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PDF file - 265K, Supplementary Figure 1. Experimental scheme of metastatic melanoma in C57BL/6 mice.

PDF file - 1470K, Supplementary Figure 2. Evaluation of the Luc-B16-F10 cells delivery efficiency in vivo. Bioluminescence live images of day 0, day 7 and day 14 provided an estimation of the number of metastatic cells upon injection.

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The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial–mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma. Mol Cancer Ther; 12(6); 1016–25. ©2013 AACR.

PDF file - 1237K, Supplementary Figure 3. POMC gene transfer inhibited neovascularization of metastatic melanoma in vivo. (A) Growth of metastatic GFP-B16-F10 cells in lung was observed by merging the images of GFP (green) and rhodamine label-dextran (red). (B) Blood vessels were labeled by an antibody directed against CD31, a specific marker of endothelial cells. The number of blood vessels within the nodules was counted by image analysis. (Magnification, 4x and Bar, 1.0 mm; 20x and Bar, 200 μm) (n = 5; **: p < 0.01)

Though infective endocarditis (IE) is a life-threatening cardiac infection with a high mortality rate, the effective diagnostic and prognostic biomarkers for IE are still lacking. The aim of this study was to explore the potential applicable proteomic biomarkers for IE through the Immunome™ Protein Array system. The system was employed to profile those autoantibodies in IE patients and control subjects. Our results showed that interleukin-1 alpha (IL1A), nucleolar protein 4 (NOL4), tudor and KH domain-containing protein (TDRKH), G antigen 2B/2C (GAGE2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and X antigen family member 2 (XAGE2) are highly differentially-expressed among IE and non-IE control. Furthermore, bactericidal permeability-increasing protein (BPI), drebrin-like protein (DBNL), signal transducing adapter molecule 2 (STAM2), cyclin-dependent kinase 16 (CDK16), BAG family molecular chaperone regulator 4 (BAG4), and nuclear receptor-interacting protein 3 (NRIP3) are differentially-expressed among IE and healthy controls. On the other hand, those previously identified biomarkers for IE, including erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, procalcitonin, and N-terminal-pro-B-type natriuretic peptide demonstrated only minor significance. With scientific rationalities for those highly differentially-expressed proteins, they could serve as potential candidates for diagnostic biomarkers of IE for further analysis.

Ching-Hui Huang,1–3,* Ya-Yun Lai,4,* Yu-Jui Kuo,4,5 Su-Ching Yang,6 Yu-Jun Chang,7 Kuo-Kuan Chang,8 Wen-Kang Chen4 1Division of Cardiology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 2Department of Beauty Science, Graduate Institute of Beauty Science Technology, Chienkuo Technology University, Changhua, Taiwan; 3School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Applied Cosmetology, National Tainan Junior College of Nursing, Tainan, Taiwan; 5Department of Traditional Chinese Medicine, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan; 6Department of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan; 7Epidemiology and Biostatistics Center, Changhua Christian Hospital, Changhua, Taiwan; 8Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan *These authors contributed equally to this work Background: Liver cirrhosis is an uncommon but not rare side effect of amiodarone-induced hepatotoxicity. Patients with hepatitis B virus and hepatitis C virus infections are at a high risk for developing liver cirrhosis. However, the relationship between this treatment and risk of liver cirrhosis in high-risk chronic hepatitis B and chronic hepatitis C patients is unknown.Patients and methods: The present study identified amiodarone users (N=8,081) from the Taiwan National Health Insurance Research Database from 1997 through 2013. A total of 32,324 subjects with age, comorbidities, gender, and index date-matched non-amiodarone users were selected as controls (non-amiodarone cohort). The incidences of cumulative liver cirrhosis were compared between cohorts. Stratified Cox’s regression hazard models were used to assess possible comorbidity-attributable risks for liver cirrhosis.Results: The amiodarone cohort had a nonsignificant risk of liver cirrhosis compared with the non-amiodarone cohort, with a HR of 1.17 (95% CI: 0.93–1.47; P=0.1723). Patients with specific comorbid diseases, including type 2 diabetes mellitus, chronic hepatitis B, chronic hepatitis C, and heart failure, were probably at a high risk of developing liver cirrhosis. The use of statins was associated with a significant 42% reduction in the risk of liver cirrhosis.Conclusion: Patients in the amiodarone cohort had no excess risk of liver cirrhosis compared with patients in the non-amiodarone cohort. Long-term surveillance for liver toxicity in high-risk patients with amiodarone treatment is suggested. Keywords: amiodarone, liver cirrhosis, Taiwan, hepatitis

Though infective endocarditis (IE) is a life-threatening cardiac infection with a high mortality rate, the effective diagnostic and prognostic biomarkers for IE are still lacking. The aim of this study was to explore the potential applicable proteomic biomarkers for IE through the Immunome™ Protein Array system. The system was employed to profile those autoantibodies in IE patients and control subjects. Our results showed that interleukin-1 alpha (IL1A), nucleolar protein 4 (NOL4), tudor and KH domain-containing protein (TDRKH), G antigen 2B/2C (GAGE2), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and X antigen family member 2 (XAGE2) are highly differentially-expressed among IE and non-IE control. Furthermore, bactericidal permeability-increasing protein (BPI), drebrin-like protein (DBNL), signal transducing adapter molecule 2 (STAM2), cyclin-dependent kinase 16 (CDK16), BAG family molecular chaperone regulator 4 (BAG4), and nuclear receptor-interacting protein 3 (NRIP3) are differentially-expressed among IE and healthy controls. On the other hand, those previously identified biomarkers for IE, including erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, procalcitonin, and N-terminal-pro-B-type natriuretic peptide demonstrated only minor significance. With scientific rationalities for those highly differentially-expressed proteins, they could serve as potential candidates for diagnostic biomarkers of IE for further analysis.

Advanced glycation end-products (AGEs) form during oxidative stress, which is increased in diabetes mellitus (DM). Uromodulin is a protein with a renal protective effect, and may be subject to glycation. The implications of uromodulin glycation and AGEs in the urine are not understood. Here, immunoprecipitation and liquid chromatography–mass spectrometry identified glycated uromodulin (glcUMOD) in the urine of 62.5% of patients with diabetic kidney disease (DKD), 20.0% of patients with non-diabetic chronic kidney disease (CKD), and no DM patients with normal renal function or healthy control participants; a finding replicated in a larger cohort of 84 patients with CKD in a case–control study (35 with DM, 49 without). Uromodulin forms high molecular weight polymers that associate with microvesicles and exosomes. Differential centrifugation identified uromodulin in the supernatant, microvesicles, and exosomes of the urine of healthy participants, but only in the supernatant of samples from patients with DKD, suggesting that glycation influences uromodulin function. Finally, the diagnostic and prognostic utility of measuring urinary glcUMOD concentration was examined. Urinary glcUMOD concentration was substantially higher in DKD patients than non-diabetic CKD patients. Urinary glcUMOD concentration predicted DKD status, particularly in patients with CKD stages 1–3a aged

BACKGROUND Left ventricular (LV) shape influences LV systolic function. It is possible to assess LV shape using 3-D echocardiography sphericity index (SI). Maintaining mitochondrial DNA copy number (MCN) is important for preserving mitochondrial function and LV systolic function after acute myocardial infarction (AMI). Information is limited, however, regarding the relationship between leukocyte MCN and the subsequent change in LV shape after AMI.Methods and Results:Fifty-five AMI patients undergoing primary angioplasty were recruited. Plasma MCN was measured before primary angioplasty using quantitative polymerase chain reaction. 3-D echocardiography measurement of SI was performed at baseline, and at 1-, 3-, and 6-month follow-up. AMI subjects with MCN lower than the median had a higher 6-month SI and LV volume compared with those with higher MCN. Baseline echocardiographic parameters were similar between the 2 groups. MCN was negatively correlated with 3- and 6-month SI, and 3- and 6-month LV volume. On multiple linear regression analysis, baseline plasma MCN could predict LV SI and LV volume at 6 months after primary angioplasty for AMI, even after adjusting for traditional prognostic factors. CONCLUSIONS In AMI patients, higher plasma leukocyte MCN at baseline was associated with favorable LV shape and remodeling at 6-month follow-up. Plasma leukocyte MCN may provide a novel prognostic biomarker for LV remodeling after AMI.

Introduction Cell-free deoxyribonucleic acid DNA (cf-DNA) in urine is promising due to the advantage of urine as an easily obtained and non-invasive sample source over tissue and blood. In clinical practice, it is important to identify non-invasive biomarkers of chronic kidney disease (CKD) in monitoring and surveillance of disease progression. Information is limited, however, regarding the relationship between urine and plasma cf-DNA and the renal outcome in CKD patients. Methods One hundred and thirty-one CKD patients were enrolled between January 2016 and September 2018. Baseline urine and plasma cell-free mitochondrial DNA (cf-mtDNA) and cell-free nuclear DNA (cf-nDNA) were isolated using quantitative real-time PCR. Estimated glomerular filtration rate (eGFR) measurement was performed at baseline and 6-month follow-up. Favorable renal outcome was defined as eGFR at 6 months minus baseline eGFR> = 0. Receiver operator characteristics (ROC) curve analysis was performed to assess different samples of cf-DNA to predict favorable renal outcomes at 6 months. A multivariate linear regression model was used to evaluate independent associations between possible predictors and different samples of cf-DNA. Results Patients with an advanced stage of CKD has significantly low plasma cf-nDNA and high plasma neutrophil gelatinase-associated lipocalin (NGAL) levels. Low urine cf-mtDNA, cf-nDNA levels and low plasma NGAL were significantly correlated with favorable renal outcomes at 6 months. The urine albumin-creatinine ratio (ACR) or urine protein-creatinine ratio (PCR) level is a robust predictor of cf-mtDNA and cf-nDNA in CKD patients. Baseline urine levels of cf-mtDNA and cf-nDNA could predict renal outcomes at 6 months. Conclusions Urinary cf-mtDNA and cf-nDNA may provide novel prognostic biomarkers for renal outcome in CKD patients. The levels of plasma cf-nDNA and plasma NGAL are significantly correlated with the severity of CKD.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by l-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.

RATIONALE Understanding drug-drug interactions and predicting the side effects induced by polypharmacy are difficult because there are few suitable platforms that can predict drug-drug interactions and possible side effects. Hence, developing a platform to identify significant protein markers of drug-drug interactions and their associated side effects is necessary to avoid adverse effects. METHODS Human liver cells were treated with ethosuximide in combination with cimetidine, ketotifen, metformin, metronidazole, or phenytoin. After sample preparation and extraction, mitochondrial proteins from liver cells were isolated and digested with trypsin. Then, peptide solutions were detected using a nano ultra-performance liquid chromatographic system combined with tandem mass spectrometry. The Ingenuity Pathway Analysis tool was used to simulate drug-drug interactions and identify protein markers associated with drug-induced adverse effects. RESULTS Several protein markers were identified by the proposed method after liver cells were co-treated with ethosuximide and other drugs. Several of these protein markers have previously been reported in the literature, indicating that the proposed platform is workable. CONCLUSIONS Using the proposed in vitro platform, significant protein markers of drug-drug interactions could be identified by mass spectrometry. This workflow can then help predict indicators of drug-drug interactions and associated adverse effects for increased safety in clinical prescriptions.

Additional file 3. Figure S3. Scatter-plots for correlation analysis between urinary cf-mtDNA and different variables. Figure S3A Correlation between urine cf-mtDNA and urine albumin/creatinine ratio. Figure S3B Correlation between urine cf-mtDNA and urine protein/creatinine ratio.

The ability to detect meniscus defects by magnetic resonance arthrography (MRA) can be highly variable. To improve the delineation of fine tears, we synthesized a cationic gadolinium complex, (Gd-DOTA-AM4 )(2+) , that can electrostatically interact with Glycosaminoglycans (GAGs). The complex has a longitudinal relaxivity (r1) of 4.2 mM(-1) s(-1) and is highly stable in serum. Its efficacy in highlighting soft tissue tears was evaluated in comparison to a clinically employed contrast agent (Magnevist) using explants obtained from adult bovine menisci. In all cases, Gd-DOTA-AM4 appeared to improve the ability to detect the soft tissue defect by providing increased signal intensity along the length of the tear. Magnevist shows a strong signal near the liquid-meniscus interface, but much less contrast is observed within the defect at greater depths. This provides initial evidence that cationic contrast agents can be used to improve the diagnostic accuracy of MRA. Copyright © 2016 John Wiley & Sons, Ltd.

Vertebral compression fractures (VCFs) are common in elderly and are treated with immobilization. Moreover, immobilization and old age may increase venous thromboembolism (VTE) risk. However, the incidence of VCFs-related VTE is unknown in elderly. The purposes of this study were to determine the incidence of VTE among VCF patients, to explore whether percutaneous vertebroplasty (PV) intervention may reduce VTE risk in VCFs patients.We conducted a population-based case-control study by using the National Health Insurance Research Database. We identified 1407 patients aged ≥65 with VCF who received PV and 1407 VCFs patients who did not receive PV after developing a 1:1 propensity score-matched study cohort and were followed up for 5 years. Using PV intervention as the exposure factor, a cause-specific Cox's proportional hazards model was used to examine the association between PV and VTE.After propensity score matching, the mean age of the study participants was 78 years and ∼23% of the analyzed participants were men, incidence of VTE in the PV and control cohorts was 5.77 and 4.19 per 1000 person-years, respectively. Both groups were nonsignificant difference after examination with different adjustment models. Patients with VCF and a history of heart failure, coronary artery disease, receiving antihypertension medication were at a significantly increased VTE risk.Elderly patients with VCF who received PV had a neutral impact on risk of VTE. VCF patients with heart failure, coronary artery disease, and receiving antihypertension medication were prone to developing VTE should be monitored cautiously.

Venous thromboembolism (VTE) is a sex-specific disease that has different presentations between men and women. Women with uterine leiomyoma can present with VTE without exhibiting the traditional risk factors. We investigated the relationship between a history of uterine leiomyoma and the risk of VTE using the National Health Insurance Research Database (NHIRD).We conducted a retrospective, nationwide, population-based case-control study using the NHIRD. We identified 2,282 patients with diagnosed VTE and 392,635 subjects without VTE from 2000 to 2013. After development of an age and index diagnosis year frequency-matched model and propensity score-matched model, 2 models with a case-to-control ratio of 1 to 4 were established. Using the diagnosis of uterine leiomyoma as the exposure factor, conditional logistic regression was performed to examine the association between uterine leiomyoma and VTE. Multiple logistic regression analysis was used to investigate the joint effect of uterine leiomyoma and comorbid diseases on the risk of VTE.A strong association was observed between uterine leiomyoma and VTE in the overall patient model, frequency-matched model and propensity score-matched model [p0.0001, odds ratio (OR): 1.547; p = 0.0005, OR: 1.486; p = 0.0405, OR: 1.26, respectively]. In the subgroup analyses, women with uterine leiomyoma who were ≥ 45 years old were less likely to experience VTE, but women with uterine leiomyoma and anemia, cancer, coronary artery disease or heart failure were more likely to experience VTE.Women with uterine leiomyomas have an increased risk of developing VTE, especially during reproductive periods or in the presence of specific diseases.

Cardiovascular disease is the main concern of breast cancer survivors who received doxorubicin treatment. Traditional Chinese medicine (TCM) provides as a complementary therapy to patients with breast cancer and is an important component of health care in Taiwan. However, the TCM utilization patterns and it's efficacy in breast cancer patients is unknown.From a sample of claims data collected over the period of 1997-2010 in Taiwan, we identified 24,457 breast cancer patients who received TCM treatments and 24,457 breast cancer patients who did not receive TCM treatments. All enrollment patients had received doxorubicin chemotherapy. These patients were paired by age; index day; and propensity score for selected comorbidities, Herceptin and tamoxifen. The incidence of cumulative congestive heart failure (CHF) was compared between cohorts. Fine and Gray regression hazard model was used to evaluate the risk of CHF.After adjusting for age, Herceptin, tamoxifen, diabetic drug, cardiovascular drug, statin and comorbidities, the stratified Fine and Gray model revealed that the TCM cohort had an adjusted subdistribution hazard ratio (sHR) of 0.68 (95% confidence interval (CI) = 0.62-0.76, p 0.0001) for the development of CHF. In addition, the sub-cohort analysis revealed that the Baihuasheshecao cohort compared to the non-TCM cohort had an adjusted sHR of 0.29 (95% CI = 0.15-0.56, p = 0.0002) for the development of CHF.Using TCM significantly decreased the incidence of CHF in patients with breast cancer who received conventional chemotherapy with or without radiotherapy.

Background: Cyclophilin A (CyPA) concentration increases in acute coronary syndrome. In an animal model of acute myocardial infarction, administration of angiotensin-converting-enzyme inhibitor was associated with lower left ventricular (LV) CyPA concentration and improved LV performance. This study investigated the relationships between changes in plasma CyPA concentrations and LV remodeling in patients with ST-elevation myocardial infarction (STEMI). Methods and Results: We enrolled 55 patients who underwent percutaneous coronary intervention for acute STEMI. Plasma CyPA, matrix metalloproteinase (MMP), interleukin-6 and high-sensitivity C-reactive protein concentrations were measured at baseline and at one-month follow-up. Echocardiography was performed at baseline and at one-, three-, and six-month follow-up. Patients with a decrease in baseline CyPA concentration at one-month follow-up (n = 28) had a significant increase in LV ejection fraction (LVEF) (from 60.2 ± 11.5% to 64.6 ± 9.9%, p < 0. 001) and preserved LV synchrony at six months. Patients without a decrease in CyPA concentration at one month (n = 27) did not show improvement in LVEF and had a significantly increased systolic dyssynchrony index (SDI) (from 1.170 ± 0.510% to 1.637 ± 1.299%, p = 0.042) at six months. Multiple linear regression analysis showed a significant association between one-month CyPA concentration and six-month LVEF. The one-month MMP-2 concentration was positively correlated with one-month CyPA concentration and LV SDI. Conclusions: Decreased CyPA concentration at one-month follow-up after STEMI was associated with better LVEF and SDI at six months. Changes in CyPA, therefore, may be a prognosticator of patient outcome.

This paper investigates the feasibility of predicting the NAND flash decoding status by machine learning algorithms. The memory system can handle the future decoding failure in advance according to the prediction results so as to relieve the penalties. Several data preprocessing techniques to improve the accuracy are addressed. A thorough analysis flow is given and the experimental results show significant improvements. Incorporating with proper memory error handling schemes, a 34% improvement in throughput can be achieved.

This study investigated the interaction effects of meteorological factors and air pollutants on the onset of acute coronary syndrome (ACS). Data of ACS patients were obtained from the Taiwan ACS Full Spectrum Registry and comprised 3164 patients with a definite onset date during the period October 2008 and January 2010 at 39 hospitals. Meteorological conditions and air pollutant concentrations at the 39 locations during the 488-day period were obtained. Time-lag Poisson and logistic regression were used to explore their association with ACS incidence. One-day lag atmospheric pressure (AP), humidity, particulate matter (PM2.5, and PM10), and carbon monoxide (CO) all had significant interaction effects with temperature on ACS occurrence. Days on which high temperatures (>26 °C) and low AP (

Interior design can be executed in various stages, during which designers (the sender) deliver their ideas to client s (the receiver) via communication channels (the medium) in the form of language, words, images, and drawings. The question is whether the sender and receiver have a mutual understanding and interpretation of the message or not determines if the design is able to satisfy the client’s needs. In order to understand the different backgrounds of receivers (professionals and non-professionals), it is important to note if they have different spatial perceptions when interpreting the same spatial image and if they use different spatial vocabulary to describe how they feel. Images and vocabulary are used as research materials. With spatial images and vocabulary as research instruments, professionals (designers with more than five years of work experience) and non-professionals (college freshmen) are asked to complete questionnaires to analyze the different spatial vocabulary used by professionals and non-professionals for the same spatial image as well as the two groups of participants’ different interpretations towards spatial vocabulary based of their written descriptions. Research findings show that: (1) spatial vocabularies that describe an interior space need to be able to clearly identify the characters, ambience, and style of the space; (2) if a space has obvious differences in style, color, and material, vocabularies become more consistent; (3) the abundance and complexity of furniture play an important role; for example, less furniture or simple furnishings tend to be interpreted as simple or basic.

Previous studies showed different dyssynchrony patterns between ischemic and normal myocardium at early post-stress using Tl-201 gated SPECT myocardial perfusion imaging (MPI). The aim of this study was to assess the relation of stress-induced dyssynchrony and the extent of angiographic coronary artery disease (CAD). The MPI images of 144 patients were retrospectively analyzed. With ≥70% stenosis as the criteria of CAD, 57 had no CAD, 32 had 1-vessel disease, 36 had 2-vessel disease, and 19 had 3-vessel disease, respectively. LV global and territorial dyssynchrony parameters were measured by the phase analysis from stress/rest Tl-201 SPECT MPI and compared between stress and rest among the patient groups. The patients with multi-vessel CAD had significantly more global dyssynchrony than the patients without ≥70% stenosis at stress. The patients with multi-vessel CAD showed significantly more global and territorial dyssynchrony on stress images than on rest. More patients with 3-vessel CAD were correctly classified as multi-vessel disease, when combining both visual interpretation and dyssynchrony assessment. The patients with multi-vessel CAD had significantly more global and territorial dyssynchrony at early post-stress than at rest. Such quantitative measures of myocardial stunning may assist in the diagnosis of multi-vessel CAD.

Background Anticoagulants are used to reduce the risk of stroke in patients with atrial fibrillation (Af) and chronic kidney disease (CKD). Warfarin is one of the commonly used anticoagulants; however, its effect on renal function remains unclear. Methods In a retrospective cohort study (January 2001 - July 2013), we surveyed data charts from 2,450 patients with stage 3 - 5 CKD, and enrolled 159 patients with Af. In total, 104 patients had a CHADS2 score of >= 2 (congestive heart failure, hypertension, >= 75 years old, diabetes, 1 point; prior stroke or transient ischemic attack or thromboembolism, 2 points). These patients were categorized into groups A and B based on warfarin treatment. Group A included 73 patients and was not undergoing warfarin treatment and group B included 31 patients undergoing warfarin treatment. The baseline demographic and biochemical data as well as changes in estimated glomerular filtration rate (eGFR) after 6, 12, and 18 months of warfarin treatment were analyzed. We also studied censored patient survival over 12 years using Kaplan-Meier model. Results The mean international normalization ratio (INR) of warfarin treatment in group B was 1.92 ± 1.04. Moreover, group B showed a significant increase in eGFR. The maximum improvement was at 6 months (mean eGFR increased from 25.97 to 31.12 mL/min; p = 0.01) and lasted for up to 18 months (eGFR 28.65 mL/min). Despite higher initial CHADS2 scores, group B showed a superior survival rate compared with group A (p = 0.02). Conclusion Lower doses of warfarin may protect against renal dysfunction and could be beneficial for treatment of stage 3 - 5 CKD with Af.

Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression as well as resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent for imaging the acidic tumor microenvironment. The preparation included the conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water-soluble glycol chitosan (GC) polymer, which contains pH-titrable primary amines, followed by gadolinium complexation (GC-NH2-GdDOTA). GC-NH2-GdDOTA had a chelate-to-polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM(-1) s(-1). GC-NH2-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor-bearing mice 2 h postinjection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment.

The prognosis of malignant melanoma is poor due to high incidence of metastasis, underscoring the demand for development of novel therapeutic strategies. Stress hormone pro-opiomelanocortin (POMC) is the precursor for several anti-inflammatory peptides that hold promise for management of cancer-related diseases. The present study evaluated the antimetastatic potential and mechanism of POMC therapy for metastatic melanoma. Adenovirus-mediated POMC gene delivery potently inhibited the invasiveness of human and mouse melanoma cells. Moreover, after induction of lung metastasis, systemic POMC expression significantly reduced the foci formation and neovascularization in lungs. Mechanistic studies revealed that POMC therapy inhibited the epithelial–mesenchymal transition (EMT) of melanoma cells by upregulation of E-cadherin and downregulation of vimentin and α-smooth muscle actin (α-SMA). In addition, microarray analysis unveiled POMC gene transfer reduced the mRNA level of multiple prometastatic factors, including hepatoma-derived growth factor (HDGF). Cell culture and immunohistochemical studies further confirmed that POMC gene delivery significantly decreased the expression of HDGF in melanoma cells and tissues. Despite stimulating the invasion and EMT, exogenous HDGF supply only partially attenuated the POMC-mediated invasion inhibition and EMT change in melanoma cells. Finally, we delineated the contribution of melanocortins to POMC-induced inhibition of invasion, HDGF downregulation, and E-cadherin upregulation. Together, these results indicate that HDGF downregulation participates in POMC-induced suppression of metastasis and EMT in melanoma. Mol Cancer Ther; 12(6); 1016–25. ©2013 AACR.

As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice. Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes. One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd). These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies. In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high "relaxivity per particle" and "relaxivity density", and biodegradability.

Substrate property is related to the genesis and maintenance of atrial fibrillation (AF). The aim of the study was to investigate the impact of substrate property on the electrocardiogram (ECG) in patients with AF originating from the superior vena cava (SVC).Seventy-six patients with AF originating from SVC who underwent catheter ablation were included from 2004 to 2013. Of these patients, 16 had a presentation of atrial flutter (AFL)-pattern ECG during AF (group 1), and 60 patients did not (group 2). There was no significant difference in clinical characteristics between the groups. The percentage of low voltage zone (LVZ) in SVC below the level of pulmonary artery in group 1 was significantly larger than that in group 2. The polarities of the flutter wave in 12-lead ECG were compared with another 26 subjects with reverse typical AFL. The ECG morphology was characterized by negative or biphasic P waves in lead VThe ECG characteristics of AF originating from SVC can mimic atypical AFL. LVZ in the SVC may be associated with the presentation of AFL-pattern ECG.

Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia–reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI). We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers. Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline. Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction.

A 25-year-old man suffered from repeated attacks of orthodromic atrioventricular reciprocating tachycardia utilizing a left lateral accessory pathway (AP) for retrograde conduction. The catheter was approached through the aorta to map the AP and was entrapped in the mitral valve apparatus, and it had a broken internal wire. A snareassisted technique was successfully utilized to retrieve the catheter.