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2.  ER stress and ER stress-induced apoptosis are activated in gastric SMCs in diabetic rats 
AIM: To investigate the gastric muscle injury caused by endoplasmic reticulum (ER) stress in rats with diabetic gastroparesis.
METHODS: Forty rats were randomly divided into two groups: a control group and a diabetic group. Diabetes was induced by intraperitoneal injection of 60 mg/kg of streptozotocin. Gastric emptying was determined at the 4th and 12th week. The ultrastructural changes in gastric smooth muscle cells (SMCs) were investigated by transmission electron microscopy. TdT-mediated dUTP nick end labeling (TUNEL) assay was performed to assess apoptosis of SMCs. Expression of the ER stress marker, glucose-regulated protein 78 (GRP78), and the ER-specific apoptosis mediator, caspase-12 protein, was determined by immunohistochemistry.
RESULTS: Gastric emptying was significantly lower in the diabetic rats than in the control rats at the 12th wk (40.71% ± 2.50%, control rats vs 54.65% ± 5.22%, diabetic rats; P < 0.05). Swollen and distended ER with an irregular shape was observed in gastric SMCs in diabetic rats. Apoptosis of gastric SMCs increased in the diabetic rats in addition to increased expression of GRP78 and caspase-12 proteins.
CONCLUSION: ER stress and ER stress-mediated apoptosis are activated in gastric SMCs in diabetic rats with gastroparesis.
PMCID: PMC4081701  PMID: 25009401
Diabetic gastroparesis; Apoptosis; Endoplasmic reticulum stress; glucose-regulated protein 78 kD; Caspase-12
3.  Variants Identified by Hepatocellular Carcinoma and Chronic Hepatitis B Virus Infection Susceptibility GWAS Associated with Survival in HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2014;9(7):e101586.
Recent genome-wide association studies (GWAS) have identified several common susceptibility loci associated with the risk of hepatocellular carcinoma (HCC) or chronic hepatitis B infection (CHB). However, the relationship between these genetic variants and survival of patients with hepatitis B virus (HBV)-related HCC is still unknown. In this study, 22 single nucleotide polymorphisms (SNPs) were genotyped among 330 HBV-related HCC patients using the MassARRAY system from Sequenom. Cox proportional hazards regression was used to examine the effects of genotype on survival time under an additive model with age, sex, smoking status and clinical stage as covariates. We identified four SNPs on 6p21 (rs1419881 T>C, rs7453920 G>A,rs3997872 G>A and rs7768538 T>C), and two SNPs on 8p12 (rs2275959 C>T and rs7821974 C>T) significantly associated with survival time of HBV-related HCC patients. Our results suggest that HCC or CHB susceptibility loci might also affect the prognosis of patients with HBV-related HCC.
PMCID: PMC4079718  PMID: 24987808
4.  The effects and outcomes of electrolyte disturbances and asphyxia on newborns hearing 
To determine the effect of electrolyte disturbances (ED) and asphyxia on infant hearing and hearing outcomes.
Study Design
We conducted newborn hearing screening with transient evoked otoacoustic emission (TEOAE) test on a large scale (>5,000 infants). The effects of ED and asphyxia on infant hearing and hearing outcomes were evaluated.
The pass rate of TEOAE test was significantly reduced in preterm infants with ED (83.1%, multiple logistic regression analysis: P<0.01) but not in full-term infants with ED (93.6%, P=0.41). However, there was no significant reduction in the pass rate in infants with asphyxia (P=0.85). We further found that hypocalcaemia significantly reduced the pass rate of TEOAE test (86.8%, P<0.01). In the follow-up recheck at 3 months of age, the pass rate remained low (44.4%, P<0.01).
ED is a high-risk factor for preterm infant hearing. Hypocalcaemia can produce more significant impairment with a low recovery rate.
PMCID: PMC3738180  PMID: 23648318
OAE; newborn hearing screening; electrolyte disturbances; hearing loss; infant
5.  Roles of Tregs in development of hepatocellular carcinoma: A meta-analysis 
AIM: To assess systematically the association between regulatory T cells (Tregs) and hepatocellular carcinoma (HCC).
METHODS: We searched Medline, Embase and Wanfang databases for literature on the populations of Tregs in HCC patients and controls, using the pooled OR and 95%CIs for assessment. There were no limitations with respect to publication date or language. The references of qualifying articles were also searched. We excluded studies with unclear data or overlapping studies. Twenty-three studies met our criteria, and the quality of these studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN). The meta-analysis of association between Tregs and HCC was undertaken using the random-effects approach, as described by DerSimonian and Laird. Subgroup analysis was performed when at least three studies were available. Potential publication bias was assessed by visual inspection of the funnel plot, and an asymmetric plot suggested possible publication bias.
RESULTS: Twenty-three studies with a total of 1279 HCC patients and 547 healthy volunteers as controls were enrolled. The frequency of circulating Tregs in HCC patients was 87% higher than in healthy controls (OR = 1.87, 95%CI: 1.49-2.34). The frequency of Tregs in the HCC tumor microenvironment was significantly higher than that in tumor-surrounding tissue and biopsy specimens from healthy livers (OR = 4.04, 95%CI: 2.10-7.79, P = 0.000; OR = 2.869, 95%CI: 2.16-3.82, P = 0.000). However, subgroup analyses based on the different types of tumors or patient characteristics such as tumor size, tumor number or α fetoprotein (AFP) levels in HCC patients, showed that populations of Tregs as a whole were not significantly changed between groups (P > 0.05 for all).
CONCLUSION: There is an obvious association between Tregs and pathogenesis of HCC. Further well-designed clinical studies are warranted to illustrate the potential role of Tregs in HCC.
PMCID: PMC4069325  PMID: 24976734
Hepatocellular carcinoma; Regulatory T cells; Meta-analysis; Tumor escape; Cellular immunity
6.  Correlation of Structure and Function in the Human Hotdog-fold Enzyme hTHEM4† 
Biochemistry  2012;51(33):6490-6492.
Human THEM4 (hTHEM4) is comprised of a catalytically active hotdog-fold acyl-CoA thioesterase domain and an N-terminal domain of unknown fold and function. hTHEM4 has been linked to Akt1 regulation and cell apoptosis. Herein, we report the X-ray structure of hHTEM4 bound with undecan-2-one-CoA. Structure guided mutagenesis was carried out to confirm the catalytic residues. The N-terminal domain is shown to be partially comprised of irregular and flexible secondary structure, reminiscent of a protein-binding domain. We demonstrate direct hTHEM4-Akt1 binding by immunoprecipitation and by inhibition of Akt1 kinase activity, thus providing independent evidence that hTHEM4 is an Akt1 negative regulator.
PMCID: PMC4066673  PMID: 22871024
7.  Human Brown Fat Inducible Thioesterase Variant 2 (BFIT2) Cellular Localization and Catalytic Function# 
Biochemistry  2012;51(35):6990-6999.
The mammalian brown fat inducible thioesterase variant 2 (BFIT2), also known as ACOT11, is a multi-modular protein containing two consecutive hotdog-fold domains and a C-terminal steroidogenic acute regulatory protein related lipid transfer (START) domain (StarD14). In this study, we demonstrate that the N-terminal region of human BFIT2 (hBFIT2) constitutes a mitochondrial location signal sequence, which undergoes mitochondria-dependent posttranslational cleavage. The mature hBFIT2 is shown to be located in the mitochondrial matrix whereas the paralog “cytoplasmic acetyl-CoA hydrolase” (CACH, also known as ACOT12) was found in the cytoplam. In-vitro activity analysis of full-length hBFIT2 isolated from stably transfected HEK293 cells demonstrates selective thioesterase activity directed towards long chain fatty acyl-CoA thioesters, thus distinguishing BFIT2 catalytic function from that of CACH. The results from a protein-lipid overlay test indicate that the hBFIT2 StarD14 domain binds phosphatidylinositol 4-phosphate.
PMCID: PMC4066737  PMID: 22897136
thioesterase; mitochondria; START domain; hotdog-fold; thioester hydrolysis; lipid metabolism; ACOT11; ACOT12; BFIT; CACH; StarD14; StarD15; fatty acid
8.  Exploiting Synthetic Lethality for the Therapy of ABC Diffuse Large B Cell Lymphoma 
Cancer cell  2012;21(6):723-737.
Knowledge of oncogenic mutations can inspire therapeutic strategies that are synthetically lethal, affecting cancer cells while sparing normal cells. Lenalidomide is an active agent in the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), but its mechanism of action is unknown. Lenalidomide kills ABC DLBCL cells by augmenting interferon β (IFNβ) production, owing to the oncogenic MYD88 mutations in these lymphomas. In a cereblon-dependent fashion, lenalidomide downregulates IRF4 and SPIB, transcription factors that together prevent IFNβ production by repressing IRF7 and also amplify pro-survival NF-κB signaling by transactivating CARD11. Blockade of B cell receptor (BCR) signaling using the BTK inhibitor ibrutinib also downregulates IRF4 and consequently synergizes with lenalidomide in killing ABC DLBCLs, suggesting attractive therapeutic strategies.
PMCID: PMC4059833  PMID: 22698399
9.  Prognosis of patients with hepatocellular carcinoma and hypersplenism after surgery: a single-center experience from the People’s Republic of China 
OncoTargets and therapy  2014;7:957-964.
As prognosis of patients with hepatocellular carcinoma (HCC) and hypersplenism is rarely reported, this study examined prognostic factors for patients who underwent surgery for this condition.
Patients and methods
This study retrospectively analyzed prognostic factors in 181 consecutive HCC patients using univariate and multivariate analyses, as well as subgroup analyses for disease-free survival (DFS) and overall survival (OS) of two groups: one group who received splenectomies (Sp) and one group who did not (non-Sp).
1, 3, and 5 year OS rates were 88.4%, 67.1%, and 52.8%, respectively; corresponding DFS rates were 67.0%, 43.8%, and 31.6%, respectively. Age ≥55 years old, cigarette smoking, tumor size ≥5 cm, microvascular invasion, and Child-Pugh grade B (versus A) correlated significantly with OS (P<0.05). Interestingly, in patients with tumor lymph node metastasis (TNM) stage I disease, DFS of the Sp-group (median DFS, 24.1 months; n=34) was significantly lower than that of the non-Sp group (median DFS, 62.1 months; n=74), P=0.034; whereas at TNM stage II, OS of the Sp-group (median OS, 79.1 months; n=21) was significantly better than that of the non-Sp group (median OS, 23.3 months; n=30), P=0.018.
Hepatectomy without concomitant splenectomy can contribute to improved DFS of TNM stage I HCC patients with hypersplenism, whereas simultaneous hepatectomy and splenectomy can prolong OS for patients at TNM stage II.
PMCID: PMC4061180  PMID: 24959082
hepatectomy; splenectomy; overall survival; disease-free survival
10.  A Genetic Screen Identifies Interferon-α Effector Genes Required to Suppress Hepatitis C Virus Replication 
Gastroenterology  2013;144(7):1438-1449.e9.
Background & Aims
Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease. Interferon (IFN)-α is an important component of anti-HCV therapy; it upregulates transcription of IFN-stimulated genes (ISGs)—many of which have been investigated for their anti-viral effects. However, all the genes required for the anti-viral function of IFN-α (IFN effector genes, IEGs) are not known. IEGs include not only ISGs, but other non-transcriptionally induced genes that are required for the anti-viral effect of IFN-α. In contrast to candidate approaches based on analyses mRNA expression, identification of IEGs requires a broad functional approach.
We performed an unbiased genome-wide small-interfering (si)RNA screen to identify IEGs that inhibit HCV. Huh7.5.1 hepatoma cells were transfected with siRNAs, incubated with IFN-α, and then infected with JFH1 HCV. Cells were stained using HCV core antibody, imaged, and analyzed to determine the percent infection. Candidate IEGs detected in the screen were validated and analyzed further.
The screen identified 120 previously unreported IEGs. From these, we more fully evaluated 9 (ALG10, BCHE, DPP4, GCKR, GUCY1B3, MYST1, PPP3CB, PDIP1, SLC27A2) and demonstrated that they enabled IFN-α–mediated suppression of HCV at multiple steps of its lifecycle. Expression of these genes had more potent effects against flaviviridae, because a subset were required for IFN-α to suppress dengue virus but not influenza A virus. Furthermore, many of the host genes detected in this screen (92%) were not transcriptionally stimulated by IFN-α; these genes represent a heretofore unknown class of non-ISG IEGs.
We performed a whole-genome loss-of-function screen to identify genes that mediate the effects of IFN-α against human pathogenic viruses. We found that IFN-α restricts HCV via actions of general and specific IEGs.
PMCID: PMC3665646  PMID: 23462180
treatment; gene regulation; virology; mechanism
11.  Hypothermia-induced neuroprotection is associated with reduced mitochondrial membrane permeability in a swine model of cardiac arrest 
Increasing evidence has shown that mild hypothermia is neuroprotective for comatose patients resuscitated from cardiac arrest, but the mechanism of this protection is not fully understood. The aim of this study was to determine whether prolonged whole-body mild hypothermia inhibits mitochondrial membrane permeability (MMP) in the cerebral cortex after return of spontaneous circulation (ROSC). Thirty-seven inbred Chinese Wuzhishan minipigs were successfully resuscitated after 8 minutes of untreated ventricular fibrillation (VF) and underwent recovery under normothermic (NT) or prolonged whole-body mild hypothermic (HT; 33°C) conditions for 24 or 72 hours. Cerebral samples from the frontal cortex were collected at 24 and 72 hours after ROSC. Mitochondria were isolated by differential centrifugation. At 24 hours, relative to NT, HT was associated with reductions in opening of the mitochondrial permeability transition pore, release of pro-apoptotic substances from mitochondria, caspase 3 cleavage, apoptosis, and neurologic deficit scores, as well as increases in mitochondrial membrane potential and mitochondrial respiration. Together, these findings suggest that mild hypothermia inhibits ischemia-induced increases in MMP, which may provide neuroprotection against cerebral injury after cardiac arrest.
PMCID: PMC3677114  PMID: 23486294
cardiac arrest; mitochondria; mild hypothermia; neuroprotection; pig; reperfusion
12.  The carina is approximately 1-2 cm above the pericardial reflection among Chinese patients 
Journal of Thoracic Disease  2014;6(6):845-849.
Central venous catheters (CVCs) and central venous pressure (CVP) monitor is essential in fluid resuscitation and management for critically ill patients. Accuracy of the CVP is mainly dependent on the proper position of the catheter tip. Although the X-ray visible carina was generally recommended as the alternative of pericardial reflection (PR) to guide the placement of CVCs, few data was available with respect to the distance between the carina and PR among Chinese patients. The purpose of this study was to explore the topographic relationship between the trachea carina and PR among Chinese patients by using computed tomography (CT) images.
CT images of 172 patients who underwent CT pulmonary angiogram or CT angiogram for aorta from January 1, 2013 to November 30, 2013 were retrospectively reviewed. Distances between upper margin of the right clavicular notch, trachea carina, PR and atriocaval junction (ACJ) were calculated using the table positions on axial images.
The mean length of extrapericardial superior vena cava (SVC) was 2.5 cm. For all patients, the PR was lower than the carina by average 1.6 cm.
Given the PR was average 1.6 cm lower than the carina among Chinese patients, placing the CVCs tip approximate 1.6 cm lower the carina among Chinese patients would be more likely to result in a satisfactory placement.
PMCID: PMC4073397  PMID: 24977011
Central venous catheter (CVC); carina; pericardial reflection (PR)
13.  Molecular Phylogeny of Tribe Theeae (Theaceae s.s.) and Its Implications for Generic Delimitation 
PLoS ONE  2014;9(5):e98133.
Tribe Theeae, which includes some economically important and widely grown plants, such as beverage tea and a number of woody ornamentals, is the largest member of the Theaceae family. Using five genomic regions (chloroplast: atpI-H, matK, psbA5'R-ALS-11F, rbcL; nuclear: LEAFY) and 30 species representing four of the five genera in this tribe (Apterosperma, Camellia, Polyspora, and Pyrenaria s.l.), we investigated the phylogeny of Theeae and assessed the delimitation of genera in the tribe. Our results showed that Polyspora was monophyletic and the sister of the three other genera of Theeae investigated, Camellia was paraphyletic and Pyrenaria was polyphyletic. The inconsistent phylogenetic placement of some species of Theeae between the nuclear and chloroplast trees suggested widespread hybridization between Camellia and Pyrenaria, Polyspora and Parapyrenaria. These results indicate that hybridization, rather than morphological homoplasy, has confused the current classification of Theeae. In addition, the phylogenetic placement and possible allies of Laplacea are also discussed.
PMCID: PMC4029964  PMID: 24848365
14.  Identification of biomarkers for hepatocellular carcinoma by semiquantitative immunocytochemistry 
AIM: To investigate the expression of key biomarkers in hepatoma cell lines, tumor cells from patients’ blood samples, and tumor tissues.
METHODS: We performed the biomarker tests in two steps. First, cells plated on coverslips were used to assess biomarkers, and fluorescence intensities were calculated using the NIH Image J software. The measured values were analyzed using the SPSS 19.0 software to make comparisons among eight cell lines. Second, eighty-four individual samples were used to assess the biomarkers’ expression. Negative enrichment of the blood samples was performed, and karyocytes were isolated and dropped onto pre-treated glass slides for further analysis by immunofluorescence staining. Fluorescence intensities were compared among hepatocellular carcinoma (HCC) patients, chronic HBV-infected patients, and healthy controls following methods similar to those used for cell lines. The relationships between the expression of biomarkers and clinical pathological parameters were analyzed by Spearman rank correlation tests. In addition, we studied the distinct biomarkers’ expression with three-dimensional laser confocal microscopy reconstructions, and Kaplan-Meier survival analysis was performed to understand the clinical significance of these biomarkers.
RESULTS: Microscopic examination and fluorescence intensity calculations indicated that cytokeratin 8/18/19 (CK) expression was significantly higher in six of the seven HCC cell lines examined than in the control cells, and the expression levels of asialoglycoprotein receptor (ASGPR) and glypican-3 (GPC3) were higher in all seven HCC cell lines than in the control. Cells obtained from HCC patients’ blood samples also displayed significantly higher expression levels of ASGPR, GPC3, and CK than cells from chronic HBV-infected patients or healthy controls; these proteins may be valuable surface biomarkers for identifying HCC circulating tumor cells isolated and enriched from the blood samples. The stem cell-like and epithelial-mesenchymal transition-related biomarkers could be detected on the karyocyte slides. ASGPR and GPC3 were expressed at high levels, and thus three-dimensional reconstructions were used to observe their expression in detail. This analysis indicated that GPC3 was localized in the cytoplasm and membrane, but that ASGPR had a polar localization. Survival analyses showed that expression of GPC3 and ASGPR is associated with a patient’s overall survival (OS).
CONCLUSION: ASGPR, GPC3, and CK may be valuable HCC biomarkers for CTC detection; the expression of ASGPR and GPC3 might be helpful for understanding patients’ OS.
PMCID: PMC4024792  PMID: 24914343
Hepatocellular carcinoma; Biomarker; Immunocytochemistry; Semiquantitative analysis; Three-dimensional reconstruction
15.  Inducible knockout mutagenesis reveals compensatory mechanisms elicited by constitutive BK channel deficiency in overactive murine bladder 
The FEBS journal  2008;276(6):1680-1697.
The large-conductance, voltage-dependent and Ca2+-dependent K+ (BK) channel links membrane depolarization and local increases in cytosolic free Ca2+ to hyperpolarizing K+ outward currents, thereby controlling smooth muscle contractility. Constitutive deletion of the BK channel in mice (BK−/−) leads to an overactive bladder associated with increased intravesical pressure and frequent micturition, which has been revealed to be a result of detrusor muscle hyperexcitability. Interestingly, time-dependent and smooth muscle-specific deletion of the BK channel (SM-BK−/−) caused a more severe phenotype than displayed by constitutive BK−/− mice, suggesting that compensatory pathways are active in the latter. In detrusor muscle of BK−/− but not SM-BK−/− mice, we found reduced L-type Ca2+ current density and increased expression of cAMP kinase (protein kinase A; PKA), as compared with control mice. Increased expression of PKA in BK−/− mice was accompanied by enhanced β-adrenoceptor/cAMP-mediated suppression of contractions by isoproterenol. This effect was attenuated by about 60–70% in SM-BK−/− mice. However, the Rp isomer of adenosine-3′,5′-cyclic monophosphorothioate, a blocker of PKA, only partially inhibited enhanced cAMP signaling in BK−/− detrusor muscle, suggesting the existence of additional compensatory pathways. To this end, proteome analysis of BK−/− urinary bladder tissue was performed, and revealed additional compensatory regulated proteins. Thus, constitutive and inducible deletion of BK channel activity unmasks compensatory mechanisms that are relevant for urinary bladder relaxation.
PMCID: PMC4025950  PMID: 19220851
cAMP/PKA signaling; overactive urinary bladder; proteomic adaptation; smooth muscle-specific BK channel knockout mice; time-dependent BK channel deletion
16.  Association between mammographic features and clinicopathological characteristics in invasive ductal carcinoma of breast cancer 
Molecular and Clinical Oncology  2014;2(4):623-629.
The aim of the present study was to evaluate the association between mammographic features and clinicopathological characteristics in invasive ductal carcinoma. A total of 231 patients were retrospectively reviewed from January, 2011 to December, 2012. Statistical analysis was performed using Fisher’s exact test, χ2 test, Spearman’s correlation and logistic regression, as appropriate. Of the 231 patients who underwent mammography, malignant calcifications were significantly more frequent in carcinomas that were human epidermal growth factor receptor 2 (HER2)-positive (P=0.001) or had a >2 cm size tumor (P=0.006). The pleomorphic-type was correlated with a p53-positive status (P=0.039) or lymph node metastasis (P=0.048), whereas the indistinct amorphous-type was associated with a HER2-positive status (P=0.026). An evident mass was frequently observed in higher Ki-67 expression-level tumors (P=0.002). In conclusion, the aforementioned correlations are noteworthy as they potentially reflect tumor attributes and may serve as a guide for treatment.
PMCID: PMC4051570  PMID: 24940507
mammography; breast neoplasm; clinic; invasive ductal carcinoma; pathology
17.  Clinical findings of 40 patients with nocardiosis: A retrospective analysis in a tertiary hospital 
To the best of our knowledge, no Chinese case studies concerning Nocardia infection have been published to date. Therefore, the present study aimed to retrospectively evaluate the risk factors, clinical features, imaging results, laboratory abnormalities, treatments and outcomes of nocardiosis in a Chinese tertiary hospital. Data collected from patients with laboratory-confirmed nocardiosis were retrospectively analyzed. A total of 40 patients who had a positive culture of Nocardia were included. The median time between the onset of symptoms and diagnosis was 42 days. Underlying diseases were identified in 72.5% of the patients of which diabetes was the most common (32.5%). The most important risk factor was corticosteroid administration. Fever and cough were common clinical symptoms. The pleuropulmonary (85%) were the most frequently involved sites and the disseminated disease rate was 30.0%. Frequent chest computed tomography scans revealed the presence of airspace opacities, nodules and masses, in addition to cavitary lesions that were particularly common among the study group. Brain images revealed lesions associated with abscesses. The majority of the patients (71.1%) were treated with trimethoprim sulfamethoxazole alone or in combination with other drugs. The in-hospital mortality rate was 15.0%. Disseminated disease, immunocompromised patients, an older age, brain involvement and concomitant infections were associated with a poor prognosis. Nocardiosis is an uncommon but emerging disease. The present study reports the first case series on nocardiosis from China and provides important information on the clinical features and risk factors of nocardiosis. Early recognition of the disease and the initiation of appropriate treatment are essential for a good prognosis.
PMCID: PMC4061227  PMID: 24944592
Nocardia; corticosteroids; opportunistic disease; pulmonary nocardiosis; brain abscess
18.  The Screening Research of Anti-Inflammatory Bioactive Markers from Different Flowering Phases of Flos Lonicerae Japonicae 
PLoS ONE  2014;9(5):e96214.
Flos Lonicerae Japonicae (FLJ) is an important cash crop in eastern Asia, and it is an anti-inflammatory Traditional Chinese Medicine. There are large variations in the quality of the marketed FLJ products. To find marker ingredients useful for quality control, a tandem technology integrating ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF), principal component analysis (PCA), heat map analysis and hierarchical cluster analysis coupled with a NF-κB luciferase reporter gene assay were used to identify the different ingredients from the green bud, white bud, flowering stage and leaf stages, as well as to screen the anti-inflammatory activity of FLJ compositions. As flowering progressed, the anti-inflammatory effects of FLJ gradually decreased; however, chlorogenic acid, swertiamarin and sweroside should be used to evaluate the quality of FLJ products.
PMCID: PMC4014484  PMID: 24809338
19.  Overexpressions of MicroRNA-9 and MicroRNA-200c in Human Breast Cancers Are Associated with Lymph Node Metastasis 
The aim of this study was to investigate the relationship between the expressions of microRNA-9 (miR-9) and microRNA-200c (miR-200c) in human breast cancers and clinicopathological features.
We investigated the expressions of miR-9 and miR-200c in 68 patients with breast cancers using the quantitative reverse transcription–polymerase chain reaction method, and assessed the E-cadherin status using the immunohistochemistry method.
The relative expression levels of miR-9 and miR-200c in breast cancer patients with lymph node metastasis were higher than that of patients without lymph node metastasis. The expression of miR-9 correlated inversely with E-cadherin expression.
The results showed that higher expressions of miR-9 and miR-200c in human breast cancers were associated with lymph node metastasis. This study indicated that the elevation of miR-9 and miR-200c in human breast cancers can induce an invasive phenotype and may serve as a molecular diagnostic marker for patients with breast cancer.
PMCID: PMC3653379  PMID: 23617747
breast cancer; E-cadherin; metastasis; microRNA-9; microRNA-200c
20.  Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases 
Cancer research  2013;73(20):6149-6163.
A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target–disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.
PMCID: PMC4005386  PMID: 24097821
21.  Claims-based algorithms for identifying Medicare beneficiaries at high estimated risk for coronary heart disease events: a cross-sectional study 
Databases of medical claims can be valuable resources for cardiovascular research, such as comparative effectiveness and pharmacovigilance studies of cardiovascular medications. However, claims data do not include all of the factors used for risk stratification in clinical care. We sought to develop claims-based algorithms to identify individuals at high estimated risk for coronary heart disease (CHD) events, and to identify uncontrolled low-density lipoprotein (LDL) cholesterol among statin users at high risk for CHD events.
We conducted a cross-sectional analysis of 6,615 participants ≥66 years old using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study baseline visit in 2003–2007 linked to Medicare claims data. Using REGARDS data we defined high risk for CHD events as having a history of CHD, at least 1 risk equivalent, or Framingham CHD risk score >20%. Among statin users at high risk for CHD events we defined uncontrolled LDL cholesterol as LDL cholesterol ≥100 mg/dL. Using Medicare claims-based variables for diagnoses, procedures, and healthcare utilization, we developed algorithms for high CHD event risk and uncontrolled LDL cholesterol.
REGARDS data indicated that 49% of participants were at high risk for CHD events. A claims-based algorithm identified high risk for CHD events with a positive predictive value of 87% (95% CI: 85%, 88%), sensitivity of 69% (95% CI: 67%, 70%), and specificity of 90% (95% CI: 89%, 91%). Among statin users at high risk for CHD events, 30% had LDL cholesterol ≥100 mg/dL. A claims-based algorithm identified LDL cholesterol ≥100 mg/dL with a positive predictive value of 43% (95% CI: 38%, 49%), sensitivity of 19% (95% CI: 15%, 22%), and specificity of 89% (95% CI: 86%, 90%).
Although the sensitivity was low, the high positive predictive value of our algorithm for high risk for CHD events supports the use of claims to identify Medicare beneficiaries at high risk for CHD events.
PMCID: PMC4101858  PMID: 24779477
High risk; Coronary heart disease; Risk stratification; Medicare claims
22.  Fatal Interstitial Lung Disease after Addition of Sorafenib to a Patient with Lung Adenocarcinoma Who Had Failed to Improve with Erlotinib Alone 
Case Reports in Oncology  2014;7(1):273-276.
Interstitial lung disease (ILD) induced by epidermal growth factor receptor tyrosine kinase inhibitors has been extensively documented with decreasing incidence after appropriate patient selection due to increasing awareness over the years. However, ILD induced by sorafenib was mentioned with lower frequency only in patients with hepatocellular and renal cell carcinoma living in Japan but not in patients with other carcinomas or living outside Japan, and it has been overlooked in clinical practice. In the present case, sorafenib was added to the treatment of a 60-year-old non-smoking patient with non-small cell lung cancer (NSCLC). After his failing to improve with erlotinib alone, erlotinib was continued to be given in combination with sorafenib as a salvage therapy. Although clinical signs of ILD were observed 2 weeks after the addition of sorafenib, the radiological diagnosis of ILD was only made 41 days after the initiation of the combination treatment, and the patient died 56 days after treatment onset. It was concluded that ILD was indeed induced by sorafenib. This is the first report of ILD induced by sorafenib in a patient with NSCLC living outside Japan. Oncologists should be aware of this fatal complication for its early detection in order to avoid a severe course of ILD leading to a decrease in the ILD mortality rate.
PMCID: PMC4036133  PMID: 24926256
Erlotinib; Interstitial lung disease; Non-small cell lung cancer; Sorafenib
23.  Efficacy and tolerability of low-dose interferon-α in hemodialysis patients with chronic hepatitis C virus infection 
AIM: To evaluate the efficacy and tolerability of low-dose standard or pegylated interferon (PEG-IFN) in hepatitis C virus (HCV)-positive hemodialysis patients.
METHODS: In total, 19 patients were enrolled in this study, of which 12 received PEG-IFNα-2a 67.5 μg 1 time/wk (Group 1) and 7 received standard interferon α-2b subcutaneously 1.5 × 106 U 3 times/wk (Group 2). The treatment durations were 48 wk for patients infected with HCV genotype 1 and 24 wk for patients infected with HCV genotype 2/3. All patients were prospectively followed after the completion of therapy. The efficacy and tolerability of the treatment were evaluated based on the sustained virological response (SVR) and treatment-related drop-out rate.
RESULTS: In Group 1, 11 of the 12 patients completed the treatment. Early virological response (EVR) and sustained virological response (SVR) rates were 83.3% and 91.7%, respectively. One patient withdrew from treatment due to an adverse event (leukopenia). The drop-out rate was 8.3% in this group. In Group 2, 5 of the 7 patients completed the treatment with an EVR and SVR of 85.7% and 71.4%, respectively. Two patients withdrew due to treatment-related adverse events (nausea and depression). In this group, the drop-out rate was 28.6%. In total, 16 of the patients attained EVR, and 15 of them completed the treatment. The SVR rate for the patients who attained EVR was 93.7%. Anemia was the most frequent side effect and was observed in 10/19 patients (55.5%), but could be effectively managed with erythropoietin.
CONCLUSION: Low-dose interferon monotherapy, either with PEG-IFNα-2a or standard interferon α-2b, is an effective treatment option for hemodialysis patients with chronic hepatitis C.
PMCID: PMC3983465  PMID: 24744598
Chronic hepatitis C; End-stage renal disease; Hemodialysis; Hepatitis C virus; Peginterferon
24.  Relationship of renin-angiotensin-aldosterone system polymorphisms and phenotypes to mortality in Chinese coronary atherosclerosis patients 
Scientific Reports  2014;4:4600.
We performed a large, long-term cohort study to evaluate the association of renin-angiotensin-aldosterone system gene polymorphisms and baseline phenotypes to all-cause mortality among patients with angiographically confirmed coronary atherosclerosis. The study included 1075 subjects who underwent coronary angiography. Patients were genotyped for eight polymorphisms (rs4343, rs5186, rs5182, rs5049, rs5051, rs699, rs4762, and rs1799998), and their baseline plasma angiotensin II and aldosterone levels were measured. The interval between baseline and follow-up time-points ranged from 6.39 to 9.59 years. The results of multivariate regression analysis further indicated that high baseline angiotensin II levels (1.226 (1.024–1.468), p = 0.027) were independently associated with all-cause death. Therefore, we found that an increased baseline plasma angiotensin II level was associated with higher long-term all-cause mortality, even after correcting for established cardiovascular risk factors.
PMCID: PMC3983573  PMID: 24722536
25.  Host-to-Pathogen Gene Transfer Facilitated Infection of Insects by a Pathogenic Fungus 
PLoS Pathogens  2014;10(4):e1004009.
Metarhizium robertsii is a plant root colonizing fungus that is also an insect pathogen. Its entomopathogenicity is a characteristic that was acquired during evolution from a plant endophyte ancestor. This transition provides a novel perspective on how new functional mechanisms important for host switching and virulence have evolved. From a random T-DNA insertion library, we obtained a pathogenicity defective mutant that resulted from the disruption of a sterol carrier gene (Mr-npc2a). Phylogenetic analysis revealed that Metarhizium acquired Mr-npc2a from an insect by horizontal gene transfer (HGT). Mr-NPC2a binds to cholesterol, an animal sterol, rather than the fungal sterol ergosterol, indicating it retains the specificity of insect NPC2 proteins. Mr-NPC2a is an intracellular protein and is exclusively expressed in the hemolymph of living insects. The disruption of Mr-npc2a reduced the amount of sterol in cell membranes of the yeast-like hyphal bodies that facilitate dispersal in the host body. These were consequently more susceptible to insect immune responses than the wild type. Transgenic expression of Mr-NPC2a increased the virulence of Beauveria bassiana, an endophytic insect-pathogenic fungus that lacks a Mr-NPC2a homolog.
Author Summary
The ability of infectious agents to evolve different host ranges contributes to the emergence of new diseases, and this host switching could also account for the wide variety of fungal associations with animals, plants and other fungi. There must be mechanisms for such host shifts, but these remain largely unknown. In this study, we phylogenetically predict that the endophytic fungus Metarhizium robertsii acquired a sterol carrier gene from insects through horizontal gene transfer (HGT). This sterol carrier is involved in maintaining cell membrane sterols, and thus membrane integrity, when M. robertsii proliferates in the haemocoel of living insects. Therefore, the acquisition of genetic material from a host has contributed to the development of fungal entomopathogenicity. In order to simulate this evolutionary event, the sterol carrier gene was transformed into an endophytic insect-pathogenic fungus (Beauveria bassiana) that lacks an endogenous Mr-NPC2a homolog. The virulence of B. bassiana was increased by expression of Mr-NPC2a.
PMCID: PMC3983072  PMID: 24722668

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