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1.  Comprehensive Approach for Hypertension Control in Low-income Populations: Rationale and Study Design for the Hypertension Control Program in Argentina (HCPIA) 
Although the efficacy and effectiveness of lifestyle modifications and antihypertensive pharmaceutical treatment for the prevention and control of hypertension and concomitant cardiovascular disease have been demonstrated in randomized controlled trials, this scientific knowledge has not been fully applied in the general population, especially in low-income communities. This paper summarizes interventions to improve hypertension management and describes the rationale and study design for a cluster randomized trial testing whether a comprehensive intervention program within a national public primary care system will improve hypertension control among uninsured hypertensive men and women and their families. We will recruit 1,890 adults from 18 clinics within a public primary care network in Argentina. Clinic patients with uncontrolled hypertension, their spouses and hypertensive family members will be enrolled. The comprehensive intervention program targets the primary care system through health care provider education, a home-based intervention among patients and their families (home delivery of antihypertensive medication, self-monitoring of blood pressure, health education for medication adherence and lifestyle modification) conducted by community health workers, and a mobile health intervention. The primary outcome is net change in systolic blood pressure from baseline to month 18 between intervention and control groups among hypertensive study participants. The secondary outcomes are net change in diastolic blood pressure, blood pressure control, and cost-effectiveness of the intervention. This study will generate urgently needed data on effective, practical, and sustainable intervention programs aimed at controlling hypertension and concomitant cardiovascular disease in underserved populations in low- and middle-income countries.
doi:10.1097/MAJ.0000000000000298
PMCID: PMC4108545  PMID: 24978148
2.  Twice-Weekly and Incremental Hemodialysis Treatment for Initiation of Kidney Replacement Therapy 
Mortality is highest in the first months of maintenance hemodialysis (HD). In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with more thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this paper we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors such as RKF (including urine output >0.5 L/day), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin, comorbid conditions, hospitalizations, and health related quality of life. These ten clinical criteria may identify which patients might benefit from beginning maintenance HD twice-weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly vs. thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.
doi:10.1053/j.ajkd.2014.04.019
PMCID: PMC4111970  PMID: 24840669
Transition of care; residual kidney function; incremental dialysis; incremental hemodialysis; end-stage renal disease; kidney replacement therapy; renal replacement therapy
3.  Genome-Wide Linkage and Regional Association Study of Blood Pressure Response to the Cold Pressor Test in Han Chinese: The GenSalt Study 
Background
Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT.
Methods and Results
A total of 1,961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds, LOD ≥ 2). A suggestive linkage signal was identified for systolic BP (SBP) response to CPT at 20p13-20p12.3, with a maximum multipoint LOD score of 2.37. Based on regional association analysis with 1,351 SNPs in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure (MAP) responses to CPT (P = 8.8×10−6) after FDR adjustment for multiple comparisons. A similar trend was also observed for SBP response (P = 0.03) and DBP response (P = 4.6×10−5). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with SBP response to CPT (P = 4.0×10−5 and 2.7×10−4, respectively), and variants in genes MCM8 and STK35 were associated with MAP response to CPT (P = 1.5×10−5 and 5.0×10−5, respectively).
Conclusions
Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2 and STK35 in this region. Further work is warranted to confirm these findings.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov; Unique identifier: NCT00721721.
doi:10.1161/CIRCGENETICS.113.000332
PMCID: PMC4264620  PMID: 25028485
blood pressure; linkage; genetic association
4.  Structure-Guided Functional Characterization of Enediyne Self-Sacrifice Resistance Proteins, CalU16 and CalU19 
ACS Chemical Biology  2014;9(10):2347-2358.
Calicheamicin γ1I (1) is an enediyne antitumor compound produced by Micromonospora echinospora spp. calichensis, and its biosynthetic gene cluster has been previously reported. Despite extensive analysis and biochemical study, several genes in the biosynthetic gene cluster of 1 remain functionally unassigned. Using a structural genomics approach and biochemical characterization, two proteins encoded by genes from the 1 biosynthetic gene cluster assigned as “unknowns”, CalU16 and CalU19, were characterized. Structure analysis revealed that they possess the STeroidogenic Acute Regulatory protein related lipid Transfer (START) domain known mainly to bind and transport lipids and previously identified as the structural signature of the enediyne self-resistance protein CalC. Subsequent study revealed calU16 and calU19 to confer resistance to 1, and reminiscent of the prototype CalC, both CalU16 and CalU19 were cleaved by 1in vitro. Through site-directed mutagenesis and mass spectrometry, we identified the site of cleavage in each protein and characterized their function in conferring resistance against 1. This report emphasizes the importance of structural genomics as a powerful tool for the functional annotation of unknown proteins.
doi:10.1021/cb500327m
PMCID: PMC4201346  PMID: 25079510
5.  Krüppel-like factor 12 is a novel negative regulator of forkhead box O1 expression: a potential role in impaired decidualization 
Background
Decidualization is a prerequisite for successful implantation and the establishment of pregnancy. Krüppel-like factor 12 (KLF12) is a negative regulator of endometrial decidualization in vitro. We investigated whether KLF12 was associated with impaired decidualization under conditions of repeated implantation failure (RIF).
Methods
Uterine tissues were collected from a mouse model of early pregnancy and artificial decidualization for immunohistochemistry, Western blot and real-time PCR analysis. Reporter gene assays, chromatin immunoprecipitation-PCR and avidin-biotin conjugate DNA precipitation assays were performed to analyze the transcriptional regulation of forkhead box O1 (FOXO1) by KLF12. Furthermore, the protein levels of KLF12 and FOXO1 in patients with RIF were analyzed by Western blot and immunohistochemistry.
Results
KLF12 led to defective implantation and decidualization in the mouse uterine model of early pregnancy and artificial decidualization by directly binding to the FOXO1 promoter region and inhibiting its expression in human endometrial stromal cells. Elevated KLF12 expression was accompanied by decreased FOXO1 expression in the endometria of patients with RIF.
Conclusions
As a novel regulator, KLF12 predominantly controls uterine endometrial differentiation during early pregnancy and leads to implantation failure.
Electronic supplementary material
The online version of this article (doi:10.1186/s12958-015-0079-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12958-015-0079-z
PMCID: PMC4520059
KLF12; FOXO1; Decidualization; RIF
6.  Apoptosis of human pancreatic carcinoma cell-1 cells induced by Yin Chen Hao Decoction 
AIM: To evaluate human pancreatic carcinoma cell line (PANC-1) cells apoptosis and Bcl-2 and Bax expression induced by Yin Chen Hao Decoction (YCHD).
METHODS: The cell growth inhibitory rate was determined by MTT assay. Apoptosis of PANC-1 cells before and after treatment with YCHD was determined by TUNEL staining. Expression of the apoptosis-associated genes, Bcl-2 and Bax, was detected by immunohistochemical staining and reverse transcription -PCR.
RESULTS: YCHD inhibited the growth of PANC-1 cells. Following treatment with YCHD for 24-96 h, the apoptotic rate of PANC-1 cells increased with time. In addition, the positive rate of Bcl-2 protein expression decreased in a time-dependent manner, whereas the positive rate of Bax protein expression increased in a time-dependent manner. Following treatment of with YCHD for 24-96h, expression of BAX mRNA increased gradually and BCL-2 mRNA reduced gradually with time.
CONCLUSION: YCHD induces apoptosis of PANC-1 cells mediated in part via up-regulation of BAX and down-regulation of BCL-2.
doi:10.3748/wjg.v21.i27.8352
PMCID: PMC4507104  PMID: 26217086
Apoptosis; Pancreatic carcinoma; Yin Chen Hao Decoction
7.  Targeting Glucose Metabolism in Patients With Cancer 
Cancer  2013;120(6):774-780.
Nearly a century ago, Otto Warburg made the astute observation that the metabolic properties of cancer cells differ markedly from those of normal cells. Several decades passed before the concept of exploiting cancer cell metabolism came into clinical practice with the advent of chemotherapy, the underlying principle of which is to target rapidly dividing cells by interfering with critical processes that are all, on some level, driven by cell metabolism. Although chemotherapy can be quite effective, success rates are highly variable and the adverse effects associated with treatment often outweigh the benefits due to the fact that chemotherapy is indiscriminately cytotoxic against all rapidly dividing cells, cancerous or healthy. During the past several years, a more intricate understanding of cancer cell metabolism has permitted the development of targeted therapies that aim to specifically target cancer cells and spare healthy tissue by exploiting the altered metabolism of cancer cells. The identification of new metabolic targets and the subsequent development of small-molecule inhibitors of metabolic enzymes have demonstrated the utility and promise of targeting cancer cell metabolism as an anticancer strategy. This review summarizes recent advances in the identification and characterization of several metabolic enzymes as emerging anticancer targets.
doi:10.1002/cncr.28501
PMCID: PMC4507501  PMID: 24374503
the Warburg effect; cancer metabolism; metabolic enzymes; small-molecule inhibitors; anticancer targets
8.  Evaluating the Association of Eight Polymorphisms with Cancer Susceptibility in a Han Chinese Population 
PLoS ONE  2015;10(7):e0132797.
Background
The identification of susceptibility genes for specific types of cancer can provide necessary information for the complete characterization of cancer syndromes. Eight single nucleotide polymorphisms (SNPs), rs465498, rs17728461, rs4488809, rs753955, rs13361707, rs9841504, rs2274223, and rs13042395, were reported by genome wide association studies (GWASs) to be closely related to the susceptibility of lung cancer (LC), gastric cancer (GC) or esophageal cancer (EC) in Han population from northern or southern China. However, Chinese Han people from different geographic areas may have different genetic backgrounds. This study aims to assess the genetic associations of the eight SNPs mentioned above with three cancers risk in a Han population from northwest China.
Methods
A total of 186 cancer-free controls and 436 cases with non-small cell lung cancer (NSCLC) (159 cases), non-cardia GC (167 cases) or EC (110 cases) were enrolled in this study. Chi-square test and polytomous logistic regression analyses were used to estimate the association between eight cancer-related SNPs and three cancers in a Han Chinese population from northwest China. The logistic regression results were adjusted for confounding factors and Benjamini and Hochberg False Discovery Rate (FDR) method was used to adjust the multiple hypothesis tests. Association analyses by cigarette smoking or alcohol drinking status were analyzed by crossover analyses.
Results
One of the eight SNPs, rs17728461 was associated with NSCLC susceptibility (in a heterozygous model, OR = 0.44, 95% CI = 0.27–0.72, p = 0.001). Two SNPs, rs753955 and rs13042395, were associated with the risk of non-cardia GC in different genetic models (p < 0.05). No SNPs were associated with EC. The crossover analyses showed that the rs13042395 CT genotype, combined with cigarette smoking or alcohol drinking, could further increase the risk for non-cardia GC (p < 0.05).
Conclusions
These results indicated that rs17728461 may be specifically associated with the risk of NSCLC. rs753955 and rs13042395 were specifically associated with susceptibility to non-cardia GC in Ningxia Han Chinese. Susceptibility-associated polymorphisms in the northwestern Han Chinese were not very consistent with those in the northern Han Chinese or southern Han Chinese. The validation of these findings with a functional evaluation and a larger population is still required.
doi:10.1371/journal.pone.0132797
PMCID: PMC4503434  PMID: 26176862
9.  Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice 
PLoS ONE  2015;10(7):e0132643.
The mouse model of laser-induced choroidal neovascularization (CNV) has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.
doi:10.1371/journal.pone.0132643
PMCID: PMC4498645  PMID: 26161975
10.  Increased dietary intake of ω-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis 
Nature medicine  2007;13(7):868-873.
Many sight-threatening diseases have two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. These diseases include retinopathy of prematurity and diabetic retinopathy, leading causes of blindness in childhood and middle age affecting over 4 million people in the United States. We studied the influence of ω-3- and ω-6-polyunsaturated fatty acids (PUFAs) on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy1. We show that increasing ω-3-PUFA tissue levels by dietary or genetic means decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The bioactive ω-3-PUFA-derived mediators neuroprotectinD1, resolvinD1 and resolvinE1 also potently protected against neovascularization. The protective effect of ω-3-PUFAs and their bioactive metabolites was mediated, in part, through suppression of tumor necrosis factor-α. This inflammatory cytokine was found in a subset of microglia that was closely associated with retinal vessels. These findings indicate that increasing the sources of ω-3-PUFA or their bioactive products reduces pathological angiogenesis. Western diets are often deficient in ω-3-PUFA, and premature infants lack the important transfer from the mother to the infant of ω-3-PUFA that normally occurs in the third trimester of pregnancy2. Supplementing ω-3-PUFA intake may be of benefit in preventing retinopathy.
doi:10.1038/nm1591
PMCID: PMC4491412  PMID: 17589522
11.  Draft Genome Sequence of Jiangella alkaliphila KCTC 19222T, Isolated from Cave Soil in Jeju, Republic of Korea 
Genome Announcements  2015;3(4):e00721-15.
We report the draft genome sequence of Jiangella alkaliphila KCTC 19222T, isolated from cave soil in Jeju, Republic of Korea. This genome sequence, together with the previously sequenced J. gansuensis strain DSM 44835T, identified from a desert environmental source, will give us a better understanding of the school of “evolutionary taxonomy.”
doi:10.1128/genomeA.00721-15
PMCID: PMC4490849  PMID: 26139721
12.  Glycoproteomic Analysis of Prostate Cancer Tissues by SWATH Mass Spectrometry Discovers N-acylethanolamine Acid Amidase and Protein Tyrosine Kinase 7 as Signatures for Tumor Aggressiveness* 
The identification of biomarkers indicating the level of aggressiveness of prostate cancer (PCa) will address the urgent clinical need to minimize the general overtreatment of patients with non-aggressive PCa, who account for the majority of PCa cases. Here, we isolated formerly N-linked glycopeptides from normal prostate (n = 10) and from non-aggressive (n = 24), aggressive (n = 16), and metastatic (n = 25) PCa tumor tissues and analyzed the samples using SWATH mass spectrometry, an emerging data-independent acquisition method that generates a single file containing fragment ion spectra of all ionized species of a sample. The resulting datasets were searched using a targeted data analysis strategy in which an a priori spectral reference library representing known N-glycosites of the human proteome was used to identify groups of signals in the SWATH mass spectrometry data. On average we identified 1430 N-glycosites from each sample. Out of those, 220 glycoproteins showed significant quantitative changes associated with diverse biological processes involved in PCa aggressiveness and metastasis and indicated functional relationships. Two glycoproteins, N-acylethanolamine acid amidase and protein tyrosine kinase 7, that were significantly associated with aggressive PCa in the initial sample cohort were further validated in an independent set of patient tissues using tissue microarray analysis. The results suggest that N-acylethanolamine acid amidase and protein tyrosine kinase 7 may be used as potential tissue biomarkers to avoid overtreatment of non-aggressive PCa.
doi:10.1074/mcp.M114.038273
PMCID: PMC4083113  PMID: 24741114
13.  Low-bias phosphopeptide enrichment from scarce samples using plastic antibodies 
Scientific Reports  2015;5:11438.
Phosphospecific enrichment techniques and mass spectrometry (MS) are essential tools for comprehending the cellular phosphoproteome. Here, we report a fast and simple approach for low sequence-bias phosphoserine (pS) peptide capture and enrichment that is compatible with low biological or clinical sample input. The approach exploits molecularly imprinted polymers (MIPs, “plastic antibodies”) featuring tight neutral binding sites for pS or pY that are capable of cross-reacting with phosphopeptides of protein proteolytic digests. The versatility of the resulting method was demonstrated with small samples of whole-cell lysate from human embryonic kidney (HEK) 293T cells, human neuroblastoma SH-SY5Y cells, mouse brain or human cerebrospinal fluid (CSF). Following pre-fractionation of trypsinized proteins by strong cation exchange (SCX) chromatography, pS-MIP enrichment led to the identification of 924 phosphopeptides in the HEK 293T whole-cell lysate, exceeding the number identified by TiO2-based enrichment (230). Moreover, the phosphopeptides were extracted with low sequence bias and showed no evidence for the characteristic preference of TiO2 for acidic amino acids (aspartic and glutamic acid). Applying the method to human CSF led to the discovery of 47 phosphopeptides belonging to 24 proteins and revealed three previously unknown phosphorylation sites.
doi:10.1038/srep11438
PMCID: PMC4486973  PMID: 26126808
14.  Interrelationship of Multiple Endothelial Dysfunction Biomarkers with Chronic Kidney Disease 
PLoS ONE  2015;10(7):e0132047.
The interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) μmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) μmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.
doi:10.1371/journal.pone.0132047
PMCID: PMC4488859  PMID: 26132137
15.  A Probabilistic Analysis of Sparse Coded Feature Pooling and Its Application for Image Retrieval 
PLoS ONE  2015;10(7):e0131721.
Feature coding and pooling as a key component of image retrieval have been widely studied over the past several years. Recently sparse coding with max-pooling is regarded as the state-of-the-art for image classification. However there is no comprehensive study concerning the application of sparse coding for image retrieval. In this paper, we first analyze the effects of different sampling strategies for image retrieval, then we discuss feature pooling strategies on image retrieval performance with a probabilistic explanation in the context of sparse coding framework, and propose a modified sum pooling procedure which can improve the retrieval accuracy significantly. Further we apply sparse coding method to aggregate multiple types of features for large-scale image retrieval. Extensive experiments on commonly-used evaluation datasets demonstrate that our final compact image representation improves the retrieval accuracy significantly.
doi:10.1371/journal.pone.0131721
PMCID: PMC4489107  PMID: 26132080
16.  FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation 
Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21’s effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1α in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.
doi:10.1111/jcmm.12530
PMCID: PMC4511354  PMID: 25823710
fibroblast growth factor 21; diabetic cardiomyopathy; CD36; cardiac lipotoxicity
17.  Hibiscus sabdariffa Leaf Extract Inhibits Human Prostate Cancer Cell Invasion via Down-Regulation of Akt/NF-κB/MMP-9 Pathway 
Nutrients  2015;7(7):5065-5087.
Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non-cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-κB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-κB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-κB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells.
doi:10.3390/nu7075065
PMCID: PMC4516987  PMID: 26115086
Hibiscus sabdariffa leaf; metastasis; polyphenols; human prostate cancer; Akt/NF-κB/MMP-9 cascade pathway
18.  Manganese superoxide dismutase promotes interaction of actin, S100A4 and Talin, and enhances rat gastric tumor cell invasion 
It has been demonstrated that cancer cells are under high levels of oxidative stress and express high levels of Manganese superoxide dismutase (MnSOD) to protect themselves and support the anabolic metabolism needed for growth and cell motility. The aim of this study was to identify proteins that may have a correlation with invasion and redox regulation by mitochondrial reactive oxygen species (ROS). MnSOD scavenges superoxide anions generated from mitochondria and is an important regulator of cellular redox status. Oxidative posttranslational modification of cysteine residues is a key mechanism that regulates protein structure and function. We hypothesized that MnSOD regulates intracellular reduced thiol status and promotes cancer invasion. A proteomic thiol-labeling approach with 5-iodoacetamidofluorescein was used to identify changes in intracellular reduced thiol-containing proteins. Our results demonstrate that overexpression of MnSOD maintained the major structural protein, actin, in a reduced state, and enhanced the invasion ability in gastric mucosal cancer cells, RGK1. We also found that the expression of Talin and S100A4 were increased in MnSOD-overexpressed RGK1 cells. Moreover, Talin bound not only with actin but also with S100A4, suggesting that the interaction of these proteins may, in part, contribute to the invasive ability of rat gastric cancer.
doi:10.3164/jcbn.14-146
PMCID: PMC4512892
reduced form of actin; actin binding protein; cancer invasion; MnSOD; ROS
19.  Did the tobacco industry inflate estimates of illicit cigarette consumption in Asia? An empirical analysis 
Tobacco Control  2015;24(e2):e161-e167.
Objective
Estimates of illicit cigarette consumption are limited and the data obtained from studies funded by the tobacco industry have a tendency to inflate them. This study aimed to validate an industry-funded estimate of 35.9% for Hong Kong using a framework taken from an industry-funded report, but with more transparent data sources.
Methods
Illicit cigarette consumption was estimated as the difference between total cigarette consumption and the sum of legal domestic sales and legal personal imports (duty-free consumption). Reliable data from government reports and scientifically valid routine sources were used to estimate the total cigarette consumption by Hong Kong smokers and legal domestic sales in Hong Kong. Consumption by visitors and legal duty-free consumption by Hong Kong passengers were estimated under three scenarios for the assumptions to examine the uncertainty around the estimate. A two-way sensitivity analysis was conducted using different levels of possible undeclared smoking and under-reporting of self-reported daily consumption.
Results
Illicit cigarette consumption was estimated to be about 8.2–15.4% of the total cigarette consumption in Hong Kong in 2012 with a midpoint estimate of 11.9%, as compared with the industry-funded estimate of 35.9% of cigarette consumption. The industry-funded estimate was inflated by 133–337% of the probable true value. Only with significant levels of under-reporting of daily cigarette consumption and undeclared smoking could we approximate the value reported in the industry-funded study.
Conclusions
The industry-funded estimate inflates the likely levels of illicit cigarette consumption.
doi:10.1136/tobaccocontrol-2014-051937
PMCID: PMC4484498  PMID: 25566812
20.  Assessment of Double Outlet Right Ventricle Associated with Multiple Malformations in Pediatric Patients Using Retrospective ECG-Gated Dual-Source Computed Tomography 
PLoS ONE  2015;10(6):e0130987.
Purpose
To evaluate the feasibility and diagnostic accuracy of retrospective electrocardiographically (ECG)-gated dual-source computed tomography (DSCT) for the assessment of double outlet right ventricle (DORV) and associated multiple malformations in pediatric patients.
Materials and Methods
Forty-seven patients <10 years of age with DORV underwent retrospective ECG-gated DSCT. The location of the ventricular septal defect (VSD), alignment of the two great arteries, and associated malformations were assessed. The feasibility of retrospective ECG-gated DSCT in pediatric patients was assessed, the image quality of DSCT and the agreement of the diagnosis of associated malformations between DSCT and transthoracic echocardiography (TTE) were evaluated, the diagnostic accuracies of DSCT and TTE were referred to surgical results, and the effective doses were calculated.
Results
Apart from DORV, 109 associated malformations were confirmed postoperatively. There was excellent agreement (κ = 0.90) for the diagnosis of associated malformations between DSCT and TTE. However, DSCT was superior to TTE in demonstrating paracardiac anomalies (sensitivity, coronary artery anomalies: 100% vs. 80.00%, anomalies of great vessels: 100% vs. 88.57%, separate thoracic and abdominal anomalies: 100% vs. 76.92%, respectively). Combined with TTE, DSCT can achieve excellent diagnostic performance in intracardiac anomalies (sensitivity, 91.30% vs. 100%). The mean image quality score was 3.70 ± 0.46 (κ = 0.76). The estimated mean effective dose was < 1 mSv (0.88 ± 0.34 mSv).
Conclusions
Retrospective ECG-gated DSCT is a better diagnostic tool than TTE for pediatric patients with complex congenital heart disease such as DORV. Combined with TTE, it may reduce or even obviate the use of invasive cardiac catheterization, and thus expose the patients to a much lower radiation dose.
doi:10.1371/journal.pone.0130987
PMCID: PMC4482600  PMID: 26115034
21.  Impact of Childhood Abuse on the Risk of Non-Suicidal Self-Injury in Mainland Chinese Adolescents 
PLoS ONE  2015;10(6):e0131239.
Background
Childhood abuse has been associated with significant increases in non-suicidal self-injury (NSSI) behaviors in adolescents; however, only general definitions of this risk indicator have been examined. This study identified relationships between specific forms of childhood abuse and NSSI in mainland Chinese adolescents.
Method
A total of 14,221 cases were retained from an epidemiological study involving adolescents from junior and senior middle schools. Information relating to the perpetrator, perceived harm, timing of exposure to different types of childhood abuse, and NSSI were obtained. Logistic regression was used to analyze relationships between each form of childhood abuse and NSSI.
Results
Approximately 51.0% of the students reported at least one abusive childhood experience. Nearly one in four students (24.9%) reported that they had engaged in NSSI in the past 12 months. Each type of childhood abuse, occurring at any time within the first 16 years of life, especially in situations of continuous exposure, was significantly associated with NSSI. A significant graded relationship was found between number of abusive childhood experiences and NSSI. Students maltreated by parents or others were at high risk of engaging in NSSI, the risk was greater in students maltreated by both; students who had been exposed to childhood abuse with no perceived harm still demonstrated an elevated risk for NSSI. The pattern of associations did not vary by gender.
Conclusions
These findings suggest that experiencing any of various forms of childhood abuse should be considered a risk factor for NSSI during adolescence. Further research should focus upon psychosocial, neural, and genetic factors that might moderate or mediate the onset of NSSI in adolescents who have experienced childhood abuse.
doi:10.1371/journal.pone.0131239
PMCID: PMC4482708  PMID: 26114574
22.  Beyond Gisin’s Theorem and its Applications: Violation of Local Realism by Two-Party Einstein-Podolsky-Rosen Steering 
Scientific Reports  2015;5:11624.
We demonstrate here that for a given mixed multi-qubit state if there are at least two observers for whom mutual Einstein-Podolsky-Rosen steering is possible, i.e. each observer is able to steer the other qubits into two different pure states by spontaneous collapses due to von Neumann type measurements on his/her qubit, then nonexistence of local realistic models is fully equivalent to quantum entanglement (this is not so without this condition). This result leads to an enhanced version of Gisin’s theorem (originally: all pure entangled states violate local realism). Local realism is violated by all mixed states with the above steering property. The new class of states allows one e.g. to perform three party secret sharing with just pairs of entangled qubits, instead of three qubit entanglements (which are currently available with low fidelity). This significantly increases the feasibility of having high performance versions of such protocols. Finally, we discuss some possible applications.
doi:10.1038/srep11624
PMCID: PMC4479990  PMID: 26108704
23.  Demonstrating quantum contextuality of indistinguishable particles by a single family of noncontextuality inequalities 
Scientific Reports  2015;5:11637.
Quantum theory has the intriguing feature that is inconsistent with noncontextual hidden variable models, for which the outcome of a measurement does not depend on which other compatible measurements are being performed concurrently. While various proofs of such contextual behavior of quantum systems have been established, relatively little is known concerning the possibility to demonstrate this intriguing feature for indistinguishable particles. Here, we show in a simple and systematic manner that with projective measurements alone, it is possible to demonstrate quantum contextuality for such systems of arbitrary Hilbert space dimensions, including those corresponding to a qubit. Our demonstration is applicable to a single fermion as well as multiple fermions, and thus also a composite boson formed from an even number of fermions. In addition, our approach gives a clear demonstration of the intimate connection between complementarity and contextuality, two seemingly unrelated aspects of quantum theory.
doi:10.1038/srep11637
PMCID: PMC4480019  PMID: 26109325
24.  Multi-Agent Patrolling under Uncertainty and Threats 
PLoS ONE  2015;10(6):e0130154.
We investigate a multi-agent patrolling problem where information is distributed alongside threats in environments with uncertainties. Specifically, the information and threat at each location are independently modelled as multi-state Markov chains, whose states are not observed until the location is visited by an agent. While agents will obtain information at a location, they may also suffer damage from the threat at that location. Therefore, the goal of the agents is to gather as much information as possible while mitigating the damage incurred. To address this challenge, we formulate the single-agent patrolling problem as a Partially Observable Markov Decision Process (POMDP) and propose a computationally efficient algorithm to solve this model. Building upon this, to compute patrols for multiple agents, the single-agent algorithm is extended for each agent with the aim of maximising its marginal contribution to the team. We empirically evaluate our algorithm on problems of multi-agent patrolling and show that it outperforms a baseline algorithm up to 44% for 10 agents and by 21% for 15 agents in large domains.
doi:10.1371/journal.pone.0130154
PMCID: PMC4472811  PMID: 26086946
25.  Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill® via ameliorate of multiple mitochondrial dysfunctions 
Aim
To investigate the potential cardioprotective effects of QiShenYiQi Pill® (QSYQ) on myocardial ischemia/reperfusion (I/R) injury through antioxidative stress and mitochondrial protection.
Methods and results
Sprague Dawley rats were pretreated with QSYQ or saline for 7 days and subjected to ischemia (30 minutes occlusion of the left anterior descending coronary artery) and reperfusion (120 minutes). Cardiac functions were evaluated by echocardiogram and hemodynamics. Myocardial mitochondria were obtained to evaluate changes in mitochondrial structure and function, immediately after 120 minutes reperfusion. Pretreatment with QSYQ protected against I/R-induced myocardial structural injury and improved cardiac hemodynamics, as demonstrated by normalized serum creatine kinase and suppressed oxidative stress. Moreover, the impaired myocardial mitochondrial structure and function decreased level of ATP (accompanied by reduction of ATP5D and increase in the expression of cytochrome C). Myocardial fiber rupture, interstitial edema, and infiltrated leukocytes were all significantly ameliorated by pretreatment with QSYQ.
Conclusion
Pretreatment of QSYQ in Sprague Dawley rats improves ventricular function and energy metabolism and reduces oxidative stress via ameliorating multiple mitochondrial dysfunctions during I/R injury.
doi:10.2147/DDDT.S82146
PMCID: PMC4474392  PMID: 26109848
QSYQ; ischemia/reperfusion injury; energy metabolism; mitochondria

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