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1.  Retinal Ganglion Cell Layer Thickness and Local Visual Field Sensitivity in Glaucoma 
Archives of ophthalmology  2011;129(12):1529-1536.
To compare loss in sensitivity measured using standard automated perimetry (SAP) with local retinal ganglion cell layer (RGC) thickness measured using frequency-domain optical coherence tomography in the macula of patients with glaucoma.
To compare corresponding locations of RGC thickness with total deviation (TD) of 10-2 SAP for 14 patients with glaucoma and 19 controls, an experienced operator hand-corrected automatic segmentation of the combined RGC and inner plexiform layer (RGC + IPL) of 128 horizontal B-scans. To account for displacement of the RGC bodies around the fovea, the location of the SAP test points was adjusted to correspond to the location of the RGC bodies rather than to the photoreceptors, based on published histological findings. For analysis, RGC + IPL thickness vs SAP (TD) data were grouped into 5 eccentricities, from 3.4° to 9.7° radius on the retina with respect to the fovea.
The RGC + IPL thickness correlated well with SAP loss within approximately 7.2° of the fovea (Spearman ρ = 0.71–0.74). Agreement was worse (0.53–0.65) beyond 7.2°, where the normal RGC layer is relatively thin. A linear model relating RGC + IPL thickness to linear SAP loss provided a reasonable fit for eccentricities within 7.2°.
In the central 7.2°, local RGC + IPL thickness correlated well with local sensitivity loss in glaucoma when the data were adjusted for RGC displacement.
PMCID: PMC4331118  PMID: 22159673
2.  Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing 
JAMA  2014;312(18):1870-1879.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
PMCID: PMC4326249  PMID: 25326635
3.  Angiogenin Promotes U87MG Cell Proliferation by Activating NF-κB Signaling Pathway and Downregulating Its Binding Partner FHL3 
PLoS ONE  2015;10(2):e0116983.
Angiogenin (Ang) is known to induce cell proliferation and inhibit apoptosis by cellular signaling pathways and its direct nuclear functions, but the mechanism of action for Ang in astrocytoma is not yet clear. Astrocytoma is the most frequent one among various neurogliomas, of which a subtype known as glioblastoma multiforme (GBM) is the most malignant brain glioma and seriously influences the life quality of the patients. The expression of Ang and Bcl-xL were detected in 28 cases of various grades of astrocytoma and 6 cases of normal human tissues by quantitative real-time PCR. The results showed that the expression of Ang and Bcl-xL positively correlated with the malignant grades. Cytological experiments indicated that Ang facilitated human glioblastoma U87MG cell proliferation and knock-down of endogenous Ang promoted cell apoptosis. Furthermore, Ang activated NF-κB pathway and entered the U87MG cell nuclei, and blocking NF-κB pathway or inhibiting Ang nuclear translocation partially suppressed Ang-induced cell proliferation. The results suggested that Ang participated in the regulation of evolution process of astrocytoma by interfering NF-κB pathway and its nucleus function. In addition, four and a half LIM domains 3 (FHL3), a novel Ang binding partner, was required for Ang-mediated HeLa cell proliferation in our previous study. We also found that knockdown of FHL3 enhanced IκBα phosphorylation and overexpression of Ang inhibited FHL3 expression in U87MG cells. Together our findings suggested that Ang could activate NF-κB pathway by regulating the expression of FHL3. In conclusion, the present study established a link between Ang and FHL3 proteins and identifies a new pathway for regulating astrocytoma progression.
PMCID: PMC4320115  PMID: 25659096
4.  Fabrication of high-Q lithium niobate microresonators using femtosecond laser micromachining 
Scientific Reports  2015;5:8072.
We report on fabrication of high-Q lithium niobate (LN) whispering-gallery-mode (WGM) microresonators suspended on silica pedestals by femtosecond laser direct writing followed by focused ion beam (FIB) milling. The micrometer-scale (diameter ~82 μm) LN resonator possesses a Q factor of ~2.5 × 105 around 1550 nm wavelength. The combination of femtosecond laser direct writing with FIB enables high-efficiency, high-precision nanofabrication of high-Q crystalline microresonators.
PMCID: PMC4308694  PMID: 25627294
5.  Perioperative dynamics and significance of amino acid profiles in patients with cancer 
Metabolome analysis including amino acid profile is under investigation as an approach in cancer screening. The present study aims to analyze plasma free amino acid (PFAA) profiles in cancer patients and investigate their potential as biomarkers of malignancy.
Plasma samples from 56 gastric cancer patients, 28 breast cancer patients, 33 thyroid cancer patients, and 137 age-matched healthy controls were collected in the study. PFAA levels were measured and their perioperative alterations were analyzed. Biological effects of ten cancer-related amino acids were further validated in gastric and breast cancer cells.
We found that PFAA profiles of cancer patients differed significantly from those of healthy controls. Decreased concentrations of PFAAs were associated with lymph node metastases in gastric cancer. Levels of PFAAs such as aspartate and alanine increased after tumor resection. PFAA levels correlated with clinical tumor markers in gastric cancer patients and pathological immunohistochemistry markers in breast cancer patients. Specifically, alanine, arginine, aspartate and cysteine had proliferative effects on breast cancer cells. Proliferation of gastric cancer cells was promoted by cysteine, but inhibited by alanine and glutamic acid. Furthermore, alanine treatment decreased total and stable fraction of gastric cancer cells, and alanine and glutamic acid induced apoptosis of gastric cancer cells.
PFAA patterns in cancer patients are altered perioperatively. Tumor-related amino acids identified by dynamic study of PFAA patterns may have the potential to be developed as novel biomarkers for diagnosis and prognosis of cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0408-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4332895  PMID: 25622826
Amino acid profile; Plasma; Metabolism; Cancer; Perioperation
6.  Encapsulation of Acetylshikonin by Polyamidoamine Dendrimers for Preparing Prominent Nanoparticles 
AAPS PharmSciTech  2014;15(2):425-433.
Acetylshikonin (AS) has demonstrated antitumor potential. However, the development of therapeutic applications utilizing AS is inhibited by its poor solubility in water. In the present work, polyamidoamine (PAMAM) dendrimers and their PEGylated derivatives were employed to increase the solubility of AS. A distinct color transition was observed during the encapsulation of AS suggesting strong intermolecular forces between PAMAM and AS. Ultraviolet–visible, high-performance liquid chromatography, and 1H NMR were used to verify the interaction between PAMAM and AS. The maximum amount of combined AS to each PAMAM molecule was determined. The cytotoxicity of AS nanoparticles was evaluated against leukemia (K562) and breast cancer (SK-BR-3) cell lines; the AS nanoparticles were shown to effectively inhibit tumor cells.
PMCID: PMC3969479  PMID: 24449188
acetylshikonin (AS); color transition; polyamidoamine (PAMAM) dendrimer
7.  Predictors of intent to pursue a college health science education among high achieving minority 10th graders 
Minority populations are underrepresented in fields of science, perhaps limiting scientific perspectives. Informed by recent studies using Social Cognitive Career Theory, this study examined whether three conceptual constructs: self-efficacy, perceived adult support, and perceptions of barriers, as well as several discrete and immutable variables, were associated with intent to pursue college science education in a sample (N = 134) of minority youth (70.1% female and 67.2% African American). A paper-and-pencil survey about pursuit of college science was administered to 10th graders with a B- or better grade point average from six high schools in an underserved community. Results indicated that the three conceptual constructs were bivariate correlates of intent to pursue college science education. Only perceived adult support and knowing whether a parent received college education were significant predictors in multivariate modeling. These results build on previous research and provide further insight into youth decision-making regarding pursuit of college science.
PMCID: PMC4296255  PMID: 25598654
minority; youth; self-efficacy; adult support; college education; science
8.  Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint 
Cancer research  2013;74(2):508-519.
Improved clinical management of prostate cancer (PCa) has been impeded by an inadequate understanding of molecular genetic elements governing tumor progression. Gene signatures have provided improved prognostic indicators of human PCa. The TGFβ/BMP-SMAD4 signaling pathway, which induces epithelial mesenchymal transition (EMT), is known to constrain prostate cancer progression induced by Pten deletion. Herein, cyclin D1 inactivation reduced cellular proliferation in the murine prostate in vivo and in isogenic oncogene-transformed prostate cancer cell lines. The in vivo cyclin D1-mediated molecular signature predicted poor outcome of recurrence free survival for prostate cancer patients (K-means hazard ratio 3.75, P-value=0.02) and demonstrated that endogenous cyclin D1 restrains TGFβ, Snail, Twist and Goosecoid signaling. Endogenous cyclin D1 enhanced Wnt and ES cell gene expression and expanded a prostate stem cell population. In ChIP-Seq, cyclin D1 occupied genes governing stem cell expansion and induced their transcription. The coordination of EMT restraining and stem cell expanding gene expression by cyclin D1 in the prostate may contribute to its strong prognostic value for poor outcome in biochemical free recurrence in human prostate cancer.
PMCID: PMC3914674  PMID: 24282282
Cyclin D1; gene network; prostate cancer; siRNA; shRNA
9.  Procalcitonin as a diagnostic marker of ventilator-associated pneumonia in cardiac surgery patients 
The aim of the present study was to assess whether procalcitonin (PCT) can be used as a diagnostic marker for ventilator-associated pneumonia (VAP) in cardiac surgery patients. Between January 2012 and June 2013, a total of 92 patients were recruited and divided into non-VAP (59 patients) and VAP (33 patients) groups. The preoperative and postoperative characteristics of the patients were recorded. Serum levels of PCT, interleukin (IL)-6 and C-reactive protein (CRP) were measured using an electrochemiluminescence immunoassay. Subsequently, receiver operating characteristic curves of the PCT, IL-6 and CRP levels were constructed. In addition, associations between the sequential organ failure assessment (SOFA) scores and the serum levels of PCT, IL-6 and CRP in the VAP patients were analyzed. No statistically significant difference was observed between the non-VAP and VAP patients in the occurrence of postoperative complications. However, the SOFA scores (days 1 and 7), the duration of stay in the intensive care unit and the mechanical ventilation time were all significantly higher in the VAP group when compared with the non-VAP group (P<0.05). The optimum PCT cut-off value for VAP diagnosis on day 1 was 5.0 ng/ml, with a sensitivity of 91% and a specificity of 71%. The serum PCT levels on days 1 and 7 were found to correlate positively with the SOFA scores (r=0.54 and r=0.66 for days 1 and 7, respectively). Therefore, the results suggested that serum PCT may be used as diagnostic marker for VAP in patients following cardiac surgery.
PMCID: PMC4316963  PMID: 25667677
procalcitonin; ventilator-associated pneumonia; cardiac surgery; diagnostic marker
10.  Phosphine-Catalyzed [3+2] and [4+3]Annulation Reactions of C,N-Cyclic Azomethine Imines with Allenoates 
Advanced synthesis & catalysis  2012;354(6):1023-1034.
Phosphine-catalyzed [3+2] and [4+3]annulation reactions of C,N-cyclic azomethine imines with allenoates have been developed to give a variety of pharmaceutically attractive tetrahydroisoquinoline derivatives in moderate to excellent yields. The two distinct reaction pathways, [3+2] and [4+3]cyclization, depend on the nature of the nucleophilic phosphine and the allenoate. Generally, for α-alkylallenoates, the reactions always proceed with [3 +2]cyclization as the major pathway no matter what phosphine was used; for α-ArCH2-substituted allenoates, the reaction pathway was controlled by the phosphine catalyst used.
PMCID: PMC4266944  PMID: 25525424
allenoates; annulation; azomethine imines; catalysis; phosphines
11.  Validation of ELISA for Quantitation of Artemisinin-Based Antimalarial Drugs 
The circulation of counterfeit or substandard artemisinins (ARTs) in malaria-endemic areas poses a serious threat to the long-term use of these drugs. Here, we validated an indirect competitive enzyme-linked immunosorbent assay (icELISA) for quantification of ARTs and found that 50% of inhibitory concentrations of dihydroartemisinin, artemether, and artesunate were 8.1, 207.0, and 4.7 ng/mL, respectively. We compared the icELISA with high-performance liquid chromatography (HPLC) for quantifying ART and its derivatives in 22 convenience samples of commercial antimalarial drugs. Paired t tests showed a borderline significant difference between the two methods (mean = 0.03, 95% confidence interval [CI] 0.00–0.07, P = 0.074) and the icELISA results were more variable than those of the HPLC analysis (P < 0.001), suggesting that further improvement is needed to enhance the performance of the icELISA. Our results showed that the icELISA has the potential to be improved for quality assurance of ARTs at the point of care in endemic settings.
PMCID: PMC3854889  PMID: 24080636
12.  Inhibition of Neutrophil Collagenase/MMP-8 and Gelatinase B/MMP-9 and Protection against Endotoxin Shock 
Journal of Immunology Research  2014;2014:747426.
Endotoxin shock is a life-threatening disorder, associated with the rapid release of neutrophil enzymes, including neutrophil collagenase/matrix metalloproteinase-8 (MMP-8) and gelatinase B/matrix metalloproteinase-9 (MMP-9). After activation, these enzymes cleave extracellular matrix components and cytokines and thus may contribute to shock syndrome development. MMP inhibitors have been suggested as immunotherapy of endotoxin shock. However, little is known about the therapeutic time window of MMP inhibition. Here, a sublethal endotoxin shock mouse model was used to evaluate the effect of an MMP inhibiting peptide (P2) after intravenous or intraperitoneal injection and to study the time window between LPS and inhibitor injections. With the use of a specific ELISA the plasma P2 concentrations were monitored. Whereas we corroborated the treatment strategy of MMP targeting in endotoxin shock with a new inhibitor, we also demonstrated that the time window, within which effective MMP inhibition increased the survival rates, is rather limited.
PMCID: PMC4265539
13.  Study on acute recent stage pancreatitis 
World Journal of Gastroenterology : WJG  2014;20(43):16138-16145.
Acute pancreatitis (AP) is an inflammatory disease of the pancreas which involves the pancreas and surrounding tissue, and systemic inflammation with a characteristic systemic increase of vascular permeability and increased risk of multiple organ dysfunction. Currently, the pathogenesis of AP is fuzzy, and the diagnosis and treatment need to be standardized. Nevertheless, increased knowledge of AP may achieve more thorough understanding of the pathogenesis. The use of further advanced diagnostic tools and superior treatment, potentially will help clinicians to manage AP at an appropriate stage. However, in view of the multi factorial disease and the complex clinical manifestations, the management of patients with AP is also remaining areas for improvement.
PMCID: PMC4239500  PMID: 25473166
Acute pancreatitis; Organ failure; Necrosis; Inflammation; Management
14.  Fecal microbiota transplantation and prednisone for severe eosinophilic gastroenteritis 
World Journal of Gastroenterology : WJG  2014;20(43):16368-16371.
Eosinophilic gastroenteritis is a rare disease of unknown etiology. It is characterized by patchy or diffuse eosinophilic infiltration of the bowel wall to a variable depth and various gastrointestinal manifestations. We describe a case of severe eosinophilic gastroenteritis presenting as frequent bowel obstruction and diarrhea in a 35-year-old man. The patient was misdiagnosed and underwent surgery because of intestinal obstruction when he was first admitted to a local hospital. Then he was misdiagnosed as having Crohn’s disease in another university teaching hospital. Finally, the patient asked for further treatment from our hospital because of the on-going clinical trial for treating refractory Crohn’s disease by fecal microbiota transplantation. Physical examination revealed a slight distended abdomen with diffuse tenderness. Laboratory investigation showed the total number of normal leukocytes with neutrophilia as 90.5%, as well as eosinopenia, monocytopenia and lymphocytopenia. Barium radiography and sigmoidoscopy confirmed inflammatory stenosis of the sigmoid colon. We diagnosed the patient as having eosinophilic gastroenteritis by multi-examinations. The patient was treated by fecal microbiota transplantation combined with oral prednisone, and was free from gastrointestinal symptoms at the time when we reported his disease. This case highlights the importance of awareness of manifestations of a rare disease like eosinophilic gastroenteritis.
PMCID: PMC4239532  PMID: 25473198
Eosinophilic gastroenteritis; Bowel obstruction; Diarrhea; Fecal microbiota transplantation; Prednisone
15.  Adoptive Immunotherapy of Cytokine-Induced Killer Cell Therapy in the Treatment of Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(11):e112662.
The aim of this study was to systemically evaluate the therapeutic efficacy of cytokine-induced killer (CIK) cells for the treatment of non-small cell lung cancer.
Materials and Methods
A computerized search of randomized controlled trials for CIK cell-based therapy was performed. The overall survival, clinical response rate, immunological assessment and side effects were evaluated.
Overall, 17 randomized controlled trials of non-small cell lung cancer (NSCLC) with a total of 1172 patients were included in the present analysis. Our study showed that the CIK cell therapy significantly improved the objective response rate and overall survival compared to the non-CIK cell-treated group. After CIK combined therapy, we observed substantially increased percentages of CD3+, CD4+, CD4+CD8+, CD3+CD56+ and NK cells, whereas significant decreases were noted in the percentage of CD8+ and regulatory T cell (Treg) subgroups. A significant increase in Ag-NORs was observed in the CIK-treated patient group (p = 0.00001), whereas carcinoembryonic antigen (CEA) was more likely to be reduced to a normal level after CIK treatment (p = 0.0008). Of the possible major side effects, only the incidence of fever in the CIK group was significantly higher compared to the group that received chemotherapy alone.
The CIK cell combined therapy demonstrated significant superiority in the overall survival, clinical response rate, and T lymphocytes responses and did not present any evidence of major adverse events in patients with NSCLC.
PMCID: PMC4239020  PMID: 25412106
17.  Neuroprotection by Acetyl-11-Keto-β-Boswellic Acid, in Ischemic Brain Injury Involves the Nrf2/HO-1 defense Pathway 
Scientific Reports  2014;4:7002.
Stroke is a complex disease involved oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway has been considered a potential target for neuroprotection in stroke. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is an active triterpenoid compound from the extract of Boswellia serrate. The present study was to determine whether AKBA, a novel Nrf2 activator, can protect against cerebral ischemic injury. The stroke model was produced in Sprague–Dawley rats via middle cerebral artery occlusion. To model ischemia-like conditions in vitro, primary cultured cortical neurons were exposed to transient oxygen and glucose deprivation (OGD). Treatment of AKBA significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores by elevating the Nrf2 and HO-1 expression in brain tissues in middle cerebral artery occlusion (MCAO) rats at 48 hours post reperfusion. In primary cultured neurons, AKBA increased the Nrf2 and HO-1 expression, which provided protection against OGD-induced oxidative insult. Additionally, AKBA treatment increased Nrf2 binding activity to antioxidant-response elements (ARE). The protective effect of AKBA was attenuated by knockdown of Nrf2 or HO-1. In conclusion, these findings provide evidence that AKBA protects neurons against ischemic injury, and this neuroprotective effect involves the Nrf2/HO-1 pathway.
PMCID: PMC4227012  PMID: 25384416
18.  Ginsenoside Rb1 Prevents H2O2-Induced HUVEC Senescence by Stimulating Sirtuin-1 Pathway 
PLoS ONE  2014;9(11):e112699.
We have previously reported that Ginsenoside Rb1 may effectively prevent HUVECs from senescence, however, the detailed mechanism has not demonstrated up to now. Recent studies have shown that sirtuin-1 (Sirt1) plays an important role in the development of endothelial senescence. The purpose of this study was to explore whether Sirt1 is involved in the action of Ginsenoside Rb1 regarding protection against H2O2-induced HUVEC Senescence.
Methods and Results
Senescence induced by hydrogen peroxide (H2O2) in human umbilical vein endothelial cells (HUVECs) was examined by analyzing plasminogen activator inhibitor-1 (PAI-1) expression, cell morphology, and senescence-associated beta-galactosidase (SA-β-gal) activity. The results revealed that 42% of control-treated HUVECs were SA-β-gal positive after treatment by 60 µmol/L H2O2, however, this particular effect of H2O2 was decreased more than 2-fold (19%) in the HUVECs when pretreated with Rb1 (20 µmol/L) for 30 min. Additionally, Rb1 decreased eNOS acetylation, as well as promoted more NO production that was accompanied by an increase in Sirt1 expression. Furthermore, upon knocking down Sirt1, the effect of Rb1 on HUVEC senescence was blunted.
The present study indicated that Ginsenoside Rb1 acts through stimulating Sirt1 in order to protect against endothelial senescence and dysfunction. As such, Sirt1 appears to be of particular importance in maintaining endothelial functions and delaying vascular aging.
PMCID: PMC4227851  PMID: 25386949
19.  Antioxidant and Anti-Inflammatory Activities of Phenolic-Enriched Extracts of Smilax glabra 
Smilax glabra Roxb. has been used for a long time as both food and folk medicine. In the present study, phenolic-enriched extract of S. glabra (PEESG) was extracted with 70% ethanol and purified by HP-20 column chromatography. Its antioxidant and anti-inflammatory activities were evaluated by radical scavenging assay, reducing power determination, and lipopolysaccharide (LPS)-induced RAW264.7 cells assays, respectively. PEESG exhibited obviously scavenging capacity for DPPH and ABTS radicals, as well as significant reducing power for ferric ion. Particularly, PEESG (12.5–50 μg/mL) showed a significantly higher efficiency for scavenging ABTS than that of ascorbic acid and no significant difference with ascorbic acid for DPPH scavenging. PEESG also possessed a significant suppression effect on proinflammatory mediators production, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), in LPS-induced RAW264.7 cells. In addition, the main ingredients of PEESG were identified using ultrahigh pressure liquid chromatography coupled to electrospray mass spectrometry (U-HPLC-ESI-MS). Seventeen components, including 5-O-caffeoylshikimic acid, neoastilbin, astilbin, neoisoastilbin, isoastilbin, engetin and isoengeletin were identified. These findings strongly suggest the potential of PEESG as a natural antioxidant and anti-inflammatory agent.
PMCID: PMC4244943  PMID: 25477999
20.  Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1) 
Human Molecular Genetics  2013;22(21):4329-4338.
We undertook a gene identification and molecular characterization project in a large kindred originally clinically diagnosed with SCA-X1. While presenting with ataxia, this kindred also had some unique peripheral nervous system features. The implicated region on the X chromosome was delineated using haplotyping. Large deletions and duplications were excluded by array comparative genomic hybridization. Exome sequencing was undertaken in two affected subjects. The single identified X chromosome candidate variant was then confirmed to co-segregate appropriately in all affected, carrier and unaffected family members by Sanger sequencing. The variant was confirmed to be novel by comparison with dbSNP, and filtering for a minor allele frequency of <1% in 1000 Genomes project, and was not present in the NHLBI Exome Sequencing Project or a local database at the BCM HGSC. Functional experiments on transfected cells were subsequently undertaken to assess the biological effect of the variant in vitro. The variant identified consisted of a previously unidentified non-synonymous variant, GJB1 p.P58S, in the Connexin 32/Gap Junction Beta 1 gene. Segregation studies with Sanger sequencing confirmed the presence of the variant in all affected individuals and one known carrier, and the absence of the variant in unaffected members. Functional studies confirmed that the p.P58S variant reduced the number and size of gap junction plaques, but the conductance of the gap junctions was unaffected. Two X-linked ataxias have been associated with genetic loci, with the first of these recently characterized at the molecular level. This represents the second kindred with molecular characterization of X-linked ataxia, and is the first instance of a previously unreported GJB1 mutation with a dominant and permanent ataxia phenotype, although different CNS deficits have previously been reported. This pedigree has also been relatively unique in its phenotype due to the presence of central and peripheral neural abnormalities. Other X-linked SCAs with unique features might therefore also potentially represent variable phenotypic expression of other known neurological entities.
PMCID: PMC3792691  PMID: 23773993
21.  The sociocultural health behavioral model and disparities in colorectal cancer screening among Chinese Americans 
The purpose of this study was to validate a Sociocultural Health Behavior Model using a structural equation analysis to determine the direction and magnitude of the interdependence of model components in relation to health behavior associated with colorectal cancer (CRC) screening among Chinese Americans.
A cross-sectional design included a sample of 311 Chinese American men and women age 50 and older. The initial step involved use of confirmatory factor analysis which included the following variables: access/satisfaction with health care, enabling, predisposing, cultural, and health belief factors. Structural equation modeling analyses were conducted on factors for CRC screening.
Education and health insurance status were significantly related to CRC screening. Those with less than a high school education and without health insurance were more likely to be “never screened” for CRC than those having more education and health insurance. The path analysis findings also lend support for components of the Sociocultural Health Belief Model and indicated that there was a positive and significant relationship between CRC screening and the enabling factors, between cultural factors and predisposing, enabling, and access/satisfaction with health care factors and between enabling factors and access/satisfaction with health care.
The model highlights the significance that sociocultural factors play in relation to CRC screening and reinforced the need to assist Chinese with poor English proficiency in translation and awareness of the importance of CRC screening. The use of community organizations may play a role in assisting Chinese to enhance colorectal cancer screening rates.
PMCID: PMC4214268  PMID: 25364475
Colorectal cancer; Cancer screening; Chinese Americans; Sociocultural health behavior model; Structural equation modeling
22.  Perceptions of High Achieving African American/Black 10th Graders from a Low Socioeconomic Community Regarding Health Scientists and Desired Careers 
Journal of allied health  2014;43(3):133-139.
Measures are needed to assess youth perceptions about health science careers to facilitate research aimed at facilitating youth pursuit of health science. Although the Indiana Instrument provides an established measure of perceptions regarding nursing and ideal careers, we were interested in learning how high achieving 10th graders from relatively low socioeconomic areas who identify as Black/African American (Black) perceive health science and ideal careers. The Indiana Instrument was modified, administered to 90 youth of interest, and psychometrically analyzed. Reliable subscales were identified that may facilitate parsimonious, theoretical, and reliable study of youth decision-making regarding health science careers. Such research may help to develop and evaluate strategies for increasing the number of minority health scientists.
PMCID: PMC4212893  PMID: 25194058
23.  Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders 
The New England journal of medicine  2013;369(16):1502-1511.
Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders.
We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients.
We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic pheno-types. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had auto-somal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders.
Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)
PMCID: PMC4211433  PMID: 24088041
24.  Transcriptome analysis of epithelioma papulosum cyprini cells after SVCV infection 
BMC Genomics  2014;15(1):935.
Spring viraemia of carp virus (SVCV) has been identified as the causative agent of spring viraemia of carp (SVC) and it has caused significant losses in the cultured common carp (Cyprinus carpio) industry. The molecular mechanisms that underlie the pathogenesis of the disease remain poorly understood. In this study, deep RNA sequencing was used to analyse the transcriptome and gene expression profile of EPC cells at progressive times after SVCV infection. This study addressed the complexity of virus–cell interactions and added knowledge that may help to understand SVCV.
A total of 33,849,764 clean data from 36,000,000 sequence reads, with a mean read length 100 bp, were obtained. These raw data were assembled into 88,772 contigs. Of these contigs, 19,642 and 25,966 had significant hits to the NR and Uniprot databases where they matched 17,642 and 13,351 unique protein accessions, respectively. At 24 h post SVCV infection (1.0 MOI), a total of 623 genes were differentially expressed in EPC cells compared to non-infected cells, including 288 up-regulated genes and 335 down-regulated genes. These regulated genes were primarily involved in pathways of apoptosis, oxidative stress and the interferon system, all of which may be involved in viral pathogenesis. In addition, 8 differentially expressed genes (DEGs) were validated by quantitative PCR.
Our findings demonstrate previously unrecognised changes in gene transcription that are associated with SVCV infection in vitro, and many potential cascades identified in the study clearly warrant further experimental investigation. Our data provide new clues to the mechanism of viral susceptibility in EPC cells.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-935) contains supplementary material, which is available to authorized users.
PMCID: PMC4221675  PMID: 25344771
25.  Whole-Exome Sequencing Reveals GPIHBP1 Mutations in Infantile Colitis With Severe Hypertriglyceridemia 
Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycer-ides in gastrointestinal mucosal injury.
PMCID: PMC4203304  PMID: 24614124
chylomicronemia; colitis; hyperlipoproteinemia; lipoprotein lipase; next-generation sequencing

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