Retraction Notice to: Circular RNA circFOXM1 Plays a Role in Papillary Thyroid Carcinoma by Sponging miR-1179 and Regulating HMGB1 Expression.

[This retracts the article DOI: 10.1016/j.omtn.2019.12.014.].

Molecular and cellular role of variants of the promoter region of HAND1 gene in sporadic and isolated ventricular septal defect.

Ventricular septal defect (VSD) is the most common type of congenital heart disease. HAND1 gene plays a crucial role in the development of the heart, but the role of the variants in the HAND1 gene promoter region in patients with VSD has not been explored yet. From 588 participants (300 with isolated and sporadic VSD and 288 healthy controls), DNA was extracted from blood samples. Variants at the HAND1 gene promoter region were analyzed through Sanger sequencing. Subsequently, cell functional validation was conducted through cell experiments, including dual-luciferase reporter gene analysis, electrophoretic mobility shift analysis, and bioinformatics analysis was also conducted. The promoter region of HAND1 gene had a total of 9 identified variant sites. Among them, 4 variants were exclusively found in VSD patients, and 1 variant (g.3631A>C) was newly discovered. Cell functional experiments indicated that all four variants decreased the transcriptional activity of HAND1 gene promoter with three of them reached statistical significance (p < 0.05). Subsequent analysis using JASPAR (a transcription factor binding profile database) suggests that these variants may alter the binding sites of transcription factors, potentially contributing to the formation of VSD. Our study for the first time identified variants in the promoter region of HAND1 gene in Chinese patients with isolated and sporadic VSD. These variants significantly decreased the expression of HAND1 gene, impacting transcription factor binding sites, and thereby demonstrating pathogenicity. This study offers new insights into the role of HAND1 gene promoter region, contributing to a better understanding of the genetic basis of VSD formation.

CXCR4 promotes migration, invasion, and epithelial-mesenchymal transition of papillary thyroid carcinoma by activating STAT3 signaling pathway.

AIMS: Papillary thyroid cancer (PTC) is a serious threat to human health worldwide, while metastasis in the early phase limits therapeutic success and leads to poor survival outcomes. The CXC chemokine receptor type 4 (CXCR4) plays an important role in many cellular movements such as transcriptional modulation, cell skeleton rearrangement, and cell migration, and the change in CXCR4 levels are crucial in various diseases including cancer. In this study, we explored the role of CXCR4 in the migration and invasion of PTC and investigated the potential mechanisms underlying its effects. SUBJECTS AND METHODS: We analyzed the expression levels of CXCR4 in PTC tissues and cell lines. Would healing migration, Transwell invasion assay in vitro, and tail-vein lung metastasis assay In vivo were performed to evaluated the migration and invasion abilities of PTC cells with stable CXCR4 knockdown or overexpression. Signal transducers and activators of transcription (STAT3) signaling pathway-related protein expressions were examined by Western blotting assays. RESULTS: The results showed that CXCR4 was highly expressed in PTC cell lines and PTC tissues. CXCR4 knockdown in PTC cells dampened the migration, invasion, and epithelial-mesenchymal transition (EMT), whereas CXCR4 overexpression enhanced these properties. In vivo, we also found that CXCR4 promoted the metastasis of PTC. Mechanistic studies showed that CXCR4 played these vital roles through the STAT3 signaling pathway. Furthermore, PTC patients with high CXCR4 or p-STAT3 expression correlated with aggressive clinical characteristics such as extrathyroidal extension (ETE), and lymph node metastasis (LNM). CONCLUSIONS: We provided evidence that CXCR4 might activate the STAT3 signaling pathway and further promote PTC development. Thus, CXCR4 might be a novel therapeutic target for PTC.

Metabolomics Analysis Identifies Differential Metabolites as Biomarkers for Acute Myocardial Infarction.

Myocardial infarction (MI), including ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI), is still a leading cause of death worldwide. Metabolomics technology was used to explore differential metabolites (DMs) as potential biomarkers for early diagnosis of STEMI and NSTEMI. In the study, 2531 metabolites, including 1925 DMs, were discovered. In the selected 27 DMs, 14 were successfully verified in a new cohort, and the AUC values were all above 0.8. There were 10 in STEMI group, namely L-aspartic acid, L-acetylcarnitine, acetylglycine, decanoylcarnitine, hydroxyphenyllactic acid, ferulic acid, itaconic acid, lauroylcarnitine, myristoylcarnitine, and cis-4-hydroxy-D-proline, and 5 in NSTEMI group, namely L-aspartic acid, arachidonic acid, palmitoleic acid, D-aspartic acid, and palmitelaidic acid. These 14 DMs may be developed as biomarkers for the early diagnosis of MI with high sensitivity and specificity. These findings have particularly important clinical significance for NSTEMI patients because these patients have no typical ECG changes.

Metabolomics and Biomarkers for Paroxysmal and Persistent Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of arrhythmia worldwide and is associated with serious complications. This study investigated the metabolic biomarkers associated with AF and the differences in metabolomics and associated metabolic biomarkers between paroxysmal AF (AFPA) and persistent AF. METHODS AND RESULTS: Plasma samples were prospectively collected from patients with AF and patients in sinus rhythm with negative coronary angiography. The patients were divided into 3 groups: AFPA, persistent AF, and sinus rhythm (N=54). Metabolomics (n=36) using ultra-high-performance liquid chromatography mass spectrometry was used to detect differential metabolites that were validated in a new cohort (n=18). The validated metabolites from the validation phase were further analyzed by receiver operating characteristic. Among the 36 differential metabolites detected by omics assay, 4 were successfully validated with area under the curve >0.8 (P<0.05). Bioinformatics analysis confirmed the enrichment pathways of unsaturated fatty acid biosynthesis, glyoxylate and dicarboxylate metabolism, and carbon metabolism. Arachidonic acid was a potential biomarker of AFPA, glycolic acid and L-serine were biomarkers of AFPA and persistent AF, and palmitelaidic acid was a biomarker of AFPA. CONCLUSIONS: In this metabolomics study, we detected 36 differential metabolites in AF, and 4 were validated with high sensitivity and specificity. These differential metabolites are potential biomarkers for diagnosis and monitoring of disease course. This study therefore provides new insights into the precision diagnosis and management of AF.

Homocysteine impairs the anticontractile/vasorelaxing activity of perivascular adipose tissue surrounding human internal mammary artery.

OBJECTIVES: Perivascular adipose tissue (PVAT) surrounding human internal mammary artery (IMA) possesses anticontractile property. Its function under pathological conditions is barely studied. We previously reported that homocysteine impairs the vasodilator function of IMA through endothelium and smooth muscle-dependent mechanisms. This study investigated the effect of homocysteine on the function of PVAT and the associated mechanisms. METHODS: Residual IMA tissues were collected from patients undergoing coronary artery bypass grafting. Vasoreactivity was studied using myograph. Adiponectin was measured by ELISA. Expressions of adiponectin receptors (AdipoRs), eNOS and p-eNOS were determined by RT-qPCR and Western blot. RESULTS: Exposure to homocysteine augmented the contractile responses of PVAT-intact IMA to U46619 and potassium chloride, regardless with or without endothelium. Such augmentation was also observed in skeletonized IMA with transferred, homocysteine-exposed PVAT. Homocysteine attenuated the relaxant response of PVAT-intact while endothelium-denuded vessels to acetylcholine. Homocysteine lowered adiponectin content in the PVAT, downregulated the expression of AdipoR1 and AdipoR2 as well as eNOS and p-eNOS in skeletonized IMA. The relaxant response of skeletonized IMA to AdipoR agonist AdipoRon was blunted by homocysteine or eNOS inhibitor, and homocysteine significantly attenuated the inhibitory effect of eNOS inhibitor on AdipoRon-induced relaxation. CONCLUSIONS: Homocysteine impairs the anticontractile/vasorelaxing activity of PVAT surrounding the IMA through inhibiting adiponectin/AdipoR/eNOS/nitric oxide signalling pathway.

Identification and Functional Verification of CITED2 Gene Promoter Region in Patients with Patent Ductus Arteriosus.

Patent ductus arteriosus (PDA) is a common congenital heart disease. CITED2 plays an important role in the development of the heart, and genetic variants in its coding region are significantly associated with cardiac malformations. However, the role of variants in the promoter region of CITED2 in the development of PDA remains unclear. We extracted the peripheral blood of 646 subjects (including 353 PDA patients and 293 unrelated healthy controls) for sequencing. We identified 13 promoter variants of the CITED2 gene (including 2 novel heterozygous variants). Of the 13 variants, 10 were found only in PDA patients. In mouse cardiomyocytes (HL-1) and rat cardiac myocytes (RCM), the transcriptional activity of the CITED2 gene promoter was significantly changed by the variants (p < 0.05). The results of the experiments of electrophoretic mobility indicated that these variants may affect the transcription of the CITED2 gene by influencing the binding ability of transcription factors. These results, combined with the JASPAR database analysis, showed that the destruction/production of transcription factor binding sites due to the variants in the promoter region of the CITED2 gene may directly or indirectly affect the binding ability of transcription factors. Our results suggest for the first time that variants at the CITED2 promoter region may cause low expression of CITED2 protein related to the formation of PDA.

Establishment and application of cricothyrotomy in vivo.

BACKGROUND: Cricothyrotomy is a procedure performed to establish an airway in critical airway events. It is performed only rarely and anesthesiologists are often unprepared when called upon to perform it. This study aimed to simulate cricothyrotomy using pig larynx and trachea models to help anesthesiologists master cricothyrotomy and improve the ability to establish cricothyrotomy quickly. METHODS: The porcine larynx and trachea were dissected and covered with pigskin to simulate the structure of the anterior neck of a human patient. An animal model of cricothyrotomy was established. Forty anesthesiologists were randomly divided into four groups. Each physician performed three rounds of cricothyrotomy, and recorded the time to accomplish each successful operation. After training the cricothyrotomy procedure, a questionnaire survey was conducted for the participating residents using a Likert scale. The participants were asked to score the utility of the training course on a scale of 1 ((minimum) to 5 ((maximum). RESULTS: Through repeated practice, compared with the time spent in the first round of the operation (67 ± 29 s), the time spent in the second round of the operation (47 ± 21 s) and the time spent in the third round of the operation (36 ± 11 s) were significantly shortened (P < 0.05). Results of the survey after training were quite satisfied, reflecting increased the ability of proficiency in locating the cricothyroid membrane and performing a surgical cricothyrotomy. CONCLUSION: The porcine larynx and trachea model is an excellent animal model for simulating and practicing cricothyrotomy, helping anesthesiologists to master cricothyrotomy and to perform it proficiently when required.

Lysine crotonylation of SERCA2a correlates to cardiac dysfunction and arrhythmia in Sirt1 cardiac-specific knockout mice.

Protein post-translational modifications (PTMs) are important regulators of protein functions and produce proteome complexity. SIRT1 has NAD+-dependent deacylation of acyl-lysine residues. The present study aimed to explore the correlation between lysine crotonylation (Kcr) on cardiac function and rhythm in Sirt1 cardiac-specific knockout (ScKO) mice and related mechanism. Quantitative proteomics and bioinformatics analysis of Kcr were performed in the heart tissue of ScKO mice established with a tamoxifen-inducible Cre-loxP system. The expression and enzyme activity of crotonylated protein were assessed by western blot, co-immunoprecipitation, and cell biology experiment. Echocardiography and electrophysiology were performed to investigate the influence of decrotonylation on cardiac function and rhythm in ScKO mice. The Kcr of SERCA2a was significantly increased on Lys120 (1.973 folds). The activity of SERCA2a decreased due to lower binding energy of crotonylated SERCA2a and ATP. Changes in expression of PPAR-related proteins suggest abnormal energy metabolism in the heart. ScKO mice had cardiac hypertrophy, impaired cardiac function, and abnormal ultrastructure and electrophysiological activities. We conclude that knockout of SIRT1 alters the ultrastructure of cardiac myocytes, induces cardiac hypertrophy and dysfunction, causes arrhythmia, and changes energy metabolism by regulating Kcr of SERCA2a. These findings provide new insight into the role of PTMs in heart diseases.

The effect of preoperative sleep quality on the target plasma concentration of propofol and postoperative sleep in patients undergoing painless gastroscopy.

BACKGROUND: This study aims to investigate the effect of preoperative sleep quality on the target plasma concentration of propofol and postoperative sleep in patients undergoing painless gastroscopy. METHODS: Ninety-three outpatients aged 45 to 64 years with body mass index (BMI) of 18.5-30 kg/m2 and ASA grades of I or II, who underwent painless gastroscopy, were selected. All patients were evaluated by the Athens insomnia scale (AIS) before the painless gastroscopy. The patients were divided into two groups according to the AIS score evaluated before painless gastroscopy: normal sleep group (group N, AIS score < 4 points, 47 cases) and sleep disorder group (group D, AIS score > 6 points, 46 cases). The target-controlled infusion (TCI) of propofol (Marsh model) was used for general anesthesia, the Bispectral index (BIS) was used to monitor the depth of anesthesia, and the BIS was maintained between 50 and 65 during the painless gastroscopy. The target plasma concentration (Cp) of propofol was recorded when the patient's eyelash reflex disappeared (T1), before the painless gastroscopy (T2), at the time of advancing the gastroscope (T3) and during the painless gastroscopy (T4), and the infusion rate per body surface area of propofol was calculated. The patient's AIS score was followed up by telephone at day 1, day 3, 1 week, and 1 month after the painless gastroscopy to assess the postoperative sleep of the patient. The occurrence of adverse reactions during the painless gastroscopy was recorded; the patient's satisfaction and the endoscopist's satisfaction with the anesthesia effect were compared between the two groups. RESULTS: Compared with group N, the Cp at each time point and the infusion rate per body surface area of propofol in group D was increased significantly (P < 0.05); compared with the AIS scores before the painless gastroscopy, the AIS scores of the two groups of patients were significantly increased day 1 after the painless gastroscopy (P < 0.05); there were no significant differences in the AIS scores of the two groups at day 3, 1 week, and 1 month after the painless gastroscopy (P > 0.05). There were no statistically significant differences in the occurrence of adverse reactions and the patient's satisfaction and the endoscopist's satisfaction with the anesthesia effect between the two groups (P > 0.05). CONCLUSION: The preoperative sleep disturbance will increase the Cp and the infusion rate per body surface area of propofol in patients undergoing painless gastroscopy. Propofol only affects the patients' sleep for day 1 after the painless gastroscopy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100045332) on 12/04/2021.

Antispastic Effect of Fasudil and Cocktail of Fasudil and Nitroglycerin in Internal Thoracic Artery.

BACKGROUND: Spasm of arterial grafts in coronary artery bypass grafting is a clinical problem and can occasionally be lethal. Perioperative spasm in the internal thoracic artery (ITA) and coronary arteries occurs in 0.43% of patients. This study aimed to investigate the antispastic effect of a RhoA/Rho-kinase (Rho-associated coiled-coil-containing protein kinase [ROCK]) inhibitor (fasudil) with and without nitroglycerin in combination in the ITA. METHODS: Isolated human ITA rings taken from 68 patients who were undergoing coronary bypass were studied in a myograph. Cumulative concentration-relaxation curves for fasudil (-9 to -3.5 log M) were established in the ITA, which was precontracted with potassium chloride or U46619. The inhibitory effect of fasudil (-6.3 or -5.3 log M) or fasudil in combination with nitroglycerin were also tested. The ROCK2 protein was measured by Western blot. RESULTS: Fasudil caused similar relaxation in ITA rings contracted by potassium chloride or U46619. Pretreatment with -5.3 log M fasudil significantly depressed contraction induced by potassium chloride (P = .004 vs control; P = .017 vs -6.3 log M) and U46619 (P = .010 vs control; P = .041 vs. -6.3 log M). Fasudil in combination with nitroglycerin had more effect and more rapid and sustained relaxation than either vasodilator alone. Fasudil caused a decrease of ROCK2 protein content (P = .014). CONCLUSIONS: Fasudil fully relaxes some vasoconstrictor-induced contraction and decreases ROCK2 protein content in the ITA. The combination of fasudil and nitroglycerin has a superior effect than either vasodilator alone. The new cocktail solution composed of fasudil and nitroglycerin (pH 7.4) has effective antispastic action and may prove to be a new antispastic method for arterial conduits during coronary bypass surgery.

Catalpol regulates the proliferation and apoptosis of breast cancer MCF-7 cells through the FOXO3-FOXM1 signal axis / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨中药地黄提取物梓醇（Cat）对乳腺癌MCF-7细胞增殖与凋亡，以及裸鼠移植瘤生长的影响及其机制。方法：以不同质量浓度（0、5、25、50、100、200 μg/mL）Cat处理人乳腺癌MCF-7细胞，用MTT法筛选Cat给药浓度。将MCF-7细胞分为空白对照组、Cat低剂量组、Cat中剂量组、Cat高剂量组、Cat+sh-NC组和Cat+sh-FOXO3组，采用Edu细胞增殖实验、平板克隆实验、流式细胞术分别检测各组细胞的增殖与克隆形成能力、凋亡率和细胞周期，WB法检测各组细胞中FOXO3、FOXM1、caspase-3和caspase-8蛋白表达。构建乳腺癌MCF-7细胞裸鼠移植瘤模型，观察Cat对移植瘤生长的影响，WB法检测移植瘤组织中FOXO3和FOXM1蛋白表达。结果：Cat低（50 μg/mL）、中（100 μg/mL）、高（200 μg/mL）剂量处理的MCF-7细胞的增殖能力均显著下降（均P<0.05）。与空白对照组比较，Cat低、中、高剂量组Edu阳性细胞率、克隆形成数、S期与G2/M期细胞比例及FOXO3蛋白表达均显著降低（均P<0.05），细胞凋亡率、G0/G1期细胞比例及FOXM1、caspase-3、caspase-8蛋白表达均显著升高（均P<0.05）；与Cat+sh-NC组比较，Cat+sh-FOXO3组Edu阳性细胞率、克隆形成数、S期与G2/M期细胞比例及FOXO3蛋白表达均显著升高（均P<0.05），细胞凋亡率、G0/G1期细胞比例及FOXM1、caspase-3和caspase-8蛋白表达均显著下降（均P<0.05）。Cat组MCF-7细胞裸鼠移植瘤体积、质量和FOXO3蛋白表达均显著降低（均P<0.05），FOXM1的蛋白表达显著升高（P<0.05）。结论：Cat抑制乳腺癌MCF-7细胞增殖并促进凋亡，在体内抑制裸鼠移植瘤的生长，其机制可能与上调FOXO3、下调FOXM1的表达有关。

Pathophysiological Role of Variants of the Promoter Region of CITED2 Gene in Sporadic Tetralogy of Fallot Patients with Cellular Function Verification.

Tetralogy of Fallot (TOF) is a common congenital heart malformation. Genetic variants in the CITED2 coding region are known to be significantly associated with cardiac malformation, but the role of variants in the CITED2 promoter region in the development of TOF remains unclear. In this study, we investigated CITED2 promoter variants in the DNA of 605 subjects, including 312 TOF patients and 293 unrelated healthy controls, by Sanger sequencing. We identified nine CITED2 gene promoter variants (including one novel heterozygous variant). Six were found only in patients with TOF and none in the control group. The transcriptional activity of the CITED2 gene promoter in mouse cardiomyocyte (HL-1) cells was significantly altered by the six variants (p < 0.05). The results of the electrophoretic mobility change assay and JASPAR database analysis showed that these variants generated or destroyed a series of possible transcription factor binding sites, resulting in changes in the CITED2 protein expression. We conclude that CITED2 promoter variants in TOF patients affect transcriptional activity and may be involved in the occurrence and progression of TOF. These findings may provide new insights into molecular pathogenesis and potential therapeutic insights in patients with TOF.

Genetic Variants of CITED2 Gene Promoter in Human Atrial Septal Defects: Case-Control Study and Cellular Functional Verification.

Atrial septal defect (ASD) is one of the most common forms of congenital heart disease (CHD). Genetic variants in the coding region of the CITED2 gene are known to be significantly correlated with CHD, but the role of variants in the promoter region of CITED2 is unknown. We investigated variants in the promoter of the CITED2 gene in 625 subjects (332 ASD and 293 healthy controls) through Sanger sequencing. Four variants in the CITED2 gene promoter were found only in eight ASD patients with zero occurrence in the control subjects (one case of g.4078A>C(rs1165649373), one case of g.4240C>A(rs1235857801), four cases of g.4935C>T(rs111470468), two cases of g.5027C>T(rs112831934)). Cellular functional analysis showed that these four variants significantly changed the transcriptional activity of the CITED2 gene promoter in HEK-293 and HL-1 cells. Electrophoretic mobility change assay results and JASPAR database analysis demonstrated that these variants created or destroyed a series of possible transcription factor binding sites, resulting in changes in the expression of CITED2 protein. We conclude that the variants of CITED2 promoter in ASD patients affect the transcriptional activity and are likely involved in the occurrence and development of ASD. These findings provide new perspectives on the pathogenesis and potential therapeutic insights of ASD.

The effects of morning/afternoon surgeries on the early postoperative sleep quality of patients undergoing general anesthesia.

OBJECTIVE: This study aimed to investigate the effects of morning and afternoon surgeries on the early postoperative sleep function in patients undergoing general anesthesia. METHODS: Fifty nine patients, aged 18-60 years, American society of anaesthesiologists (ASA) grade I or II, Body mass index of 18.5-28 kg/m2, undergoing laparoscopic myomectomy under total intravenous anesthesia, were included in the study. These patients were divided into two groups according to the start time of anesthesia: morning surgery group (group A, 8:00-12:00) and afternoon surgery group (group P, 14:00-18:00). The sleep conditions of the two groups of patients were evaluated by the Athens Insomnia Scale (AIS) one day before and one day after the operation. A total score of > 6 was regarded as postoperative sleep disturbance. The incidences of sleep disturbance one day after the operation in two groups were compared. The bispectral Index assessed the patient's total sleep duration, sleep efficiency, and overall quality of sleep from 21:00 to 6:00 on the first night after surgery. Plasma concentrations of melatonin and cortisol at 6:00 am 1 day before surgery, 1 day after surgery were measured by ELISA, and rapid random blood glucose was measured. RESULTS: The total AIS score, overall quality of sleep, total sleep duration, and final awakening earlier than desired scores of the two groups of patients on the first night after surgery were significantly increased compared with preoperative scores (P < 0.01). In group P, the sleep induction and the physical and mental functioning during the day scores increased significantly after surgery compared with preoperative scores (P < 0.05). The postoperative AIS scores in group P increased significantly compared with those in group A (P < 0.01). The incidence of postoperative sleep disturbances (70.0%) in group P was significantly higher than that in group A (37.9%) (P < 0.05). Compared with group A, the total sleep duration under BIS monitoring in group P was significantly shorter, the sleep efficiency and the overall quality of sleep was significantly reduced (P < 0.01). Compared with those in group A, the level of melatonin on 1 d after surgery in group P was significantly decreased, and the level of cortisol in group P was significantly increased. There were no significant differences between the two groups in the levels of postoperative blood glucose and pain. CONCLUSION: Both morning and afternoon surgeries have significant impacts on the sleep function in patients undergoing general anesthesia, while afternoon surgery has a more serious impact on sleep function. TRIAL REGISTRATION: ClinicalTrials, NCT04103528. Registered 24 September 2019-Retrospectively registered, http://www. CLINICALTRIALS: gov/ NCT04103528.

Identification of novel rare copy number variants associated with sporadic tetralogy of Fallot and clinical implications.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Highly penetrant copy number variants (CNVs) and genes related to the etiology of TOF likely exist with differences among populations. We aimed to identify CNV contributions to sporadic TOF cases in Han Chinese. Genomic DNA was extracted from peripheral blood in 605 subjects (303 sporadic TOF and 302 unaffected Han Chinese [Control] from cardiac centers in China) and analyzed by genome-wide association study (GWAS). The GWAS results were compared with existing Database of Genetic Variants. These CNVs were further validated by qPCR. Bioinformatics analyses were performed with protein-protein interaction (PPI) network and KEGG pathway enrichment. Across all chromosomes 119 novel "TOF-specific CNVs" were identified with prevalence of CNVs of 21.5% in chromosomes 1-20 and 37.0% including Chr21/22. In chromosomes 1-20, CNVs on 11q25 (encompasses genes ACAD8, B3GAT1, GLB1L2, GLB1L3, IGSF9B, JAM3, LOC100128239, LOC283177, MIR4697, MIR4697HG, NCAPD3, OPCML, SPATA19, THYN1, and VPS26B) and 14q32.33 (encompasses genes THYN1, OPCML, and NCAPD3) encompass genes most likely to be associated with TOF. Specific CNVs found on the chromosome 21 (6.3%) and 22(11.9%) were also identified in details. PPI network analysis identified the genes covering the specific CNVs related to TOF and the signaling pathways. This study for first time identified novel TOF-specific CNVs in the Han Chinese with higher frequency than in Caucasians and with 11q25 and 14q32.33 not reported in TOF of Caucasians. These novel CNVs identify new candidate genes for TOF and provide new insights into genetic basis of TOF.

Endoplasmic reticulum stress mediates homocysteine-induced hypertrophy of cardiac cells through activation of cyclic nucleotide phosphodiesterase 1C.

Although the association of elevated homocysteine level with cardiac hypertrophy has been reported, the molecular mechanisms by which homocysteine induces cardiac hypertrophy remain inadequately understood. In this study we aim to uncover the roles of cyclic nucleotide phosphodiesterase 1 (PDE1) and endoplasmic reticulum (ER) stress and their relationship to advance the mechanistic understanding of homocysteine-induced cardiac cell hypertrophy. H9c2 cells and primary neonatal rat cardiomyocytes are exposed to homocysteine with or without ER stress inhibitor TUDCA or PDE1-specific inhibitor Lu AF58027, or transfected with siRNAs targeting PDE1 isoforms prior to homocysteine-exposure. Cell surface area is measured and ultrastructure is examined by transmission electron microscopy. Hypertrophic markers, PDE1 isoforms, and ER stress molecules are detected by q-PCR and western blot analysis. Intracellular cGMP and cAMP are measured by ELISA. The results show that homocysteine causes the enlargement of H9c2 cells, increases the expressions of hypertrophic markers ß-MHC and ANP, upregulates PDE1A and PDE1C, promotes the expressions of ER stress molecules, and causes ER dilatation and degranulation. TUDCA and Lu AF58027 downregulate ß-MHC and ANP, and alleviate cell enlargement. TUDCA decreases PDE1A and PDE1C levels. Silencing of PDE1C inhibits homocysteine-induced hypertrophy, whereas PDE1A knockdown has minor effect. Both cAMP and cGMP are decreased after homocysteine-exposure, while only cAMP is restored by Lu AF58027 and TUDCA. TUDCA and Lu AF58027 also inhibit cell enlargement, downregulate ANP, ß-MHC and PDE1C, and enhance cAMP level in homocysteine-exposed primary cardiomyocytes. ER stress mediates homocysteine-induced hypertrophy of cardiac cells via upregulating PDE1C expression Cyclic nucleotide, especially cAMP, is the downstream mediator of the ER stress-PDE1C signaling axis in homocysteine-induced cell hypertrophy.

Plasma Concentrations of Trace Elements Selenium and Cobalt During and After Coronary Artery Bypass Grafting Surgery.

Trace elements selenium (Se) and cobalt (Co) are essential in the human body, and a correlation between Se and cardiac surgery has been suggested. We investigated the plasma concentrations of Se and Co during and after coronary artery bypass grafting (CABG) surgery under cardiopulmonary bypass (CPB). From December 2019 to January 2020, preoperative plasma samples from isolated first-time CABG patients (n=20; 10 males, 10 females) were prospectively collected post-anesthesia and before CPB (T1), 45 min after CPB started (T2), 90 min after CPB started (T3), and postoperative days 1 (T4), and day 4 (T5). The plasma concentrations of Se and Co were measured. The Se concentration was significantly decreased at T2 (105.24±4.08 vs. 68.56±2.42 µg/L, p<0.001) and T3 (105.24±4.08 vs. 80.41±3.40 µg/L, p<0.001). The Co concentration was significantly decreased at T4 (0.35±0.19 vs. 0.26±0.13 µg/L, p<0.01) and T5 (0.35±0.19 vs. 0.23±0.11 µg/L, p<0.001). Five patients developed atrial fibrillation (AF); there was no other operative mortality or major morbidity. This is the first report of alterations of plasma Se and Co concentrations during and after CABG surgery. Our results may indicate that Se supplementation before or during CABG and Co supplementation after CABG may become necessary for patients undergoing CABG.