibit good selectivity and sensitivity to detect Fe3+ and Cr2O72− in water.

Propionate is a short-chain fatty acid (SCFA) mainly produced from carbohydrates by gut microbiota. Sodium propionate (SP) has shown to suppress the invasion in G protein-coupled receptor 41 (GPR41) and GPR43-overexpressing breast cancer cells. In this study we investigated the effects of SP on the proliferation, apoptosis, autophagy, and antioxidant production of breast cancer cells. We showed that SP (5−20 mM) dose-dependently inhibited proliferation and induced apoptosis in breast cancer cell lines JIMT-1 (ER-negative and HER2-expressing) and MCF7 (ER-positive type), and this effect was not affected by PTX, thus not mediated by the GPR41 or GPR43 SCFA receptors. Meanwhile, we demonstrated that SP treatment increased autophagic and antioxidant activity in JIMT-1 and MCF7 breast cancer cells, which might be a compensatory mechanism to overcome SP-induced apoptosis, but were not sufficient to overcome SP-mediated suppression of proliferation and induction of apoptosis. We revealed that the anticancer effect of SP was mediated by inhibiting JAK2/STAT3 signaling which led to cell-cycle arrest at G(0)/G(1) phase, and increasing levels of ROS and phosphorylation of p38 MAPK which induced apoptosis. In nude mice bearing JIMT-1 and MCF7 cells xenograft, administration of SP (20 mg/mL in drinking water) significantly suppressed tumor growth by regulating STAT3 and p38 in tumor tissues. These results suggest that SP suppresses proliferation and induces apoptosis in breast cancer cells by inhibiting STAT3, increasing the ROS level and activating p38. Therefore, SP is a candidate therapeutic agent for breast cancer.

Cost-utility analysis (CUA) is widely used for health technology assessment; however, concerns exist that cost-utility analysts may suggest higher cost-effectiveness thresholds (CETs) to compensate for technologies of relatively lower value. We explored whether selection of a CUA study’s CET was endogenous to estimated incremental cost-effectiveness ratios (ICERs). We systematically reviewed the US cost-effectiveness literature between 2000 and 2017 where studies with explicit CET and ICERs were included. We classified the ratio of studies hypothesized to analyze cost-effective technologies at low CETs (i.e., less than $100,000/quality-adjusted life-year [QALY]) vs higher CETs (i.e., $100,000–$150,000/QALY) relative to their ICER, using a Chi square test to examine whether technologies that were cost effective at high CETs would still be cost effective at lower thresholds. We also performed fixed-effects linear regression exploring the associations between ICERs and reported CETs over time. Among 317 ICERs reviewed: (A) 185 had an ICER

Metabolic responses are important for plant adaptation to abiotic stress. To investigate the responses of Phlox subulata L. to drought stress, we analyzed its physiological and metabolic changes using gas chromatography-mass spectrometer. Based on the physiological indices, P. subulata L. has tolerance to drought to some degree. Our results showed that there were a total of 30 key metabolites induced by drought stress, including amino acids, organic acids, sugars and sugar alcohols, nucleic acid and its derivatives, and other organic compounds. The glutamic acid-mediated proline biosynthesis pathway is continuously upregulated under drought stress, which could regulate osmotic pressure and maintain intracellular environmental stability. More secondary metabolites are used to increase glycolysis and tricarboxylic acid cycle, to accelerate energy production and to enhance the glutamic acid-mediated proline biosynthesis pathway, which are necessary to increase osmotic regulation. Prolonged drought stress induced progressive accumulation of compatible osmolytes, such as proline and inositol, sugars, and amino acids. Therefore, drought caused systemic alterations in metabolic networks involving transamination, TCA cycle, gluconeogenesis/glycolysis, glutamate-mediated proline biosynthesis, shikimate-mediated secondary metabolisms, and the metabolism of pyrimidine. These data suggest that plants may utilize these physiological and metabolomic adjustments as adaptive responses in the early stages of drought stress. These results deepen our understanding of the mechanisms involved in P. subulata L. drought tolerance, which will help improve the understanding of drought’s effects on plant systems.

Polymer-based thermal management composites have been widely utilized in the electronics industry for heat dissipation. Filled with thermal conductive fillers, binary blend polymer-based composite can obtain higher thermal conductivity than single polymer-based composite, however, with impaired mechanical performances. In this study, a tailor-made “core–shell” structure based on high-density polyethylene (PE), high-density polyethylene grafted with maleic anhydride (PE-g-MA) and multiwalled carbon nanotubes (CNTs) was fabricated and introduced into boron nitride (BN) filled polyamide 6 (PA6). In the “core–shell” structure, PE domains acted as the “core,” while CNTs and CNTs-localizing PE-g-MA constituted the “shell.” As-fabricated composite exhibited thermal conductivity of 1.65 W/m K, which was 36.5% higher than that of PA6/PE/BN composite at the same BN loading, and maintained excellent electrical insulating. Meanwhile, benefited from the novel “core–shell” structure, the mechanical properties of PA6/PE-g-MA/PE/CNTs/BN composite were comprehensively balanced.

LaFeO3 perovskite with a porous fibrous structure was successfully synthesized using a sunflower seed shell as a template. To investigate the effects of this template, a sample was prepared without a template via the same procedure. Through various characterization techniques, such as X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, N2 adsorption-desorption analysis, X-ray photoelectron spectroscopy, oxygen temperature programed desorption, and hydrogen temperature programed reduction, the physiochemical properties of the samples were investigated. The results showed that the sample made with a template had a larger surface area and a larger amount of adsorbed oxygen, which further illustrated that the sunflower seed shell template had a significant impact on the physiochemical properties of the samples. Furthermore, we explored the catalytic activity for nitric oxide (NO) oxidation, and studied the factors affecting it, which highlighted its potential application in automobile exhausts.

Chinese adolescents and young adults who migrate from rural to urban areas have many emotional problems such as low self-esteem, high levels of anxiety and depression due to the striking social and cultural differences between rural and urban China. To effectively assess their emotion regulation and promote their mental health and growth, this study aimed to explore the psychometric properties of the Emotion Regulation Questionnaire (ERQ) in Chinese rural-to-urban migrant adolescents and young adults. A total of 397 rural-to-urban migrant adolescents and young adults (age 16.78 ± 1.92 years old) were enrolled. Two common factors were obtained in exploratory factor analysis (EFA), which is similar to both the original English version and the Chinese version for college students. Besides, the ERQ was significantly correlated with subjective well-being, psychological well-being, and academic emotion, which indicated the criterion validity of the ERQ is good (r = 0.17 ~ 0.41, all ps

A Gram-stain-negative, aerobic, and motile strain, TJ48T, was isolated from pakchoi-cultivated soil contaminated with Cd and Pb in Xinxiang (China). Cells of the strain were rod-shaped and colonies on LB agar were faint yellow. Strain TJ48T was positive for catalase and oxidase and the optimal condition for growth was 28 °C, with 1% (w/v) NaCl and at pH 7.0. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain TJ48T was closely related to the genus Rhodobacter and the closest relatives were Rhodobacter ovatus JA234T (97.4%, 16S rRNA gene sequence similarity) and Rhodobacter azotoformans KA25T (96.5%). The DNA G + C content of strain TJ48T was 64.7 mol%. Genome-to-genome distance calculations (GGDC) and ANIb values from genomic comparison between the genomes of strain TJ48T and the related reference species were less than 70% and 95%, respectively. The major cellular fatty acids were summed feature 8 (C18:1ω7c and/or C18:1ω6c) and C17:0. The only isoprenoid quinone detected was Ubiquinone-10 (Q-10). The polar lipid profile contains diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminophospholipid, one unidentified phospholipids, and three unidentified lipids. Strain TJ48T significantly increased the dry weight of roots (26.2–66.3%) and shoots (16.7–37.8%) of pakchoi and reduced the Cd (50.2–60.1%) and Pb (55.6–60.9%) contents in pakchoi shoots and roots. On the basis of the physiological, genotypic and genomic characteristics, the strain TJ48T represent a novel species of the genus Rhodobacter, and the name Rhodobacter xinxiangensis sp. nov. is proposed (type strain TJ48T = CCTCC AB2019120T = KCTC 72510T).

Because there is a lack of evidence, it is not generally recommended to use adjuvant radiotherapy plus chemotherapy to treat lymph node disease in penile cancer. The aim of this study was to determine the benefit of using adjuvant radiotherapy after inguinal surgery for penile cancer. Multi-institutional data were obtained from a total of nine centers from April 2003 to April 2015 and retrospectively analyzed. pN3 patients with an extracapsular nodal extension who received adjuvant therapy after inguinal surgery were included. Cancer-specific survival (CSS) was estimated using the Kaplan–Meier method. The multivariate analysis was performed using a Cox proportional hazards model. A total of 93 pN3 patients met the inclusion criteria. During the study period, 32 (34.4%) and 61 (65.6%) of these patients received adjuvant radiotherapy plus chemotherapy (AR + AC) or adjuvant chemotherapy alone (AC). The median CSS in all patients was 12.0 months (interquartile range [IQR] 7.5–16.5). The Kaplan–Meier estimated 3-year CSS rate was significantly longer in the AR + AC group (28.5%) than the AC group (16.2%) (p = 0.036). AC + AR was associated with an improvement in CSS by 7.7 months (17.7 [IQR 3.8–31.6] vs. 10.0 [IQR 6.6–13.4] months). In the Cox regression analysis, AR + AC was an independent predictor of CSS [model a: HR 0.486 (95% CI 0.258–0.916), model b: HR 0.527 (95% CI 0.286–0.972)]. In conclusions, AR + AC was associated with improved CCS in patients with penile cancer who displayed an extracapsular nodal extension after inguinal surgery. This hypothesis requires further confirmation.

Polypharmacy has been an important strategy for the management of hypertension. The aim of this study was to investigate the effect of combined treatment of losartan with ramipril on hypertension, myocardial infarction and vascular remodeling in disease animal models. In 8-telemetered spontaneous hypertensive rats (SHRs) orally treated with various doses of drugs or vehicle by cross-over protocol, systolic blood pressure (SBP), mean arterial pressure (MAP) and heart rate (HR) were measured. The infarct size was measured in rats subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 150 min reperfusion in myocardial ischemia/reperfusion (MI/R) rats injected drugs or vehicle once through femoral vein 15 min before inducing ischemia. The neointima formation and DNA synthesis in intima and media layer of the blood vessels were measured in cuff-induced vascular injury mice orally treated with drugs for 2 weeks. As compared with single treatment, the combination therapy of both drugs significantly decreased SBP and MAP without significant reflex tachycardia. The combined treatment of both drugs significantly increased the expression of endothelial nitric oxide synthase (eNOS) in coronary arterial tissues including area at occlusion. The combination therapy significantly decreased the thickness of vascular media layer and the number of bromodeoxyuridine (BrdU)-positive cells in both intima and media. The present data suggest that the combination therapy with fixed doses of losartan and ramipril may exert greater BP-lowering effects with protection against myocardial infarction and vascular remodeling.