Multi-feature Fusion Network on Gray Scale Ultrasonography: Effective Differentiation of Adenolymphoma and Pleomorphic Adenoma.

RATIONALE AND OBJECTIVES: to develop a deep learning radiomics graph network (DLRN) that integrates deep learning features extracted from gray scale ultrasonography, radiomics features and clinical features, for distinguishing parotid pleomorphic adenoma (PA) from adenolymphoma (AL) MATERIALS AND METHODS: A total of 287 patients (162 in training cohort, 70 in internal validation cohort and 55 in external validation cohort) from two centers with histologically confirmed PA or AL were enrolled. Deep transfer learning features and radiomics features extracted from gray scale ultrasound images were input to machine learning classifiers including logistic regression (LR), support vector machines (SVM), KNN, RandomForest (RF), ExtraTrees, XGBoost, LightGBM, and MLP to construct deep transfer learning radiomics (DTL) models and Rad models respectively. Deep learning radiomics (DLR) models were constructed by integrating the two features and DLR signatures were generated. Clinical features were further combined with the signatures to develop a DLRN model. The performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis, calibration, decision curve analysis (DCA), and the Hosmer-Lemeshow test. RESULTS: In the internal validation cohort and external validation cohort, comparing to Clinic (AUC=0.767 and 0.777), Rad (AUC=0.841 and 0.748), DTL (AUC=0.740 and 0.825) and DLR (AUC=0.863 and 0.859), the DLRN model showed greatest discriminatory ability (AUC=0.908 and 0.908) showed optimal discriminatory ability. CONCLUSION: The DLRN model built based on gray scale ultrasonography significantly improved the diagnostic performance for benign salivary gland tumors. It can provide clinicians with a non-invasive and accurate diagnostic approach, which holds important clinical significance and value. Ensemble of multiple models helped alleviate overfitting on the small dataset compared to using Resnet50 alone.

Research progress in pulmonary rehabilitation in patients who have been weaned off mechanical ventilation: A review article.

BACKGROUND: Patients who have been treated with mechanical ventilation for more than 72 hours are susceptible to symptoms such as hypoxia and respiratory muscle fatigue after weaning, which may result in weaning difficulty and delay, as well as an increased incidence of negative emotions such as anxiety and depression. Correct pulmonary rehabilitation exercise technique and timing can improve the weaning success rate, reduce the disability rate, and reduce the incidence of pulmonary infection, as well as reduce medical expenses. OBJECTIVE: This article provides a review of pulmonary rehabilitation interventions for mechanically ventilated patients, searching relevant literature through databases such as CNKI and PubMed, aiming to provide guidance for the successful weaning of mechanically ventilated patients. METHODS: We selected articles related to pulmonary rehabilitation interventions for mechanically ventilated patients from CNKI (China National Knowledge Infrastructure) and PubMed over the years. RESULTS: This article provides a comprehensive review of the research on lung rehabilitation for patients who are mechanically ventilated during the weaning process in an effort to serve as a guide for a successful transition from mechanical ventilation. CONCLUSION: Early pulmonary rehabilitation training can effectively increase the pulmonary function level and ventilation function of patients and reduce the duration of mechanical ventilation and hospitalization, and is an effective, safe, and feasible treatment method.

The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway.

Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

The mechanisms of natural products for eye disorders by targeting mitochondrial dysfunction.

The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products.

UPLC-qTOF-MS phytochemical profile of Commiphora gileadensis leaf extract via integrated ultrasonic-microwave-assisted technique and synthesis of silver nanoparticles for enhanced antibacterial properties.

The utilization of metallic nanoparticles in bio-nanofabrication holds significant potential in the field of applied research. The current study applied and compared integrated ultrasonic-microwave-assisted extraction (US/MICE), ultrasonic extraction (USE), microwave-assisted extraction (MICE), and maceration (MAE) to extract total phenolic content (TPC). In addition, the study examined the antioxidant activity of Commiphora gileadensis (Cg) leaf. The results demonstrated that the TPC of US/MICE exhibited the maximum value at 59.34 ± 0.007 mg GAE/g DM. Furthermore, at a concentration of 10 µg/mL, TPC displayed a significant scavenging effect on DPPH (56.69 %), with an EC50 (6.48 µg/mL). Comprehensive metabolite profiling of the extract using UPLC-qTOF-MS/MS was performed to identify active agents. A total of 64 chromatographic peaks were found, out of which 60 were annotated. The most prevalent classes of metabolites found were polyphenols (including flavonoids and lignans), organic compounds and their derivatives, amides and amines, terpenes, and fatty acid derivatives. Transmission electron microscopy (TEM) revealed the aggregate size of the synthesized nanoparticles and the spherical shape of C. gileadensis-mediated silver nanoparticles (Cg-AgNPs). The nanoparticles had a particle size ranging from 7.7 to 42.9 nm. The Cg-AgNPs exhibited more inhibition zones against S. aureus and E. coli. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Cg-extract, AgNPs, and Cg-AgNPs were also tested. This study demonstrated the feasibility of using combined ultrasonic-microwave-assisted extraction to separate and extract chemicals from C. gileadensis on a large scale. These compounds have potential use in the pharmaceutical industry. Combining antibacterial and biocompatible properties in materials is vital for designing new materials for biomedical applications. Additionally, the results showed that the biocompatibility of the Ag-NPs using C. gileadensis extracts demonstrated outstanding antibacterial properties.

Clinical application of medical adhesive in endovascular embolization treatment of peripheral pseudoaneurysm.

Objectives: This study explores the clinical application value of medical adhesive in endovascular embolization treatment of peripheral pseudoaneurysm. Material and Methods: This was a retrospective review on 31 patients with peripheral pseudoaneurysm treated with medical adhesive endovascular embolization at the First Affiliated Hospital of Shihezi University from July 2021 to July 2023. Follow-up for 3-6 months was to observe the clinical efficacy and postoperative complications of medical adhesive embolization treatment. Results: A total of 32 pseudoaneurysms were embolized in 31 patients with peripheral pseudoaneurysms. All pseudoaneurysms originated from visceral arteries. Among them, 29 pseudoaneurysms were embolized with medical adhesive alone, and three pseudoaneurysms were embolized with coil-assisted medical adhesive. After endovascular embolization with medical adhesive, all pseudoaneurysms were successfully embolized. Technical success was 100%. All patients experienced cessation of bleeding after endovascular embolization with medical adhesive, and there were no serious post-operative complications. Clinical success was 100%. During the follow-up period, two patients experienced recurrent bleeding but no pseudoaneurysm recurrence was observed. Conclusion: Endovascular medical adhesive embolization is a safe and effective method for treating pseudoaneurysm, with high hemostatic efficiency and permanent occlusion of the pseudoaneurysm after embolization, which is worthy of clinical promotion and application.

Intrathecal morphine delivery at prepontine cistern to control refractory cancer-related pain: a case report of extensive metastatic and refractory cancer pain.

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.

The Complement System and C4b-Binding Protein: A Focus on the Promise of C4BPα as a Biomarker to Predict Clopidogrel Resistance.

The complement system plays a dual role in the body, either as a first-line defense barrier when balanced between activation and inhibition or as a potential driver of complement-associated injury or diseases when unbalanced or over-activated. C4b-binding protein (C4BP) was the first circulating complement regulatory protein identified and it functions as an important complement inhibitor. C4BP can suppress the over-activation of complement components and prevent the complement system from attacking the host cells through the binding of complement cleavage products C4b and C3b, working in concert as a cofactor for factor I in the degradation of C4b and C3b, and consequently preventing or reducing the assembly of C3 convertase and C5 convertase, respectively. C4BP, particularly C4BP α-chain (C4BPα), exerts its unique inhibitory effects on complement activation and opsonization, systemic inflammation, and platelet activation and aggregation. It has long been acknowledged that crosstalk or interplay exists between the complement system and platelets. Our unpublished preliminary data suggest that circulating C4BPα exerts its antiplatelet effects through inhibition of both complement activity levels and complement-induced platelet reactivity. Plasma C4BPα levels appear to be significantly higher in patients sensitive to, rather than resistant to, clopidogrel, and we suggest that a plasma C4BPα measurement could be used to predict clopidogrel resistance in the clinical settings.

p32/OPA1 axis-mediated mitochondrial dynamics contributes to cisplatin resistance in non-small cell lung cancer.

Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.

3D walkable DNA gears for ultrasensitive detection of multiple microRNAs in lung cancer cell lysates.

As a tumor biomarker with therapeutic application potential, microRNA (miRNA) was crucial for the accurate and sensitive detection of early-stage tumors. Herein, a unique three dimensional (3D) DNA nanomachine (DNM) was created, which was capable detecting lung cancer-related biomarkers miRNA-21, miRNA-205 and miRNA-125b in lung cancer cell lysates with extreme sensitivity. The 3D DNM was composed of DNA scissors and three flexible walkable DNA gears modified with various species of silver nanoclusters (AgNCs). Based on the flexibility of DNA scissors and the walkability of DNA gears, neighboring DNA gears closed the distance between different species of AgNCs by walking in the presence of targets, generating fluorescence resonance energy transfer (FRET) effect and emitting different kinds of fluorescence to complete the highly sensitive detection of single targets and multiple targets. The findings demonstrated that a linear model provided an excellent match for the association between fluorescence signal and target miRNAs. For miRNA-21, miRNA-205, and miRNA-125b, the limits of detection (LODs) (signal/noise = 3) were 4.2 pmol/L (pM), 6.3 pM, and 10.2 pM, respectively. Their recoveries in A549 cell lysate samples ranged from 95.3 to 108.8 % with relative standard deviations of 1.26 %-4.88 %. Satisfactorily, the 3D DNM displayed exceptional analytical performance with high sensitivity and stability, strong specificity and reproducibility, which was triumphantly employed to identify miRNAs in tumor cell lysates, providing a workable technique in creating adaptable nanostructure for dependable bioanalysis and clinical diagnosis of cancer biomarkers.

Effects of ivabradine on ventricular electrophysiological remodeling after myocardial infarction in rats.

Introduction: This study aims to investigate the effects of ivabradine (IVA) on ventricular electrophysiological remodeling after myocardial infarction (MI) in rats. Material and methods: A total of 60 male Sprague-Dawley rats were randomly divided into five groups: an MI group, an IVA group, a metoprolol (MET) group, an IVA + MET group, and a sham group. After a four-week intervention, the ventricular electrophysiological parameters were detected by multichannel electrophysiological polygraph. Then, the morphological characteristics were evaluated using hematoxylin and eosin (H&E) and Masson's staining, and the expression of phosphorylated connexin 43 (p-Cx43) in the left ventricular wall was detected through immunohistochemistry and the Western blot test. Results: The electrophysiological examination revealed that the induction rate and fatality rate of ventricular tachycardia (VT)/ventricular fibrillation (VF) were lower in both the IVA and the MET group, compared with the MI group (6/12, 6/12 vs. 10/11; and 1/12, 1/12 vs. 5/11; all p < 0.05), as well as the IVA + MET group (1/11 vs. 10/11, p < 0.01; and 1/11 vs. 5/11, p < 0.05). The induction rate of VT/VF was lower in the IVA + MET group, compared to the MET group (1/11 vs. 6/12, p < 0.05). H&E and Masson's staining revealed that compared with the MI group, the left ventricular infarction area was lower in the IVA, MET, and IVA + MET groups (p < 0.05, p < 0.05, and p < 0.01, respectively), while collagen volume fraction (CVF) also was lower in the other groups (all p < 0.01). The left ventricular infarction area and CVF both were lower in the IVA + MET group, compared to the MET group (p < 0.05 and p < 0.01, respectively). The immunohistochemistry and Western blot revealed that p-Cx43 expression was higher in the treatment groups, compared with the MI group (all p < 0.01). Conclusions: IVA can reduce the incidence of ventricular arrhythmia after MI in male rats by improving both structural and electrical remodeling, and the combination of IVA and MET is even more effective.

An In Situ Investigation of the Protein Corona Formation Kinetics of Single Nanomedicine Carriers by Self-Regulated Electrochemiluminescence Microscopy.

Protein coronas are present extensively at the bio-nano interface due to the natural adsorption of proteins onto nanomaterials in biological fluids. Aside from the robust property of nanoparticles, the dynamics of the protein corona shell largely define their chemical identity by altering interface properties. However, the soft coronas are normally complex and rapidly changing. To real-time monitor the entire formation, we report here a self-regulated electrochemiluminescence (ECL) microscopy based on the interaction of the Ru(bpy)3 3+ with the nanoparticle surface. Thus, the heterogeneity of the protein corona is in situ observed in single nanoparticle "cores" before and after loading drugs in nanomedicine carriers. The label-free, optical stable and dynamic ECL microscopy minimize misinterpretations caused by the variation of nanoparticle size and polydispersity. Accordingly, the synergetic actions of proteins and nanoparticles properties are uncovered by chemically engineered protein corona. After comparing the protein corona formation kinetics in different complex systems and different nanomedicine carriers, the universality and accuracy of this technique were well demonstrated via the protein corona formation kinetics curves regulated by competitive adsorption of Ru(bpy)3 3+ and multiple proteins on surface of various carriers. The work is of great significance for studying bio-nano interface in drug delivery and targeted cancer treatment.

A retrospective analysis of coping competence among community health centers during the COVID-19 pandemic in Shanghai, China: Coping strategies for future public health emergency events.

This study aims to investigate the coping competence of 12 community health centers through nursing workforce, emergency preparation, emergency response training, and emergency support in a district of Shanghai during the coronavirus disease 2019 (COVID-19) pandemic in 2022 to propose coping strategies and implication for Future Public Health Emergency Events for community health centers. A cross-sectional survey was conducted on June 2022, and 12 community health centers (servicing a population of 104,472.67 ± 41,421.18, with 125 ± 36 health care providers per center) were then divided into group A (n = 5, medical care ratio ≥ 1:1) and group B (n = 7, medical care ratio < 1:1) according to collected data, and the nursing human resources management and coping competence of the centers with COVID-19 of both groups were retrospectively analyzed. Nursing shortages were obvious across all 12 centers. Certain deficiencies in the coping competence of community health centers with emergencies must be addressed (possession rate < 70% in both groups, p > 0.05). Community health centers need to enhance hospital-to-hospital collaboration and the ability to transport emergency staff to the post promptly during outbreaks. Emergency coping assessments, emergency drills at different levels, and mental health support need to be implemented regularly among community health centers, and effective donation management should be pursued as well. We expect that this study could support efforts by leaders of community health centers to conclude coping strategies including increasing nursing workforce, optimizing human recourse management, and identifying areas of improvement of centers for emergency coping during public health events.

Antioxidant activity and total phenolic compounds of Commiphora gileadensis extracts obtained by ultrasonic-assisted extraction, with monitoring antiaging and cytotoxicity activities.

Commiphora gileadensis (C. gileadensis) has been identified and linked with various health benefits and pharmaceutical potential for its phytochemical activities and chemical constituents. This study aimed to evaluate ultrasonic-assisted extraction (USE) technique for total phenols content from C. gileadensis leaf compared to the hydrodistillation extraction (HDE). Our results showed that the USE operating conditions were identified as: MeOH·H2O solvent-to-fresh sample ratio of 80:20 (v/v); ultrasonic power/frequency at 150 W/20 kHz; and a temperature of 40 ± 1°C; subjected to acoustic waves intermittently for a calculated time (5 min) during the total programmed time of 12 min. The USE exhibited (118.71 ± 0.009 mg GAE/g DM) more amounts of all phenols than HDE (101.47 ± 0.005 mg GAE/g DM), and antioxidant (77.78 ± 0.73%, 75.27 ± 0.59% scavenging inhibition of DPPH), respectively. Anti-aging and Cytotoxicity activities were investigated. The results of biological evaluations showed that the crude extracts of C. gileadensis significantly extended the replicative lifespan of K6001 yeast. In addition, in vitro cytotoxicity against the HepG2 cell line showed significant anticancer activity, and approximately 100 µg/mL is required to decrease viability compared with that of the control. This study is proven for a larger scale to extract and isolate compounds of C. gileadensis for potential utilization in the pharmaceutical industry. In conclusion, advanced methods afford an extract with high activity in the biological properties of the extract.

Enhanced photocatalytic CO2 reduction on biomineralized CdS via an electron conduit in bacteria.

There is an increasing trend in semi-artificial photosynthesis systems that combine living cells with inorganic semiconductors to activate a bacterial catalytic network. However, these systems face various challenges, including electron-hole recombination, photocorrosion, and the generation of photoexcited radicals by semiconductors, all of which impair the efficiency, stability, and sustainability of biohybrids. We first focus on a reverse strategy to improve highly efficient CO2 photoreduction on biosynthesized inorganic semiconductors using an electron conduit in the electroactive bacterium S. oneidensis MR-1. Due to the suppressed charge recombination and photocorrosion on CdS, the maximum photocatalytic production rate of formate in water was 2650 µmol g-1 h-1 (with a selectivity of ca.100%), which ranks high among all photocatalysts and is the highest for inorganic-biological hybrid systems in an all-inorganic aqueous environment. The reverse enhancement effect of electrogenic bacteria on photocatalysis on semiconductors inspires new insight to develop a new generation of bio-semiconductor catalysts for solar chemical production.

Metformin protects against retinal ischemia/reperfusion injury through AMPK-mediated mitochondrial fusion.

Retinal ischemia/reperfusion (I/R) injury is a common pathological process responsible for cellular damage in glaucoma, diabetic retinopathy and hypertensive retinopathy. Metformin is a biguanide drug that exerts strong effects on multiple diseases. This study aims to evaluate the protective effect of metformin against retinal I/R injury and its underlying mechanism. I/R induced reduction in retina thickness and cell number in ganglion cell layer, and metformin alleviated I/R-induced retinal injury. Both retinal I/R and simulated ischemia/reperfusion (SIR) in R28 cells down-regulated expression of mitochondrial fusion protein Mfn2 and OPA1, which led to mitochondrial fission. Metformin also alleviated damage in R28 cells, and reversed the alteration in Mfn2 and OPA1, mitochondrial fission and mitochondrial membrane potential (MMP) disruption-induced by I/R or SIR as well. Intriguingly, inhibition of AMPK by compound C or siRNA prevented metformin-mediated up-regulation of Mfn2 and OPA1. Compound C and knockdown of Mfn2 or OPA1 dramatically alleviated the protective effect of metformin against intracellular ROS generation, MMP disruption, mitochondrial fission and loss of RGCs in ganglion cell layer induced by SIR or I/R. Moreover, scavenging mitochondrial ROS (mito-ROS) by mito-TEMPO exerted the similar protection against I/R-induced retinal injury or SIR-induced damage in R28 cells as metformin. Our data show for the first time that metformin protects against retinal I/R injury through AMPK-mediated mitochondrial fusion and the decreased mito-ROS generation. These findings might also repurpose metformin as a therapeutic agent for retinal I/R injury.

Knockdown of the long non­coding RNA MALAT1 ameliorates TNF­α­mediated endothelial cell pyroptosis via the miR­30c­5p/Cx43 axis.

Long noncoding RNAs (lncRNAs) are related to the development of atherosclerosis (AS). However, the role of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in tumor necrosis factor­α (TNF­α)­induced rat aortic endothelial cell (RAOEC) pyroptosis, as well as the underlying mechanisms, remain unclear. RAOEC morphology was assessed using an inverted microscope. The mRNA and/or protein expression levels of MALAT1, microRNA(miR)­30c­5p and connexin 43 (Cx43) were assessed using reverse transcription­quantitative PCR (RT­qPCR) and/or western blotting, respectively. The relationships among these molecules were validated by dual­luciferase reporter assays. Biological functions, such as LDH release, pyroptosis­associated protein levels and the proportion of PI­positive cells, were evaluated using a LDH assay kit, western blotting and Hoechst 33342/PI staining, respectively. The present study demonstrated that compared with the control group, the mRNA expression levels of MALAT1 and protein expression levels of Cx43 were significantly up­regulated, whereas miR­30c­5p mRNA expressions levels were significantly decreased in TNF­α­treated RAOEC pyroptosis. Knockdown of MALAT1 or Cx43 significantly attenuated the increase in LDH release, pyroptosis­associated protein expression and PI­positive cell numbers among RAOEC treated using TNF­α, whereas an miR­30c­5p mimic exerted the opposite effect. Furthermore, miR­30c­5p was demonstrated to be a negative regulator of MALAT1 and could also target Cx43. Finally, co­transfection with siMALAT1 and miR­30c­5p inhibitor could attenuate the protective effect of MALAT1 knockdown against TNF­α­mediated RAOEC pyroptosis by upregulation of Cx43 expression. In conclusion, MALAT1 might serve an important role in TNF­α­mediated RAOEC pyroptosis by regulating the miR­30c­5p/Cx43 axis, which would provide a potential novel diagnostic and therapeutic target for AS.

Enhanced metabolic activation of and platelet response to clopidogrel in T cell-deficient mice through induction of Cyp2c and Cyp3a and inhibition of Ces1.

BACKGROUND: T cells and platelets reciprocally coordinate mutual functions through crosstalk or interaction. However, it is not known whether metabolic activation of and platelet response to clopidogrel could be changed if T cells were deficient or impaired in some cases and, if any, how it would work. OBJECTIVES: The objective of this study was to dissect the potential changes in platelet responses to and metabolic activation of clopidogrel in the case of T cell deficiency and to elucidate their mechanisms involved. METHODS: BALB/c athymic nude mice or euthymic mice (controls) pretreated with cyclosporine A (CsA), thymosin α1 (Tα1), or their combination were used to investigate the changes in ADP-induced platelet activation and aggregation, systemic exposure of clopidogrel and its metabolites, and mRNA/protein expression and activity levels of clopidogrel-metabolizing enzymes in the liver, respectively. RESULTS: Nude mice exhibited significantly enhanced antiplatelet effects of clopidogrel due to increased formation of clopidogrel active metabolite in the liver, where the enzyme activity levels of Cyp2c and Cyp3a were significantly elevated compared with control mice. Furthermore, the effects of CsA pretreatment on the metabolism of clopidogrel in euthymic mice were identical to those seen in athymic mice. As expected, concomitant use of Tα1 reversed all the observed effects of CsA on clopidogrel metabolism and relevant metabolic enzymes. CONCLUSIONS: T cell deficiency or suppression enhances the antiplatelet effects of clopidogrel due to the boosted metabolic activation of clopidogrel in the liver through a dramatic induction of Cyp2c and Cyp3a in mice, suggesting that the metabolism of substrate drugs of Cyp2c and Cyp3a may be enhanced by T cell impairment.

Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway.

BACKGROUND: Trimethylamine N-oxide (TMAO), a gut microbe-generated metabolite, elicits thrombotic events by enhancing platelet reactivity; however, no studies have reported the effects of TMAO on the metabolism of and response to clopidogrel. OBJECTIVES: To determine whether choline and TMAO could significantly impair metabolic activation of and platelet response to clopidogrel in choline- or TMAO-fed mice and the mechanisms involved. METHODS: Male mice were fed with vehicle control (Ctrl), TMAO, choline alone or in combination with 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 for 14 days and then treated with Ctrl or a single oral dose of clopidogrel. Plasma TMAO, protein levels of clopidogrel-metabolizing enzymes in the liver, plasma concentrations of clopidogrel and its metabolites, and adenosine diphosphate-induced platelet aggregation and activation were measured. In addition, HepG2 cells were treated with Ctrl or TMAO alone or in combination with N-acetyl-L-cysteine, ML385, or apocynin, and CES1, reactive oxygen species (ROS), and Nrf2 protein levels were measured, respectively. RESULTS: TMAO significantly increased Ces1 protein expression and activity and clopidogrel hydrolysis in the liver as well as intracellular ROS and CES1 levels and Nrf2 nucleus translocation in HepG2 cells but decreased the formation of clopidogrel active metabolite and impaired platelet response to clopidogrel. Furthermore, concomitant use of 3,3-dimethyl-1-butanol, N-acetyl-L-cysteine, or ML385 effectively reversed choline- or TMAO-induced impairment of inhibition of platelet aggregation by clopidogrel in mice, respectively. CONCLUSIONS: Choline and TMAO impair the metabolic activation of and platelet response to clopidogrel through the activation of the NOX-dependent ROS/Nrf2/CES1 pathway, suggesting novel strategies for overcoming clopidogrel resistance from bench to bedside.

The value of contrast-enhanced ultrasound in the diagnosis of BI-RADS-US 4a lesions less than 2 cm in diameter.

BACKGROUND: Breast cancer is the most common malignant tumor in women. Early diagnosis of benign and malignant breast tumors is of great significance. OBJECTIVE: To retrospectively analyze the value of contrast-enhanced ultrasonography (CEUS) in the diagnosis of Breast Imaging-Reporting and Data System (BI-RADS) 4a breast lesions less than 2 cm in diameter. METHODS: CEUS was performed for 143 breast masses less than 2 cm in diameter that were diagnosed as BI-RADS 4a by ultrasound and reclassified. Considering pathological diagnosis as the gold standard, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of reclassified lesions after CEUS for the diagnosis of benign and malignant masses were analyzed. RESULTS: BI-RADS 4a breast masses with a diameter less than 2 cm (n = 143) were confirmed by pathology; 103 and 40 were classified as benign and malignant, respectively. The sensitivity, specificity, PPV, and NPV of CEUS for the diagnosis were 90%, 86%, 72%, and 95%, respectively. The area under the receiver operating characteristic (ROC) curve of CEUS for the diagnosis of benign and malignant tumors after CEUS was 0.904. CONCLUSION: CEUS can help to improve the diagnostic accuracy of BI-RADS 4a masses with a diameter less than 2 cm.