Abnormal RNA methylation and dysregulation of miRNA are frequently occurred in bladder cancer. Melittin is a potential drug candidate for intravesical chemotherapy against bladder cancer. However, ...the underlying epigenetic mechanism by which melittin-induced anti-tumor effect remains unclear. Here, we showed that melittin selectively induced apoptosis of bladder cancer cells in a METTL3-dependent manner. Ectopic expression of METTL3 significantly blocked melittin-induced apoptosis in vitro and in vivo. MicroRNA-sequence analysis identified miR-146a-5p suppression contributed to the melittin-induced selective antitumor effect. Further investigation revealed that METTL3-guided m6A modification methylated pri-miR-146 at the flanking sequence, which was responsible for the pri-miR-146 maturation. Moreover, NUMB/NOTCH2 axis was identified as a downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of patients with bladder cancer. Our study indicates that METTL3 acts as a fate determinant that controls the sensitivity of bladder cancer cells to melittin treatment. Moreover, METTL3/miR-146a-5p/NUMB/NOTCH2 axis plays an oncogenic role in bladder cancer pathogenesis and could be a potential therapeutic target for recurrent bladder cancer treatment.
•Melittin reprograms m6A methylation pattern by selectively inhibiting METTL3.•The maturation of pri-miR-146a is governed by METTL3 in bladder cancer.•METTL3 controls sensitivity of bladder cancer cells to melittin treatment.•miR-146a-5p signaling is a potential therapeutic target for bladder cancer treatment.•METTL3/miR146a-5p axis exhibits an oncogenic role in patients with bladder cancer.
Using a gemini surfactant (C18H37(CH3)2-N+-(CH2)3-N+-(CH3)2C18H37Cl2) as the directing agent, K2SiO3 and KAlO2 as the source of silicon and aluminum, a Nano-crystal has been successfully synthesized ...under a strong alkali hydrothermal condition. The material shows hexahedron morphology and its crystal size is between around 250-500 nm. Its liquid specific surface area is 1313.2 m2and#183;g-1. The adsorption process of Pb on the Nano-crystal follows quasi-second-order kinetic model and Langmuir adsorption isotherm equation. The maximum Pb adsorption capacity of Nano-crystal is around 1105 mgand#183;g-1.
Nanocomposite fiber is one of the most fascinating materials with broad applications. In the present work, nanocomposite fibers were prepared by using a low-cost, simple, and “green” process as ...follows. Regenerated cellulose (RC) fibers were spun from cellulose dope in 7 wt % NaOH/12 wt % urea aqueous solution precooled to −12 °C, and magnetic nanocomposite fibers were fabricated by introducing in situ synthesized iron oxide (Fe2O3) nanoparticles into the wet cellulose fibers spun via a small-scale pilot machine. The results from transmission electron microscopy and X-ray diffraction showed that the magnetic Fe2O3 nanoparticles with a mean diameter of 18 nm were uniformly dispersed in the cellulose matrix. The composite fibers exhibited a higher mechanical strength than RC fibers, as well as a strong capability to absorb UV rays, superparamagnetic properties, and a relatively high dielectric constant. FT-IR results indicated that there is a strong interaction between cellulose and Fe2O3 in the fibers, leading to the formation and stabilization of the novel magnetic materials. The nanocomposite fibers will be important for the development of functional fabrics and protective clothing for ultraviolet radiation or microwaves.
Abstract
Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 ...receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S
470–495
on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S
450–458
in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.
Lung adenocarcinoma (LUAD) is a common pathological type of non-small cell lung cancer; identifying preferable biomarkers has become one of the current challenges. Given that VTA1 has been reported ...associated with tumor progression in various human solid cancers but rarely reported in LUAD, herein, RNA sequencing data from TCGA and GTEx were obtained for analysis of VTA1 expression and differentially expressed gene (DEG). Furthermore, functional enrichment analysis of VTA1-related DEGs was performed by GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network. In addition, the clinical significance of VTA1 in LUAD was figured out by Kaplan-Meier Cox regression and prognostic nomogram model. R package was used to analyze incorporated studies. As a result, VTA1 was highly expressed in various malignancies, including LUAD, compared with normal samples. Moreover, high expression of VTA1 was associated with poor prognosis in 533 LUAD samples, as well as T stage T2&T3&T4, N stage N1&N2&N3, M stage M1, pathologic stage II&III&IV, and residual tumor R1&R2, et al. (P < 0.05). High VTA1 was an independent prognostic factor in Cox regression analysis; Age and cytogenetics risk were included in the nomogram prognostic model. Furthermore, a total of 4232 DEGs were identified between the high- and the low-expression group, of which 736 genes were up-regulated and 3496 genes were down-regulated. Collectively, high expression of VTA1 is a potential biomarker for adverse outcomes in LUAD. The DEGs and pathways recognized in the study provide a preliminary grasp of the underlying molecular mechanisms of LUAD carcinogenesis and progression.
An atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive pediatric central nervous system neoplasm. However, a universal clinical consensus or reliable prognostic evaluation system ...for this malignancy is lacking. Our study aimed to develop a risk model based on comprehensive clinical data to assist in clinical decision-making.
We conducted a retrospective study by examining data from the Surveillance, Epidemiology, and End Results (SEER) repository, spanning 2000 to 2019. The external validation cohort was sourced from the Children's Hospital Affiliated to Chongqing Medical University, China. To discern independent factors affecting overall survival (OS) and cancer-specific survival (CSS), we applied Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) regression analyses. Based on these factors, we structured nomogram survival predictions and initiated a dynamic online risk-evaluation system. To contrast survival outcomes among diverse treatments, we used propensity score matching (PSM) methodology. Molecular data with the most common mutations in AT/RT were extracted from the Catalogue of Somatic Mutations in Cancer (COSMIC) database.
The annual incidence of AT/RT showed an increasing trend (APC, 2.86%; 95% CI:0.75-5.01). Our prognostic study included 316 SEER database participants and 27 external validation patients. The entire group had a median OS of 18 months (range 11.5 to 24 months) and median CSS of 21 months (range 11.7 to 29.2). Evaluations involving C-statistics, DCA, and ROC analysis underscored the distinctive capabilities of our prediction model. An analysis via PSM highlighted that individuals undergoing triple therapy (integrating surgery, radiotherapy, and chemotherapy) had discernibly enhanced OS and CSS. The most common mutations of AT/RT identified in the COSMIC database were SMARCB1, BRAF, SMARCA4, NF2, and NRAS.
In this study, we devised a predictive model that effectively gauges the prognosis of AT/RT and briefly analyzed its genomic features, which might offer a valuable tool to address existing clinical challenges.
Glioblastoma is the most common and aggressive form of primary brain cancer and the lack of viable treatment options has created an urgency to develop novel treatments. Personalized or predictive ...medicine is still in its infancy stage at present. This research aimed to discover biomarkers to inform disease progression and to develop personalized prophylactic and therapeutic strategies by combining state-of-the-art technologies such as single-cell RNA sequencing, systems pharmacology, and a polypharmacological approach. As predicted in the pyroptosis-related gene (PRG) transcription factor (TF) microRNA (miRNA) regulatory network, TP53 was the hub gene in the pyroptosis process in glioblastoma (GBM). A LASSO Cox regression model of pyroptosis-related genes was built to accurately and conveniently predict the one-, two-, and three-year overall survival rates of GBM patients. The top-scoring five natural compounds were parthenolide, rutin, baeomycesic acid, luteolin, and kaempferol, which have NFKB inhibition, antioxidant, lipoxygenase inhibition, glucosidase inhibition, and estrogen receptor agonism properties, respectively. In contrast, the analysis of the cell-type-specific differential expression-related targets of natural compounds showed that the top five subtype cells targeted by natural compounds were endothelial cells, microglia/macrophages, oligodendrocytes, dendritic cells, and neutrophil cells. The current approach—using the pharmacogenomic analysis of combined therapies—serves as a model for novel personalized therapeutic strategies for GBM treatment.
APOBEC family play an important role in cancer mutagenesis and tumor development. The role of APOBEC family in lung adenocarcinoma (LUAD) has not been studied comprehensively.
The expression data of ...pan-cancer as well as LUAD was obtained from public databases. The expression level of APOBEC family genes was analyzed in different normal and cancer tissues. APOBEC mutagenesis enrichment score (AMES) was utilized to evaluate the APOBEC-induced mutations and the relation of APOBEC with genomic instability. Gene set enrichment analysis was used to identify differentially enriched pathways. Univariate Cox regression and Lasso regression were applied to screen key prognostic genes. The immune cell infiltration was estimated by CIBERSORT. RT-qPCR assay, CCK-8 and Transwell assay were conducted to explore gene expression and lung cancer cell invasion.
Cancer tissues had significantly altered expression of APOBEC family genes and the expression patterns of APOBEC family were different in different cancer types. APOBEC3B was the most aberrantly expressed in most cancer types. In LUAD, we observed a significantly positive correlation of AMES with intratumor heterogeneity (ITH), tumor neoantigen burden (TNB), and tumor mutation burden (TMB). High AMES group had high mutation counts of DNA damage repair pathways, and high enrichment of cell cycle and DNA repair pathways. We identified four prognostic genes (LYPD3, ANLN, MUC5B, and FOSL1) based on AMES, and constructed an AMES-related gene signature. The expressions of four genes were enhanced and accelerated the invasion ability and viability of lung cancer cells. Furthermore, we found that high group increased oxidative stress level.
APOBEC family was associated with genomic instability, DNA damage-related pathways, and cell cycle in LUAD. The AMES-related gene signature had a great potential to indicate the prognosis and guide immunotherapy/chemotherapy for patients suffering from LUAD.
Alkaline fermentation is an effective way for short-chain fatty acids recovery from waste activated sludge. However, there is always a high content of calcium ions in waste activated sludge, which ...may inhibit alkaline fermentation resulting in a low short-chain fatty acids production. The inhibition effect and mechanisms of calcium ions on short-chain fatty acids production from waste activated sludge was investigated and studied in this work. The results showed that when the calcium ions concentration increased from 0 to 5000 mg/L, the short-chain fatty acids production decreased from 307.8 ± 0.7 to 226.8 ± 1.1 mg chemical oxygen demand/g volatile suspended solid. Mechanism study revealed that about 2-fold extracellular polymeric substances were secreted with 5000 mg/L calcium ions addition than that of calcium ions absence to resist the toxic effect of calcium ions, thus inhibiting waste activated sludge disintegration, and less organic substrate were released for the short-chain fatty acids production. Furthermore, flocculation of calcium ions and short-chain fatty acids reduced the short-chain fatty acids concentration in fermentation liquid.
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•5000 mg/L calcium inhibited fermentation with 26.3% reduction of SCFAs production.•Aggregation effect of calcium on sludge resulting in the fermentation inhibition.•Complexation of EPS with calcium caused 2-fold EPS remaining in sludge cells.•Flocculation effect of calcium results in SCFAs in liquid lower than expected.
Facing the imminent need for vaccine candidates with cross-protection against globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants, we present a conserved ...antigenic peptide RBD9.1 with both T-cell and B-cell epitopes. RBD9.1 can be recognized by coronavirus disease 2019 (COVID-19) convalescent serum, particularly for those with high neutralizing potency. Immunization with RBD9.1 can successfully induce the production of the receptor-binding domain (RBD)-specific antibodies in Balb/c mice. Importantly, the immunized sera exhibit sustained neutralizing efficacy against multiple dominant SARS-CoV-2 variant strains, including B.1.617.2 that carries a point mutation (S
) within the sequence of RBD9.1. Specifically, S
and S
are identified as the key amino acids for the binding of the induced RBD-specific antibodies to RBD9.1. Furthermore, we have confirmed that the RBD9.1 antigenic peptide can induce a S
(NYNYLYRLF)-specific CD8
T-cell response. Both RBD9.1-specific B cells and the S
-specific T cells can still be activated more than 3 months post the last immunization. This study provides a potential vaccine candidate that can generate long-term protective efficacy over SARS-CoV-2 variants, with the unique functional mechanism of activating both humoral and cellular immunity.
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