METTL3 attenuates ferroptosis sensitivity in lung cancer via modulating TFRC.

Overexpression of methyltransferase-like 3 (METTL3) is significantly correlated with the malignancy of lung cancer (LC). In the present study, we demonstrated that METTL3 had higher levels in LC tissues relative to normal tissues. METTL3 showed superior sensitivity and specificity for diagnosis and identification of LC functions. In addition, silencing METTL3 resulted in enhanced ferroptosis sensitivity, whereas overexpression of METTL3 exhibited the opposite effect. Inhibition of METTL3 impeded LC growth in cell-derived xenografts. Further exploratory studies found that METTL3 stimulated the low expression of transferrin receptor (TFRC), which was critical for ferroptosis sensitization in LC cells induced by silenced METTL3, as silencing of TFRC caused a decrease in negative regulators of ferroptosis (FTH1 and FTL) in METTL3 knockdown A549 and PC9 cells. Finally, we confirmed that METTL3 attenuation effectively maintained the stability of TFRC mRNA. In conclusion, we reported a novel mechanism of METTL3 desensitization to ferroptosis via regulating TFRC, and an appropriate reduction of METTL3 might sensitize cancer cells to ferroptosis-based therapy.

Comprehensive comparative analysis of the prognostic impact of systemic inflammation biomarkers for patients underwent cardiac surgery.

Background: Inflammation plays an integral role in the development of cardiovascular disease, and few studies have identified different biomarkers to predict the prognosis of cardiac surgery. But there is a lack of reliable and valid evidence to determine the optimal systemic inflammatory biomarkers to predict prognosis. Methods: From December 2015 and March 2021, we collected 10 systemic inflammation biomarkers among 820 patients who underwent cardiac surgery. Time-dependent receiver operating characteristic curves (ROC) curve at different time points and C-index was compared at different time points. Kaplan-Meier method was performed to analyze overall survival (OS). Cox proportional hazard regression analyses were used to assess independent risk factors for OS. A random internal validation was conducted to confirm the effectiveness of the biomarkers. Results: The area under the ROC of lymphocyte-to-C-reactive protein ratio (LCR) was 0.655, 0.620 and 0.613 at 1-, 2- and 3-year respectively, and C-index of LCR for OS after cardiac surgery was 0.611, suggesting that LCR may serve as a favorable indicator for predicting the prognosis of cardiac surgery. Patients with low LCR had a higher risk of postoperative complications. Besides, Cox proportional hazard regression analyses indicated that LCR was considered as an independent risk factor of OS after cardiac surgery. Conclusion: LCR shows promise as a noteworthy representative among the systemic inflammation biomarkers in predicting the prognosis of cardiac surgery. Screening for low LCR levels may help surgeons identify high-risk patients and guide perioperative management strategies.

Thoracic sarcopenia predicts clinical outcomes in patients undergoing coronary artery bypass grafting: A 6-year cohort study.

BACKGROUND: The relationship between thoracic sarcopenia and clinical outcomes in patients underwent coronary artery bypass grafting (CABG) is unclear. This study aims to evaluate whether thoracic sarcopenia has a satisfactory prognostic effect on adverse outcomes after CABG. METHODS: From December 2015 to May 2021, 338 patients who underwent isolated CABG at our institution were recruited in this study. Skeletal muscle area at T12 level acquired by chest computed tomography (CT) was normalized to assess thoracic sarcopenia. Univariate and multivariate analyses were performed to evaluate the risk factors of postoperative complications and overall survival (OS). RESULTS: The prevalence of thoracic sarcopenia in patients underwent CABG was 13.02%. The incidence of total major complication was significantly higher in thoracic sarcopenia group (81.8% vs 61.9%, p = 0.010). Thoracic sarcopenic patients also had longer postoperative hospital stays (p = 0.047), intensive care unit (ICU) stays (p = 0.001), higher costs (p = 0.001) and readmission rates within 30 days of discharge (18.2% vs 4.4%, p = 0.001). Patients without thoracic sarcopenia showed significantly higher OS at the 2-year follow-up period (93.9% vs 72.7%, p<0.001). Multivariate analyses demonstrated that thoracic sarcopenia was significantly and independently associated with postoperative complications and long-term OS after CABG. CONCLUSION: Thoracic sarcopenia is an effective clinical predictor of adverse postoperative complications and long-term OS in patients underwent CABG. Thoracic sarcopenia based on chest CT should be included in preoperative risk assessment of CABG.

Prognostic implications of Global Leadership Initiative on Malnutrition-defined malnutrition in older patients who underwent cardiac surgery in China.

BACKGROUND: The proportion of older patients who are candidates for cardiac surgery is increasing. Growing evidence has shown that malnutrition is associated with a poor prognosis after cardiac surgery. The present study aimed to investigate the prognostic implications of malnutrition defined by the Global Leadership Initiative on Malnutrition in older patients who underwent cardiac surgery. METHODS: From November 2015 to January 2021, 401 older patients who underwent cardiac surgery were retrospectively enrolled and evaluated using the Global Leadership Initiative on Malnutrition criteria. The perioperative characteristics and clinical outcomes were collected. The independent risk factors for postoperative complications and overall survival were analyzed. RESULTS: The prevalence of Global Leadership Initiative on Malnutrition-defined malnutrition was 22.7% in this study. Patients with Global Leadership Initiative on Malnutrition-defined malnutrition had higher risks of postoperative complications (65.9% vs 49.7%, P = .006) and poor overall survival (68.1% vs 83.9%, P = .0019). Global Leadership Initiative on Malnutrition-defined malnutrition was also related to a longer postoperative hospital stay and prolonged intensive care stay. Five factors were identified as independent risk factors for overall survival: Global Leadership Initiative on Malnutrition-defined malnutrition (P = .009), chronic heart failure (P = .007), atrial fibrillation (P = .029), operative time (P < .001) and hemoglobin (P = .044). CONCLUSION: We demonstrated the prognostic implications of Global Leadership Initiative on Malnutrition-defined malnutrition in older patients who underwent cardiac surgery for the first time. This study highlights the necessity of using the Global Leadership Initiative on Malnutrition assessment in the comprehensive preoperative risk assessment of cardiac surgery.

Only transesophageal echocardiography guided patent foramen ovale closure: A single-center experience.

Background: An increasing number of studies have proved that patent foramen ovale (PFO) occlusion could reduce the incidence of recurrent stroke more than drug therapy alone under certain conditions. Which is the "best" guidance technique still remains to be discussed. Methods: A single center retrospective study enrolled 120 patients (mean age 52.51 ± 14.29 years) who underwent PFO closure between April 2019 and March 2021. 87 patients (72.5%) had suffered cryptogenic stroke (CS) at least one time, and 24 patients (20%) had repetitive episodes of hemicrania unsourced. 65 patients were in the transesophageal echocardiography (TEE) guidance group (T-group), and the other 55 patients were in the angiographic guidance group (A-group). Results: There were no significant differences in crucial clinical characteristics between the two groups. In T-group, the procedural success rate was higher (100% vs. 92.7%, P = 0.028), and the procedural time was shorter (23.15 ± 13.87 vs. 25.75 ± 7.19, P = 0.001). No difference was detected in the procedural complication rate. Follow-up were performed at least 12 months. At 12 months, new atrial fibrillation occurred in 1 patient (1.5%) in the T-group and in 1 patient (1.8%) in the A-group (P = 0.905). Residual shunt occurred in 1 patient (1.5%) in the T-group and in 3 patients (5.5%) in the A-group (P = 0.236). Recurrent cerebral ischemia occurred in 2 patient (3.1%) in the T-group and in 2 patients (3.6%) in the A-group (P = 0.865). Conclusion: The use of only intra-procedural TEE guidance for PFO closure is safe and effective. The whole procedure can be performed without fluoroscopy and contrast medium. The short and medium follow-up results are satisfactory, especially in the residual shunt.

Prognostic Effect of Thoracic Sarcopaenia on Short- and Long-Term Clinical Outcomes in Patients Who Underwent Cardiac Valve Surgery.

BACKGROUND: As the proportion of elderly patients increases, higher incidence of malnutrition is found among patients with valvular heart disease. Sarcopaenia is one of the main manifestations of malnutrition. Studies have shown the certain predictive effect of sarcopaenia on the clinical outcome in different cases. This study aims to clarify the impact of computed tomography (CT)-derived thoracic sarcopaenia on clinical outcomes of patients who underwent cardiac valve surgery. METHODS: The clinical data of 216 patients who underwent cardiac valve surgery from December 2015 to June 2020 were retrospectively collected. Skeletal muscle mass at 12th thoracic vertebra level was measured to diagnose thoracic sarcopaenia. Postoperative complications and follow-up data were collected. Medium follow-up was 3.2 years. RESULTS: The prevalence of thoracic sarcopaenia was 16.7% in this study. The incidence of total complications and in-hospital mortality were higher in thoracic sarcopaenia group (p=0.024 and p=0.014, respectively). Multivariate analysis revealed that thoracic sarcopaenia is a significant predictor for postoperative complications (OR 2.319; 95% CI 1.003-5.366; p=0.049). Decreased long-term survival was observed in patients with thoracic sarcopaenia. Thoracic sarcopaenia (HR 4.178; 95% CI 2.062-8.465; p<0.001) was determined to be an independent risk factor for late mortality. CONCLUSION: Thoracic sarcopaenia defined by chest CT was independently associated with higher incidence of postoperative complications and long-term mortality. Routine preoperative evaluation of thoracic sarcopaenia deserves further consideration to enhance the predictive performance for operation risk.

Development and Validation of Global Leadership Initiative on Malnutrition for Prognostic Prediction in Patients Who Underwent Cardiac Surgery.

The Global Leadership Initiative on Malnutrition (GLIM) has achieved a consensus for the diagnosis of malnutrition in recent years. This study aims to determine the prognostic effect of the GLIM after cardiac surgery. A total of 603 patients in the training cohort and 258 patients in the validation cohort were enrolled in this study. Perioperative characteristics and follow-up data were collected. A nomogram based on independent prognostic predictors was developed for survival prediction. In total, 114 (18.9%) and 48 (18.6%) patients were defined as being malnourished according to the GLIM criteria in the two cohorts, respectively. Multivariate regression analysis showed that GLIM-defined malnutrition was an independent risk factor of total complication (OR 1.661, 95% CI: 1.063-2.594) and overall survival (HR 2.339, 95% CI: 1.504-3.637). The c-index was 0.72 (95% CI: 0.66-0.79) and AUC were 0.800, 0.798, and 0.780 for 1-, 2-, and 3-year survival prediction, respectively. The calibration curves of the nomogram fit well. In conclusion, GLIM criteria can efficiently identify malnutrition and has a prognostic effect on clinical outcomes after cardiac surgery. GLIM-based nomogram has favorable performance in survival prediction.

Single-Stage Pulmonary Resection via a Combination of Single Hookwire Localization and Video-Assisted Thoracoscopic Surgery for Synchronous Multiple Pulmonary Nodules.

Purpose: To retrospectively analyze the incidence and predictors of complications related to hookwire localization in patients with single and multiple nodules, and to evaluate the usefulness of a single-stage surgical method of single hookwire localization combined with video-assisted thoracoscopic surgery (VATS) in synchronous multiple pulmonary nodules (SMPNs). Methods: A total of 200 patients who underwent computed tomography (CT)-guided hookwire localization and subsequent VATS resection were enrolled in this study. For each patient, only 1 indeterminate nodule was implanted with a hookwire. There were 145 patients in the single-nodule group (Group S) and 55 in the multiple-nodule group (Group M). Univariate and binary logistic regression analyses were used to assess incidence and predictors of complications associated with hookwire localization. Results: The technical success rate of hookwire implantation was 97.5%. The incidence of pneumothorax and hookwire dislodgement was 17.0% and 2.5%, respectively. Binary logistic regression analysis showed that 1 transpleural puncture through the pleura (odds ratio [OR] = 0.433, P = .033) was the only independent protective factor for pneumothorax, and pneumothorax (OR = 26.114, P < .01) was the only independent risk factor for dislodgement. The volume of blood loss during VATS was significantly higher in group M than in group S, and the time of postoperative hospitalization was significantly longer in group M than in group S. About 44 patients in group M with additional 58 nodules without localization had undergone direct surgical resection simultaneously, and bilateral surgery was performed in 13 patients (29.5%). The intrathoracic recurrence rate was 4.8% during follow-up CT. Conclusion: Single-stage surgery via an approach of single hookwire localization combined with VATS is feasible and safe for SMPNs.

ATF3: a novel biomarker for the diagnosis of acute kidney injury after cardiac surgery.

BACKGROUND: To investigate the expression of ATF3 in the blood and urine of adult patients undergoing cardiopulmonary bypass (CPB) surgery and to identify the changes during the perioperative period of CPB, and to determine whether ATF3 can be used as a biological marker for the early diagnosis of acute kidney injury (AKI). METHODS: We prospectively studied 83 patients who underwent elective CPB (ECB). Relevant clinical information was collected. Blood and urine samples were collected preoperatively (T0) and at 2 h (T1), 6 h (T2), 12 h (T3), 24 h (T4), and 48 h (T5) after surgery, and grouped according to the occurrence of AKI. The changes in ATF3 levels were observed, and the accuracy of the diagnosis of AKI was compared through receiver operating characteristic (ROC) curve analysis. Factors influencing the expression of ATF3 at baseline were also analyzed. RESULTS: A total of 83 adult patients undergoing cardiac surgery with CPB were included, and 42 of them developed AKI. The levels of serum ATF3 (sATF3) in the AKI group were significantly higher than those in the non-AKI group 24 h after surgery, and the difference was statistically significant (662.62±204.72 vs. 586.93±175.87; P=0.0345). Urinary ATF3 (uATF3) increased significantly 6 h after surgery, and the area under the ROC curve (AUC) for diagnosing AKI 12 h after surgery was 0.691 (95% CI: 0.576-0.807). When uATF3 was higher than 1,216 pg/mL, the sensitivity and specificity for the diagnosis of AKI were 0.43 and 0.85, respectively. On the other hand, the preoperative expression of ATF3 was negatively correlated with the preoperative creatinine level, but not affected by the patient's age, weight, gender, preoperative cardiac function, preoperative blood routine examination and liver function. CONCLUSIONS: ATF3 can be expressed early in the blood and urine of patients after CPB and can be used as a diagnostic marker for AKI after CPB in adult patients.

Total Endovascular Repair of Post-dissection Aortic Arch Aneurysm With Chimney Technique.

Open surgery remains the standard procedure for treatment of aortic arch pathologies. However, total endovascular repair can be a safe option for patients who are poor candidates for surgery because of compromised physiology. We report the case of a 63-year-old man with a post-dissection aortic arch aneurysm. We repaired the aneurysm using thoracic endovascular aortic repair (TEVAR) and used the chimney technique to reconstruct the supra-aortic branches. The patient is doing well after 12-month follow-up, demonstrating that TEVAR with the chimney technique can be used successfully for the treatment of post-dissection arch aneurysm.

Pregnancy mitigates cardiac pathology in a mouse model of left ventricular pressure overload.

In Western countries heart disease is the leading cause of maternal death during pregnancy. The effect of pregnancy on the heart is difficult to study in patients with preexisting heart disease. Since experimental studies are scarce, we investigated the effect of pressure overload, produced by transverse aortic constriction (TAC) in mice, on the ability to conceive, pregnancy outcome, and maternal cardiac structure and function. Four weeks of TAC produced left ventricular (LV) hypertrophy and dysfunction with marked interstitial fibrosis, decreased capillary density, and induced pathological cardiac gene expression. Pregnancy increased relative LV and right ventricular weight without affecting the deterioration of LV function following TAC. Surprisingly, the TAC-induced increase in relative heart and lung weight was mitigated by pregnancy, which was accompanied by a trend towards normalization of capillary density and natriuretic peptide type A expression. Additionally, the combination of pregnancy and TAC increased the cardiac phosphorylation of c-Jun, and STAT1, but reduced phosphoinositide 3-kinase phosphorylation. Finally, TAC did not significantly affect conception rate, pregnancy duration, uterus size, litter size, and pup weight. In conclusion, we found that, rather than exacerbating the changes associated with cardiac pressure overload, pregnancy actually attenuated pathological LV remodeling and mitigated pulmonary congestion, and pathological gene expression produced by TAC, suggesting a positive effect of pregnancy on the pressure-overloaded heart.

Preserving prostaglandin E2 level prevents rejection of implanted allogeneic mesenchymal stem cells and restores postinfarction ventricular function.

BACKGROUND: Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function. METHODS AND RESULTS: Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)-induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3 × 10(6) cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved. CONCLUSIONS: Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function.

Interleukin-6 downregulation with mesenchymal stem cell differentiation results in loss of immunoprivilege.

Allogeneic mesenchymal stem cell (MSC) transplantation improves cardiac function, but cellular differentiation results in loss of immunoprivilege and rejection. To explore the mechanism involved in this immune rejection, we investigated the influence of interleukin-6 (IL-6), a factor secreted by MSCs, on immune privilege after myogenic, endothelial and smooth muscle cell differentiation induced by 5-azacytidine, VEGF, and transforming growth factor-ß (TGF-ß), respectively. Both RT-PCR and ELISA showed that myogenic differentiation of MSCs was associated with significant downregulation of IL-6 expression (P < 0.01), which was also observed following endothelial (P < 0.01) and smooth muscle cell differentiation (P < 0.05), indicating that IL-6 downregulation was dependent on differentiation but not cell phenotype. Flow cytometry demonstrated that IL-6 downregulation as a result of myogenic differentiation was associated with increased leucocyte-mediated cell death in an allogeneic leucocyte co-culture study (P < 0.01). The allogeneic reactivity associated with IL-6 downregulation was also observed following MSC differentiation to endothelial and smooth muscle cells (P < 0.01), demonstrating that leucocyte-mediated cytotoxicity was also dependent on differentiation but not cell phenotype. Restoration of IL-6 partially rescued the differentiated cells from leucocyte-mediated cell death. These findings suggest that rejection of allogeneic MSCs after implantation may be because of a reduction in cellular IL-6 levels, and restoration of IL-6 may be a new target to retain MSC immunoprivilege.

Mutations of the epidermal growth factor receptor gene in NSCLC patients.

Mutations of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) were identified by re-sequencing all exons of this gene to evaluate the frequencies of EGFR gene mutation and identify rare or novel EGFR mutations. A total of 55 NSCLC samples from 55 patients were included in the study. Genomic DNA was extracted and exons 1-28 of the EGFR gene were sequenced to identify mutations. The cDNA of the EGFR gene with P848L and T790M double mutants was constructed by introducing point mutations into the wild-type EGFR vector using a site-directed mutagenesis kit. Among the 55 patients with NSCLC, 8 patients carried mutations of the EGFR gene. Notably, of the mutation-harboring patients with a pathological type of adenocarcinoma, 6 were non-smokers. The in vitro study demonstrated that the P848L mutant had a similar response to that of the wild-type EGFR after gefitinib treatment, and the P848L and T790M double mutant exhibited high resistance to gefitinib. These EGFR mutations preferentially occurred in lung adenocarcinoma patients, most of whom were non-smokers. In the in vitro study, P848L mutant EGFR had a similar response as the wild-type EGFR to gefitinib treatment, suggesting that lung cancer patients with a rare mutation of EGFR, such as the P848L mutation, do not respond to gefitinib treatment.

Surgical treatment of cardiac pheochromocytoma: a case report.

Primary cardiac pheochromocytoma is an extremely rare neoplasm. We report a 15-year-old girl who was presented with paroxysmal hypertension. An iodine-131 metaiodobenzylguanidine scintigraphy scanning showed a pheochromocytoma in her right atrial and ventricular wall. The tumor was subsequently confirmed by magnetic resonance imaging and coronary angiogram. This patient underwent a successful surgical resection of the tumor, a reconstruction of the atrial ventricular wall and right coronary artery bypass grafting. Her blood pressure remained normal thereafter. A follow-up coronary angiogram revealed a patent saphenous vein graft 4 months after the operation.

A primary right atrium paraganglioma in a 15-year-old patient.

Thoracic pheochromocytomas account for less than 2% of reported cases, while primary cardiac paragangliomas are even rare. The following case illustrates a 15-year-old patient with primary right atrium paraganglioma. This patient was referred for paroxysmal hypertension and excessive perspiration. Pheochromocytoma was suspected and then confirmed by very high serum nor-metanephrine which increased more than 30-fold above the upper limit of normal. 131I-metaiodobenzylguanidine (MIBG) scintigraphy showed high uptake only in the middle mediastinum, but not in the adrenal glands or elsewhere. Both contrast CT and gated MRI of the chest disclosed a 5.0 x 4.0 cm2 mass in the right atrium. Coronary angiography demonstrated the mass with feeding vessels from the right coronary artery. When the patient's blood pressure was well controlled with doxazosin and metoprolol, surgery was then performed. A 6.0 x 4.9 x 4.0 cm3 round solid right atrium paraganglioma weighing 41.7 g was resected. The second day after surgery, serum nor-metanephrine and urinary noradrenaline levels dropped rapidly to normal range, and the patient was free of clinical symptoms with normal BP. Postoperative cardiac function, as measured by echocardiogram, was normal. Although cardiac paraganglioma may be difficult to resect, it can be cured.