Causal association of TSH with ischemic heart diseases and heart failure: A 2-sample Mendelian randomization study.

Thyroid dysfunction is associated with the risk of cardiovascular disease; however, whether plasma thyroid-stimulating hormone (TSH) levels in subjects with euthyroidism affect the risk of cardiovascular disease remains unclear. This study aimed to investigate the causal association between plasma TSH levels and cardiovascular diseases, particularly ischemic heart disease and heart failure (HF). Summary statistics from the Integrative Epidemiology Unit Open genome-wide association studies Project and FinnGen consortium were used to investigate the causal relationship between plasma TSH levels and the risk of cardiovascular diseases. Two-sample Mendelian randomization analysis using inverse-variance weighting as the primary method was performed. The MR Pleiotropy RESidual Sum and Outlier and leave-one-out methods were used to ensure the robustness of our findings. Genetically determined plasma TSH levels were associated with major coronary heart disease events (OR 1.0557, 95% CI 1.0141-1.0991), all-cause HF (OR 0.9587, 95% CI 0.9231-0.9956), and HF + non-ischemic cardiomyopathy (OR 0.9318, 95% CI 0.8786-0.9882). After the Bonferroni correction, the causation described above disappeared. In the secondary analysis, genetically determined higher TSH levels were associated with a higher risk for unstable angina pectoris (OR 1.0913, 95% CI 1.0350-1.1507), but were associated with a lower risk for HF + overweight (OR 0.9265, 95% CI 0.8821-0.9731). These results were further validated using sensitivity analysis. Our findings show that increased plasma TSH levels in patients with euthyroidism may increase the risk of unstable angina pectoris but reduce the risk of HF in overweight patients. This evidence indicates that plasma TSH levels may need to be carefully controlled in specific patients.

Nicotinamide phosphoribose transferase facilitates macrophage-mediated pulmonary fibrosis through the Sirt1-Smad7 pathway in mice.

Pulmonary fibrosis is a challenging lung disease characterized by a bleak prognosis. A pivotal element in the progression of this disease is the dysregulated recruitment of macrophages. Nicotinamide phosphoribose transferase (NAMPT), secreted by alveolar epithelial cells and inflammatory cells, has been previously identified to influence macrophage inflammation in acute lung injury through the nicotinamide adenine dinucleotide (NAD) rescue synthesis pathway. Nonetheless, the exact role of NAMPT in the regulation of lung fibrosis is yet to be elucidated. In our research, we employed bleomycin (BLM) to induce pulmonary fibrosis in Namptflox/flox;Cx3cr1CreER mice, using Namptflox/flox mice as controls. Our findings revealed an augmented expression of NAMPT concurrent with a marked increase in the secretion of NAD and inflammatory cytokines such as IL-6, TNF-α, and TGF-ß1 post-BLM treatment. Furthermore, an upsurge in NAMPT-positive macrophages was observed in the lungs of BLM-treated Namptflox/flox mice. Notably, a conditional knockout of NAMPT (NAMPT cKO) in lung macrophages curtailed the BLM-induced inflammatory responses and significantly mitigated pulmonary fibrosis. This was associated with diminished phospho-Sirt1 (p-Sirt1) expression levels and a concomitant rise in mothers against decapentaplegic homolog 7 (Smad7) expression in BLM-treated mouse lungs and murine RAW 264.7 macrophage cells. Collectively, our data suggests that NAMPT exacerbates macrophage-driven inflammation and pulmonary fibrosis via the Sirt1-Smad7 pathway, positioning NAMPT as a promising therapeutic target for pulmonary fibrosis intervention.

Therapeutic method for early-stage second primary non-small lung cancer: analysis of a population-based database.

BACKGROUND: Early-stage non-small lung cancer patients may survive long enough to develop second primary lung cancers. However, few studies have accurately described the therapeutic method, evaluation or prognostic factors for long-term survival in this complex clinical scenario. METHODS: Patients who had first and second primary non-small lung cancer in the Surveillance, Epidemiology, and End Results database between 2004 and 2015 were evaluated. Patients were included when their tumors were pathologically diagnosed as non-small lung cancer and in the early-stage (less than 3 cm and with no lymph node metastasis). Therapeutic methods were categorized as lobectomy, sublobectomy or no surgery. The influence of different therapeutic methods on the overall survival rate was compared. RESULTS: For the first primary tumor, patients who underwent lobectomy achieved superior survival benefits compared with patients who underwent sublobectomy. For the second primary tumor, long-term survival was similar in patients who underwent lobectomy and those who underwent sublobectomy treatment. The multivariate analysis indicated that age, disease-free time interval, sex, and first and second types of surgery were independent prognostic factors for long-term survival. Our results showed that the 5-year overall survival rate was 91.9% when the disease-free interval exceeded 24 months. CONCLUSION: Lobectomy for the first primary tumor followed by sublobectomy for the second primary tumor may be a beneficial therapeutic method for patients. If the disease-free interval exceeds 24 months, the second primary tumor will have no influence on the natural course for patients diagnosed with a first primary non-small lung cancer.

Integrating network pharmacology and experimental evidence to decipher the cardioprotective mechanism of Yiqihuoxue decoction in rats after myocardial infarction.

ETHNOPHARMACOLOGICAL RELEVANCE: "Qi deficiency and blood stasis" syndrome is one of the most common syndromes treated with Traditional Chinese Medicine among ischemic heart disease (IHD) patients in clinic. As a Chinese herbal formula with the function of tonifying Qi and activating blood, Yiqihuoxue Decoction (YQHX) has been frequently proven to be effective in the clinical treatment of IHD. AIM OF THE STUDY: The cardioprotective mechanisms of YQHX in treating ischemic heart disease were investigated, with emphasis on the key targets and pathways. MATERIALS AND METHODS: In the present study, the potential targets of compounds identified in YQHX were predicted using PharmMapper, Symmap, and STITCH databases, and a "herb-compound-target" network was constructed using Cytoscape. Subsequently, the GO and KEGG functional enrichment analyses were analyzed using the DAVID database. Furthermore, a protein-protein interaction network was constructed using STRING to obtain the key target information. Besides, we used a myocardial ischemia rat model to investigate the cardioprotective effects of YQHX. Transmission electron microscopy and Western blotting were used to observe apoptotic bodies and confirm protein expressions of key candidate targets, respectively. RESULTS: Network pharmacology showed that a total of 141 potential targets were obtained from these databases. The functional analysis results revealed that the targets of YQHX were largely associated with apoptosis, and the PI3K-AKT and MAPK pathways might represent key functional pathways. The hub genes of network include ALB, TP53, AKT1, TNF, VEGFA, EGFR, MAPK1, CASP3, JUN, FN1, MMP9, and MAPK8. In vivo, YQHX significantly improved cardiac function and suppressed apoptosis in ischemic rat myocardium. Furthermore, YQHX could significantly upregulate Nrf2 and HO-1 expression, and inhibit JNK phosphorylation. CONCLUSIONS: Based on network pharmacology and experimental evidence, this study proves that the cardioprotective effects and mechanisms of YQHX depend on multi-component, multi-target, and multi-pathway. In particular, YQHX exerts anti-apoptotic effects potentially by regulating the Nrf2/HO-1 and JNK-MAPK pathways.

Erratum to laparoscopic needle catheter jejunostomy by using a double semipurse string suture method in minimally invasive Ivor Lewis esophagectomy.

[This corrects the article DOI: 10.21037/jtd.2020.01.53.].

Correction to: Comparison of minimally invasive Ivor Lewis esophagectomy and left transthoracic esophagectomy in esophageal squamous cell carcinoma patients: a propensity score-matched analysis.

An amendment to this paper has been published and can be accessed via the original article.

FLIM-FRET-Based Structural Characterization of a Class-A GPCR Dimer in the Cell Membrane.

Class-A G protein-coupled receptors (GPCRs) are known to homo-dimerize in the membrane. Yet, methods to characterize the structure of GPCR dimer in the native environment are lacking. Accordingly, the molecular basis and functional relevance of the class-A GPCR dimerization remain unclear. Here, we present the dimeric structural model of GPR17 in the cell membrane. The dimer mainly involves transmembrane helix 5 (TM5) at the interface, with F229 in TM5, a critical residue. An F229A mutation makes GPR17 monomeric regardless of the expression level of the receptor. Monomeric mutants of GPR17 display impaired ERK1/2 activation and cannot be properly internalized upon agonist treatment. Conversely, the F229C mutant is cross-linked as a dimer and behaves like wild-type. Importantly, the GPR17 dimer structure has been modeled using sparse inter-protomer FRET distance restraints obtained from fluorescence lifetime imaging microscopy. The same approach can be applied to characterizing the interactions of other important membrane proteins in the cell.

Laparoscopic needle catheter jejunostomy by using a double semipurse string suture method in minimally invasive Ivor Lewis esophagectomy.

BACKGROUND: To investigate the safety and effectiveness of a double semipurse string suture method for jejunum fixation in laparoscopic needle catheter jejunostomy in minimally invasive Ivor Lewis esophagectomy (MIILE). METHODS: Two hundred and six esophageal cancer patients continuously receiving MIILE from March 2014 to February 2018 were enrolled. In all patients, the double semipurse string suture method was applied for jejunum fixation in laparoscopic needle catheter jejunostomy. The methods and details of this technique are introduced herein. General information, clinical data, postoperative complications and follow-up results were retrospectively analyzed, and the complication causes and treatment methods are discussed. RESULTS: Laparoscopic needle catheter jejunostomy-using the double semipurse string suture method was successfully performed in 206 patients. The operative time of laparoscopic needle catheter jejunostomy was 10.56±2.04 min. No conversion to laparotomy or postoperative death or serious infection associated with the jejunostomy tube occurred. The incidence of complications associated with the jejunostomy tube was 16.50% (34/206), and most of the complications were mild. Severe complications occurred in 2 cases (0.97%), which were cured after reoperation, without serious consequence. CONCLUSIONS: The double semipurse string suture method is safe, simple and feasible for the jejunum fixation in laparoscopic needle catheter jejunostomy in MIILE. It is worth popularization and clinical application.

Cangrelor alleviates bleomycin-induced pulmonary fibrosis by inhibiting platelet activation in mice.

Pulmonary fibrosis is a progressive chronic inflammatory lung disease whose pathogenesis is complicated. Platelets and neutrophils play important roles in the progression of pulmonary inflammation. We have reported that cangrelor, a non-sepesific GPR17 antagonist, alleviates pulmonary fibrosis partly by inhibiting macrophage inflammation in mice. Cangrelor is also a well-known anti-platelet agent. To test whether cangrelor mitigated pulmonary fibrosis partly through the inhibition of platelets, bleomycin (BLM) was used to induce pulmonary fibrosis in C57BL/6 J mice. We found that cangrelor (10 mg/kg) not only significantly decreased BLM-induced release of inflammatory cytokines (PF4, CD40 L and MPO), but also decreased the increment of platelets, neutrophils and platelet-neutrophil aggregates in the fibrotic lung and in the peripheral blood of BLM-treated mice. In addition, cangrelor decreased the number of CD40 and MPO double positive neutrophils and the expression level of CD40 in BLM-treated mouse lungs. Based on these results we conclude that cangrelor alleviates BLM-induced lung inflammation and pulmonary fibrosis in mice, partly through inhibition of platelet activation, therefore reducing the infiltration of neutrophils due to the adhesion of platelets and neutrophils mediated by CD40 - CD40 L interaction. Cangrelor could be a potential therapeutic medicine for pulmonary fibrosis.

Comparison of minimally invasive Ivor Lewis esophagectomy and left transthoracic esophagectomy in esophageal squamous cell carcinoma patients: a propensity score-matched analysis.

BACKGROUND: To investigate the long-term efficacy of the minimally invasive Ivor Lewis esophagectomy (MIILE) in esophageal squamous cell carcinoma (ESCC) patients, a retrospective comparison of the quality of life (QOL) and survival between patients who underwent MIILE and left transthoracic esophagectomy (Sweet approach) was conducted. METHODS: A detailed database search identified 614 patients who underwent MIILE and 243 patients who underwent Sweet esophagectomy between January 2011 and December 2017. After propensity score matching, 216 paired cases were selected for statistical analysis. Survival was evaluated with Kaplan-Meier curves or Cox models. RESULTS: MIILE was associated with a longer duration, less blood loss and more lymph node dissected than Sweet esophagectomy. MIILE patients suffered from less pain, less frequently developed pneumonia, and had fewer postoperative complications. Additionally, MIILE patients began oral intake earlier and had a shorter postoperative hospital stay, and enhanced recovery of QOL. There was no significant difference between the approaches regarding the recurrence pattern, 2-year and 5-year overall survival (OS) or disease-free survival (DFS), except that patients with tumor-node-metastasis (TNM) stage I in the MIILE group demonstrated superior OS and DFS. Pathological TNM stage and postoperative complications were determined to be independent prognostic factors based on the multivariate analysis. CONCLUSION: MIILE is a safe and feasible approach for treating ESCC patients. MIILE approach may provide more postoperative advantages, enhanced QOL improvement, and more favorable long-term survival in early stage patients than the Sweet procedure.

Thoracoscopic surgery for management of pleuroperitoneal communication complicating continuous ambulatory peritoneal dialysis: A case report.

RATIONALE: Pleuroperitoneal communication (PPC) has been reported to complicate continuous ambulatory peritoneal dialysis (CAPD). However, cases of patients in whom the results of the methylene blue dye test and peritoneopleural scintigraphy were negative and treatment was thoracoscopic surgery have been rarely reported. PATIENT CONCERNS: A 58-year-old man with end-stage chronic renal failure who underwent CAPD presented with massive right-sided hydrothorax. The pleural fluid glucose level was high. Results of both the methylene blue dye test and peritoneopleural scintigraphy were negative. DIAGNOSIS: The presence of end-stage chronic renal failure and diaphragm defects amenable to repair, which were identified during thoracoscopic surgery, indicated a definite diagnosis of PPC complicating CAPD. INTERVENTIONS AND OUTCOMES: CAPD was performed twice after the defects were repaired during thoracoscopic surgery. There was no evidence that the repaired sites were leaking again, and the patient did not complain of any discomfort during the second CAPD. LESSON: Although special methods such as the methylene blue dye test and peritoneopleural scintigraphy may not be useful in some cases, thoracoscopic surgery is still effective and reliable in diagnosing and repairing diaphragmatic defects.

The clinical efficacy and safety of the Chinese herbal medicine Astragalus (Huangqi) preparation for the treatment of acute myocardial infarction: A systematic review of randomized controlled trials.

BACKGROUND: In recent years, with the enormous advances in the field of cardiac intervention technology, the survival rate of patients with acute myocardial infarction (AMI) has been improved significantly. However, the risk of arrhythmias and heart failure remains very high in AMI patients for long-term prognosis. Chinese herbal medicine (CHM) is more and more used in the treatment of AMI because of its good curative effect and less side effects. The target of this research is to analyze the efficacy and safety of Astragalus (Huangqi) preparation in the treatment of AMI by meta-analysis and also to provide a better evidence for clinical practice. METHODS: Seven databases will be searched in this study: The Cochrane Library, PubMed, Web of Science, the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database (CSJD), the Chinese Biomedical Literature Database (CBM), and Wanfang DATA. The following search terms will be used: (Huangqi OR Huang Qi OR Astragalus OR radix astragali) AND (acute myocardial infaction OR myocardial infaction OR AMI) AND (randomized controlled trial OR RCT OR randomized). No language limitations and the searches will be conducted up to March, 2019. INCLUSION CRITERIA: randomized controlled trial (RCT) of Astragalus (Huangqi) preparation in patients with AMI. Main outcome measures will be left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), recanalization rate, mortality rate, incidence of reperfusion arrhythmias, postinfarction angina pectoris, and re-infarction rate. Secondary outcome indicators were the incidence of adverse reactions and the effective rate of traditional Chinese medicine (TCM) treatment. Two independent reviewers will filter the literature and extract data which based to the Cochrane manual. The relevant data, including bias risk assessment, data synthesis, subgroup analysis, meta-analysis, and final meta-analysis, will be analyzed with RevMan 5.3 software. The funnel diagram will be used to evaluate the reported deviation, and the Egger test will be used to evaluate the symmetry of the funnel graph. RESULTS: This systematic review study will provide a clear basis for evaluating the efficacy and safety of Astragalus (Huangqi) preparation with the treatment of AMI. CONCLUSION: This study will provide an up-to-date evidence for evaluating the efficacy and safety of Astragalus (Huangqi) preparation. PROSPERO REGISTRATION NUMBER: CRD42019124843.

Three-port single-intercostal versus multiple-intercostal thoracoscopic lobectomy for the treatment of lung cancer: a propensity-matched analysis.

BACKGROUND: In this retrospective study, we aimed to demonstrated that three-port single-intercostal (SIC) thoracoscopic lobectomy is an effective choice for lung cancer by comparing the perioperative outcomes of patients with non-small-cell lung cancer treated with three-port SIC and conventional multiple-intercostal (MIC) thoracoscopic lobectomy. METHODS: From January 2013 to January 2018, 642 non-small-cell lung cancer patients underwent thoracoscopic lobectomy via a three-port SIC or MIC technique. Propensity-matched analysis incorporating preoperative clinical variables was used to compare the perioperative outcomes between the two groups. RESULTS: The first 20 patients were excluded to account for the learning curve effect in the SIC group. Propensity matching yielded 186 patients in each group. A small percentage of patients had major morbidity, including 4.8% in the SIC group and 6.5% in the MIC group; there was no significant difference between the two groups. Although the total number of lymph nodes harvested (25.3 vs. 23.8, p = 0.160) and stations removed (6.5 vs. 6.7, p = 0.368) were similar between the two groups, more subcarinal lymph nodes were removed (6.9 vs. 5.2, p < 0.001) in the SIC group than in the MIC group. Furthermore, other perioperative outcomes in the SIC group were not fewer than those in the MIC group. CONCLUSIONS: Both techniques are acceptable for the treatment of non-small-cell lung cancer. Three-port SIC VATS lobectomy can provide an alternative procedure in thoracoscopic surgery.

SHP2 protects endothelial cell barrier through suppressing VE-cadherin internalization regulated by MET-ARF1.

Vascular endothelial (VE)-cadherin junctional localization is known to play a central role in vascular development, endothelial barrier integrity, and homeostasis. The sarcoma homology domain containing protein tyrosine phosphatase (SHP)2 has been shown to be involved in regulating endothelial barrier function; however, the mechanisms remain largely unknown. In this work SHP2 knockdown in an HUVEC monolayer increased VE-cadherin internalization and endothelial barrier permeability. Loss of SHP2 specifically augmented the GTPase activity of ADP-ribosylation factor (ARF)-1. ARF1 knockdown or inhibition of its guanine nucleotide exchange factors (GEFs) markedly attenuated VE-cadherin internalization and barrier hyperpermeability induced by SHP2 deficiency. SHP2 knockdown increased the total and phosphorylated levels of MET, whose activity was necessary for ARF1 activation and VE-cadherin internalization. Furthermore, constitutive endothelium-specific deletion of Shp2 in mice led to disrupted endothelial cell junctions, massive hemorrhage, and lethality in embryos. Induced and endothelium-specific deletion of Shp2 in adult mice resulted in lung hyperpermeability. Inhibitors for ARF1-GEF or MET used in pregnant mice prevented the vascular leakage in endothelial Shp2-deleted embryos. Together, our findings define a novel role of SHP2 in stabilizing junctional VE-cadherin in the resting endothelial barrier through suppressing MET and ARF1 activation.-Zhang, J., Huang, J., Qi, T., Huang, Y., Lu, Y., Zhan, T., Gong, H., Zhu, Z., Shi, Y., Zhou, J., Yu, L., Zhang, X., Cheng, H., Ke, Y. SHP2 protects endothelial cell barrier through suppressing VE-cadherin internalization regulated by MET-ARF1.

Cangrelor alleviates pulmonary fibrosis by inhibiting GPR17-mediated inflammation in mice.

Pulmonary fibrosis is a progressive and intractable lung disease. Macrophages play a critical role in the progression of pulmonary fibrosis. Cangrelor, an anti-platelet agent, is also a non-selective Gprotein-coupled receptor 17 (GPR17) antagonist. GPR17 mediates microglial inflammation in the chronic phase of cerebral ischemia and regulates allergic pulmonary inflammation. In this study, we observed the effects of cangrelor on bleomycin (BLM)-induced macrophage cellular inflammation and BLM-induced pulmonary fibrosis in C57BL/6J mice. We found that BLM significantly increased GPR17 expression, the mRNA synthesis and release of inflammatory cytokines including TNF-α, IL-6 and TGF-ß1 in murine RAW 264.7 macrophage cells. Knockdown of GPR17 attenuated the BLM-induced inflammatory responses. Cangrelor (2.5 µM-10 µM) significantly alleviated BLM-induced inflammatory response in RAW 264.7 macrophage cells in concentration-dependent manner. In BLM-induced fibrotic mouse lungs, GPR17 expression and GPR17-positive macrophages were increased. Cangrelor (2.5 mg/kg-10 mg/kg) alleviated pulmonary fibrosis in dose-dependent manner. Cangrelor not only reduced the number of GPR17-positive macrophages, but also decreased BLM-induced mRNA synthesis and release of inflammatory cytokine. As such, we concluded that cangrelor alleviates BLM-induced pulmonary fibrosis by suppressing GPR17-mediated inflammation. Cangrelor could be a potential therapeutic drug for pulmonary fibrosis.

Patient-Controlled Paravertebral Block for Video-Assisted Thoracic Surgery: A Randomized Trial.

BACKGROUND: Paravertebral block (PVB) has been proven to be an efficient way to control postoperative pain in patients who have undergone a thoracotomy. This study explored whether the use of a patient-controlled PVB can provide benefits over intravenous patient-controlled analgesia (PCA) for 3-port single-intercostal video-assisted thoracic surgery. METHODS: From May 2015 to December 2016, patients who had solitary pulmonary nodules or spontaneous pneumothorax and underwent single-intercostal video-assisted thoracic surgery were randomly allocated to receive patient-controlled PVB or intravenous PCA. Intramuscular dezocine (10 mg) was used as a rescue medication. None of the surgeons, patients, or investigators assessing outcomes or analyzing the data were blinded to the group assignments. Pain level was measured by the visual analog score. RESULTS: There were 86 patients assigned to the PVB group and 85 patients assigned to the PCA group. The difference in the mean visual analog score between these two groups was not significant (p = 0.115). For patients who needed rescue medication, the cumulative dezocine dose in the PVB group was significantly lower than that in the PCA group (21.7 mg vs 30.9 mg, p = 0.001) throughout the 4 postoperative days. The frequencies of severe vomiting (p = 0.003) and hypotension (p = 0.005) were significantly lower in the PVB group. CONCLUSIONS: PVB, which resulted in lower cumulative dezocine doses and produced fewer side effects than PCA, can provide effective pain relief for patients undergoing video-assisted thoracic surgery.

Home enteral nutrition after minimally invasive esophagectomy can improve quality of life and reduce the risk of malnutrition.

BACKGROUND AND OBJECTIVES: The potential benefits of home enteral nutrition (HEN) and the effects of HEN on quality of life (QOL) after esophagectomy remain unclear. The aim was to investigate the effect of 3 months HEN on health related QOL and nutritional status of esophageal cancer patients who were preoperatively malnourished. METHODS AND STUDY DESIGN: 142 malnourished (PG-SGA stage B or C) patients with esophageal cancer were assigned to receive Ivor Lewis minimally invasive esophagectomy (MIE group) with laparoscopic jejunal feeding tube placement or open esophagectomy (OE group) with nasojejunal feeding tube placement. After discharge, patients in the MIE group received HEN with 500-1000 kcal/d for 3 months, while the OE group patients did not receive HEN, as nasojejunal feeding tubes had been removed. QLQ-C30 and PG-SGA questionnaires were used to evaluate the QOL and the risk of malnutrition. RESULTS: 67 patients were enrolled in the MIE group and 75 patients were enrolled in the OE group. Symptoms related to fatigue, nausea, vomiting, pain, and appetite loss were significantly decreased in the patients treated with 3 months HEN. Similarly, patients treated with 3 months HEN had a lower risk of malnutrition than patients did not receive HEN (PG-SGA score, 5.7 vs 7.9, p<0.01). More patients in the MIE group (received 3 months HEN) were able to complete postoperative chemoradiotherapy than patients in the OE group (p<0.01). CONCLUSIONS: MIE and subsequent treatment with 3 months HEN can improve the QOL and reduce the risk of malnutrition in preoperatively malnourished patients.