Loss of NDUFS1 promotes gastric cancer progression by activating the mitochondrial ROS-HIF1α-FBLN5 signaling pathway.

BACKGROUND: Recent studies suggested that NDUFS1 has an important role in human cancers; however, the effects of NDUFS1 on gastric cancer (GC) are still not fully understood. METHODS: We confirmed that NDUFS1 is downregulated in GC cells through western blot immunohistochemistry and bioinformation analysis. The effect of NDUFS1 on GC was studied by CCK-8, colony formation, transwell assay in vitro and Mouse xenograft assay in vivo. Expression and subcellular localization of NDUFS1 and the content of mitochondrial reactive oxygen species (mROS) was observed by confocal reflectance microscopy. RESULTS: Reduced expression of NDUFS1 was found in GC tissues and cell lines. Also, NDUFS1 overexpression inhibited GC cell proliferation, migration, and invasion in vitro as well as growth and metastasis in vivo. Mechanistically, NDUFS1 reduction led to the activation of the mROS-hypoxia-inducible factor 1α (HIF1α) signaling pathway. We further clarified that NDUFS1 reduction upregulated the expression of fibulin 5 (FBLN5), a transcriptional target of HIF1α, through activation of mROS-HIF1α signaling in GC cells. CONCLUSIONS: The results of this study indicate that NDUFS1 downregulation promotes GC progression by activating an mROS-HIF1α-FBLN5 signaling pathway.

Identification and validation of crucial lnc-TRIM28-14 and hub genes promoting gastric cancer peritoneal metastasis.

BACKGROUND: Gastric cancer peritoneal metastasis (GCPM) is an important cause of cancer-related deaths worldwide. Long non-coding RNAs (lncRNAs) play a key role in the regulation of GCPM, but the underlying mechanisms have not been elucidated. METHODS: High-throughput RNA sequencing (RNA-seq) was performed on four groups of clinical specimens (non-metastatic gastric cancer primary tumor, adjacent normal gastric mucosal tissue, gastric cancer primary tumor with peritoneal metastasis and adjacent normal gastric mucosal tissue). After sequencing, many lncRNAs and mRNAs were screened for further Weighted Gene Co-expression Network Analysis (WGCNA). GCPM-related hub lncRNAs and genes were identified by cytoHubba and validated by Quantitative real-time PCR (qRT-PCR), Receiver operating characteristic curve (ROC) analysis and Kaplan-Meier survival analysis. GO, KEGG and GSEA showed GCPM-related pathways. Correlation analysis revealed the potential relationship between hub lncRNAs and genes. RESULTS: By analyzing lncRNA expression data by WGCNA, we found that blue module was highly correlated with GCPM (r = 0.44, p = 0.04) and six lncRNAs involved in this module (DNM3OS, lnc-MFAP2-53, lnc-PPIAL4C-4, lnc-RFNG-1, lnc-TRIM28-14 and lnc-YARS2-4) were identified. We then performed qRT-PCR validation of gastric cancer specimens and found that the expression of lnc-RFNG-1 and lnc-TRIM28-14 was significantly increased in gastric cancer tissues with peritoneal metastasis. Kaplan-Meier survival analysis showed shorter overall survival time (OS) for gastric cancer patients with high expression of lnc-TRIM28-14. Receiver operating characteristic curve (ROC) analysis showed that lnc-TRIM28-14 could improve the sensitivity and specificity of GCPM diagnosis. In addition, we identified three key mRNAs (CD93, COL3A1 and COL4A1) associated with gastric cancer peritoneal metastasis through WGCNA analysis and clinical specimen validation. Moreover, there was a positive correlation between lnc-TRIM28-14 and the expression of CD93 and COL4A1 in gastric cancer peritoneal metastasis, suggesting a regulatory relationship between them. Subsequent GO, KEGG and GSEA analysis suggested that ECM-receptor interaction and focal adhesion were the hub pathways of GCPM. CONCLUSION: In summary, lnc-RFNG-1, lnc-TRIM28-14, CD93, COL3A1 and COL4A1 could be novel tumor biomarkers and potential therapeutic targets for GCPM.

Impact of red blood cell distribution width on long-term mortality in patients with ST-elevation myocardial infarction.

OBJECTIVES: Recent studies have reported increased red blood cell distribution width (RDW) has been associated with adverse outcomes in heart failure and stable coronary disease. We investigated the association between RDW and risk of all-cause mortality in patients with ST-elevation myocardial infarction (STEMI) who were free of heart failure at baseline. METHODS: We enrolled 691 patients with STEMI who were free of heart failure at baseline confirmed by coronary angiography in Beijing Friendship Hospital from January 2007 to December 2008. According to the median RDW at baseline (13.0%) on admission, the patients were divided into two groups: a low-RDW group (RDW <13.0%, n = 329) and a high-RDW group (RDW ≥13.0%, n = 362). All-cause mortality rates were compared between groups. Mean duration of follow-up was 41.8 months. The relation between RDW and clinical outcomes after hospital discharge were tested using Cox regression models, adjusting for clinical variables. At the same time, the sensitivity and specificity of RDW were analyzed by ROC analysis. RESULTS: Forty-seven patients (6.8%) died during follow-up. The cumulative incidence of all-cause death was significantly higher in the high-RDW group than in the low-RDW group (log-rank p = 0.007). Multivariate analysis revealed that high RDW was associated with all-cause mortality (hazard ratio: 3.43; 95% confidence interval: 1.17-8.32; p = 0.025). The area under the ROC curve was 0.562. CONCLUSION: From the statistical point of view, increased RDW is associated with all-cause and cardiac mortality rates in patients with STEMI who were free of heart failure at baseline. But RDW is a marker with a very low prognostic accuracy that does not seem to be clinically helpful.

Capture of regulatory factors via CRISPR-dCas9 for mechanistic analysis of fine-tuned SERRATE expression in Arabidopsis.

SERRATE (SE) plays an important role in many biological processes and under biotic stress resistance. However, little about the control of SE has been clarified. Here we present a method named native chromatin-associated proteome affinity by CRISPR-dCas9 (CASPA-dCas9) to holistically capture native regulators of the SE locus. Several key regulatory factors including PHYTOCHROME RAPIDLY REGULATED 2 (PAR2), WRKY DNA-binding protein 19 (WRKY19) and the MYB-family protein MYB27 of SE are identified. MYB27 recruits the long non-coding RNA-PRC2 (SEAIR-PRC2) complex for H3K27me3 deposition on exon 1 of SE and subsequently represses SE expression, while PAR2-MYB27 interaction inhibits both the binding of MYB27 on the SE promoter and the recruitment of SEAIR-PRC2 by MYB27. The interaction between PAR2 and MYB27 fine-tunes the SE expression level at different developmental stages. In addition, PAR2 and WRKY19 synergistically promote SE expression for pathogen resistance. Collectively, our results demonstrate an efficient method to capture key regulators of target genes and uncover the precise regulatory mechanism for SE.

ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis.

The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.

CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1.

Metastasis is an important factor contributing to poor prognosis in patients with gastric cancer; yet, the molecular mechanism leading to this cell behavior is still not well understood. In this study, we explored the role of cysteine protease inhibitor SN (Cystatin SN, CST1) in promoting gastric cancer metastasis. We hypothesized that CST1 could regulate gastric cancer progression by regulating GPX4 and ferroptosis. Whole transcriptome sequencing suggested that the expression of CST1 was significantly increased in metastatic cancer, and high CST1 expression was correlated with a worse prognosis. Our data further confirmed that the overexpression of CST1 may significantly promote the migration and invasion of gastric cancer cells in vitro and enhance liver, lung, and peritoneal metastasis of gastric cancer in nude mice. Meanwhile, high expression of CST1 promoted the epithelial-mesenchymal transition (EMT) of gastric cancer cells. Mechanistically, a co-immunoprecipitation experiment combined with mass spectrometry analysis confirmed that CST1 could interact with GPX4, a key protein regulating ferroptosis. CST1 relieves GPX4 ubiquitination modification by recruiting OTUB1, improving GPX4 protein stability and reducing intracellular reactive oxygen species (ROS), thereby inhibiting ferroptosis and, in turn, promoting gastric cancer metastasis. Moreover, clinical data suggested that CST1 is significantly increased in peripheral blood and ascites of gastric cancer patients with metastasis; multivariate Cox regression model analysis showed that CST1 was an independent risk factor for the prognosis of gastric cancer patients. Overall, our results elucidated a critical pathway through which high CST1 expression protects gastric cancer cells from undergoing ferroptosis, thus promoting its progression and metastasis. CST1 may be used as a new oncological marker and potential therapeutic target for gastric cancer metastasis.

Risk Factors and Timing of Additional Surgery after Noncurative ESD for Early Gastric Cancer.

Background: Patients with early gastric cancer undergoing noncurative endoscopic submucosal dissection (ESD) have a risk of tumor recurrence and metastasis, and some patients need additional surgery. The purpose of this study was to explore the risk factors of cancer residue and lymph node (LN) metastasis after noncurative ESD for early gastric cancer and to compare the short outcome of early and delayed additional surgery. Methods: The clinicopathological characteristics of 30 early gastric cancer patients who received noncurative ESD and additional surgery were studied retrospectively. Multivariable regression was utilized to examine the independent risk factors for residual cancer and LN metastasis. Receiver operating characteristic curve was used to analyze the multivariable model's predictive performance. Furthermore, the perioperative safety and radical tumor performance of early surgery (≤30 days, n = 11), delayed surgery (>30 days, n = 11) after ESD, and upfront surgery (n = 59) were compared. Results: Multivariable regression showed that diffuse type of Lauren classification, submucosal invasion, and positive human epidermal growth factor receptor-2 (HER-2) were risk factors for residual cancer. Undifferentiated carcinoma, vascular invasion, and positive vertical margin were risk factors for LN metastasis. The area under the curve (AUC) of the multifactor model predicting cancer residue and LN metastasis was 0.761 and 0.792, respectively. The early surgery group experienced higher intraoperative blood loss and a longer operation time than the delayed surgery and upfront surgery groups. There was no significant difference in the number of LN dissections, LN metastasis rate, and postoperative complications among the three groups. Conclusion: Diffuse type of Lauren classification, submucosal invasion, and positive HER-2 are risk factors for residual cancer, while undifferentiated carcinoma, vascular invasion, and positive vertical margin are risk factors for LN metastasis. Delayed additional surgery after ESD (>30 days) has higher intraoperative safety, without affecting the radical resection in early gastric cancer patients.

Huaier increases the antitumor effect of gemcitabine on pancreatic cancer in vitro and in vivo.

BACKGROUND: Pancreatic cancer has a high degree of malignancy and poor prognosis. As the first-line chemotherapy drug for pancreatic cancer, gemcitabine is widely used but is limited in its efficacy due to the development of chemoresistance. Huaier is a traditional Chinese medicine with anticancer effects. This present study explored the antitumor effect of gemcitabine combined with Huaier on pancreatic cancer in vitro and in vivo. METHODS: After treatment with gemcitabine combined with Huaier in PaTu8988 pancreatic cancer cells, including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, wound healing, and Transwell invasion in vitro assays were performed to investigate the proliferation, migration and invasion of cells, respectively. The apoptotic rate of cells was detected by propidium iodide-annexin V staining and flow cytometry. In vivo PaTu8988 pancreatic cancer xenograft and tail vein injection into lung metastasis nude mice models were used to determine the tumor growth and lung metastasis efficiency. RESULTS: Huaier could not only inhibit the proliferation, migration, and invasion of cancer cells, but could also induce the apoptosis of pancreatic cancer in vitro and suppress tumor growth and lung metastasis in vivo. It further significantly increased the tumor suppressing effects of gemcitabine, and combined use of the two drugs exhibited a synergistic effect. CONCLUSIONS: Our present study concluded that Huaier was capable of enhancing the antitumor effect of gemcitabine in pancreatic cancer in vitro and in vivo. Therefore, Huaier may be a potential drug to increase the therapy sensitivity of gemcitabine and improve the prognosis of pancreatic cancer patients.

IL-36ß promotes anti-tumor effects in CD8+ T cells by downregulating micro-RNA let-7c-5p.

BACKGROUND: The anti-tumor effect of interleukin (IL)-36ß-mediated activation of CD8+ T cells has been reported, but the molecular mechanism is largely undefined. METHODS: The levels of IL-36ß in pancreatic cancer were examined by quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. Cytology and animal experiments were performed to study the effects of IL-36ß on the growth of pancreatic cancer cells. We then examined the changes of CD8+ T cells and natural killer (NK) cells in the tumor by flow cytometry. The microRNA expression profiles were determined by microarray analysis. RESULTS: The results revealed decreased levels of IL-36ß in pancreatic cancer tissues. In addition, IL-36ß inhibited tumor growth and promoted CD8+ T and NK cell proliferation in the tumor microenvironment (TME). Moreover, IL-36ß stimulated CD8+ T cells to synthesize high amounts of interferon-gamma (IFN-γ) and IL-2. Microarray analysis showed that IL-36ß administration to human and mouse CD8+ T cells consistently downregulated the miRNA, let-7c-5p. Downregulation of let-7c-5p resulted in IFN-γ and IL-2 upregulation in CD8+ T cells, whereas its upregulation had the opposite effect. Further experiments demonstrated that IL-36ß downregulated IFN-γ in let-7c-5p+ CD8+ T cells. CONCLUSIONS: These findings suggest IL-36ß promotes IFN-γ and IL-2 production in CD8+ T cells, as well as anti-tumor effects in CD8+ T cells by downregulating let-7c-5p.

IL-9 Exerts Antitumor Effects in Colon Cancer and Transforms the Tumor Microenvironment In Vivo.

As a newly discovered cytokine, interleukin 9 was initially considered a T-lymphocyte growth factor. Interleukin 9 affects target cells by binding to a member of the γc-family of receptors and is involved in inflammation, autoimmune diseases, and other ailments. In recent years, mounting evidence reveals that interleukin 9 exerts antitumor effects, which has attracted considerable attention. Many previous studies were performed in vivo by establishing a mouse model of melanoma. Here, interleukin 9 protein and messenger RNA expression levels were both low in colon carcinoma tissue specimens, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction. In addition, interleukin 9 expression in these samples was correlated with TNM staging, Dukes staging, lymph node metastasis, and good prognosis, but not with gender, age, tumor size, tumor differentiation, and hepatic metastasis. In vivo, by establishing a mouse subcutaneous allograft model, we found that interleukin 9 overexpression inhibited tumor growth and resulted in longer survival time. Then, antitumor immune responses were increased by interleukin 9 as demonstrated by flow cytometry. Furthermore, interleukin 9 was shown to exert antitumor effects by regulating T-cell function and killing tumor cells in the tumor microenvironment. Overall, this study revealed that interleukin 9 exerts robust antitumor effects in colon cancer and transforms the tumor microenvironment in vivo.

Interleukin enhancer binding factor 2 is a prognostic biomarker for breast cancer that also predicts neoadjuvant chemotherapy responses.

Interleukin enhancer binding factor 2 (ILF2) participates in several aspects of DNA and RNA metabolism and regulates gene expression at multiple levels; however, its role in breast cancer remains undefined. The variant statuses of ILF2 in human breast cancer were evaluated using the COSMIC database. Altered ILF2 expression in normal breast tissue relative to cancer tissue and in breast cancer patients with different clinicopathological characteristics, molecular subtypes, clinical outcomes and chemotherapy responses were examined using the Oncomine, GOBO, Kaplan-Meier plotter and GEO datasets. To explore possible biological networks connected to ILF2 in breast cancer, we performed ingenuity pathway analysis on ILF2-related differentially expressed genes. We found that many breast cancers had increased ILF2 copy number variations and increased ILF2 expression. We also observed that elevated ILF2 expression was correlated with aggressive features, such as high histological grade, BRCA1 mutations, and the triple-negative/basal-like subtype, which resulted in shorter survival in these cases. Moreover, ILF2 expression predicted responses to anthracycline/taxane-based treatment. Ingenuity pathway analysis revealed that ILF2-related biological functions included promoting cell survival, viability, and proliferation, as well as cell cycle progression and DNA repair. Certain well-known oncogenes (MYC and HGF), cytokines (CSF2, IFNG and IL5) and microRNAs (miR-21, miR-155-5p and let-7) may participate in the ILF2 expression network in breast cancer. In summary, ILF2 is involved in the development and progression of breast cancer and may be a predictive biomarker for better responses to anthracycline/taxane-based treatments.

Platelet to Lymphocyte Ratio Predicts Contrast-Induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

We investigated the relationship between platelet to lymphocyte ratio (PLR) and contrast-induced nephropathy (CIN) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). We enrolled 5719 patients in 3 tertiary hospitals from January 2005 to December 2010. The PLR was calculated as the ratio of platelet to lymphocyte counts on admission. Serum creatinine level was measured before and within 72 hours after contrast medium administration. To evaluate the relation between PLR and CIN, the 5719 patients were divided into a CIN group and a non-CIN group. Contrast-induced nephropathy occurred in 252 (4.4%) patients. Patients in the CIN group had significantly higher PLR than those in the non-CIN group (173.8 [62.3] and 116.2 [51.7], respectively; P < .001). In logistic regression analysis, PLR was an independent predictor of CIN (odds ratio: 1.432, 95% confidence interval: 1.205-1.816, P = .031), along with age, diabetes mellitus, creatinine, estimated glomerular filtration rate, and neutrophil to lymphocyte ratio. In conclusion, a higher PLR was an independent risk factor for the development of CIN in patients with STEMI undergoing pPCI.

Impact of Platelet-to-Lymphocyte Ratio on Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction.

We investigated the association between platelet-to-lymphocyte ratio (PLR) and clinical outcomes (including all-cause mortality, recurrent myocardial infarction, heart failure, serious cardiac arrhythmias and ischemic stroke) in patients with ST-segment elevation myocardial infarction (STEMI). Based on PLR quartiles, 5886 patients with STEMI were categorized into 4 groups: <98.8 (n = 1470), 98.8 to 125.9 (n = 1474), 126.0 to 163.3 (n = 1478), >163.3 (n = 1464), respectively. We used Cox proportional hazards models to examine the relation between PLR and clinical outcomes. Mean duration of follow-up was 81.6 months, and 948 patients (16.1%) died during follow-up. The lowest mortality occurred in the lowest PLR quartile group ( P = 0.006), with an adjusted hazard ratio of 1.18 (95% confidence interval [CI], 1.04-1.55), 1.31 (95% CI, 1.18-1.64), and 1.59 (95% CI, 1.33-1.94) in patients with PLR of 98.8 to 125.9, 126.0 to 163.3, >163.3, respectively. Higher levels of PLR were also associated with recurrent myocardial infarction ( Ptrend = .023), heart failure ( Ptrend = .018), and ischemic stroke ( Ptrend = .043). In conclusion, a higher PLR was associated with recurrent myocardial infarction, heart failure, ischemic stroke, and all-cause mortality in patients with STEMI.

B7-H3 combats apoptosis induced by chemotherapy by delivering signals to pancreatic cancer cells.

OBJECTIVE: This study aimed to investigate the role of B7-H3 in chemotherapy resistance of pancreatic cancer cells and discover the potential signal transduction pathway and molecular targets involved. METHODS: Immunohistochemical staining and real-time polymerase chain reaction (PCR) were used to determine the expression of B7-H3 in clinical specimens. Clinical data were applied to survival analysis. Phosphoprotein was purified from cultured Patu8988 cells using the Phosphoprotein Purification Kit. Cell apoptosis was detected using propidium iodide-Annexin V staining to investigate the relation between the expression of B7-H3 and Patu8988 cells treated with gemcitabine. Western blot was used to determine the effect of B7-H3 on the expression of proteins including extracellular signal-regulated kinase (ERK)1/2, epidermal growth factor receptor (EGFR), and Inhibitor of NF-κB(IκB) in Patu8988 cells; B7-H3 was activated by 4H7, which as an agonist monoclonal antibody to B7-H3. RESULTS: The expression of B7-H3 was found to be higher in tumor tissues than in normal tissues of pancreatic carcinoma. Survival analysis revealed that patients in the low-B7-H3 expression group were likely to have a longer overall survival compared with those in the high-expression group (P < 0.05). B7-H3 activated by 4H7 could reduce gemcitabine-induced apoptosis in Patu8988 cells. Activation of B7-H3 by 4H7 induced variations in p-ERK1/2, EGFR, and IκB protein levels. When B7-H3 was upregulated, the expression levels of EGFR and p-ERK1/2 proteins significantly increased (P < 0.05), but the expression level of IκB significantly decreased (P < 0.05), especially in the gemcitabine-treated group. CONCLUSION: This study demonstrated that B7-H3 could deliver signals to pancreatic cancer cells to combat apoptosis induced by gemcitabine.

Can axillary radiotherapy replace axillary dissection for patients with positive sentinel nodes? A systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of axillary radiotherapy (ART) with that of completion axillary lymph node dissection (cALND) in clinically node-negative breast cancer patients with a positive sentinel lymph node. METHODS: A literature search was performed in PubMed, EMBASE and Cochrane Library by using the search terms "breast cancer", "sentinel lymph node biopsy", "axillary radiotherapy" or "regional node irradiation" for articles published between 2004 and 2016. Only randomized controlled trials that included patients with positive sentinel nodes were included in the meta-analysis. RESULTS: Two randomized controlled trials and three retrospective studies were identified. The reported overall survival rate (hazard ratio [HR] = 1.09, 95% confidence interval [CI]: 0.75-1.43, P = 0.365), disease-free survival rate (HR = 1.01, 95% CI: 0.58-1.45, P = 0.144), and axillary recurrence rate (1.2% and 0.4%, and 1.3% and 0.8%, respectively) were similar in both groups. The absence of knowledge on the extent of nodal involvement in the ART group appeared to have no major impact on the administration of adjuvant systemic therapy. CONCLUSIONS: ART is not inferior to cALND in the patients with clinically node-negative breast cancer who had a positive sentinel lymph node. Information obtained by using cALND after SLNB may have no major impact on the administration of adjuvant systemic therapy.

Short- and Long-term Outcomes in Patients with Connective Tissue Diseases Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in patients with connective tissue diseases (CTDs). Risk factors and clinical characteristics in these patients are not equivalent to those in traditional CAD patients. The objective of this study was to report short- and long-term clinical outcomes in a consecutive series of patients with CTD who underwent percutaneous coronary intervention (PCI) with stent implantation. METHODS: The study group comprised 106 consecutive patients with CTD who underwent PCI in Beijing Friendship Hospital between January 2009 and June 2012. Medical records were analyzed retrospectively including clinical basic material, coronary angiogram data, and the incidence of major adverse cardiac events (MACEs) during the short- and long-term (median 3 years) follow-up. RESULTS: Ninety-two of the patients (86.8%) had one or more traditional CAD risk factors. Multivessel disease was present in more than 2/3 of patients (73.6%). The left anterior descending coronary artery was the most commonly affected vessel (65.1%). Five bare-metal stents and 202 drug-eluting stents were implanted. After a median follow-up period of 36 months, thirteen patients (12.3%) died from cardiac causes, the rate of stent thrombosis was 9.4%, and the rate of target vessel revascularization (TVR) was 14.2%. Multivariate analysis revealed that hypertension (hazard ratio [HR] = 3.07, 95% confidence interval [CI]: 1.30-7.24, P = 0.041), anterior myocardial infarction (HR = 2.77, 95% CI: 1.06-7.03, P = 0.04), longer duration of steroid treatment (HR = 3.60, 95% CI: 1.43-9.08, P = 0.032), and C-reactive protein level >10 mg/L (HR = 3.98, 95% CI: 1.19-12.56, P = 0.036) were independent predictors of MACEs. CONCLUSIONS: Patients with CTD and CAD may have severe coronary lesions. PCI in these patients tends to result in an increased rate of stent thrombosis and TVR during long-term follow-up, which may be influenced by traditional and nontraditional risk factors.

Associations between human aldosterone synthase CYP11B2 (-344T/C) gene polymorphism and antihypertensive response to valsartan in Chinese patients with essential hypertension.

Aldosterone synthase is a mitochondrial enzyme that catalyzes the conversion of 11-deoxycorticosterone to the potent mineralocorticoid aldosterone. The gene encoding aldosterone synthase, CYP11B2, is associated with essential hypertension. But if the genetic variations in aldosterone synthesis could influence the antihypertensive response to Valsartan is not clear. A Chinese sample of 502 persons (217 women) was studied, which was divided into the hypertensive group (EH) of 345 persons and the normotensive group (NB) of 157 persons. Subjects were genotyped through the use of the polymerase chain reaction for the diallelic polymorphisms in CYP11B2. 98 persons of the essential hypertension group received 4 weeks therapy with valsartan. Blood pressure, 24-hour ambulatory blood pressure, biochemical index were also determined. The frequency of CC+CT genotypes in hypertensive group was significantly higher than that in normotensive group (P<0.05), the frequency of C allele of gene CYP11B2 (-344T/C) in hypertensive group was significantly higher than that in normotensive group (P<0.01). The descending values of SBP (systolic blood pressure), DBP (diastolic blood pressure), MAP (mean arterial pressure), 24 h SBP (mean SBP of 24 hours), 24 h DBP (mean DBP of 24 hours), 24 h MAP (mean arterial pressure of 24 hours) of CC+CT genotype group were significantly higher than those of the TT genotype group (P<0.05). The aldosterone synthase CYP11B2 (-344T/C) gene polymorphism is associated with essential hypertension in Chinese. And the aldosterone synthase CYP11B2 (-344T/C) gene polymorphism may be the predictor of the antihypertensive response to Valsartan.

Remodeling of small intramyocardial coronary arteries distal to total occlusions after myocardial infarction in pigs.

OBJECTIVE: The present study was designed to investigate whether microvascular remodeling could occur in hibernating myocardium and infarction regions distal to a total occluded coronary artery after acute myocardial infarction. MATERIALS AND METHODS: Copper stents were implanted in the left descending coronary arteries of 64 pigs to induce anterior wall myocardial infarction. The pigs were assigned randomly to group A (n=8; killed at 1 week), group B (n=8; killed at 2 weeks), group C (n=16; killed at 4 weeks), group D (n=16; killed at 3 months), and group E (n=16; killed at 6 months). The control group included six pigs that were subjected to the same procedures but without implantation of copper stents. The wall area (WA) and lumen area (LA) of small intramyocardial coronary arteries (SIMCA) distal to occlusions were measured and the ratios of WA/LA and LA/total vessel area (%L) were calculated. The composition of the arterial wall was determined by Masson's trichrome stain, transmission electron microscope. RESULTS: A significant increase in WA/LA and decrease %L in SIMCA were observed in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control. There was increased area of collagen fiber in the thickened arterial wall in group C (P<0.05), group D (P<0.01), and group E (P<0.01) compared with the control group, group A, and group B. A significantly increased ratio of the synthetic phenotype vascular smooth muscle cells were found in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control group. CONCLUSION: Several weeks after occlusion of epicardial coronary, the SIMCAs distal to occlusion developed remodeling, with an increase in wall thickness and a decrease in lumen size. These structural changes may restrict blood flow to ischemic or hibernating myocardium after revascularization.