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Background: Patients with acute myocardial infarction (AMI) are usually treated with angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) if ACEIs are not tolerated. However, there is no data regarding the impact of switching from ACEIs to ARBs on long-term clinical outcomes in AMI patients with preserved left ventricular (LV) systolic function especially beyond 1 year. To investigate the effectiveness of treatment with ACEIs or ARBs on clinical outcomes over 3 years in AMI patients with preserved LV systolic function following percutaneous coronary intervention.Method: It is a prospective cohort study using data from a nationwide large scale registry with 53 hospitals involved in treatment of acute myocardial infarction (AMI) in Korea. Between March 2011 and September 2015, we enrolled 6236 patients with AMI who underwent primary percutaneous coronary intervention and had a left ventricular ejection fraction ≥ 50%. Main outcome measures composite of total death or recurrent AMI over 3 years after AMI. Patients were divided into an ACEI group (n = 2945), ARB group (n = 2197), or no renin-angiotensin system inhibitor (RASI) treatment (n = 1094). We analyzed patients who changed treatment. Inverse probability of treatment weighting (IPTW) analysis was also performed.Results: After the adjustment with inverse probability weighting, the primary endpoints at 1 year, AMI patients receiving ACEIs showed overall better outcomes than ARBs [ARBs hazard ratio (HR) compared with ACEIs 1.384, 95% confidence interval (CI) 1.15-1.71; P = 0.003]. However, 33% of patients receiving ACEIs switched to ARBs during the first year, while only about 1.5% switched from ARBs to ACEIs. When landmark analysis was performed from 1 year to the end of the study, RASI group showed a 31% adjusted reduction in primary endpoint compared to patients with no RASI group (HR, 0.74; 95% CI 0.56-0.97; P = 0.012).Conclusions: This result suggests that certain patients got benefit from treatment with ACEIs in the first year if tolerated, but switching to ARBs beyond the first year produced similar outcomes. RASI beyond the first year reduced death or recurrent AMI in AMI patients with preserved LV systolic function. CRIS Registration number: KCT0004990. [ABSTRACT FROM AUTHOR]

Background: The polysaccharide component of Angelica gigas induces immuno-stimulatory effects on innate immune cells. However, it is unclear whether A. gigas' adjuvant activity on the immune system can elicit anti-cancer responses. Methods: A water-soluble immuno-stimulatory component of A. gigas was prepared. How this ISAg modulated the activation of innate immune cells such as dendritic cells (DCs) was examined. ISAg-induced cytotoxic activity via natural killer (NK) and NKT cells was also tested using a tumor-bearing mouse model. Results: ISAg treatment induced nitric oxide (NO) production and cytokine gene expression involved in innate immune responses. ISAg activated macrophages and DCs to secrete cytokine IL-12, through the TLR4 signaling pathway. IL-12 plays a crucial role in ISAg-mediated NK and NKT cell activation. Thus, the anti-cancer activity of NK and NKT cells induced ISAg-mediated cytotoxicity of B16 melanoma cells in mice. Conclusions: These results indicated that the natural ingredient, ISAg, has adjuvant activity to induce strong anti-cancer activity of NK and NKT cells in vivo. [ABSTRACT FROM AUTHOR]

Background: Resistance to 5-fluorouracil (5-FU) in patients with colorectal cancer prevents effective treatment and leads to unnecessary and burdensome chemotherapy. Therefore, prediction of 5-FU resistance is imperative.Methods: To identify the proteins linked to 5-FU resistance, two-dimensional gel electrophoresis-based proteomics was performed using the human colon cancer cell line SNU-C4R with induced 5-FU resistance. Proteins showing altered expression in SNU-C4R were identified by matrix-associated laser desorption/ionization-time-of-flight analysis, and their roles in susceptibility to 5-FU or radiation were evaluated in various cell lines by transfection of specific siRNA or creation of overexpression constructs. Changes in cellular signaling and expression of mitochondrial apoptotic factors were investigated by Western Blot analysis. A mitochondrial membrane potential probe (JC-1 dye) and a flow cytometry system were employed to determine the mitochondrial membrane potential. Finally, protein levels were determined by Western Blot analysis in tissues from 122 patients with rectal cancer to clarify whether each identified protein is a useful predictor of a chemoradiation response.Results: We identified mitochondrial phosphoenolpyruvate carboxykinase (mPEPCK) as a candidate predictor of 5-FU resistance. PEPCK was downregulated in SNU-C4R compared with its parent cell line SNU-C4. Overexpression of mPEPCK did not significantly alter the susceptibility to either 5-FU or radiation. Suppression of mPEPCK led to a decrease in both the cellular level of phosphoenolpyruvate and the susceptibility to 5-FU and radiation. Furthermore, the cellular levels of phosphoenolpyruvate (an end product of PEPCK and a substrate of pyruvate kinase), phosphorylated AKT, and phosphorylated 4EBP1 were decreased significantly secondary to the mPEPCK suppression in SNU-C4. However, mPEPCK siRNA transfection induced changes in neither the mitochondrial membrane potential nor the expression levels of mitochondrial apoptotic factors such as Bax, Bcl-2, and Bad. Downregulation of total PEPCK was observed in tissues from patients with rectal cancer who displayed poor responses to preoperative 5-FU-based radiation therapy.Conclusion: Our overall results demonstrate that mPEPCK is a useful predictor of a response to chemoradiotherapy in patients with rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Over the last few years, the use of phosphodiesterase type 5 (PDE5) inhibitors has been expanded to management of various cardiovascular disorders beyond pulmonary arterial hypertension. This study is designed to investigate the ability of udenafil, a newly developed long-acting PDE5 inhibitor, to improve functional capacity and hemodynamic status in a cohort of chronic systolic heart failure (SHF) patients.Methods/design: Stable, chronic SHF patients will be randomly assigned to placebo (26 patients) or udenafil at a dose of 50 mg twice per day (26 patients) for the first 4 weeks followed by 100 mg twice daily for the next 8 weeks. Eligibility criteria will be age ≥ 18 years, clinical diagnosis of chronic SHF with current New York Heart Association class II to IV symptoms, left ventricular ejection fraction ≤ 40%, and experience of at least one of following during the 12 months prior to study entry: hospitalization for decompensated heart failure, acute treatment with intravenous loop diuretics or hemofiltration, or pulmonary artery systolic pressure ≥ 40 mmHg on transthoracic echocardiography. Pharmacological therapy for SHF will be optimized in all patients at least 30 days before study entry. The primary outcome will be the change of maximal oxygen uptake, assessed by cardiopulmonary exercise testing. Secondary outcomes will include changes in ventilatory efficiency (minute ventilation/carbon dioxide production slope), left ventricular systolic and diastolic parameters, pulmonary artery systolic pressure, plasma concentration of brain natriuretic peptide, occurrence of mortality or hospitalization for heart failure, and the occurrence of any adverse event.Clinical Trial Registration: Unique identifier: NCT01646515. [ABSTRACT FROM AUTHOR]

Background: Caldesmon (CaD), a major actin-associated protein, is found in smooth muscle and non-muscle cells. Smooth muscle caldesmon, h-CaD, is a multifunctional protein, and non-muscle cell caldesmon, l-CaD, plays a role in cytoskeletal architecture and dynamics. h-CaD is thought to be an useful marker for smooth muscle tumors, but the role(s) of l-CaD has not been examined in tumors.Methods: Primary colon cancer and liver metastasis tissues were obtained from colon cancer patients. Prior to chemoradiotherapy (CRT), normal and cancerous tissues were obtained from rectal cancer patients. Whole-tissue protein extracts were analyzed by 2-DE-based proteomics. Expression and phosphorylation level of main cellular signaling proteins were determined by western blot analysis. Cell proliferation after CaD siRNA transfection was monitored by MTT assay.Results: The expression level of l-CaD was significantly increased in primary colon cancer and liver metastasis tissues compared to the level in the corresponding normal tissues. In cancerous tissues obtained from the patients showing poor response to CRT (Dworak grade 4), the expression of l-CaD was increased compared to that of good response group (Dworak grade 1). In line with, l-CaD positive human colon cancer cell lines were more resistant to 5-fluorouracil (5-FU) and radiation treatment compared to l-CaD negative cell lines. Artificial suppression of l-CaD increased susceptibility of colon cancer cells to 5-FU, and caused an increase of p21 and c-PARP, and a decrease of NF-kB and p-mTOR expression.Conclusion: Up-regulated expression of l-CaD may have a role for increasing metastatic property and decreasing CRT susceptibility in colorectal cancer cells. [ABSTRACT FROM AUTHOR]

Background: Non-Hodgkin lymphoma (NHL) is a hematologic malignancy for which good diagnostic markers are lacking. Despite continued improvement in our understanding of NHL, efforts to identify diagnostic markers have yielded dismal results. Here, we translated low-mass-ion information in urine samples from patients with NHL into a diagnostic marker.Methods: To minimize experimental error, we tested variable parameters before MALDI-TOF analysis of low-mass ions in urine. Urine from 30 controls and 30 NHL patients was analyzed as a training set for NHL prediction. All individual peak areas were normalized to total area up to 1000 m/z. The training set analysis was repeated four times. Low-mass peaks that were not affected by changes in experimental conditions were collected using MarkerView software. Human Metabolome Database (HMDB) searches and ESI LC-MS/MS analyses were used to identify low-mass ions that exhibited differential patterns in control and NHL urines. Identified low-mass ions were validated in a blinded fashion in 95 controls and 66 NHL urines to determine their ability to discriminate NHL patients from controls.Results: The 30 highest-ranking low-mass-ion peaks were selected from the 60-urine training set, and three low-mass-ion peaks with high intensity were selected for identification. Of these, a 137.08-m/z ion showed lower mass-peak intensity in urines of NHL patients, a result that was validated in a 161-urine blind validation set (95 controls and 66 NHL urines). The 130.08-m/z ion was identified from HMDB searches and ESI LC-MS/MS analyses as hypoxanthine (HX). The HX concentration in urines of NHL patients was significantly decreased (P < 0.001) and was correlated with the mass-peak area of the 137.08-m/z ion. At an HX concentration cutoff of 17.4 microM, sensitivity and specificity were 79.2% and 78.4%, respectively.Conclusions: The present study represents a good example of low-mass-ion profiling in the setting of disease screening using urine. This technique can be a powerful non-invasive diagnostic tool with high sensitivity and specificity for NHL screening. Furthermore, HX identified in the study may be a useful single urine marker for NHL screening. [ABSTRACT FROM AUTHOR]

Background: A low-mass-ion discriminant equation (LOME) was constructed to investigate whether systematic low-mass-ion (LMI) profiling could be applied to ovarian cancer (OVC) screening., Results: Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry was performed to obtain mass spectral data on metabolites detected as LMIs up to a mass-to-charge ratio ( m/z ) of 2500 for 1184 serum samples collected from healthy individuals and patients with OVC, other types of cancer, or several types of benign tumor. Principal component analysis-based discriminant analysis and two search algorithms were employed to identify discriminative low-mass ions for distinguishing OVC from non-OVC cases. OVC LOME with 13 discriminative LMIs produced excellent classification results in a validation set (sensitivity, 93.10 %; specificity, 100.0 %). Among 13 LMIs showing differential mass intensities in OVC, 3 metabolic compounds were identified and semi-quantitated. The relative amount of LPC 16:0 was somewhat decreased in OVC, but not significantly so. In contrast, D,L - glutamine and fibrinogen alpha chain fragment were significantly increased in OVC compared to the control group ( p  = 0.001 and 0.002, respectively)., Conclusion: The present study suggested that OVC LOME might be a useful non-invasive tool with high sensitivity and specificity for OVC screening. The LOME approach could enable screening for multiple diseases, including various types of cancer, based on a single blood sample. Furthermore, the serum levels of three metabolic compounds- D,L - glutamine, LPC 16:0 and fibrinogen alpha chain fragment-might facilitate screening for OVC.

Introduction: Moyamoya disease is characterized by progressive steno-occlusive changes of the distal internal carotid and developed collateral vasculature, so called 'moyamoya' vessels at the base of the brain. Variant angina is a rare occurrence in patients with moyamoya disease., Case Presentation: Here we report the case of a 41-year-old Korean woman who developed chest pain after indirect revascularization surgery of moyamoya disease. A treadmill test and an exercise stress echocardiograph showed positive results, but there was no significant major coronary arteries stenosis. Suspicious of vasospasm, we conducted an ergonovine spasm stimulation test, which demonstrated tight stenosis of her proximal left anterior descending artery. At the site of spasm, intravascular ultrasound virtual histology showed intraluminal fibrous plaque., Conclusion: Physicians who follow up patients with moyamoya disease would need to be aware of the possibility of cardiac ischemia as well as neurological manifestations.

A dwarf rabbit presented with unilateral aberrant conjunctival growth. Allgoewer's U-suture therapy was initially used to correct the overgrowth. Centrifugal incisions extending up to the limbus were made on the hypertrophic conjunctiva. Transpalpebral limbal fixation was performed next. When the symptoms recurred 3 weeks later, a second operation was performed using the Lembert suture method instead. The overgrowing membrane was excised radically just posterior to the limbus. The conjunctiva was then sutured using the Lembert pattern. The rabbit recovered with no further complications.

Background: Although chronic effects of exercise on endothelial function are established, the impact of acute exercise on flow-mediated dilatation (FMD) of brachial artery has not been elucidated yet., Methods: Eighty-six young healthy volunteers were prospectively enrolled from January 2011 to December 2011. The subjects completed FMD tests at rest and immediately after treadmill exercise test. Primary outcome was the impact of acute exercise on FMD, measured by the difference of FMD before and after exercise. Secondary outcomes were the relationship of gender and exercise habit with FMD., Results: Seventy-four subjects who met the eligibility criteria were included for analysis. Thirty-five (47.3%) were male, and the mean age was 22.7±2.7 years. FMD was reduced after exercise (8.98±4.69 to 7.51±4.03%; P=0.017) and the reduction was found in female group (10.36±5.26 to 7.62±3.71%; P=0.002) but not in male group. Post-exercise FMD was significantly impaired in subjects who did not exercise regularly (6.92±3.13% versus 8.95±5.33%; P=0.003). The decrease of FMD after exercise was greater in female group (-2.75±5.28% versus 0.27±3.24%; P=0.003) and was associated with exercise habit (β=2.532; P=0.027)., Conclusions: In healthy young subjects, FMD was reduced after a bout of acute exercise. The impact of acute exercise showed significant differences according to gender and exercise habit. FMD impairment after acute exercise was observed in females and subjects without regular exercise.

Purpose: To evaluate the degree of biological healing response that occurs between the anterior horn of the medial meniscus (MM) and the tibial plateau and investigate the biological healing response after injection of human bone marrow stem cells (hBMSCs) in a rabbit model., Materials and Methods: Twenty-five rabbits with a mean body weight of 2.5 kg were chosen for this study. On the left knee, a complete radial tear was made at the anterior tibial attachment site of MM and after removal of tibial cartilage, pullout repair of the torn MM was performed on the tibial plateau. On the right knee, the same procedure was performed, and a scaff old (matrix gel) that contained human bone marrow stem cell was implanted between MM and the tibial plateau. A biopsy was performed at 2 (group 1), 4 (group 2), and 8 (group 3) weeks postoperatively. The authors compared the differences in the degree of biological healing of each group and investigated the degree of biologic healing after hBMSC implantation by comparing the left knee with the right knee., Results: On the biopsy of 40 knees of 20 rabbits that survived after operation, all groups did not show the healing response between the undersurface of MM and the tibial plateau. There was no significant difference in terms of the pathological criteria such as fibroblasts and fibrochondrocytes etc., with and without hBMSC implantation., Conclusions: There was no attachment between the repaired MM and the tibial plateau after complete radial tear on MM and the authors could not identify the effect of hBMSC.

Background: Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer., Methods: To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR) cells., Results: Heat-shock protein 27 (HSP27) expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex., Conclusion: Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.