The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors.

INTRODUCTION: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. METHODS: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. RESULT: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2-10 months). CONCLUSION: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

Protocatechuic acid prevents isoproterenol-induced heart failure in mice by downregulating kynurenine-3-monooxygenase.

Protocatechuic acid (3,4-dihydroxybenzoic acid) prevents oxidative stress, inflammation and cardiac hypertrophy. This study aimed to investigate the therapeutic effects of protocatechuic acid in an isoproterenol-induced heart failure mouse model and to identify the underlying mechanisms. To establish the heart failure model, C57BL/6NTac mice were given high-dose isoproterenol (80 mg/kg body weight) for 14 days. Echocardiography revealed that protocatechuic acid reversed the isoproterenol-induced downregulation of fractional shortening and ejection fraction. Protocatechuic acid attenuated cardiac hypertrophy as evidenced by the decreased heart-weight-to-body-weight ratio and the expression of Nppb. RNA sequencing analysis identified kynurenine-3-monooxygenase (Kmo) as a potential target of protocatechuic acid. Protocatechuic acid treatment or transfection with short-interfering RNA against Kmo ameliorated transforming growth factor ß1-induced upregulation of Kmo, Col1a1, Col1a2 and Fn1 in vivo or in neonatal rat cardiac fibroblasts. Kmo knockdown attenuated the isoproterenol-induced increase in cardiomyocyte size, as well as Nppb and Col1a1 expression in H9c2 cells or primary neonatal rat cardiomyocytes. Moreover, protocatechuic acid attenuated Kmo overexpression-induced increases in Nppb mRNA levels. Protocatechuic acid or Kmo knockdown decreased isoproterenol-induced ROS generation in vivo and in vitro. Thus, protocatechuic acid prevents heart failure by downregulating Kmo. Therefore, protocatechuic acid and Kmo constitute a potential novel therapeutic agent and target, respectively, against heart failure.

Syringic acid mitigates isoproterenol-induced cardiac hypertrophy and fibrosis by downregulating Ereg.

Gallic acid has been reported to mitigate cardiac hypertrophy, fibrosis and arterial hypertension. The effects of syringic acid, a derivative of gallic acid, on cardiac hypertrophy and fibrosis have not been previously investigated. This study aimed to examine the effects of syringic acid on isoproterenol-treated mice and cells. Syringic acid mitigated the isoproterenol-induced upregulation of heart weight to bodyweight ratio, pathological cardiac remodelling and fibrosis in mice. Picrosirius red staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting analyses revealed that syringic acid markedly downregulated collagen accumulation and fibrosis-related factors, including Fn1. The results of RNA sequencing analysis of Ereg expression were verified using qRT-PCR. Syringic acid or transfection with si-Ereg mitigated the isoproterenol-induced upregulation of Ereg, Myc and Ngfr. Ereg knockdown mitigated the isoproterenol-induced upregulation of Nppb and Fn1 and enhancement of cell size. Mechanistically, syringic acid alleviated cardiac hypertrophy and fibrosis by downregulating Ereg. These results suggest that syringic acid is a potential therapeutic agent for cardiac hypertrophy and fibrosis.

Long-term clinical outcomes of type 1 vs. type 2 myocardial infarction in patients who underwent angiography: data from the Korea acute myocardial infarction-national institute of health registry.

Background: In the cause of increase the clinical research observational evidence on type 2 myocardial infraction (T2MI), the study compared the characteristics of T2MI and T1MI with respect to major adverse cardiac events (MACE) and mortality as long-term outcomes from a large, nationwide, prospective Korean cohort registry. Methods: From 13,105 consecutively enrolled individuals in the Korea Acute Myocardial Infarction-National Institute of Health (KAMIR-NIH) registry between October 2011 and December 2015, 11,053 acute myocardial infarction (AMI) patients were divided into the T1MI (n=10,545) and T2MI (n=508) groups. All patients completed ≥3 years of follow-up. Results: The Kaplan-Meier curve analysis and Cox proportional hazard regression models showed that the cumulative rate of MACE was similar between the 2 groups (11.4% vs. 13.4%, log-rank P=0.185) at 3 years. However, the T2MI group showed higher rates of all-cause death [12.6% vs. 9.4%, log-rank P=0.019; hazard ratio (HR), 1.42; 95% CI: 1.08-1.85; P=0.012] and non-cardiac death (3.5% vs. 5.3%, log-rank P=0.043; HR, 1.55; 95% CI: 1.01-2.37; P=0.043) than the T1MI group. Male sex (HR 1.540; 95% CI: 1.218-1.947, P<0.001), old age (≥65 years; HR, 3.546; 95% CI: 2.645-4.753, P<0.001), low hemoglobin level (<12 g/dL; HR, 2.335; 95% CI: 1.841-2.961, P<0.001), high heart rate (>100 beats/min; HR, 1.852; 95% CI: 1.436-2.388, P<0.001), low glomerular filtration rate (GFR) (<60 mL/min/1.73 m2; HR, 2.373; 95% CI: 1.874-3.005, P<0.001), high body mass index (>25 kg/m2; HR, 0.644; 95% CI: 0.514-0.805, P<0.001), and low left ventricular ejection fraction (LVEF) (<40%; HR, 1.487; 95% CI: 1.095-2.020, P=0.011) were the independent predictors for 3-year non-cardiac mortality. Conclusions: Although the 2 groups did not differ in MACE, the total mortality rate was higher in T2MI than in T1MI, especially non-cardiac mortality. The independent predictors for non-cardiac mortality were male sex, old age, anemia, low GFR, tachycardia, obesity, and low LVEF.

Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1-Sp1-PKCγ axis.

Cardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Here, we investigated the protective effects and the regulatory mechanism of protocatechuic acid, a phenolic compound, using a mouse model of isoproterenol-induced cardiac hypertrophy. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment also reduced the expression of isoproterenol-induced ROCK1, Sp1, and PKCγ both in vivo and in vitro. To investigate the mechanism, we performed knockdown and overexpression experiments. The knockdown of ROCK1, Sp1, or PKCγ decreased the isoproterenol-induced cell area and the expression of hypertrophic markers, while the overexpression of Sp1 or PKCγ increased the levels of hypertrophic markers. Protocatechuic acid treatment reversed these effects. Interestingly, the overexpression of Sp1 increased cell area and induced PKCγ expression. Furthermore, experiments using transcription inhibitor actinomycin D showed that ROCK1 and Sp1 suppression by protocatechuic acid was not regulated at the transcriptional level. Our results indicate that protocatechuic acid acts via the ROCK1/Sp1/PKCγ axis and therefore has promising therapeutic potential as a treatment for cardiac hypertrophy.

Selective HDAC8 Inhibition Attenuates Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis via p38 MAPK Pathway.

Histone deacetylase (HDAC) expression and enzymatic activity are dysregulated in cardiovascular diseases. Among Class I HDACs, HDAC2 has been reported to play a key role in cardiac hypertrophy; however, the exact function of HDAC8 remains unknown. Here we investigated the role of HDAC8 in cardiac hypertrophy and fibrosis using the isoproterenol-induced cardiac hypertrophy model system.Isoproterenol-infused mice were injected with the HDAC8 selective inhibitor PCI34051 (30 mg kg-1 body weight). Enlarged hearts were assessed by HW/BW ratio, cross-sectional area, and echocardiography. RT-PCR, western blotting, histological analysis, and cell size measurements were performed. To elucidate the role of HDAC8 in cardiac hypertrophy, HDAC8 knockdown and HDAC8 overexpression were also used. Isoproterenol induced HDAC8 mRNA and protein expression in mice and H9c2 cells, while PCI34051 treatment decreased cardiac hypertrophy in isoproterenol-treated mice and H9c2 cells. PCI34051 treatment also reduced the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), transcription factors (Sp1, Gata4, and Gata6), and fibrosis markers (collagen type I, fibronectin, and Ctgf) in isoproterenol-treated mice. HDAC8 overexpression stimulated cardiac hypertrophy in cells, whereas HDAC8 knockdown reversed those effects. HDAC8 selective inhibitor and HDAC8 knockdown reduced the isoproterenol-induced activation of p38 MAPK, whereas HDAC8 overexpression promoted p38 MAPK phosphorylation. Furthermore, p38 MAPK inhibitor SB203580 significantly decreased the levels of p38 MAPK phosphorylation, as well as ANP and BNP protein expression, induced by HDAC8 overexpression.Here we show that inhibition of HDAC8 activity or expression suppresses cardiac hypertrophy and fibrosis. These findings suggest that HDAC8 could be a promising target to treat cardiac hypertrophy and fibrosis by regulating p38 MAPK.

Association between interleukin gene polymorphisms and susceptibility to gastric cancer in the Qinghai population.

OBJECTIVE: To investigate the associations between interleukin (IL) gene polymorphisms and susceptibility to gastric cancer in the Qinghai population, China. METHODS: Patients with gastric cancer and cancer-free controls were enrolled into the study from Qinghai Provincial People's Hospital between September 2016 and September 2018. Single nucleotide polymorphisms (SNPs) were genotyped with the Sequenom MassARRAY® SNP genotype system. The Hardy-Weinberg equilibrium in allele and genotype frequencies, and general characteristics between patients with gastric cancer and cancer-free controls, were evaluated using χ2-test. Potential associations between interleukin gene variants and the risk of gastric cancer were analysed by logistic regression. RESULTS: Among eight candidate SNPs, the allele and genotype frequency distribution of IL-1B rs1143634 polymorphism was significantly different between patients with gastric cancer (n = 190) and cancer-free controls (n = 186). The IL-1B rs1143634 GA genotype and IL-1B rs1143634 GA + AA genotype were associated with a reduced risk of gastric cancer, however, the remaining SNPs were not statistically associated with gastric cancer risk in the Qinghai population. CONCLUSION: The IL-1B rs1143634 polymorphism might be associated with a decreased risk of gastric cancer, and may be a protective factor against gastric cancer.

Higher Long-Term Mortality in Patients with Non-ST-Elevation Myocardial Infarction than ST-Elevation Myocardial Infarction after Discharge.

PURPOSE: This study aimed to compare mortality rates after discharge between the patients with non-ST-elevation myocardial infarction (NSTEMI) and those with ST-elevation myocardial infarction (STEMI), and identify each mortality risk factors in these two types of myocardial infarction. MATERIALS AND METHODS: Between 2011 and 2015, 13105 consecutive patients were enrolled in the Korea Acute Myocardial Infarction-National Institute of Health registry (KAMIR-NIH); 12271 patients with acute myocardial infarction met the inclusion criteria and were further stratified into the STEMI (n=5828) and NSTEMI (n=6443) groups. The occurrence of mortality and cardiac mortality at 3 years were compared between groups, and the factors associated with mortality for NSTEMI and STEMI were evaluated. RESULTS: The comparison between these two groups and long-term follow-up outcomes showed that the cumulative rates of all-cause and cardiac mortality were higher in the NSTEMI group than in the STEMI group [all-cause mortality: 10.9% vs. 5.8%; hazards ratio (HR), 0.464; 95% confidence interval (CI), 0.359-0.600, p<0.001; cardiac mortality: 6.6% vs. 3.5%, HR, 0.474; 95% CI, 0.344-0.654, p<0.001, respectively). In the NSTEMI group, low left ventricular ejection fraction (LVEF; <40%), no percutaneous coronary intervention (PCI), old age (≥65 years), and low hemoglobin level (<12 g/dL) were identified as risk factors for 3-year mortality. In the STEMI group, old age, low glomerular filtration rate (<60 mL/min/1.73 m²), low LVEF, high heart rate (>100 beats/min), no PCI, and low hemoglobin level were identified as the risk factors for 3-year mortality. CONCLUSION: The NSTEMI group had higher mortality compared to the STEMI group during the 3-year clinical follow-up after discharge. Low LVEF and no PCI were the main risk factors for mortality in the NSTEMI group. In contrast, old age and renal dysfunction were the risk factors for long-term mortality in the STEMI group.

HDAC5 inhibition reduces angiotensin II-induced vascular contraction, hypertrophy, and oxidative stress in a mouse model.

Non-specific histone deacetylase (HDAC) inhibition reduces high blood pressure in essential hypertensive animal models. However, the exact HDAC isoforms that play a critical role in controlling hypertension are not known. Here, we investigated the role of HDAC5 in vascular contraction, hypertrophy, and oxidative stress in the context of angiotensin II (Ang II)-induced hypertension. Genetic deletion of HDAC5 and treatment with class IIa HDAC inhibitors (TMP269 and TMP195) prevented Ang II-induced increases in blood pressure and arterial wall thickness. Hdac5-knockout mice were also resistant to the thromboxane A2 agonist (U46619)-induced vascular contractile response. Furthermore, the expression of Rho-associated protein kinase (ROCK) 2 was downregulated in the aortas of Ang II-treated Hdac5-knockout mice. Knockdown of HDAC5, RhoA, or ROCK2 reduced collagen gel contraction, whereas silencing of ROCK1 increased it. VSMC hypertrophy reduced on knocking down HDAC5, ROCK1, and ROCK2. Here we showed that genetic deletion of HDAC5 and pharmacological inhibition of class IIa HDACs ameliorated Ang II-induced ROS generation. Moreover, ROCK1 and ROCK2, the downstream targets of HDAC5, influenced ROS generation. The relative protein levels of HDAC5, ROCK1, and ROCK2 were increased both in the cytoplasm and nuclear fraction in response to Ang II stimulation in vascular smooth muscle cells. Inhibition of HDAC5 expression or activity reduced vascular hypertrophy, vasoconstriction, and oxidative stress in the Ang II-induced hypertension model. These findings indicate that HDAC5 may serve as a potential target in the treatment of hypertension.

Long-Term Clinical Outcome according to Changes of Glomerular Filtration Rate in AMI Patients with Multivessel Disease after Percutaneous Coronary Intervention.

Glomerular filtration rate (GFR) is an important indicator of renal failure. However, regarding delta GFR in acute myocardial infarction (AMI) is rare. In this study, it was examined whether the delta GFR had an adverse effect on outcomes in patients with AMI and multivessel disease (MVD). Among 13,105 consecutive patients enrolled in the Korea Acute Myocardial Infarction-National Institute of Health registry, 2619 with AMI and MVD who underwent percutaneous cardiac intervention (PCI) were assigned to the better delta GFR (group I, n=1432 [54.7%]) or worse delta GFR (group II, n=1187 [45.3%]) groups and followed for 3 or more years. The mean age of group I was lower than that of group II (62.64±11.52 years vs. 64.29±11.64 years; p<0.001). On multivariate analysis, delta GFR (hazard ratio, 1.50; 95% confidence interval, 1.05-2.13; p=0.024) was a negative risk factor for adverse cardiac events. Age over 65 years (p<0.001), history of MI (p=0.008), low hemoglobin (p<0.001), high triglyceride (p=0.008), low high-density lipoprotein cholesterol (p=0.002), and low left ventricular ejection fraction (LVEF) (p<0.001) were prognostic factors for major adverse cardiac events (MACE). In patients with a GFR <60 mL/min/1.73 m2, mortality was increased by 0.9% in the multivessel PCI group and 0.7% in the IRA-only PCI group at the 1-year follow-up. According to the 3-year clinical follow-up analysis, prognosis was better in better delta GFR patients with AMI and MVD who underwent PCI than in worse delta GFR patients.

LncRNA SNHG16 Functions as an Oncogene by Sponging MiR-135a and Promotes JAK2/STAT3 Signal Pathway in Gastric Cancer.

lncRNA can serve as a miRNA sponge and block the function of miRNA. High expression of lncRNA SNHG16 (small nucleolar RNAhostgene16) was discovered in gastric cancer (GC) and many other tumors. However, the mechanism of SNHG16 in GC is still unclear. In this research, we detected the expression level of SNHG16 in GC tissues and cell lines by qRT-PCR and FISH assay. RIP and Dual Luciferase Reporter Assay revealed that miR-135a is a target of SNHG16. SNHG16 gene knockdown experiment indicated that the expression level of SNHG16 can influence GC cells proliferation, colony formation, invasion ability and apoptosis in a miR-135a dependent manner. Western Blot assay showed that knockdown of SNHG16 decreased the expression of JAK2 and p-STAT3 in GC cells while miR-135a can offset the facilitated impact. Then the expression level of SNHG16 and miR-135a in the si-STAT3 GC cells was detected by qRT-PCR and the results showed that SNHG16 may be a target gene of p-STAT3. Collectively, it was suggested that SNHG16 can serve as a miR-135a sponge and block the function of miR-135a in JAK2/STAT3 pathway.