Phlorizin, an Important Glucoside: Research Progress on Its Biological Activity and Mechanism.

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1ß/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.

Modified Guo-Min decoction ameliorates PM2.5-induced lung injury by inhibition of PI3K-AKT and MAPK signaling pathways.

BACKGROUND/PURPOSE: Exposure to particles with an aerodynamic diameter of ≤2.5 µm (PM2.5) increased various lung diseases, which lack effective treatment. Massive evidence links PM2.5 to the development of allergic lung diseases like asthma. Modified Guo-Min Decoction (MGMD) is a traditional Chinese formula for allergic diseases. However, whether MGMD could improve PM2.5-induced lung injury and the underlying mechanism remain unclear and we aimed to explore. STUDY DESIGN/METHODS: Male Wistar rats (200-220 g) were intratracheally instilled of PM2.5 suspension daily for 4 weeks to establish PM2.5-induced lung injury model. MGMD (2.1 g/kg) treatment by gavage was started 1 week before, at the same time or 1 week after the instillation of PM2.5 suspension, namely the pre-, sync- or post-administration groups. HE and Masson staining were used to observe morphological changes. Immunohistochemistry staining was used to detect macrophage and neutrophil infiltration. The levels of inflammatory cytokines in the bronchoalveolar lavage fluid were detected by ELISA. The main components of MGMD were detected by UHPLC-LTQ-Orbitrap MSn. Network pharmacology was used to identify the key targets mediating the effect of MGMD in treating PM2.5-induced lung injury. Changes in the expression of target proteins were examined by western blot. In-vitro experiments were carried out in Beas2b cells to evaluate the protective effect and mechanism of MGMD against PM2.5 induced injury. RESULTS: Exposure to PM2.5 suspension resulted in disarrangement of tracheal epithelium, neutrophil and M1 macrophage infiltration and collagen deposition, and significantly increased IgE, IL-1ß and IL-17 secretion and NLRP3 expression, which were inhibited by MDMD treatment and pre-MGMD treatment showed the best effect. By UHPLC-LTQ-Orbitrap MSn, 46 main compounds were identified in MGMD. Using network pharmacology approach, we found MGMD attenuate PM2.5-induced lung damage by targeting 216 genes, and PPI network, GO and KEGG analysis all indicated that PI3K-AKT and MAPK pathways were important. Western blot showed that PM2.5 suspension exposure increased PI3K, AKT, ERK and JNK phosphorylation, which were reversed by MGMD intervention significantly. In vitro, the viability of Beas2b cells was significantly decreased after PM2.5 suspension exposure, and was obviously upregulated after MGMD-containing serum or LY294002 treatment. CONCLUSION: The present study demonstrated that MGMD could improve PM2.5-induced lung injury through reducing inflammation and pulmonary fibrosis, which was probably mediated by inhibition of the PI3K-AKT and MAPK signaling pathways, and NLRP3 inflammasome. The results of this study support and provide scientific evidence for the clinical application of MGMD on PM2.5-induced lung injury. Pre-treatment, sync-treatment, and post-treatment is the highlight of this study.

Mir-142-3P regulates MAPK protein family by inhibiting 14-3-3η to enhance bone marrow mesenchymal stem cells osteogenesis.

Clinical studies have found 14-3-3η to be associated with osteoporosis through undefined mechanisms. We aimed to investigate the role of 14-3-3η in osteoporosis and its potential associations with miRNAs. The Gene Expression Omnibus(GEO) and Human Protein Atlas 1 databases were analyzed to examine both the mRNA and protein expression of 14-3-3η in OP. Gene enrichment analyses were performed to explore the underlying mechanism of 14-3-3η based on DAVID. miRWalk was used to predict the associated miRNAs. The statistics were analysed by R software and SPSS software. 14-3-3η was overexpressed and knock down expressed in BMSCs by lentiviral vector transfecting. And BMSCs were induced by hypoxia. qRT-PCR and Western-Blot verified the expression of mRNA and protein. Scratch assay detected the migration of osteocytes. Co-immunoprecipitation and luciferase assay studied the 14-3-3η targeted protein and miRNA. overexpression and knock down of miRNA to verify the relationship of 14-3-3η and target genes. The 14-3-3η mRNA expression level was low in patients with osteoporosis, as corroborated by immunohistochemical staining images. Functional analyses revealed enrichment of the MAPK-associated cascade. 14-3-3η was correlated with MAPK family proteins and five key miRNAs, including mir-142-3p. In addition, 14-3-3η knockdown in BMSCs increased the mRNA and protein expression levels of Hif-α, VEGF, BMP-2, OPN, OST, and Runx2, and enhanced the cells migration ability. Under hypoxic conditions, Hif-α and BMP-2 protein expression levels were upregulated, whereas those of 14-3-3η and MAPK3 were downregulated. Co-immunoprecipitation experiments showed decreased binding of 14-3-3η to MAPK3. 14-3-3η knockdown produced the same results as hypoxia induction. Adding caspase3 inhibitor and knocking down 14-3-3η again prevented MAPK3 cleavage by caspase3 and inhibited BMP-2 expression. Moreover, under hypoxic conditions, miR-142-3P expression was upregulated and luciferase assays revealed 14-3-3η as its target gene. miR-142-3P overexpression decreased mRNA and protein levels of 14-3-3η and MAPK3, while increasing BMP-2 expression. miR-142-3P knockdown reversed these results. BMSC osteogenesis was suppressed by 14-3-3η, whereas miRNA-142-3p promoted it through the inhibition of 14-3-3η.

The identification of N6-methyladenosine-related miRNAs predictive of hepatocellular carcinoma prognosis and immunotherapy efficacy.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high degree of malignancy and poor prognosis. N6-methyladenosine (m6A) modifications and microRNAs (miRNAs) play pivotal roles in tumorigenesis and development. However, the role of m6A-related miRNAs in HCC has not been clarified yet. This study aimed to identify the role of m6A-miRNAs in HCC prognosis through bioinformatics analysis. METHODS: The clinicopathological information and RNA sequencing data of 369 HCC tumor tissues and 49 tumor-adjacent tissues were downloaded from the TCGA database. A total of 23 m6A regulators were extracted to evaluated the m6A-related miRNAs using Pearson's correlation analysis. Then, we selected prognosis-related m6A-miRNAs using a univariate Cox regression model and used the consensus cluster analysis to explore the characteristics of the m6A-miRNAs. The coefficient of the least absolute shrinkage and selection operator (LASSO) Cox regression was applied to construct a prognostic risk score model. The receiver operated characteristic (ROC) analysis was applied to evaluate the prognostic value of the signature. The biological functions of targeted genes were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, to validate the potential predictive value for prognosis, the miRNA expression profiles from the GSE76903 and GSE6857 were used. Single sample Gene Set Enrichment Analysis (ssGSEA) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) were applied to assess the immune microenvironment of HCC. Additionally, a meta-analysis was used to verify the prognostic value of the m6A-microRNAs. RT-PCR was applied to validated the expression of miRNAs in HCC tissues. Cell viability, transwell assay and RNA m6A dot blot assays of HCC cells was applied to access the function of miR-17-5p. RESULTS: The expression of 48 m6A-related miRNAs was identified and 17 prognostic m6A-miRNAs was discovered. The expression profile of those 17 miRNAs was divided into three clusters, and these clusters were associated with the tumor microenvironment (TME) and prognosis. The nine m6A-related miRNA signature was associated with the prognosis of HCC, the AUC of the ROC was 0.771(TCGA dataset), 0.788(GSE76903) and 0.646(GSE6857). The TME and the expression of immune checkpoint molecules were associated with the risk score. The meta-analysis also validated the prognostic value of the m6A-related miRNAs (miR182-5p (HR:1.58, 95%CI:1.04-2.40) and miR-17-5p (HR:1.58, 95%CI: 1.04-2.40)). The expression of miR-17-5p was upregulated in HCC tissues and miR-17-5p showed an oncogenic role in HCC cells. CONCLUSION: The clinical innovation is the use of m6A-miRNAs as biomarkers for predicting prognosis regarding immunotherapy response in HCC patients.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

Quantitative Analysis of Natural Gas Diffusion Characteristics in Tight Oil Reservoirs Based on Experimental and Numerical Simulation Methods.

As an important mechanism in gas injection development, the diffusion characteristics of natural gas in tight reservoirs are important in the dynamic prediction of the development effect and optimization of injection-production parameters. In this paper, a high-pressure and high-temperature oil-gas diffusion experimental device was built, which was used to study the effects of the porous medium, pressure, permeability, and fracture on oil-gas diffusion under tight reservoir conditions. Two mathematical models were used to calculate the diffusion coefficients of natural gas in bulk oil and cores. Besides, the numerical simulation model was established to study the diffusion characteristics of natural gas in gas flooding and huff-n-puff, and five diffusion coefficients were selected based on experimental results for simulation study. The remaining oil saturation of grids, the recovery of single layers, and the distribution of CH4 mole fraction in oil were analyzed based on the simulation results. The experimental results show that the diffusion process can be divided into three stages: the initial stage of instability, the diffusion stage, and the stable stage. The absence of medium, high pressure, high permeability, and the existence of fracture are beneficial to natural gas diffusion, which can also reduce the equilibrium time and increase the gas pressure drop. Furthermore, the existence of fracture is beneficial to the early diffusion of gas. The simulation results show that the diffusion coefficient has a greater influence on the oil recovery of huff-n-puff. For gas flooding and huff-n-puff, the diffusion features both perform such that a high diffusion coefficient results in a close diffusion distance, small sweep range, and low oil recovery. However, a high diffusion coefficient can achieve high oil washing efficiency near the injecting well. The study is helpful to provide theoretical guidance for natural gas injection in tight oil reservoirs.

Incidence of acute kidney injury after hematopoietic stem cell transplantation in children: a systematic review and meta-analysis.

While acute kidney injury (AKI) has been reported after hematopoietic stem cell transplantation (HCT) in children, the incidence of this condition in the pediatric population has not been fully addressed. To assess the incidence of pediatric AKI after HCT treatment,we conducted a systematic literature review. Databases PubMed, Embase, Cochrane Library, and WOS were searched as of June 2022 to identify studies on the incidence and the risk of death in AKI children undergoing HCT. Random effects and generic inverse variance methods were used, and effect estimates were subsequently derived from individual studies. Twelve cohort studies with 2 159 HCT cases were included in this analysis. The combined estimated incidence of AKI and severe AKI (stage AKI III) was 51% (95% confidence interval (CI) 39-64%) and 12% (95%CI 4-24%), respectively. The estimated incidence of AKI based on RIFLE (pRIFLE), AKIN, and KDIGO criteria was 61% (95%CI 40-82% score I 95.1%), 64% (95%CI 49-79% score I 90.4%), and 51% (95%CI 2-100% score 99.0%), respectively. However, we found no significant correlation between the years of publication of the included studies and the incidence of AKI.  Conclusions: AKI affects approximately half of the children after HCT. With the advancements in medical techniques, it is expected that AKI in this population will decrease gradually. What is Known: • Hematopoietic stem cell transplantation is recognized as a treatment for malignant and non-malignant diseases in children. • Hematopoietic stem cell transplantation causes acute kidney injury in children. What is New: • This metanalysis showed that the overall frequency of post-HCT AKI in children is 51%. • The frequency of severe AKI after HCT was found to be 12%.

Prognostic and Immunological Roles of CES2 in Breast Cancer and Potential Application of CES2-Targeted Fluorescent Probe DDAB in Breast Surgery.

Purpose: The expression and function of CES2 in breast cancer (BRCA) has not been fully elucidated. The purpose of this study was to investigate its clinical significance in BRCA. Patients and Methods: Bioinformatics analysis tools and databases, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) databases, SURVIVAL packages, STRING database, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene set variation analysis (GSVA), and Tumor Immunity Estimation Resource (TIMER), were utilized to measure the expression level and clarify the clinical significance of CES2 in BRCA. In addition, we verified the expression level of CES2 in BRCA at the cellular and tissue levels by Western blot, immunohistochemistry (IHC) and real-time fluorescence quantitative PCR assays. Furthermore, DDAB is the first reported near-infrared fluorescent probe that can be used to monitor CES2 in vivo. We applied the CES2-targeted fluorescent probe DDAB in BRCA for the first time and verified its physicochemical properties and labeling sorting ability by CCK-8, cytofluorimetric imaging, flow cytometry fluorescence detection, and isolated human tumor tissue imaging assays. Results: The expression of CES2 was higher in normal tissues than that in BRCA tissues. Patients with lower CES2 expression in the BRCA T4 stage had a poorer prognosis. Finally, we applied the CES2-targeted fluorescent probe DDAB in BRCA for the first time, which was demonstrated to have good cellular imaging performance with low biological toxicity in BRCA cells and ex vivo human breast tumor tissue models. Conclusion: CES2 can be considered a potential biomarker to predict the prognosis of breast cancer at stage T4 and might contribute to the development of immunological treatment strategies. Meanwhile, CES2 is able to distinguish between breast normal and tumor tissues, the CES2-targeting NIR fluorescent probe DDAB may have potential for surgical applications in BRCA.

Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells.

Melanoma differentiation-associated gene 9 (MDA-9) is a small adaptor protein with tandem PDZ domains that promotes tumor progression and metastasis in various human cancers. However, it is difficult to develop drug-like small molecules with high affinity due to the narrow groove of the PDZ domains of MDA-9. Herein, we identified four novel hits targeting the PDZ1 and PDZ2 domains of MDA-9, namely PI1A, PI1B, PI2A, and PI2B, using a protein-observed nuclear magnetic resonance (NMR) fragment screening method. We also solved the crystal structure of the MDA-9 PDZ1 domain in complex with PI1B and characterized the binding poses of PDZ1-PI1A and PDZ2-PI2A, guided by transferred paramagnetic relaxation enhancement. The protein-ligand interaction modes were then cross-validated by the mutagenesis of the MDA-9 PDZ domains. Competitive fluorescence polarization experiments demonstrated that PI1A and PI2A blocked the binding of natural substrates to the PDZ1 and PDZ2 domains, respectively. Furthermore, these inhibitors exhibited low cellular toxicity, but suppressed the migration of MDA-MB-231 breast carcinoma cells, which recapitulated the phenotype of MDA-9 knockdown. Our work has paved the way for the development of potent inhibitors using structure-guided fragment ligation in the future.

Genetic risk, metabolic syndrome, and gastrointestinal cancer risk: A prospective cohort study.

BACKGROUND: Gastrointestinal (GI) cancer risk has been associated with metabolic syndrome (MetS), a surrogate indicator for unhealthy lifestyles, and a number of genetic loci, but the combined effect of MetS and genetic variants on GI cancer risk is uncertain. METHODS: We included 430,036 participants with available MetS and genotype data from UK Biobank. During the follow-up time, 5494 incident GI cancer cases, including esophageal cancer, gastric cancer, and colorectal cancer, were identified. We created a GI polygenic risk score (GI-PRS) for overall GI cancer derived from three site-specific cancer PRSs. Cox proportional hazards regression was used to estimate the associations of MetS and GI-PRS with the risk of GI cancer. RESULTS: MetS was significantly associated with 28% increment in GI cancer risk (hazard ratio [HR]MetS vs. non-MetS : 1.28, 95% confidence interval [CI]: 1.21-1.35, p < 0.0001), whereas a high GI-PRS (top quintile) was associated with 2.28-fold increase in risk (HRhigh vs. low : 2.28, 95% CI: 2.09-2.49, p < 0.0001). Compared with participants without MetS and at low genetic risk (bottom quintile of GI-PRS), those with MetS and at high genetic risk had 2.75-fold increase in GI cancer risk (HR: 2.75, 95% CI: 2.43-3.12, p < 0.0001). Additionally, MetS in comparison with no MetS had 1.49‰, 2.75‰, and 3.37‰ absolute risk increases in 5 years among participants at low, intermediate (quintiles 2-4 of GI-PRS) and high genetic risk, respectively, representing the number of subjects diagnosed as MetS causing a new GI cancer case in 5 years were 669, 364, and 296, respectively. CONCLUSIONS: Metabolic and genetic factors may jointly contribute to GI cancer risk and may serve as predictors by quantitative measurements to identify high-risk populations of GI cancer for precise prevention.

Prostate transmembrane androgen inducible protein 1 (PMEPA1): regulation and clinical implications.

Prostate transmembrane androgen inducible protein 1 (PMEPA1) can promote or inhibit prostate cancer cell growth based on the cancer cell response to the androgen receptor (AR). Further, it can be upregulated by transforming growth factor (TGF), which downregulates transforming growth factor-ß (TGF-ß) signaling by interfering with R-Smad phosphorylation to facilitate TGF-ß receptor degradation. Studies have indicated the increased expression of PMEPA1 in some solid tumors and its functioning as a regulator of multiple signaling pathways. This review highlights the multiple potential signaling pathways associated with PMEPA1 and the role of the PMEPA1 gene in regulating prognosis, including transcriptional regulation and epithelial mesenchymal transition (EMT). Moreover, the relevant implications in and outside tumors, for example, as a biomarker and its potential functions in lysosomes have also been discussed.

Xianling Gubao attenuates high glucose-induced bone metabolism disorder in MG63 osteoblast-like cells.

Diabetes mellitus (DM) patients are prone to osteoporosis, and high glucose (HG) can affect bone metabolism. In the present study, we investigated the protective effects of traditional Chinese herbal formulation Xianling Gubao (XLGB) on HG-treated MG63 osteoblast-like cells. MG63 cells were incubated with control (mannitol), HG (20 mM glucose) or HG + XLGB (20 mM glucose+200 mg/L XLGB) mediums. Cell proliferation, apoptosis, migration and invasion were examined using CCK8, colony-formation, flow cytometry, Hoechst/PI staining, wound-healing and transwell assays, respectively. ELISA, RT-PCR and western blot analysis were used to detect the levels of osteogenesis differentiation-associated markers such as ALP, OCN, OPN, RUNX2, OPG, and OPGL in MG63 cells. The levels of the PI3K/Akt signaling pathway related proteins, cell cycle-related proteins, and mitochondrial apoptosis-related proteins were detected using western blot analysis. In HG-treated MG63 cells, XLGB significantly attenuated the suppression on the proliferation, migration and invasion of MG63 cells caused by HG. HG downregulated the activation of the PI3K/Akt signaling pathway and the expressions of cell cycle-related proteins, while XLGB reversed the inhibition of HG on MG63 cells. Moreover, XLGB significantly reduced the promotion on the apoptosis of MG63 cells induced by HG, the expressions of mitochondrial apoptosis-related proteins were suppressed by XLGB treatment. In addition, the expressions of osteogenesis differentiation-associated proteins were also rescued by XLGB in HG-treated MG63 cells. Our data suggest that XLGB rescues the MG63 osteoblasts against the effect of HG. The potential therapeutic mechanism of XLGB partially attributes to inhibiting the osteoblast apoptosis and promoting the bone formation of osteoblasts.

Changes in rate and socioeconomic inequality of cervical cancer screening in northeastern China from 2013 to 2018.

Objective: Cervical cancer, the fourth leading cancer diagnosed in women, has brought great attention to cervical cancer screening to eliminate cervical cancer. In this study, we analyzed two waves of provincially representative data from northeastern China's National Health Services Survey (NHSS) in 2013 and 2018, to investigate the temporal changes and socioeconomic inequalities in the cervical cancer screening rate in northeastern China. Methods: Data from two waves (2013 and 2018) of the NHSS deployed in Jilin Province were analyzed. We included women aged 15-64 years old and considered the occurrence of any cervical screening in the past 12 months to measure the cervical cancer screening rate in correlation with the annual per-capita household income, educational attainment, health insurance, and other socioeconomic characteristics. Results: A total of 11,616 women aged 15-64 years were eligible for inclusion. Among all participants, 7,069 participants (61.11%) were from rural areas. The rate of cervical cancer screening increased from 2013 to 2018 [odds ratio (OR): 1.06; 95% confidence interval (CI): 1.04-1.09, p < 0.001]. In total, the cervical cancer screening rate was higher among participants who lived in urban areas than rural areas (OR: 1.20; 95% CI: 1.03-1.39, p = 0.020). The rate was also higher among those with the highest household income per capita (OR: 1.30; 95% CI: 1.07-1.56, p = 0.007), with higher educational attainment (p < 0.001), and with health insurance (p < 0.05), respectively. The rate of cervical cancer screening was also significantly associated with parity (OR: 1.62; 95% CI: 1.23-2.41, p = 0.001) and marital status (OR: 1.45; 95% CI: 1.15-1.81, p = 0.001) but not ethnicity (OR: 1.41; 95% CI: 0.95-1.36, p = 0.164). Conclusion: Cervical cancer screening coverage improved from 2013 to 2018 in northeastern China but remains far below the target 70% screening rate proposed by the World Health Organization. Although rural-urban inequality disappeared over time, other socioeconomic inequalities remained.

Clinical Characteristics of Malignant Pulmonary Sclerosing Pneumocytoma Based on a Study of 46 Cases Worldwide.

Objective: To analyze the clinical characteristics of patients with malignant pulmonary sclerosing pneumocytoma (PSP) with metastasis, recurrence, and growth and to improve clinicians' understanding of PSP in patients with malignant tumor characteristics. Methods: A total of 46 PSP patients with malignant tumor characteristics were identified in the literature search and compared with 38 patients with benign PSP diagnosed and treated in our hospital in the past 5 years. We explored the pathogenesis, clinical symptoms, diagnostic methods, treatment strategies and prognosis of PSP patients with malignant tumor. Results: The characteristics of young age (≤41 years old), larger tumor (≥36mm), lymph node metastasis and distribution in East Asians are indicative of PSP with malignant potential. Such patients should undergo segmental resection or lobectomy, combined with necessary lymph node dissection or biopsy. All patients with PSP should have an entire course of follow-up management, because they may have an adverse prognosis such as recurrence, growth, metastasis, and even death. Conclusion: PSP has the potential for malignancy. Anatomical lobectomy or segmental resection combined with lymph node dissection should be performed in PSP with some specific characteristics. Inappropriate diagnosis and treatment may lead to poor prognosis in PSP patients.

Adsorption-enforced Fenton-like process using activated carbon-supported iron oxychloride catalyst for wet scrubbing of airborne dichloroethane.

Wet scrubbing is a low-cost process for disposing of air pollutants. Nevertheless, this method is rarely used for the treatment of volatile organic compounds (VOCs) because of their poor water solubility. In this study, we used a unique wet scrubbing system containing H2O2 and activated carbon (AC)-supported iron oxychloride (FeOCl) nanoparticles to remove airborne dichloroethane (DCE). The operating conditions of the wet scrubber were optimized, and the mechanism was explored. The results showed that the adsorption of dissolved DCE onto AC promoted its transfer from air to water, while the accumulation of DCE on AC facilitated its oxidation by •OH generated on FeOCl catalyst. The wet scrubber performed well at pH 3 and low H2O2 concentrations. By pulsed or continuous dosing H2O2, the cooperative adsorption-catalytic oxidation allowed long-term DCE removal from air. Benefiting from satisfactory cost-effectiveness, avoidance of toxic byproduct formation, and less corrosion and catalyst poisoning, wet scrubbers coupled with cooperative adsorption and heterogeneous advanced oxidation processes could have broad application potentials in VOC control.

Fragment-Based Discovery of AF9 YEATS Domain Inhibitors.

YEATS (YAF9, ENL, AF9, TAF14, SAS5) family proteins recognize acylated histones and in turn regulate chromatin structure, gene transcription, and stress signaling. The chromosomal translocations of ENL and mixed lineage leukemia are considered oncogenic drivers in acute myeloid leukemia and acute lymphoid leukemia. However, known ENL YEATS domain inhibitors have failed to suppress the proliferation of 60 tested cancer cell lines. Herein, we identified four hits from the NMR fragment-based screening against the AF9 YEATS domain. Ten inhibitors of new chemotypes were then designed and synthesized guided by two complex structures and affinity assays. The complex structures revealed that these inhibitors formed an extra hydrogen bond to AF9, with respect to known ENL inhibitors. Furthermore, these inhibitors demonstrated antiproliferation activities in AF9-sensitive HGC-27 cells, which recapitulated the phenotype of the CRISPR studies against AF9. Our work will provide the basis for further structured-based optimization and reignite the campaign for potent AF9 YEATS inhibitors as a precise treatment for AF9-sensitive cancers.

Anti-hepatitis C virus drug simeprevir: a promising antimicrobial agent against MRSA.

Staphylococcus aureus is a major human pathogen, and the appearance of methicillin-resistant S. aureus (MRSA) renders S. aureus infections more challenging to treat. Therefore, new antimicrobial drugs are urgently needed to combat MRSA infections. Drug repurposing is an effective and feasible strategy. Here, we reported that the clinically approved anti-hepatitis C virus drug simeprevir had strong antibacterial activity against MRSA, with a minimum inhibitory concentration of 2-8 µg/mL. Simeprevir did not easily induce in vitro resistance. In addition, simeprevir significantly prevented S. aureus biofilm formation. Furthermore, simeprevir displayed limited toxicity in in vitro and in vivo assays. Moreover, simeprevir showed synergistic antimicrobial effects against both type and clinical strains of S. aureus. Simeprevir combined with gentamicin effectively reduced the bacterial burden in an MRSA-infected subcutaneous abscess mouse model. Results from a series of experiments, including membrane permeability assay, membrane potential assay, intracellular ATP level assay, and electron microscope observation, demonstrated that the action of simeprevir may be by disrupting bacterial cell membranes. Collectively, these results demonstrated the potential of simeprevir as an antimicrobial agent for the treatment of MRSA infections. KEY POINTS: • Simeprevir showed strong antibacterial activity against MRSA. • The antibacterial mechanism of simeprevir was mediated by membrane disruption and intracellular ATP depletion. • In vitro and in vivo synergistic antimicrobial efficacy between simeprevir and gentamicin was found.

Prevalence of Helicobacter pylori infection in China: A systematic review and meta-analysis.

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection rates have been changing with different populations and geographic areas. We systematically evaluated the longitudinal trends in H. pylori prevalence in China over the past decades. METHODS: We performed a systematic review of literature reporting the prevalence of H. pylori infection in mainland China from 1990 to 2019 in the PubMed and China National Knowledge Infrastructure databases. We conducted a meta-analysis of qualified studies using a random effects model to estimate the pooled prevalence with a 95% confidence interval (95%CI). RESULTS: A total of 412 eligible studies with 1 377 349 subjects were included. The pooled H. pylori prevalence was 44.2% (95%CI: 43.0-45.5%) in mainland China, with an estimated 589 million individuals infected with H. pylori. The prevalence was relatively high in the Northwest (51.8%, 95%CI: 47.5-56.1%), East (47.7%, 95%CI: 45.4-50.0%), and Southwest China (46.6%, 95%CI: 42.1-51.1%). The prevalence significantly decreased from 58.3% (95%CI: 50.7-65.5%) in the period 1983-1994 to 40.0% (95%CI: 38.2-41.8%) in the period 2015-2019. The prevalence increased with age, ranging from 28.0% (95%CI: 23.9-32.5%) in children and adolescents to 46.1% (95%CI: 44.5-47.6%) in adults. CONCLUSION: Although the burden of H. pylori infections is still huge in China, the infection rate has been decreasing over the past decades. Targeted H. pylori eradication strategies may be considered in areas or populations with a high incidence of gastric cancer.

Prognostic significance of occult lymph node metastases in breast cancer: a meta-analysis.

BACKGROUND: Occult metastases in axillary lymph nodes have been reported to be associated with poor prognosis in patients with breast cancer. However, studies on the prognostic value of occult metastases have shown controversial results. This meta-analysis aimed to evaluate the prognostic significance of occult lymph node metastases in breast cancer. METHODS: Studies published until May, 2020, which retrospectively examined negative lymph nodes by stepsectioning and/or immunohistochemistry, were retrieved from MEDLINE, EMBASE, CNKI, and Cochrane Library databases. The pooled Relative Risk (RR) with 95% confidence interval (95% CI) for overall survival (OS) and disease-free survival (DFS) were calculated to examine the associations between occult metastases and prognosis. RESULTS: Patients with occult metastases in axillary lymph nodes had poorer five-year DFS (RR = 0.930; 95% CI = 0.907-0.954) and OS (RR = 0.972; 95% CI = 0.954-0.990). Furthermore, the DFS (RR = 0.887; 95% CI = 0.810-0.972) and OS (RR = 0.896; 95% CI = 0.856-0.939) of patients with occult metastases were significantly lower after a ten-year follow-up. CONCLUSIONS: Occult metastases in the axillary lymph nodes are associated with poorer DFS andOS of patients with breast cancer. Occult metastases might serve as a predictive factor of survival outcomes in patients with breast cancer.

Breast cancer organoids from malignant pleural effusion-derived tumor cells as an individualized medicine platform.

Malignant pleural effusion (MPE) presents a severe medical condition in patients with advanced breast cancer (BC). We applied organoid culture technology to culture preoperative puncture specimen and corresponding surgical specimen-derived tumor cells from early BC patients and pleural effusion-derived tumor cells from advanced BC patients with MPE to study whether in vitro models could predict therapies of clinical patients. We successfully expanded pleural effusion-derived tumor organoids from 1 advanced triple-negative breast cancer (TNBC) patient with MPE which had been continuously propagated for more than 3 months. The organoids matched the histological characteristics of primary BC and metastatic supraclavicular lymph nodes by H&E staining and retained negative expression of TNBC biomarkers: estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and positive expression of antigen Ki-67. Multiple mutations were detected from this advanced TNBC patient with MPE by high-throughput sequencing of metastatic supraclavicular lymph node and the plasma sample. We performed the 3D drug screening tests combined with the clinical medication situation of this patient. The pleural effusion-derived tumor organoids were sensitive to capecitabine (IC50 1.580 µmol) and everolimus (IC50 4.008 µmol) single-agent treatments. The sensitivity to capecitabine was consistent with the clinical treatment response of this patient for capecitabine and with the sequencing results that reported MTHFR gene polymorphism mutation and TYMS -6bp/-6bp polymorphism mutation indicating effectiveness to fluorouracil. Our results suggested that an effective platform for ex vivo pleural effusion-derived tumor organoids from advanced TNBC patients with MPE could be used to identify treatment options and explore the clinicopathological characteristics of these patients.