Efficacy and safety of sympathetic mapping and ablation of renal nerves for the treatment of hypertension (SMART): 6-month follow-up of a randomised, controlled trial.

Background: Previous trials of renal denervation (RDN) have been designed to investigate reduction of blood pressure (BP) as the primary efficacy endpoint using non-selective RDN without intraoperatively verified RDN success. It is an unmet clinical need to map renal nerves, selectively denervate renal sympathetic nerves, provide readouts for the interventionalists and avoid futile RDN. We aimed to examine the safety and efficacy of renal nerve mapping/selective renal denervation (msRDN) in patients with uncontrolled hypertension (HTN) and determine whether antihypertensive drug burden is reduced while office systolic BP (OSBP) is controlled to target level (＜140 mmHg). Methods: We conducted a randomized, prospective, multicenter, single-blinded, sham-controlled trial. The study combined two efficacy endpoints at 6 months as primary outcomes: The control rate of patients with OSBP ＜140 mmHg (non-inferior outcome) and change in the composite index of antihypertensive drugs (Drug Index) in the treatment versus Sham group (superior outcome). This design avoids confounding from excess drug-taking in the Sham group. Antihypertensive drug burden was assessed by a composite index constructed as: Class N (number of classes of antihypertensive drugs) × (sum of doses). 15 hospitals in China participated in the study and 220 patients were enrolled in a 1:1 ratio (msRDN vs Sham). The key inclusion criteria included: age (18-65 years old), history of essential HTN (at least 6 months), heart rate (≥70 bpm), OSBP (≥150 mmHg and ≤180 mmHg), ambulatory BP monitoring (ABPM, 24-h SBP ≥130 mmHg or daytime SBP ≥135 mmHg or nighttime SBP ≥120 mmHg), renal artery stenosis (＜50%) and renal function (eGFR ＞45 mL/min/1.73 m2). The catheter with both stimulation and ablation functions was inserted in the distal renal main artery. The RDN site (hot spot) was selected if SBP increased (≥5 mmHg) by intra-renal artery (RA) electrical stimulation; an adequate RDN was confirmed by repeated electronic stimulation if no increase in BP otherwise, a 2nd ablation was performed at the same site. At sites where there was decreased SBP (≥5 mmHg, cold spot) or no BP response (neutral spot) to stimulation, no ablation was performed. The mapping, ablation and confirmation procedure was repeated until the entire renal main artery had been tested then either treated or avoided. After msRDN, patients had to follow a predefined, vigorous drug titration regimen in order to achieve target OSBP (＜140 mmHg). Drug adherence was monitored by liquid chromatography-tandem mass spectrometry analysis using urine. This study is registered with ClinicalTrials.gov (NCT02761811) and 5-year follow-up is ongoing. Findings: Between July 8, 2016 and February 23, 2022, 611 patients were consented, 220 patients were enrolled in the study who received standardized antihypertensive drug treatments (at least two drugs) for at least 28 days, presented OSBP ≥150 mmHg and ≤180 mmHg and met all inclusion and exclusion criteria. In left RA and right RA, mapped sites were 8.2 (3.0) and 8.0 (2.7), hot/ablated sites were 3.7 (1.4) and 4.0 (1.6), cold spots were 2.4 (2.6) and 2.0 (2.2), neutral spots were 2.0 (2.1) and 2.0 (2.1), respectively. Hot, cold and neutral spots was 48.0%, 27.5% and 24.4% of total mapped sites, respectively. At 6 M, the Control Rate of OSBP was comparable between msRDN and Sham group (95.4% vs 92.8%, p = 0.429), achieved non-inferiority margin -10% (2.69%; 95% CI -4.11%, 9.83%, p ＜ 0.001 for non-inferiority); the change in Drug Index was significantly lower in msRDN group compared to Sham group (4.37 (6.65) vs 7.61 (10.31), p = 0.010) and superior to Sham group (-3.25; 95% CI -5.56, -0.94, p = 0.003), indicating msRDN patients need significantly fewer drugs to control OSBP ＜140 mmHg. 24-hour ambulatory SBP decreased from 146.8 (13.9) mmHg by 10.8 (14.1) mmHg, and from 149.8 (12.8) mmHg by 10.0 (14.0) mmHg in msRDN and Sham groups, respectively (p < 0.001 from Baseline; p > 0.05 between groups). Safety profiles were comparable between msRDN and Sham groups, demonstrating the safety and efficacy of renal mapping/selective RDN to treat uncontrolled HTN. Interpretation: The msRDN therapy achieved the goals of reducing the drug burden of HTN patients and controlling OSBP <140 mmHg, with only approximately four targeted ablations per renal main artery, much lower than in previous trials. Funding: SyMap Medical (Suzhou), LTD, Suzhou, China.

14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel NaV1.5.

BACKGROUND: Cardiac voltage-gated sodium channel alpha subunit 5 (NaV1.5) encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying NaV1.5 expression remains to be fully elucidated. Previous studies have reported that the 14-3-3 family acts as an adaptor involved in regulating kinetic characteristics of cardiac ion channels. OBJECTIVE: The purpose of this study was to establish 14-3-3ε/YWHAE, a member of the 14-3-3 family, as a crucial regulator of NaV1.5 and to explore the potential role of 14-3-3ε in the heart. METHODS: Western blotting, patch clamping, real-time reverse transcription-polymerase chain reaction, RNA immunoprecipitation, electrocardiogram recording, echocardiography, and histologic analysis were performed. RESULTS: YWHAE overexpression significantly reduced the expression level of SCN5A mRNA and sodium current density, whereas YWHAE knockdown significantly increased SCN5A mRNA expression and sodium current density in HEK293/NaV1.5 and H9c2 cells. Similar results were observed in mice injected with adeno-associated virus serotype 9-mediated YWHAE knockdown. The effect of 14-3-3ε on NaV1.5 expression was abrogated by knockdown of TBX5, a transcription factor of NaV1.5. An interaction between 14-3-3ε protein and TBX5 mRNA was identified, and YWHAE overexpression significantly decreased TBX5 mRNA stability without affecting SCN5A mRNA stability. In addition, mice subjected to adeno-associated virus serotype 9-mediated YWHAE knockdown exhibited shorter R-R intervals and higher prevalence of premature ventricular contractions. CONCLUSION: Our data unveil a novel regulatory mechanism of NaV1.5 by 14-3-3ε and highlight the significance of 14-3-3ε in transcriptional regulation of NaV1.5 expression and cardiac arrhythmias.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Interleukin-6 classic and trans-signaling utilize glucose metabolism reprogramming to achieve anti- or pro-inflammatory effects.

Interleukin (IL)-6 has anti- and pro-inflammatory functions, controlled by IL-6 classic and trans-signaling, respectively. Differences in the downstream signaling mechanism between IL-6 classic and trans-signaling have not been identified. Here, we report that IL-6 activates glycolysis to regulate the inflammatory response. IL-6 regulates glucose metabolism by forming a complex containing signal-transducing activators of transcription 3 (STAT3), hexokinase 2 (HK2), and voltage-dependent anion channel 1 (VDAC1). The IL-6 classic signaling directs glucose flux to oxidative phosphorylation (OxPhos), while IL-6 trans-signaling directs glucose flux to anaerobic glycolysis. Classic IL-6 signaling promotes STAT3 translocation into mitochondria to interact with pyruvate dehydrogenase kinase-1 (PDK1), leading to pyruvate dehydrogenase α (PDHA) dissociation from PDK1. As a result, PDHA is dephosphorylated, and STAT3 is phosphorylated at Ser727. By contrast, IL-6 trans-signaling promotes the interaction of sirtuin 2 (SIRT2) and lactate dehydrogenase A (LDHA), leading to the dissociation of STAT3 from SIRT2. As a result, LDHA is deacetylated, and STAT3 is acetylated and phosphorylated at Tyr705. IL-6 classic signaling promotes the differentiation of regulatory T cells via the PDK1/STAT3/PDHA axis, whereas IL-6 trans-signaling promotes the differentiation of Th17 cells via the SIRT2/STAT3/LDHA axis. Conclusion: IL-6 classic signaling generates anti-inflammatory functions by shifting energy metabolism to OxPhos, while IL-6 trans-signaling generates pro-inflammatory functions by shifting energy metabolism to anaerobic glycolysis.

Safety profile of intravenous digoxin in Chinese patients with acute heart failure with reduced ejection fraction: a small-scale prospective cohort study.

Background: Adverse effects of intravenous digoxin vary from patients and disease status, which should be closely monitored. Aims: To explore the safety profile of intravenous digoxin in acute heart failure with reduced ejection fraction (HFrEF) among Chinese patients. Methods: A clinical prospective, single-center, single-arm, open-label exploratory clinical trial was performed in patients with acute HFrEF at Wuhan Asia Heart Hospital. A fixed dose of 0.5 mg digoxin was used intravenously once per day for 3 days. The normalized dosage of digoxin (NDD), toxic serum digoxin concentration (SDC), and adverse reactions of intravenous digoxin were recorded. Results: A total of 40 patients were recruited in the study. The SDC increased from 1.03 ± 0.34 ng/mL to 1.95 ± 0.52 ng/mL during treatment. 50% (20/40) patients reached a toxic SDC of 2.0 ng/mL, and toxic effects were seen in 30% (12/40) patients. Estimated glomerular filtration rate (eGFR) < 60 mL/min [HR: 5.269; 95% CI: 1.905-14.575, p = 0.001], NDD ≥7 µg/kg [HR: 3.028; 95% CI: 1.119-8.194, p = 0.029], and ischemic cardiomyopathy [HR: 2.658; 95% CI: 1.025-6.894, p = 0.044] were independent risk factors for toxic SDC. Toxic SDC was effectively identified [area under the receiver operating characteristic (ROC) curve = 0.85, p < 0.001] using this model, and patients would have a higher risk of toxicity with more risk factors. Conclusion: Intravenous digoxin of 0.5 mg was safe and effective for initial dose but not suitable for maintenance treatment in Chinese patients with acute HFrEF. Patients who had lower eGFR, received higher NDD, and had ischemic cardiomyopathy should be closely monitored to avoid digoxin toxicity.

Leucine zipper protein 1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling.

INTRODUCTION: Cardiac hypertrophy is an important contributor of heart failure, and the mechanisms remain unclear. Leucine zipper protein 1 (LUZP1) is essential for the development and function of cardiovascular system; however, its role in cardiac hypertrophy is elusive. OBJECTIVES: This study aims to investigate the molecular basis of LUZP1 in cardiac hypertrophy and to provide a rational therapeutic approach. METHODS: Cardiac-specific Luzp1 knockout (cKO) and transgenic mice were established, and transverse aortic constriction (TAC) was used to induce pressure overload-induced cardiac hypertrophy. The possible molecular basis of LUZP1 in regulating cardiac hypertrophy was determined by transcriptome analysis. Neonatal rat cardiomyocytes were cultured to elucidate the role and mechanism of LUZP1 in vitro. RESULTS: LUZP1 expression was progressively increased in hypertrophic hearts after TAC surgery. Gain- and loss-of-function methods revealed that cardiac-specific LUZP1 deficiency aggravated, while cardiac-specific LUZP1 overexpression attenuated pressure overload-elicited hypertrophic growth and cardiac dysfunction in vivo and in vitro. Mechanistically, the transcriptome data identified Stat3 pathway as a key downstream target of LUZP1 in regulating pathological cardiac hypertrophy. Cardiac-specific Stat3 deletion abolished the pro-hypertrophic role in LUZP1 cKO mice after TAC surgery. Further findings suggested that LUZP1 elevated the expression of Src homology region 2 domain-containing phosphatase 1 (SHP1) to inactivate Stat3 pathway, and SHP1 silence blocked the anti-hypertrophic effects of LUZP1 in vivo and in vitro. CONCLUSION: We demonstrate that LUZP1 attenuates pressure overload-induced cardiac hypertrophy through inhibiting Stat3 signaling, and targeting LUZP1 may develop novel approaches to treat pathological cardiac hypertrophy.

Sintilimab-Induced Myocarditis in a Patient with Gastric Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

Nek6 knockdown polarized macrophages into a pro-inflammatory phenotype via inhibiting STAT3 expression.

Recently macrophage polarization has emerged as playing an essential role in the oathogenesis of atherosclerosis, which is the most important underlying process in many types of cardiovascular diseases. Although Nek6 has been reported to be involved in various cellular processes, the effect of Nek6 on macrophage polarization remains unknown. Macrophages exposed to lipopolysaccharide (LPS) or IL-4 were used to establish an in vitro model for the study of regulation of classically (M1) or alternatively (M2) activated macrophage. Bone marrow-derived macrophages (BMDMs) transfected with short hairpin RNA-targeting Nek6 were then in functional studies. We observed that Nek6 expression was decreased in both peritoneal macrophages (PMs) and BMDMs stimulated by LPS. This effect was seen at both mRNA and protein level. The opposite results were obtained after administration of IL-4. Macrophage-specific Nek6 knockdown significantly exacerbated pro-inflammatory M1 polarized macrophage gene expression in response to LPS challenge, but the anti-inflammatory response gene expression that is related to M2 macrophages was attenuated by Nek6 silencing followed by treatment with IL-4. Mechanistic studies exhibited that Nek6 knockdown inhibited the phosphorylated STAT3 expression that mediated the effect on macrophage polarization regulated by AdshNek6. Moreover, decreased Nek6 expression was also observed in atherosclerotic plaques. Collectively, these evidences suggested that Nek6 acts as a crucial site in macrophage polarization, and that this operates in a STAT3-dependent manner.

Angiography-based index of microcirculatory resistance (AccuIMR) for the assessment of microvascular dysfunction in acute coronary syndrome and chronic coronary syndrome.

Background: To assess the diagnostic accuracy of AccuIMR, a newly proposed, pressure wire-free index, in identifying coronary microvascular dysfunction (CMD) among patients with acute coronary syndrome [including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI)] and chronic coronary syndrome (CCS). Methods: A total of 163 consecutive patients (43 with STEMI, 59 with NSTEMI, and 61 with CCS), who underwent invasive coronary angiography (ICA) and for whom the index of microcirculatory resistance (IMR) was measured, were retrospectively enrolled at a single center. IMR measurements were made in 232 vessels. The AccuIMR based on computational fluid dynamics (CFD) was calculated from coronary angiography. The diagnostic performance of AccuIMR was assessed using wire-based IMR as a reference standard. Results: AccuIMR correlated well with IMR (overall r=0.76, P<0.001; STEMI r=0.78, P<0.001; NSTEMI r=0.78, P<0.001; CCS r=0.75, P<0.001) and had good diagnostic performance in detecting abnormal IMR [overall diagnostic accuracy, sensitivity, and specificity were 94.83% (91.14% to 97.30%), 92.11% (78.62% to 98.34%), and 95.36% (91.38% to 97.86%), respectively]. Using a cutoff value of IMR >40 U for AccuIMR in STEMI and IMR >25 U in NSTEMI and CCS, the area under the receiver operating characteristic (ROC) curve (AUC) of AccuIMR for predicting abnormal IMR value was 0.917 (0.874 to 0.949) in all patients, 1.000 (0.937 to 1.000) in patients with STEMI, 0.941 (0.867 to 0.980) in patients with NSTEMI, and 0.918 (0.841 to 0.966) in patients with CCS. Conclusions: The use of AccuIMR in the evaluation of microvascular diseases could provide valuable information and potentially increase the application of physiological assessment for microcirculation in patients with ischemic heart disease.

Major vault protein regulates tumor-associated macrophage polarization through interaction with signal transducer and activator of transcription 6.

Tumor-associated macrophages (TAMs) are critical in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Major vault protein (MVP) mediates multidrug resistance, cell growth and development, and viral immunity. However, the relationship between MVP and TAMs polarization has not been clarified in HCC. We found that MVP significantly increased M2-TAMs infiltration levels in tumor tissues of HCC patients. MVP promoted HCC proliferation, metastasis, and invasion by regulating M2 polarization in vivo and in vitro. Mechanistically, MVP associated with signal transducer and activator of transcription 6 (STAT6) and enhanced STAT6 phosphorylation. STAT6 translocated from the cytosol to the nucleus and regulated M2 macrophage-associated gene transcription. These findings suggest that MVP modulates the macrophage M2 transcriptional program, revealing its potential role in the TAMs of TME.

In Vivo Validation of a Novel Computational Approach to Assess Microcirculatory Resistance Based on a Single Angiographic View.

(1) Background: In spite of the undeniable clinical value of the index of microvascular resistance (IMR) in assessing the status of coronary microcirculation, its use globally remains very low. The aim of this study was to validate the novel single-view, pressure-wire- and adenosine-free angiographic microvascular resistance (AMR) index, having the invasive wire-based IMR as a reference standard. (2) Methods: one hundred and sixty-three patients (257 vessels) were investigated with pressure wire-based IMR. Microvascular dysfunction (CMD) was defined by IMR ≥ 25. AMR was independently computed from the diagnostic coronary angiography in a blinded fashion. (3) Results: AMR demonstrated a good correlation (r = 0.83, p < 0.001) and diagnostic performance (AUC 0.94; 95% CI: 0.91 to 0.97) compared with wire-based IMR. The best cutoff value for AMR in determining IMR ≥ 25 was 2.5 mmHg*s/cm. The overall diagnostic accuracy of AMR was 87.2% (95% CI: 83.0% to 91.3%), with a sensitivity of 93.5% (95% CI: 87.0% to 97.3%), a specificity of 82.7% (95% CI: 75.6% to 88.4%), a positive predictive value of 79.4% (95% CI: 71.2% to 86.1%) and a negative predictive value of 94.7% (95% CI: 89.3% to 97.8%). No difference in terms of CMD rate was described among different clinical presentations. (4) Conclusions: AMR derived solely from a single angiographic view is a feasible computational alternative to pressure wire-based IMR, with good diagnostic accuracy in assessing CMD.

Nimotuzumab plus induction chemotherapy followed by radiotherapy/concurrent chemoradiotherapy plus nimotuzumab for locally advanced nasopharyngeal carcinoma: protocol of a multicentre, open-label, single-arm, prospective phase II trial.

Epidermal growth factor receptor (EGFR) is a therapeutic target in nasopharyngeal carcinoma (NPC). The optimal combined modality of optimal combined modality of anti--EGFR monoclonal antibodies, induction chemotherapy (ICT), concurrent chemotherapy and radiotherapy for NPC remains poorly defined. None of previous studies have developed subsequent treatment strategies on the basis of stratification according to the efficacy following ICT plus anti-EGFR mAbs. This study aims to increase treatment intensity for patients with poor efficacy of ICT and reduce treatment toxicity for patients with favourable efficacy of ICT by assessing whether the efficacy of this treatment regimen is non-inferior to ICT plus concurrent chemoradiotherapy (historic controls). INTRODUCTION: METHODS AND ANALYSIS: Pathology-confirmed WHO type II/III NPC patients at clinical stage III-IVA (eighth American Joint Committee on Cancer/Union for International Cancer Control staging system) will be included in the study. They will receive ICT plus nimotuzumab (NTZ), followed by radiotherapy plus NTZ or concurrent chemoradiotherapy plus NTZ (stratified based on the efficacy of ICT plus NTZ). The primary endpoint is 3-year failure-free survival rate; while the secondary endpoints are 3-year overall survival rate, distant metastasis-free survival rate and locoregional recurrence-free survival rate, and short-term remission rate of tumour and treatment toxicity. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University. Our findings will be disseminated in a peer-reviewed journal. Implementation strategies are in place to ensure privacy and confidentiality of participants. TRIAL REGISTRATION NUMBER: ChiCTR2000041139.

Classification and quantification of double superior vena cava evaluated by computed tomography imaging.

BACKGROUND: A double superior vena cava (DSVC) may cause technical difficulties in some cardiovascular procedures. However, no quantitative data exist to describe the morphological features of this anomaly. METHODS: From January 2015 to January 2019, the data of 128 consecutive patients diagnosed with DSVC on computed tomography (CT) images were retrospectively analyzed. We proposed an easy and rational method for DSVC classification based on the presence or absence of the left brachiocephalic vein (LBCV), the presence or absence of an anastomotic vein bridging the bilateral superior vena cava (SVC), and the drainage pattern of the left superior vena cava (LSVC). The following classifications were established: type I, LBVC absent, LSVC drainage into the right atrium via the coronary sinus; type II, LBCV present, LSVC drainage into the right atrium via the coronary sinus; type III, LBCV absent, LSVC drainage into the right atrium via the anastomosis; type IV, LBCV present, LSVC drainage into the right atrium via the anastomosis. The length, diameter, and area of the bilateral SVC and the coronary sinus were carefully measured across the 4 types. RESULTS: Type I was the most frequently occurring type (66 of 128, 51.6%), followed by type II (43 of 128, 33.6%), then type III (15 of 128, 11.7%), and type IV (4 of 128, 3.1%). The LSVC was significantly longer than the right SVC (RSVC) in all 4 types, and the diameters of the LSVC were significantly larger in types without the LBCV (i.e., types I and III) (P<0.0001 for all). Additionally, the diameter of the coronary sinus in types I and II was triple that in types III and IV (P<0.0001), which was thought to be due to increased venous blood reflux through the coronary sinus. CONCLUSIONS: The anatomical features of DSVC can be satisfactorily depicted on CT. The quantitative measurement of this anomaly by the reporting radiologists could assist clinicians to minimize the procedure-associated risks.

BarH-like homeobox 2 represses the transcription of keratin 16 and affects Ras signaling pathway to suppress nasopharyngeal carcinoma progression.

Nasopharyngeal carcinoma (NPC) refers to a malignancy initiating from the superior mucosal epithelium of the nasopharynx. Optimal therapies for NPC are still needed. In this investigation, we attempted to explore whether BarH-like homeobox 2 (BARX2), a well-known tumor suppressor, had anti-cancer properties on NPC, and the possible mechanisms. After searching for NPC-related databases, we determined BARX2 as one of the core genes in NPC. The results of RT-qPCR and immunohistochemistry or Western blot demonstrated that BARX2 was reduced in NPC patients and cells. Ectopic expression of BARX2 reverted the malignant phenotype of NPC cells. Mechanistically, BARX2 bound to the keratin 16 (KRT16) promoter to downregulate its expression. In addition, BARX2 was found to reduce the phosphorylation levels of MEK and ERK. Further KRT16 upregulation in cells overexpressing BARX2 promoted malignant aggressiveness of C666-1 and HNE3 cells and activated the Ras signaling pathway. BARX2 inhibited the growth and metastasis of tumors and suppressed the Ras signaling pathway in vivo. In conclusion, our findings indicate that BARX2 reverts malignant phenotypes of NPC cells by downregulating KRT16 in a Ras-dependent fashion. BARX2 might act as a possible therapeutic regulator for NPC.

Atrioventricular accessory pathway unmasked by heart valve replacement.

A 50-year-old male patient with a history of severe valvular regurgitation underwent mitral and aortic valve replacement surgery 3 months ago. Preoperative 12-lead electrocardiogram presented atrial flutter (AFL) and atrial fibrillation. AFL complicated with ventricular pre-excitation was observed on current admission. The potential mechanisms underlying these changes were considered multifaceted, and valve replacement procedure may be a rare incentive factor.

Influence of LncRNA SDHAP1 on multiplication, migration and invasiveness of non-small cell lung carcinoma cells.

OBJECTIVE: To investigate the effects of lncRNA SDHAP1 on the multiplication, migration and invasiveness of NSCLC cells. METHODS: From The Cancer Genome Atlas (TCGA) database, the clinical data of NSCLC patients were retrieved to analyze the expression of lncRNA SDHAP1 in LC. In this study, lncRNA SDHAP1 in NSCLC cell lines was regulated, and its expression profiling in non- and cis-platinum (CDDP) resistant NSCLC cell lines was identified by qPCR. The levels of multidrug resistance-related protein 1 (MRP1), p-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) were measured by Western blotting (WB), the migration and invasion of LC cells were detected by Transwell assay, and the cell multiplication and activity were determined by MTT assays. RESULTS: TCGA database identified upregulated lncRNA SDHAP1 expression in LC. qPCR results revealed that lncRNA SDHAP1 was highly expressed in NSCLC. LncRNA SDHAP1 showed higher expression in patients with stage IV than in those with stage I, II or III, as well as in people aged 21-40 years old. Compared with normal lung epithelial cells, lncRNA SDHAP1 was upregulated in NSCLC cell lines, especially in those resistant to CDDP. LncRNA SDHAP1 downregulation led to a decrease in multiplication, migration and invasiveness of NSCLC cells, and a reduction in activity, migration and invasiveness of CDDP-resistant NSCLC cell lines. In addition, lncRNA SDHAP1 knockdown down-regulated the expression levels of Multidrug resistance-associated proteins MRP1, P-gp and GST-π. CONCLUSIONS: LncRNA SDHAP1 is upregulated in NSCLC and is associated with LC staging and age of patients. Silencing lncRNA SDHAP1 can suppress the multiplication, migration, invasiveness and CDDP resistance of cancer cells. Therefore, lncRNA SDHAP1 may serve as a prognostic biomarker and treatment target for NSCLC.

PAK1 Silencing Attenuated Proinflammatory Macrophage Activation and Foam Cell Formation by Increasing PPARγ Expression.

Macrophage polarization in response to environmental cues has emerged as an important event in the development of atherosclerosis. Compelling evidences suggest that P21-activated kinases 1 (PAK1) is involved in a wide variety of diseases. However, the potential role and mechanism of PAK1 in regulation of macrophage polarization remains to be elucidated. Here, we observed that PAK1 showed a dramatically increased expression in M1 macrophages but decreased expression in M2 macrophages by using a well-established in vitro model to study heterogeneity of macrophage polarization. Adenovirus-mediated loss-of-function approach demonstrated that PAK1 silencing induced an M2 macrophage phenotype-associated gene profiles but repressed the phenotypic markers related to M1 macrophage polarization. Additionally, dramatically decreased foam cell formation was found in PAK1 silencing-induced M2 macrophage activation which was accompanied with alternation of marker account for cholesterol efflux or influx from macrophage foam cells. Moderate results in lipid metabolism and foam cell formation were found in M1 macrophage activation mediated by AdshPAK1. Importantly, we presented mechanistic evidence that PAK1 knockdown promoted the expression of PPARγ, and the effect of macrophage activation regulated by PAK1 silencing was largely reversed when a PPARγ antagonist was utilized. Collectively, these findings reveal that PAK1 is an independent effector of macrophage polarization at least partially attributed to regulation of PPARγ expression, which suggested PAK1-PPARγ axis as a novel therapeutic strategy in atherosclerosis management.

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19).

Importance: Increasing numbers of confirmed cases and mortality rates of coronavirus disease 2019 (COVID-19) are occurring in several countries and continents. Information regarding the impact of cardiovascular complication on fatal outcome is scarce. Objective: To evaluate the association of underlying cardiovascular disease (CVD) and myocardial injury with fatal outcomes in patients with COVID-19. Design, Setting, and Participants: This retrospective single-center case series analyzed patients with COVID-19 at the Seventh Hospital of Wuhan City, China, from January 23, 2020, to February 23, 2020. Analysis began February 25, 2020. Main Outcomes and Measures: Demographic data, laboratory findings, comorbidities, and treatments were collected and analyzed in patients with and without elevation of troponin T (TnT) levels. Results: Among 187 patients with confirmed COVID-19, 144 patients (77%) were discharged and 43 patients (23%) died. The mean (SD) age was 58.50 (14.66) years. Overall, 66 (35.3%) had underlying CVD including hypertension, coronary heart disease, and cardiomyopathy, and 52 (27.8%) exhibited myocardial injury as indicated by elevated TnT levels. The mortality during hospitalization was 7.62% (8 of 105) for patients without underlying CVD and normal TnT levels, 13.33% (4 of 30) for those with underlying CVD and normal TnT levels, 37.50% (6 of 16) for those without underlying CVD but elevated TnT levels, and 69.44% (25 of 36) for those with underlying CVD and elevated TnTs. Patients with underlying CVD were more likely to exhibit elevation of TnT levels compared with the patients without CVD (36 [54.5%] vs 16 [13.2%]). Plasma TnT levels demonstrated a high and significantly positive linear correlation with plasma high-sensitivity C-reactive protein levels (ß = 0.530, P < .001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (ß = 0.613, P < .001). Plasma TnT and NT-proBNP levels during hospitalization (median [interquartile range (IQR)], 0.307 [0.094-0.600]; 1902.00 [728.35-8100.00]) and impending death (median [IQR], 0.141 [0.058-0.860]; 5375 [1179.50-25695.25]) increased significantly compared with admission values (median [IQR], 0.0355 [0.015-0.102]; 796.90 [401.93-1742.25]) in patients who died (P = .001; P < .001), while no significant dynamic changes of TnT (median [IQR], 0.010 [0.007-0.019]; 0.013 [0.007-0.022]; 0.011 [0.007-0.016]) and NT-proBNP (median [IQR], 352.20 [174.70-636.70]; 433.80 [155.80-1272.60]; 145.40 [63.4-526.50]) was observed in survivors (P = .96; P = .16). During hospitalization, patients with elevated TnT levels had more frequent malignant arrhythmias, and the use of glucocorticoid therapy (37 [71.2%] vs 69 [51.1%]) and mechanical ventilation (31 [59.6%] vs 14 [10.4%]) were higher compared with patients with normal TnT levels. The mortality rates of patients with and without use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 36.8% (7 of 19) and 21.4% (36 of 168) (P = .13). Conclusions and Relevance: Myocardial injury is significantly associated with fatal outcome of COVID-19, while the prognosis of patients with underlying CVD but without myocardial injury is relatively favorable. Myocardial injury is associated with cardiac dysfunction and arrhythmias. Inflammation may be a potential mechanism for myocardial injury. Aggressive treatment may be considered for patients at high risk of myocardial injury.