Quercetin activates energy expenditure to combat metabolic syndrome through modulating gut microbiota-bile acids crosstalk in mice.

Abdominal obesity-related metabolic syndrome (MetS) has emerged as a significant global public health issue that affects human health. Flavonoids, such as quercetin, have been reported to exert obvious anti-obesity and lipid-lowering effects in both humans and animal models. However, the precise underlying mechanism remains elusive. In this study, we investigated the potential roles of gut microbiota-bile acids (BAs) interactions in quercetin-induced anti-obesity effects and metabolic benefits. Oral administration of quercetin significantly enhanced energy metabolism through activating thermogenesis of brown adipose tissues (BAT) and browning of white adipose tissues (WAT), thus mitigating metabolic dysfunctions in an abdominal obesity-related MetS mouse model. Further mechanistic studies demonstrated that quercetin treatment substantially promoted the generation of non-12α-hydroxylated BAs (non-12OH BAs), particularly ursodeoxycholic acid (UDCA) and lithocholic acid (LCA), in serum via regulating the overall structure of gut microbiota and enriching Lactobacillus. High level of non-12OH BAs bind to Takeda G protein-coupled receptor 5 (TGR5) on adipocytes to stimulate thermogenesis. Remarkably, fecal microbiota transplantation (FMT) from quercetin-treated mice replicated the effects of quercetin on non-12OH BAs generation and energy expenditure, which suggested gut microbiota reshape and concomitant BAs regulation were responsible for the benefits on energy metabolism of quercetin in the MetS mouse model. Our findings not only highlighted the critical role of gut microbiota-BAs crosstalk in mediating quercetin-induced energy expenditure, but also enriched the pharmacological mechanisms of quercetin in ameliorating MetS-related diseases.

Phosphoenolpyruvate carboxykinase 2-mediated metabolism promotes lung tumorigenesis by inhibiting mitochondrial-associated apoptotic cell death.

Background: It is unknown how cancer cells override apoptosis and maintain progression under nutrition-deprived conditions within the tumor microenvironment. Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting reaction in gluconeogenesis, which is an essential metabolic alteration that is required for the proliferation of cancer cells under glucose-limited conditions. However, if PCK-mediated gluconeogenesis affects apoptotic cell death of non small cell lung cancer (NSCLC) and its potential mechanisms remain unknown. Methods: RNA-seq, Western blot and RT-PCR were performed in A549 cell lines cultured in medium containing low or high concentrations of glucose (1 mM vs. 20 mM) to gain insight into how cancer cells rewire their metabolism under glucose-restriction conditions. Stable isotope tracing metabolomics technology (LC-MS) was employed to allow precise quantification of metabolic fluxes of the TCA cycle regulated by PCK2. Flow Cytometry was used to assess the rates of early and later apoptosis and mitochondrial ROS in NSCLC cells. Transwell assays and luciferase-based in vivo imaging were used to determine the role of PCK2 in migration and invasion of NSCLC cells. Xenotransplants on BALB/c nude mice to evaluate the effects of PCK2 on tumor growth in vivo. Western blot, Immunohistochemistry and TUNEL assays to evaluate the protein levels of mitochondrial apoptosis. Results: This study report that the mitochondrial resident PCK (PCK2) is upregulated in dependent of endoplasmic reticulum stress-induced expression of activating transcription factor 4 (ATF4) upon glucose deprivation in NSCLC cells. Further, the study finds that PCK2-mediated metabolism is required to decrease the burden of the TCA cycles and oxidative phosphorylation as well as the production of mitochondrial reactive oxygen species. These metabolic alterations in turn reduce the activation of Caspase9-Caspase3-PARP signal pathway which drives apoptotic cell death. Importantly, silencing PCK2 increases apoptosis of NSCLC cells under low glucose condition and inhibits tumor growth both in vitro and in vivo. Conclusion: In summary, PCK2-mediated metabolism is an important metabolic adaptation for NSCLC cells to acquire resistance to apoptosis under glucose deprivation.

Interaction of Pb(II) with microplastic-sediment complexes: Critical effect of surfactant.

In this study, the impact of surfactants on the adsorption behavior of Pb(II) onto microplastics-sediment (MPs-S) complexes was investigated. Firstly, virgin polyamide (VPA) and polyethylene (VPE) were placed in Xiangjiang River sediment for six months to conduct in-situ aging. The results indicated that the biofilm-developed polyamide (BPA) and polyethylene (BPE) formed new oxygen-containing functional groups and different biofilm species. Furthermore, the adsorption capacity of Pb(II) in sediment (S) and MPs-S complexes was in the following order: S > BPA-S > VPE-S > VPA-S > BPE-S. The addition of sodium dodecyl benzenesulfonate (SDBS) promoted the adsorption of Pb(II), and the adsorption amount of Pb(II) increased with the higher concentration of SDBS, while adding cetyltrimethylammonium bromide (CTAB) showed the opposite result. The adsorption process of MPs-S complexes to Pb(II) was dominated by chemical adsorption, and the interaction between MPs-S complexes and Pb(II) was multilayer adsorption involving physical and chemical adsorption when the surfactants were added. Besides, the pH exerts a significant effect on Pb(II) adsorption in different MPs-S complexes, and the highest adsorption amount occurred at pH 6. Noteworthy, CTAB promoted the adsorption ability of Pb(II) when the exogenous FA was added. The binding characteristic of sediment endogenous DOM components and Pb(II) was influenced by the addition of MPs and surfactants. Finally, it confirmed that adsorption mechanisms mainly involve electrostatic and hydrophobic interaction. This study provides a new perspective to explore the environmental behaviors of Pb(II) by MPs and sediments with the addition of surfactants, which was conducive to evaluating the ecological risks of MPs and heavy metals in aquatic environments.

Incidence and clinical analysis of asymptomatic intracranial hemorrhage in neonates with cerebral hypoxic-ischaemic risk based on multisequence MR images.

The incidence and clinical distribution of intracranial haemorrhage (ICH) in neonates at risk of cerebral hypoxia-ischaemia have not been reported in specific studies. Based on conventional magnetic resonance imaging (MRI) versus susceptibility weighted imaging (SWI), this study aimed to analyse the occurrence of asymptomatic ICH in newborns with or without risk of cerebral hypoxia-ischaemia and to accumulate objective data for clinical evaluations of high-risk neonates and corresponding response strategies. 317 newborns were included. MRI revealed that the overall incidence of ICH was 59.31%. The most common subtype was intracranial extracerebral haemorrhage (ICECH) which included subarachnoid haemorrhage (SAH) and subdural haemorrhage (SDH). ICECH accounted for 92.02% of ICH. The positive detection rate of ICECH by SWI was significantly higher than that by T1WI. The incidence of total ICH, ICECH and SAH was greater among children who were delivered vaginally than among those who underwent caesarean delivery. Asymptomatic neonatal ICH may be a common complication of the neonatal birth process, and SWI may improve the detection rate. Transvaginal delivery and a weight greater than 2500 g were associated with a high incidence of ICECH in neonates. The impact of neonatal cerebral hypoxia-ischaemia risk factors on the occurrence of asymptomatic ICH may be negligible.

Evaluation of Neonatal Cerebral Circulation Under Hypoxic Ischemic Risk Factors Based on Quantitative Analysis of Cerebral Veins with Magnetic Resonance Susceptibility Weighted Imaging.

PURPOSE: To observe the regulation of cerebral circulation in vivo based on image segmentation algorithms for deep learning in medical imaging to automatically detect and quantify the neonatal deep medullary veins (DMVs) on susceptibility weighted imaging (SWI) images. To evaluate early cerebral circulation self-rescue for neonates undergoing risk of cerebral hypoxia-ischaemia in vivo. METHODS: SWI images and clinical data of 317 neonates with or without risk of cerebral hypoxia-ischaemia were analyzed. Quantitative parameters showing the number, width, and curvature of DMVs were obtained using an image segmentation algorithm. RESULTS: The number of DMVs was greater in males than in females (p < 0.01), and in term than in preterm infants (p = 0.001). The width of DMVs was greater in term than in preterm infants (p < 0.01), in low-risk than in high-risk group (p < 0.01), and in neonates without intracranial extracerebral haemorrhage (ICECH) than with ICECH (p < 0.05). The curvature of DMVs was greater in term than in preterm infants (P < 0.05). The width of both bilateral thalamic veins and anterior caudate nucleus veins were positively correlated with the number of DMVs; the width of bilateral thalamic veins was positively correlated with the width of DMVs. CONCLUSION: The DMVs quantification based on image segmentation algorithm may provide more detailed and stable quantitative information in neonate. SWI vein quantification may be an observable indicator for in vivo assessment of cerebral circulation self-regulation in neonatal hypoxic-ischemic brain injury.

Deciphering the potential role of PGRN in regulating CD8+ T cell antitumor immunity.

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8+ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8+ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8+ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8+ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8+ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN-/- mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8+ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.

Effects of microplastics on microbial community structure and wheatgrass traits in Pb-contaminated riparian sediments under flood-drainage-planting conditions.

The coexistence of microplastics (MPs) and heavy metals in sediments has caused a potential threat to sediment biota. However, differences in the effects of MPs and heavy metals on microbes and plants in sediments under different sediment conditions remain unclear. Hence, we investigated the influence of polyethylene (PE) and polylactic acid (PLA) MPs on microbial community structure, Pb bioavailability, and wheatgrass traits under sequential incubation of sediments (i.e., flood, drainage, and planting stages). Results showed that the sediment enzyme activities presented a dose-dependent effect of MPs. Besides, 10 % PLA MPs significantly increased the F1 fractions in three stages by 11.13 %, 30.10 %, and 17.26 %, respectively, thus resulting in higher Pb mobility and biotoxicity. MPs altered sediment bacterial composition and structures, and bacterial community differences were evident in different incubation stages. Moreover, the co-exposure of PLA MPs and Pb significantly decreased the shoot length and total biomass of wheatgrass and correspondingly activated the antioxidant enzyme activity. Further correlation analysis demonstrated that community structure induced by MPs was mainly driven by sediment enzyme activity. This study contributes to elucidating the combined effects of MPs and heavy metals on sediment ecosystems under different sediment conditions.

Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice.

BACKGROUND: Pulmonary emphysema is a condition that causes damage to the lung tissue over time. GBP5, as part of the guanylate-binding protein family, is dysregulated in mouse pulmonary emphysema. However, the role of GBP5 in lung inflammation in ARDS remains unveiled. METHODS: To investigate whether GBP5 regulates lung inflammation and autophagy regulation, the study employed a mouse ARDS model and MLE-12 cell culture. Vector transfection was performed for the genetic manipulation of GBP5. Then, RT-qPCR, WB and IHC staining were conducted to assess its transcriptional and expression levels. Histological features of the lung tissue were observed through HE staining. Moreover, ELISA was conducted to evaluate the secretion of inflammatory cytokines, autophagy was assessed by immunofluorescent staining, and MPO activity was determined using a commercial kit. RESULTS: Our study revealed that GBP5 expression was altered in mouse ARDS and LPS-induced MLE-12 cell models. Moreover, the suppression of GBP5 reduced lung inflammation induced by LPS in mice. Conversely, overexpression of GBP5 diminished the inhibitory impact of LPS on ARDS during autophagy, leading to increased inflammation. In the cell line of MLE-12, GBP5 exacerbates LPS-induced inflammation by blocking autophagy. CONCLUSION: The study suggests that GBP5 facilitates lung inflammation and autophagy regulation. Thus, GBP5 could be a potential therapeutic approach for improving ARDS treatment outcomes, but further research is required to validate these findings.

DUSP1 Promotes Osimertinib Drug-Tolerant Persistence by Inhibiting MAPK/ERK Signaling in Non-small Cell Lung Cancer.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) patients, which remarkably improve the clinical outcomes. However, drug resistance has greatly impaired the efficacy of EGFR-TKIs and contributes to cancer treatment failure. DUSP1, a negative regulator of MAPK signaling pathway, was discovered to mediate drug resistance in multiple types of cancers. Our study aimed to explore the role of DUSP1 in NSCLC cell resistance to osimertinib, a third-generation EGFR-TKI. Human NSCLC cell lines PC-9 and HCC827 were exposed to increasing concentrations of osimertinib for over 6 months to generate osimertinib resistant cells (PC-9-OR and HCC827-OR). The viabilities of osimertinib-resistant and parental sensitive NSCLC cells in response to osimertinib stimulation were detected by MTS assay and the IC50 values for osimertinib were obtained. The differentially expressed genes in osimertinib-resistant and sensitive NSCLC cells were identified by analyzing the GEO dataset GSE106765 using bioinformatic tools. DUSP1 expression was knocked down by using the short hairpin RNAs (shRNAs). Then, the effects of DUSP1 silencing on osimertinib-resistant and sensitive NSCLC cell resistance to osimertinib, viability, proliferation and apoptosis were assessed through loss-of-function experiments. The expression of key molecules (JNK, ERK, and p38 MAPK) in the MAPK signaling pathway was detected through western blotting analysis. DUSP1 was overexpressed in osimertinib-resistant NSCLC cells versus parental sensitive cells. DUSP1 silencing attenuated the resistance of NSCLC cells to osimertinib. DUSP1 silencing markedly inhibited osimertinib-resistant and sensitive NSCLC cell proliferation but enhanced cell apoptosis. Mechanically, DUSP1 knockdown increased phosphorylated-JNK, ERK, and p38 MAPK levels in NSCLC cells. Treatment with SB203580, the p38 MAPK inhibitor, reversed the effects of DUSP1 silencing on osimertinib-resistant NSCLC cell resistance to osimertinib, cell proliferation and apoptosis. DUSP1 downregulation restores the sensitivity of NSCLC cells to osimertinib via activating the MAPK signaling pathway.

Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.

The post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.

Effects of microplastics on sedimentary geochemical properties and microbial ecosystems combined with hydraulic disturbance.

Microplastics (MPs) pollution is widely investigated owing to its potential threats to river ecosystems. However, it remains unclear whether hydraulic disturbance deepens or mitigates the effects of MPs-contaminated sediments on the river environment. Herein, we studied the impact of sediment aggregates, organic matter, and enzyme activity, with emphasis on microbial community structure and function in sediments exposed to MPs (1 %, 5 %, and 10 % w/w) in conjunction with hydraulic disturbance. The experimental results showed that the influence of MPs on the sediment under hydraulic disturbance is more significant than that of static culture, especially for various environmental factors (MWD, MBC, and sucrase activity etc.). The proportions of the >0.05 mm-fraction aggregates increased from 74-76 % to 82-88 % in the sediment throughout the entire disturbance process. It has been found that the disturbance generally promotes the interaction between MPs and sediments. FAPROTAX analysis demonstrated that the disturbance reduced the difference in effects on microbial functional genes between the control group and the MPs-added groups by up to 10 times, suggesting that the effects of disturbance on MPs-contaminated sediments are relatively complex. This work provides new insights into the effects of hydraulic disturbance on physicochemical properties and microbial communities of MPs-contaminated sediment.

Endothelial downregulation of nuclear m6A reader YTHDC1 promotes pulmonary vascular remodeling in sugen hypoxia model of pulmonary hypertension.

Background: Pulmonary hypertension (PH) is characterized with vascular remodeling, which is intiated by vascular endothelial dysfunction. N6-methyladenosine (m6A) modification mediates gene expression in many ways including mediating RNA degradation, splicing, nuclear export et al. m6A modification have been found to be associated with the development of PH. However, the role of m6A regulators in pulmonary artery endothelial cells (PAECs) dysfunction of PH is still under research. Methods: The expression levels of m6A regulators in PAECs were analyzed with the single-cell sequencing Data(scRNA). Next, the target differentially expressed genes (DEGs) of m6A regulators in PAECs were functionally annotated. The analysis of cellular interactions included the examination of receptor-ligand pairs regulated by m6A regulators. Pseudo-time trajectory analyses and a ceRNA network involving lncRNAs, miRNAs, and mRNAs were conducted in PAECs. Furthermore, microarray data (GSE180169) for Sugen Hypoxia PH (SuHx PH) mouse models was screened for DEGs and m6A regulators in PAECs. Moreover, the expression of YTHDC1 in the lung samples of SuHx PH models was determined using immunofluorescence. In vitro, the mRNA expression of YTHDC1 in HPAECs under hypoxia conditions was detected. The effect of YTHDC1 recombinant protein on HPAEC proliferation was detected by Cell Counting Kit-8 (CCK8). Results: Dysregulation of m6A regulators was observed in mouse PAECs. The m6A reader of YTHDC1 was decreased in PAECs in scRNA data and RNAseq data of isolated PAECs of SuHx PH models. Downregulation of YTHDC1 was caused by hypoxia in PAECs in vitro and similar results was observed in PAECs of SuHx PH mouse models. Next, YTHDC1 recombinant protein was found to inhibit HPAECs proliferation. The DEGs targeted by YTHDC1 were enriched in angiogenesis, endothelial cell migration, fluid shear stress, and stem cell maintenance. Analysis indicates that interactions among endothelial cells, smooth muscle cells, fibroblasts, and immune cells, mediated by specific YTHDC1 target genes (e.g., PTPRC-MRC1, ITBG2-ICAM1, COL4A1-CD44), contribute to PH development. Also, the YTHDC1 expression were consistent with Thioredoxin interacting protein (TXNIP). What's more, the predicted transcription factors showed that NFKB1, Foxd3 may be involved in the regulation of YTHDC1. Lastly, our data suggest that YTHDC1 may be involved in regulating PAECs dysfunction through lncRNA/miRNA/mRNA network. Conclusion: For the first time, we analyzed changes in the expression and biological functions of m6A regulators in SuHx PH mouse models. We causatively linked YTHDC1 to PAECs dysfunction, providing novel insight into and opportunities to diagnose and treat PH.

Impact of polyamide microplastics on riparian sediment structures and Cd(II) adsorption: A comparison of natural exposure, dry-wet cycles, and freeze-thaw cycles.

Microplastics (MPs) accumulation in sediments has posed a huge threat to freshwater ecosystems. However, it is still unclear the effect of MPs on riparian sediment structures and contaminant adsorption under different hydrological processes. In this study, three concentrations of polyamide (PA) MPs-treated sediments (0.1%, 1%, and 10%, w/w) were subjected to natural (NA) exposure, dry-wet (DW) cycles, and freeze-thaw (FT) cycles. The results indicated that PA MPs-added sediment increased the micro-aggregates by 10.1%-18.6% after FT cycles, leading to a decrease in aggregate stability. The pH, OM, and DOC of sediments were significantly increased in DW and FT treatments. In addition, the increasing concentration of PA MPs showed an obvious decrease in aromaticity, humification, and molecular weight of sediment DOM in FT treatments. Also, high level of MPs was more likely to inhibit the formation of humic-like substances and tryptophan-like proteins. For DW and FT cycles, 0.1% and 1% PA MPs-treated sediments slightly increased the adsorption capacity of Cd(II), which may be ascribed to the aging of MPs. Further correlation analysis found that DW and FT altered the link between DOM indicators, and aggregate stability was directly related to the changes in sediment organic carbon. Our findings revealed the ecological risk of MPs accumulating in riparian sediments under typical hydrological processes.

[Impact of Folic Acid on the Resistance of Non-small Cell Lung Cancer Cells 
to Osimertinib by Regulating Methylation of DUSP1].

BACKGROUND: Drug resistance is the main cause of high mortality of lung cancer. This study was conducted to investigate the effect of folic acid (FA) on the resistance of non-small cell lung cancer (NSCLC) cells to Osimertinib (OSM) by regulating the methylation of dual specificity phosphatase 1 (DUSP1). METHODS: The OSM resistant NSCLC cell line PC9R was establishd by gradually escalation of OSM concentration in PC9 cells. PC9R cells were randomly grouped into Control group, OSM group (5 µmol/L OSM), FA group (600 nmol/L FA), methylation inhibitor decitabine (DAC) group (10 µmol/L DAC), FA+OSM group (600 nmol/L FA+5 µmol/L OSM), and FA+OSM+DAC group (600 nmol/L FA+5 µmol/L OSM+10 µmol/L DAC). CCK-8 method was applied to detect cell proliferation ability. Scratch test was applied to test the ability of cell migration. Transwell assay was applied to detect cell invasion ability. Flow cytometry was applied to measure and analyze the apoptosis rate of cells in each group. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) method was applied to detect the expression level of DUSP1 mRNA in cells. Methylation specific PCR (MSP) was applied to detect the methylation status of the DUSP1 promoter region in each group. Western blot was applied to analyze the expression levels of DUSP1 protein and key proteins in the DUSP1 downstream mitogen-activated protein kinase (MAPK) signaling pathway in each group. RESULTS: Compared with the Control group, the cell OD450 values (48 h, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of extracellular regulated protein kinases (ERK) were obviously increased (P<0.05); the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the DAC group were obviously increased (P<0.05); the apoptosis rate, the expression of p38 MAPK protein, the phosphorylation level of ERK, and the methylation level of DUSP1 were obviously reduced (P<0.05). Compared with the OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM group were obviously decreased (P<0.05); the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously increased (P<0.05). Compared with the FA+OSM group, the cell OD450 values (48, 72 h), scratch healing rate, number of cell invasions, and expression of DUSP1 in the FA+OSM+DAC group were obviously increased; the apoptosis rate, the methylation level of DUSP1, the expression of p38 MAPK protein, and the phosphorylation level of ERK were obviously reduced (P<0.05). CONCLUSIONS: FA may inhibit DUSP1 expression by enhancing DUSP1 methylation, regulate downstream MAPK signal pathway, then promote apoptosis, inhibit cell invasion and metastasis, and ultimately reduce OSM resistance in NSCLC cells.

A Systematic Review and Meta-analysis of Renin-angiotensin System Inhibitors and Angiotensin Receptor Neprilysin Inhibitors in Preventing Recurrence After Atrial Fibrillation Ablation.

ABSTRACT: To systematically evaluate the efficacy and safety of renin-angiotensin system inhibitors (RASIs) and angiotensin receptor neprilysin inhibitors in preventing the recurrence of atrial fibrillation after atrial fibrillation ablation, we have written this meta-analysis. We systematically searched randomized controlled trials or cohort studies on RASIs and angiotensin receptor neprilysin inhibitor-sacubitril/valsartan (SV) in preventing the recurrence of atrial fibrillation. Two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Afterward, the meta-analysis was performed using RevMan 5.3 software. This meta-analysis results showed that the recurrence rate of atrial fibrillation after ablation in subjects using RASIs was lower than that in subjects not using them [relative risk = 0.85, 95% confidence interval (CI) (0.72-0.99), P = 0.03]; the recurrence rate in subjects using SV was lower than that in subjects using RASIs [RR= 0.50, 95% CI (0.37-0.68), P < 0.00001]. These results show that both the use of RASIs and SV can prevent the recurrence of after atrial fibrillation ablation, among which the use of SV is more effective.

Acquired resistance to crizotinib in novel CDK14-ALK and CLTC-ALK fusions of ALK-positive large B-cell lymphoma identified by next-generation sequencing.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare subtype of non-Hodgkin lymphoma. ALK inhibitors are being tried to treat recurrent/refractory ALK+ LBCL. A majority of patients with ALK+ tumors respond to crizotinib, but partial cases ultimately develop resistance about a year later. Here, we report a case of ALK+ LBCL carrying a new fusion gene involving CDK14 and ALK, CLTC-ALK gene rearrangements and MTOR gene mutation. The patient had progressive disease after combination of crizotinib and chemotherapy treatment about 5.5 months later, accompanied by reduced abundance of CDK14-ALK, increased abundance of CLTC-ALK and a novel MFHAS1 gene mutation. However, MTOR mutation turned negative. The patient received alectinib combined with hyper-CVAD, then followed by alectinib as monotherapy for 21 months. The patient achieved partial response and remained in a stable condition. This case suggests that CDK14-ALK fusion gene may be more sensitive to crizotinib than CLTC-ALK fusion gene. MTOR is associated with the anti-tumor mechanism of ALK inhibitors. MFHAS1 gene mutation and/or CLTC-ALK gene copy number amplification may involve resistance to crizotinib. Furthermore, alectinib may inhibit the carcinogenicity of these gene changes and improve the prognosis of ALK+ LBCL.

The novel CDK14-ALK fusion gene in ALK+ LBCL was sensitive to crizotinib.MFHAS1 gene mutation and/or CLTC-ALK gene copy number amplification may involve resistance to crizotinib.

Comparative assessment of efficacy and safety of approved oral therapies for overactive bladder: a systematic review and network meta-analysis

ABSTRACT Purpose: To compare the effectiveness and safety of marketed oral drugs for overactive bladder based on a systematic review and network meta-analysis approach. Methods: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. Result: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. Conclusion: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.

A Preliminary Study of Brain Functional Magnetic Resonance Imaging in Text Reading and Comprehension.

BACKGROUND: Few studies have focused on the changes in human brain function activities caused by reading Chinese characters with different intelligibility and whether it can reflect the understanding and cognitive ability of the human brain. OBJECTIVE: Task-fMRI based on Chinese character reading tasks with different intelligibility was used to explore activated brain regions and their cognitive changes. METHODS: Volunteers were randomly recruited using advertisements. Forty volunteers were recruited based on strict inclusion and exclusion criteria, and 40 volunteers were recruited. Brain function data of 40 healthy right-handed volunteers in fuzzy/clear Chinese reading tasks were collected using a Siemens Skyra 3.0T magnetic resonance scanner. Data were preprocessed and statistically analyzed using the statistical software SPM12.0 to observe the activation of the cortex and analyze its characteristics and possible changes in cognitive function. RESULTS: Task-fMRI analysis: (1) The main brain regions activated in fuzzy/clear reading tasks were located in the occipital visual cortex (P < 0.001); (2) a paired sample t-test suggested that there was a significant difference in BOLD signals in the brain regions activated by fuzzy/clear reading tasks (P < 0.001, equiv Z = 4.25). Compared with the fuzzy reading task, the brain regions more strongly activated in the clear reading task were mainly located in the right superior frontal gyrus and the bilateral temporal lobe. Compared with the clear reading task, the brain region that was more strongly activated in the fuzzy reading task was mainly located in the right fusiform gyrus. CONCLUSION: Clear Chinese character information mainly activates the dorsal stream of the visual-spatial network. This reflects the information transmission of the brain after understanding the text content and is responsible for guiding and controlling attention. Fuzzy words that cannot provide clear text content activate the fusiform gyrus of the ventral stream of the visual-spatial network, strengthening the function of orthographic processing.

Thrombin Time is a Diagnostic Biomarker of Sudden Sensorineural Hearing Loss and Predicts the Prognosis.

OBJECTIVES: The aim of this study is to determine whether thrombin time (TT) could be used as diagnostic biomarkers and predict the prognosis for sudden sensorineural hearing loss (SSNHL). METHODS: Sixty-one patients diagnosed with SSNHL and 65 people who underwent physical examination were recruited. Data on the patient's background, clinical course, and laboratory findings were collected. SSNHL patients were divided into the effective and ineffective groups according to the hearing recovery from the treatment and were assessed by binary logistic regression. Receiver-operating characteristic (ROC) analysis was carried out for the best discriminating cutoff value of the biomarker with the corresponding sensitivity and specificity was calculated. RESULTS: The SSNHL group exhibited prolonged TT (19.11 ± 1.12 seconds) compared to the control group (17.58 ± 2.18 seconds, P < .001). Binary logistic regression analysis found a significant positive association between TT and SSNHL and was observed with an odds ratio (OR) 1.769 [95% confidence interval (CI) 1.344-2.330, P < .001] in the unadjusted model. Even after adjustment using the variables included in the multivariate models, TT was significantly predictive of SSNHL. A TT cutoff value of 17.65 seconds provides optimal separation between patients with SSNHL and controls in the ROC analysis [Area Under the Curve (AUC) 0.773, 95% CI 0.689-0.856; sensitivity, 0.918; and specificity, 0.569]. TT in the effective group of SSNHL patients was shorter (18.76 ± 1.06 seconds) than that in the ineffective group (19.43 ± 1.09 seconds, P = .018). The cutoff value of TT as progress predictors was 19.85 seconds. The TT < 19.85 seconds showed an effective rate 59.09% (26/44) higher than 17.65% (3/17) of TT ≥ 19.85 seconds. CONCLUSIONS: TT is a potential biomarker of SSNHL and is independently associated with the prognosis of patients with SSNHL.

The efficacy and safety of eltrombopag in treating TKI-induced thrombocytopenia in patients with chronic myeloid leukemia.

ABSTRACTThrombocytopenia is one of the most common hematological adverse reactions in chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKI) therapy, causing life-threatening bleeding cases. However, there are fewer therapeutic drugs for TKI-induced thrombocytopenia. Eltrombopag is a non-peptide thrombopoietin receptor agonist used for the treatment of immune thrombocytopenia， aplastic anemia, and hepatitis C-associated thrombocytopenia. Nevertheless, studies of eltrombopag for TKI-induced thrombocytopenia are still lacking. This study retrospectively analyzed the clinical and test data of 21 CML patients with TKI-related thrombocytopenia. The results demonstrated that the median baseline value of thrombocytopenia in the 21 CML patients was 15.57 × 109/L [2-28 × 109/L]. Following treatment with eltrombopag, 16 patients had a significant increase in their platelet levels. The peak median for platelet increase in effective responders was 145.12 × 109/L (51-460 × 109/L). However, 5 patients failed to respond to eltrombopag. Moreover, 4 of the 21 patients enrolled had adverse reactions, including reversible liver function impairment, palpitation, headache, insomnia, and loss of appetite. Nonetheless, no cases of disease progression, thrombotic events, or myelofibrosis were observed. Hence, eltrombopag may be a useful adjunctive therapy for relieving TKI-related thrombocytopenia in patients with CML.