Application of Online-Offline Teaching Combined with SimMan 3G Simulation Teaching Model in Critical Illness Teaching in a Department of Cardiology.

Objective: To explore the effectiveness of online-offline teaching combined with SimMan 3G simulation teaching in improving theoretical knowledge and practical skills for critical illnesses in cardiology among undergraduate students. Methods: This randomized controlled trial compared traditional bedside teaching (control group, n=120) with an innovative approach combining online education and SimMan 3G simulation teaching (experimental group, n=120) among 240 undergraduate clinical medicine students. The control group received traditional bedside teaching, while the experimental Group received a combination of online teaching plus a SimMan 3G simulation teaching. Subsequently, the theoretical and clinical practice scores and the students' satisfaction scores about the teaching methods and teaching effects were collected and analyzed. Results: The experimental group demonstrated a statistically significant improvement in both theoretical (89.42±11.28 vs. 76.49±17.42) and clinical practice scores (18.04±4.32 vs. 15.33±3.94) compared to the control group, alongside a higher satisfaction score. Conclusions: The integration of online-offline teaching with SimMan 3G simulation teaching offers a promising model for enhancing cardiology education, suggesting a valuable direction for curriculum development in medical training programs.

FIBP interacts with transcription factor STAT3 to induce EME1 expression and drive radioresistance in lung adenocarcinoma.

Cancer cells inevitably develop radioresistance during lung adenocarcinoma radiotherapy. However, the mechanisms are incompletely clarified. In this study, we show that FIBP protein expression in lung adenocarcinoma tissues is upregulated and associated with worse overall survival. Functionally, we find that depletion of FIBP inhibits lung adenocarcinoma progression and radioresistance in vitro and in vivo. Moreover, we uncover that FIBP interacts with STAT3 to enhance its transcriptional activity, thereby inducing the expression of the downstream target gene EME1. Importantly, we demonstrate that the biological effects of FIBP are partially dependent on EME1 in lung adenocarcinoma. Our work reveals that FIBP modulates the STAT3/EME1 axis to drive lung cancer progression and radioresistance, indicating that targeting FIBP may be a novel intervention strategy for lung adenocarcinoma radiotherapy.

Effect of Stereotactic Body Radiation Therapy on Diverse Organ Lesions in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

OBJECTIVE: The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. METHODS: The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. RESULTS: A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. CONCLUSION: The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.

PD-1+ mast cell enhanced by PD-1 blocking therapy associated with resistance to immunotherapy.

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear. METHODS: Bioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo. RESULTS: Bioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels. CONCLUSION: PD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.

Neutrophil-to-platelet ratio predicts mortality following percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction.

This study aimed to evaluate the value of neutrophil-to-platelet ratio (NPR) in predicting all-cause mortality in patients with ST-elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PCI). We enrolled 186 patients with STEMI who underwent primary PCI in the Third Affiliated Hospital of Guangzhou Medical University between January 2017 and December 2018. Based on the NPR values, the patients were divided into two groups: the NPR >0.035 group (n = 82) and the NPR ≤0.035 group (n = 104). All-cause mortality of the patients was followed up for 3 years. By the end of 3 years, 109 (58.6%) patients survived, 53 (28.5%) died, and 24 (12.9%) were lost to follow-up. Univariate analyses found that NPR was associated with all-cause mortality (p < 0.05). In COX regression analyses, patients in the high NPR group had a higher risk of all-cause death than those in the low NPR group (HR = 2.296, 95% CI: 1.150-4.582). These results indicate that NPR could predict all-cause death in 3 years after primary PCI in patients STEMI. NPR values may be useful in risk stratification and in specifying individualized treatment in patients with STEMI. In addition, NPR is a low-cost and easily accessible indicator, if its strong predictive value is confirmed in further studies of other large populations, it can be introduced into clinical practice for effective application.

Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer.

Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver cancer progression and fills the research gap in non-histone protein crotonylation function.

Targeting ADRB2 enhances sensitivity of non-small cell lung cancer to VEGFR2 tyrosine kinase inhibitors.

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical progress in the treatment of non-small-cell lung cancer; however, resistance has limited their therapeutic efficacy. Therefore, understanding the mechanisms of VEGF-TKI and ICI resistance will help to develop effective treatment strategies for patients with advanced NSCLC. Our results suggested that treatment with VEGFR2-TKIs upregulated ADRB2 expression in NSCLC cells. Propranolol, a common ADRB2 antagonist, significantly enhanced the therapeutic effect of VEGFR2-TKIs by inhibiting the ADRB2 signaling pathway in NSCLC cells in vitro and in vivo. Mechanically, the treatment-induced ADRB2 upregulation and the enhancement of ADRB2/VEGFR2 interaction caused resistance to VEGFR2-TKIs in NSCLC. And the inhibition of the ADRB2/CREB/PSAT1 signaling pathway sensitized cells to VEGFR2-TKIs. We demonstrated that ADRB2 signaling is crucial in mediating resistance to VEGFR2-TKIs and provided a novel promising combinatory approach to enhance the antitumor effect of VEGFR2-TKIs in NSCLC combining with propranolol.

BRD4-IRF1 axis regulates chemoradiotherapy-induced PD-L1 expression and immune evasion in non-small cell lung cancer.

BACKGROUND: Chemoradiotherapy-induced PD-L1 upregulation leads to therapeutic resistance and treatment failure. The PD-1/PD-L1 blocking antibodies sensitize cancers to chemoradiotherapy by blocking extracellular PD-1 and PD-L1 binding without affecting the oncogenic function of intracellular PD-L1. Reversing the chemoradiation-induced PD-L1 expression could provide a new strategy to achieve a greater anti-tumour effect of chemoradiotherapy. Here, we aimed to identify candidate small molecular inhibitors that might boost the anti-tumour immunity of chemoradiotherapy by decreasing treatment-induced PD-L1 expression in non-small cell lung cancer (NSCLC). METHODS: A drug array was used to recognize compounds that can suppress the cisplatin-induced and radiation-induced PD-L1 expression in NSCLC via the flow cytometry-based assay. We examined whether and how targeting bromodomain containing 4 (BRD4) inhibits chemoradiation-induced PD-L1 expression and evaluated the effect of BRD4 inhibition and chemoradiation combination in vivo. RESULTS: BRD4 inhibitors JQ1 and ARV-771 were identified as the most promising drugs both in the cisplatin and radiation screening projects in two NSCLC cell lines. Targeting BRD4 was supposed to block chemoradiotherapy inducible PD-L1 expression by disrupting the recruitment of BRD4-IRF1 complex to PD-L1 promoter. A positive correlation between BRD4 and PD-L1 expression was observed in human NSCLC tissues. Moreover, BRD4 inhibition synergized with chemoradiotherapy and PD-1 blockade to show a robust anti-tumour immunity dependent on CD8+ T cell through limiting chemoradiation-induced tumour cell surface PD-L1 upregulation in vivo. Notably, the BRD4-targeted combinatory treatments did not show increased toxicities. CONCLUSION: The data showed that BRD4-targeted therapy synergized with chemoradiotherapy and anti-PD-1 antibody by boosting anti-tumour immunity in NSCLC.

Identification of the Nerve-Cancer Cross-Talk-Related Prognostic Gene Model in Head and Neck Squamous Cell Carcinoma.

The incidence of head and neck squamous cell carcinoma (HNSC) is increasing year by year. The nerve is an important component of the tumor microenvironment, which has a wide range of cross-talk with tumor cells and immune cells, especially in highly innervated organs, such as head and neck cancer and pancreatic cancer. However, the role of cancer-nerve cross-talk-related genes (NCCGs) in HNSC is unclear. In our study, we constructed a prognostic model based on genes with prognostic value in NCCGs. We used Pearson's correlation to analyze the relationship between NCCGs and immune infiltration, microsatellite instability, tumor mutation burden, drug sensitivity, and clinical stage. We used single-cell sequencing data to analyze the expression of genes associated with stage in different cells and explored the possible pathways affected by these genes via gene set enrichment analysis. In the TCGA-HNSC cohort, a total of 23 genes were up- or downregulated compared with normal tissues. GO and KEGG pathway analysis suggested that NCCGs are mainly concentrated in membrane potential regulation, chemical synapse, axon formation, and neuroreceptor-ligand interaction. Ten genes were identified as prognosis genes by Kaplan-Meier plotter and used as candidate genes for LASSO regression. We constructed a seven-gene prognostic model (NTRK1, L1CAM, GRIN3A, CHRNA5, CHRNA6, CHRNB4, CHRND). The model could effectively predict the 1-, 3-, and 5-year survival rates in the TCGA-HNSC cohort, and the effectiveness of the model was verified by external test data. The genes included in the model were significantly correlated with immune infiltration, microsatellite instability, tumor mutation burden, drug sensitivity, and clinical stage. Single-cell sequencing data of HNSC showed that CHRNB4 was mainly expressed in tumor cells, and multiple metabolic pathways were enriched in high CHRNB4 expression tumor cells. In summary, we used comprehensive bioinformatics analysis to construct a prognostic gene model and revealed the potential of NCCGs as therapeutic targets and prognostic biomarkers in HNSC.

The construction of multifunctional nanoparticles system for dual-modal imaging and arteriosclerosis targeted therapy.

Atherosclerosis is a major risk factor for the development of cardiovascular disease. Unfortunately, due to relatively low sensitivities and poor resolution, the results of surgical resection are often largely unsatisfactory. Moreover, many chemotherapeutic agents, such as curcumin (Cur), are restricted by the low blood-brain barrier (BBB) permeability. Recently, nanotechnology proposes new opportunities to overcome these treatment barriers. In this study, superparamagnetic iron oxide nanoparticles (SPIO) was prepared by the high-temperature solid-state method, and then loaded into amphiphilic polymer DSPE-PEG to form SDP nanoparticles by hydrogen bonding in oil phase. The curcumin was encapsulated in SDP nanoparticles by self-assembly. Finally, vascular cell adhesion molecule-1 (VCAM-1) and Cy5.5 were conjugated on into SDP/Cur nanoparticles by amidation reaction. The average particle size of the prepared multifunctional SDP-VCAM-1/Cur/Cy5.5 nanoparticles is 124.4 nm, which can provide the sustained release of Cur. Moreover, the nanoparticles are proved to have superparamagnetic properties and fluorescence properties. In vitro cell experiments show that nanoparticles have excellent biocompatibility, blood compatibility and macrophage targeting. These results show that SDP-VCAM-1/Cur/Cy5.5 nanoparticles can be used not only as dual imaging probe for magnetic resonance (MR) and fluorescence imaging, but also as carriers to deliver chemotherapeutic drugs to inflammatory tissue, thus providing a promising opportunity for the treatment, molecular imaging and targeted therapy in atherosclerosis due to their established specificity and safety.

The Mitochondrial tRNAAla T5655C Mutation May Modulate the Phenotypic Expression of tRNAMet and tRNAGln A4401G Mutation in a Han Chinese Family With Essential Hypertension.

Mutations in mitochondrial DNA are associated with the pathogenesis of essential hypertension. We report here the clinical, genetic, and molecular characterization of a three-generation Han Chinese family with essential hypertension. Most strikingly, this family exhibited a high penetrance of essential hypertension. Sequence analysis of the mitochondrial genome showed the presence of a homoplasmic T5655C mutation in tRNAAla, together with the A4401G mutation in the adjacent region between tRNAMet and tRNAGln. Notably, the T5655C mutation was localized at the acceptor arm of tRNAAla, disrupted the high conserved base-pairing (1A-72T), and may impair the tRNA function. Moreover, the A4401G mutation was reported to decrease the steady-state level of tRNAMet and tRNAGln, and consequently caused the mitochondrial dysfunction responsible for hypertension. Taken together, the combination of T5655C and A4401G mutations in mitochondrial tRNA genes may account for the high penetrance and expressivity of hypertension in this Chinese family. Thus, our findings may provide new insight into the pathogenesis of this disorder.

Determination of arecoline in areca nut based on field amplification in capillary electrophoresis coupled with electrochemiluminescence detection.

A sensitive capillary electrophoresis-electrochemiluminescence (CE-ECL) assay with an ionic liquid (IL) was developed for the determination of arecoline in areca nut. The IL, 1-butyl-3-methylimidazolium tetrafluoroborate (BMImBF(4) ), was an effective additive improved not only the separation selectivity but also the detection sensitivity of the analyte. BMImBF(4) in the separation electrolyte made the resistance of the separation buffer much lower than that of the sample solution, which resulted in an enhanced field amplified electrokinetic injection CE. ECL intensity of arecoline is about two times higher than that of the analyte with phosphate-IL buffer system. Resolution between arecoline and other unknown compounds in real samples was improved. Under the optimized conditions (ECL detection at 1.2 V, 16 kV separation voltage, 20 mmol/L phosphate with 10 mmol/L BMImBF(4) buffer at pH 7.50, 5 mmol/L Ru(bpy)(3)(2+) and 50 mmol/L phosphate buffer in the detection reservoir), a detection limit of 5 × 10(-9) mol/L for arecoline was obtained. Relative standard deviations of the ECL intensity and the migration time were 4.51% and 0.72% for arecoline. This method was successfully applied to determination of the amount of arecoline in areca nut within 450 s.

[The relationship between the level of circulating endothelial progenitor cells CD34+; and carotid artery arteriosclerosis in youth and middle aged patients with essential hypertension].

OBJECTIVE: To explore the relationship between the level of circulating endothelial progenitor cells (EPCs) CD34+ with the Framingham cardiovascular risk factors, or with the carotid artery intima-media thickness (IMT), and to evaluate the value of circulating EPCs CD34+ level as a cytological marker of early vascular lesion in youth and middle aged essential hypertension (EH) patients. METHODS: A total of 62 patients with EH aged between 25 to 45 were enrolled as study group and 20 healthy people were enrolled as control group. EH patients were stratified with cardiovascular risk factors according to Framingham risk factors score into low-risk group with 18 cases, mid-risk group with 14 cases, high-risk group with 17 cases, and extremely high-risk group with 13 cases. The level of circulating EPCs CD34+, carotid artery IMT were respectively measured. The relationship between the level of circulating EPCs CD34+ and Framingham cardiovascular risk factors score, carotid artery IMT was analyzed. RESULTS: The level of circulating EPCs CD34+ was gradually decreased with an increase of the Framingham risk factors score in each hypertensive subgroup [low-risk group: (0.12+/-0.02)%, mid-risk group: (0.07+/-0.03)%, high-risk group: (0.04+/-0.03)%, extremely high-risk group: (0.01+/-0.01)%], and they were significantly lower than that in control group [(0.15+/-0.03)%], and there was a significant difference among hypertensive subgroups (P<0.05 or P<0.01). Carotid artery IMT was significantly thicker among hypertensive subgroups [low- risk group: (0.80+/-0.07) mm, mid-risk group: (1.11+/-0.08) mm, high-risk group: (1.26+/-0.10) mm, extremely high-risk group: (1.45+/-0.09) mm], and there was a significant difference between each hypertensive group and that of control group [(0.73+/-0.08) mm, all P<0.01]. There was also statistical significance among hypertensive subgroups (P<0.05 or P<0.01). There was a negative correlation between the level of circulating EPCs CD34+ and Framingham risk factors score (r=-0.875, P<0.01), and also a negative correlation with carotid artery IMT (r=-0.852, P<0.01). CONCLUSION: There was a significant correlation between the level of circulating EPCs CD34+ with Framingham risk factors score and also carotid artery IMT in EH patients. Circulating EPCs CD34+ could be a cytological marker of early vascular lesion in hypertension patients.

[Evolution of fibrinolysis status with D-dimer level and the rate of plasminogen activator inhibitor type-1/D-dimer in acute coronary syndrome patients complicated with impaired glucose tolerance].

OBJECTIVE: To study the status of fibrinolytic inhibition in patients with acute coronary syndrome (ACS) complicated with impaired glucose tolerance (IGT) and to evaluate the effect of fibrinolytic inhibition on treatment and prognosis. METHODS: The subjects were divided into three groups included 39 patients with ACS without diabetes mellitus, 37 patients with IGT+ACS and 36 patients with ACS+noninsulin-dependent diabetes mellitus (NIDDM). Twenty healthy people were randomized to be control group. The plasma levels of tissue type plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1) and plasma D-dimer were detected by enzyme linked immunoadsorbent assay (ELISA) technique. The index of status of fibrinolysis was detected with the plasma levels of PAI-1, D-dimer and the ratio of PAI-1/D-dimer. This index was used to evaluate the status of fibrinolytic inhibition and the clinical out come in patients with AMI. RESULTS: Plasma level of PAI-1 was significantly higher in IGT+ACS patients and NIDDM +ACS patients than that in ACS(P<0.05), but the plasma level of D-dimer raised from basic level was significantly lower in IGT+ ACS patients and NIDDM+ACS patients than that in ACS (P<0.05). The ratio of PAI-1/D-dimer was significantly higher in IGT+ACS patients and NIDDM +ACS patients than that in ACS or in control group (P<0.01). For AMI patients in treatment groups, the rate of reperfusion after the thrombolytic was significantly lower and the rate of incidences in pump failure was significantly higher in IGT+ACS patients and NIDDM+ACS patients than that in ACS, too (P<0.01 and P<0.05). The incidences of serious arrhythmia, re-infarction and death were also higher in IGT+ACS patients and NIDDM +ACS patients. CONCLUSION: The fibrinolytic inhibition is existed in IGT+ACS group patients. The plasma level of D-dimer combined with the ratio of PAI-1/D-dimer could be used to be the evidence and to be the index to evaluate the status of fibrinolytic inhibition and prognosis.