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1.  Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa 
BioMed Research International  2015;2015:485709.
Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced (P < 0.05). Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure (P < 0.05). Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure.
PMCID: PMC4331166
2.  Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese 
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited endocrine malignancy syndrome. Early and normative surgery is the only curative method for MEN 2-related medullary thyroid carcinoma (MTC). In patients with adrenal pheochromocytoma, cortical-sparing adrenalectomy (CSA) can be utilized to preserve adrenocortical function.
We present twenty-six of 33 MEN2 patients underwent prophylactic thyroidectomy with varying neck dissection and eight of 24 MEN2A patients with PHEO underwent adrenal-sparing surgery. Direct sequencing of entire RET exons was performed in all participants.
The RET mutations (p.C634Y [n = 10], p.C634R [n = 9], p.C634F [n = 2], p.C618Y [n = 8], p.C618R [n = 3], and p.M918T [n = 1]) were confirmed in 20 symptomatic patients and identified in 13 at-risk relatives (RET carriers). Twenty-six of 33 MEN2 patients underwent thyroidectomies with neck dissections; the mean age at the time of the first thyroid surgery and the tumor diameter of the 6 RET carriers was decreased compared with 20 symptomatic patients (P < 0.001 and P = 0.007, respectively), while the disease-free survival was increased (80% vs.10%, P = 0.0001). Seven RET carriers who were declined surgery. One of 20 symptomatic patients with MTC bone metastases after surgery received vandetanib therapy for 20 months and responded well. Additionally, 8 of 24 MEN2A patients who initially had unilateral pheochromocytomas underwent CSA, 1 developed contralateral pheochromo cytomas 10 years later, then also accepted and also agreed to a CSA. None of the patients required steroid replacement therapy.
Based on our results, integrated RET screening and the pre-operative calcitonin level is an excellent strategy to ensure earlier diagnosis and standard thyroidectomy. CSA can be utilized to preserve adrenocortical function in patients with pheochromocytomas.
PMCID: PMC4307225  PMID: 25628771
Multiple endocrine neoplasia type 2; Mutation screening; RET; Prophylactic thyroidectomy; Cortical-sparing adrenalectomy
3.  Neonatal health of infants born to mothers with asthma 
The Journal of allergy and clinical immunology  2013;133(1):10.1016/j.jaci.2013.06.012.
Maternal asthma is associated with serious pregnancy complications but newborn morbidity is understudied.
To determine if infants of asthmatic mothers have more neonatal complications.
The Consortium on Safe Labor (2002–2008), a retrospective cohort, included 223,512 singleton deliveries at ≥ 23 weeks’ gestation. Newborns of mothers with asthma (n=17,044) were compared to newborns of non-asthmatic women using logistic regression models with generalized estimating equations to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). Electronic medical record data included gestational week at delivery, birthweight, resuscitation, neonatal intensive care unit (NICU) admission, NICU length of stay, hyperbilirubinemia, respiratory distress syndrome, apnea, sepsis, anemia, transient tachypnea of the newborn, infective pneumonia, asphyxia, intracerebral hemorrhage, seizure, cardiomyopathy, peri- or intraventricular hemorrhage, necrotizing enterocolitis, aspiration, retinopathy of prematurity and perinatal mortality.
Preterm delivery was associated with maternal asthma for each week after 33 completed weeks of gestation and not earlier. Maternal asthma also increased the adjusted odds of small for gestational age (SGA, OR=1.10, CI:1.05–1.16), NICU admission (OR=1.12, CI:1.07–1.17), hyperbilirubinemia (OR=1.09, CI:1.04–1.14), respiratory distress syndrome (OR=1.09, CI:1.01–1.19), transient tachypnea of the newborn (OR=1.10, CI:1.02–1.19), and asphyxia (OR=1.34, CI:1.03–1.75). Findings persisted for term infants (≥ 37 weeks) who had additional increased odds of intracerebral hemorrhage (OR=1.84, CI: 1.11–3.03) and anemia (OR=1.30, CI: 1.04–1.62).
Maternal asthma was associated with prematurity and SGA. Adverse neonatal outcomes including respiratory complications, hyperbilirubinemia, and NICU admission were increased in association with maternal asthma even among term deliveries.
PMCID: PMC3874245  PMID: 23916153
neonatal health; maternal asthma; respiratory distress syndrome; transient tachypnea of the newborn; neonatal jaundice; preterm birth
4.  Perfluorochemicals and Human Semen Quality: The LIFE Study 
Background: The relation between persistent environmental chemicals and semen quality is evolving, although limited data exist for men recruited from general populations.
Objectives: We examined the relation between perfluorinated chemicals (PFCs) and semen quality among 501 male partners of couples planning pregnancy.
Methods: Using population-based sampling strategies, we recruited 501 couples discontinuing contraception from two U.S. geographic regions from 2005 through 2009. Baseline interviews and anthropometric assessments were conducted, followed by blood collection for the quantification of seven serum PFCs (perfluorosulfonates, perfluorocarboxylates, and perfluorosulfonamides) using tandem mass spectrometry. Men collected a baseline semen sample and another approximately 1 month later. Semen samples were shipped with freezer packs, and analyses were performed on the day after collection. We used linear regression to estimate the difference in each semen parameter associated with a one unit increase in the natural log–transformed PFC concentration after adjusting for confounders and modeling repeated semen samples. Sensitivity analyses included optimal Box-Cox transformation of semen quality end points.
Results: Six PFCs [2-(N-methyl-perfluorooctane sulfonamido) acetate (Me-PFOSA-AcOH), perfluorodecanoate (PFDeA), perfluorononanoate (PFNA), perfluorooctane sulfonamide (PFOSA), perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA)] were associated with 17 semen quality end points before Box-Cox transformation. PFOSA was associated with smaller sperm head area and perimeter, a lower percentage of DNA stainability, and a higher percentage of bicephalic and immature sperm. PFDeA, PFNA, PFOA, and PFOS were associated with a lower percentage of sperm with coiled tails.
Conclusions: Select PFCs were associated with certain semen end points, with the most significant associations observed for PFOSA but with results in varying directions.
Citation: Buck Louis GM, Chen Z, Schisterman EF, Kim S, Sweeney AM, Sundaram R, Lynch CD, Gore-Langton RE, Barr DB. 2015. Perfluorochemicals and human semen quality: the LIFE Study. Environ Health Perspect 123:57–63;
PMCID: PMC4286271  PMID: 25127343
5.  The Tumor Microenvironment and Cancer 
BioMed Research International  2014;2014:573947.
PMCID: PMC4284971  PMID: 25587537
6.  Adverse Events Associated with Prolonged Antibiotic Use 
The Infectious Diseases Society of America and US CDC recommend 60 days of ciprofloxacin, doxycycline or amoxicillin for anthrax prophylaxis. It is not possible to determine severe adverse drug event (ADE) risks from the few people thus far exposed to anthrax prophylaxis. This study’s objective was to estimate risks of severe ADEs associated with long-term ciprofloxacin, doxycycline and amoxicillin exposure using 3 large databases: one electronic medical record (General Practice Research Database) and two claims databases (UnitedHealthcare, HMO Research Network).
We include office visit, hospital admission and prescription data for 1/1/1999–6/30/2001. Exposure variable was oral antibiotic person-days (pds). Primary outcome was hospitalization during exposure with ADE diagnoses: anaphylaxis, phototoxicity, hepatotoxicity, nephrotoxicity, seizures, ventricular arrhythmia or infectious colitis.
We randomly sampled 999,773, 1,047,496 and 1,819,004 patients from Databases A, B and C respectively. 33,183 amoxicillin, 15,250 ciprofloxacin and 50,171 doxycycline prescriptions continued ≥30 days. ADE hospitalizations during long-term exposure were not observed in Database A. ADEs during long-term amoxicillin were seen only in Database C with 5 ADEs or 1.2(0.4–2.7) ADEs/100,000 pds exposure. Long-term ciprofloxacin showed 3 and 4 ADEs with 5.7(1.2–16.6) and 3.5(1.0–9.0) ADEs/100,000 pds in Databases B and C, respectively. Only Database B had ADEs during long-term doxycycline with 3 ADEs or 0.9(0.2–2.6) ADEs/100,000 pds. For most events, the incidence rate ratio, comparing >28 vs.1–28 pds exposure was <1, showing limited evidence for cumulative dose-related ADEs from long-term exposure.
Long-term amoxicillin, ciprofloxacin and doxycycline appears safe, supporting use of these medications if needed for large-scale post-exposure anthrax prophylaxis.
PMCID: PMC4269235  PMID: 18215001
Anti-infective agents; Anthrax prevention and control; Health services research; Databases; Bioterrorism
Statistica Sinica  2013;23(4):1743-1759.
Inter-rater reliability is usually assessed by means of the intraclass correlation coefficient. Using two-way analysis of variance to model raters and subjects as random effects, we derive group sequential testing procedures for the design and analysis of reliability studies in which multiple raters evaluate multiple subjects. Compared with the conventional fixed sample procedures, the group sequential test has smaller average sample number. The performance of the proposed technique is examined using simulation studies and critical values are tabulated for a range of two-stage design parameters. The methods are exemplified using data from the Physician Reliability Study for diagnosis of endometriosis.
PMCID: PMC4267541  PMID: 25525316
Interim analysis; inter-rater reliability; intraclass correlation coefficient; measurement errors; sample size and power; two-way ANOVA
8.  Resveratrol Possesses Protective Effects in a Pristane-Induced Lupus Mouse Model 
PLoS ONE  2014;9(12):e114792.
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the production of autoantibodies. To date, no therapy has been found to satisfactorily treat SLE. SIRT1 deficiency results in the development of an autoimmune syndrome in mice, including a high titer of anti-nuclear antibody in serum, immunoglobulin deposition in the kidney, and immune complex glomerulonephritis. Resveratrol is an activator of SIRT1 and possesses anti-inflammation and immune-regulatory properties.
To evaluate the preventative effects of resveratrol on a pristane-induced lupus animal model and assess its putative immune modulation effects.
BALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane on day 1 and then various doses of resveratrol were given to the mice daily starting on day 2 and continuing for seven months. The autoantibodies in serum and supernatants were measured. Single cells isolated from spleen, isolated CD4+ T cells, and CD19+ B cells were cultured with or without resveratrol in vitro and assessed by flow cytometry.
Resveratrol attenuated proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum in pristane-induced lupus mice. Resveratrol also suppressed CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation, induced CD4+ T cell apoptosis, and decreased CD4 IFNγ+ Th1 cells and the ratio of Th1/Th2 cells in vitro. In vitro antibody production and proliferation of B cells were also inhibited.
Resveratrol possesses protective effects in pristane-induced lupus mice and may represent a novel approach for the management of SLE.
PMCID: PMC4263676  PMID: 25501752
9.  Protein-Losing Enteropathy in Systemic Lupus Erythematosus: 12 Years Experience from a Chinese Academic Center 
PLoS ONE  2014;9(12):e114684.
Protein-losing enteropathy (PLE) is a complication in some systemic lupus erythematosus (SLE) patients that is often misdiagnosed. With this study, we provide insight into clinical characteristics, laboratory characteristics, diagnostic tests, risk factors, treatment, and prognosis of the disease.
A retrospective, case-control study was performed in 44 patients with SLE-related PLE (PLE group) and 88 patients with active SLE (control group) admitted to our care from January 2000−January 2012. Risk factors for SLE-related PLE were examined, and we analyzed the accuracy of single and combined laboratory characteristics in discriminating SLE-related PLE from active SLE. Serum albumin and C3 levels were measured as outcome during and after treatment with corticosteroids and immunosuppressive agents.
The PLE group had lower mean serum albumin and 24-hour urine protein levels, higher mean total plasma cholesterol levels, and greater frequencies of anti-SSA and SSB seropositivity compared with the control group. Anti-SSA seropositivity, hypoalbuminemia, and hypercholesterolemia were independent risk factors for SLE-related PLE. The simultaneous presence of serum albumin (<22 g/l) and 24-hour urine protein (<0.8 g/24 h) had high specificity, positive predictive value, negative predictive value, and positive likelihood ratio, a low negative likelihood ratio and no significant reduction in sensitivity. High dosage of glucocorticosteroid combined with cyclophosphomide were mostly prescribed for SLE-related PLE.
SLE-related PLE should be considered when an SLE patient presents with generalized edema, anti-SSA antibody seropositivity, hypercholesterolemia, severe hypoalbuminemia, and low 24-hour urine protein levels. Aggressive treatment for lupus might improve prognosis.
PMCID: PMC4260872  PMID: 25490025
10.  Trace Elements and Endometriosis: The ENDO Study 
Reproductive toxicology (Elmsford, N.Y.)  2013;0:10.1016/j.reprotox.2013.05.009.
There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18–44 years were recruited into an operative cohort, along with 131 similarly-aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research.
PMCID: PMC3836840  PMID: 23892002
arsenic; cadmium; chromium; endometriosis; lead; metals; mercury; trace elements
11.  A New Cryomacroscope Device (Type III) for Visualization of Physical Events in Cryopreservation with Applications to Vitrification and Synthetic Ice Modulators 
Cryobiology  2013;67(3):264-273.
The objective of the current study is to develop a new cryomacroscope prototype for the study of vitrification in large-size specimens. The unique contribution in the current study is in developing a cryomacroscope setup as an add-on device to a commercial controlled-rate cooler and in demonstration of physical events in cryoprotective cocktails containing synthetic ice modulators (SIM)—compounds which hinder ice crystal growth. Cryopreservation by vitrification is a highly complex application, where the likelihood of crystallization, fracture formation, degradation of the biomaterial quality, and other physical events are dependent not only upon the instantaneous cryogenic conditions, but more significantly upon the evolution of conditions along the cryogenic protocol. Nevertheless, cryopreservation success is most frequently assessed by evaluating the cryopreserved product at its end states—either at the cryogenic storage temperature or room temperature. The cryomacroscope is the only available device for visualization of large-size specimens along the thermal protocol, in an effort to correlate the quality of the cryopreserved product with physical events. Compared with earlier cryomacroscope prototypes, the new Cryomacroscope-III evaluated here benefits from a higher resolution color camera, improved illumination, digital recording capabilities, and high repeatability in tested thermal conditions via a commercial controlled-rate cooler. A specialized software package was developed in the current study, having two modes of operation: (a) experimentation mode to control the operation of the camera, record camera frames sequentially, log thermal data from sensors, and save case-specific information; and (b) post-processing mode to generate a compact file integrating images, elapsed time, and thermal data for each experiment. The benefits of the Cryomacroscope-III are demonstrated using various tested mixtures of SIMs with the cryoprotective cocktail DP6, which were found effective in preventing ice growth, even at significantly subcritical cooling rates with reference to the pure DP6.
PMCID: PMC4118937  PMID: 23993920
Cryomacroscopy; Synthetic Ice Modulators; Vitrification; Crystallization; Thermal Stress; DP6
12.  Regulation of SIRT1 by Oxidative Stress-Responsive miRNAs and a Systematic Approach to Identify Its Role in the Endothelium 
Antioxidants & Redox Signaling  2013;19(13):1522-1538.
Significance: Oxidative stress is a common denominator of various risk factors contributing to endothelial dysfunction and vascular diseases. Accumulated evidence suggests that sirtuin 1 (SIRT1) expression and/or activity is impaired by supraphysiological levels of oxidative stress, which in turn disrupts endothelial homeostasis. Recent Advances: Several microRNAs (miRNAs) are induced by oxidative stress and termed as oxidative stress-responsive miRNAs. They may play a role linking the imbalanced redox state with dysregulated SIRT1. Critical Issues: This review summarizes recent findings on oxidative stress-responsive miRNAs and their involvement in SIRT1 regulation. Because of the unique characteristics of miRNAs, research in this new area requires an integrative approach that combines bioinformatics and experimental validation. Thus, a research strategy is discussed to identify the SIRT1-regulating miRNAs under oxidative stress and their functional outcomes in relation to endothelial dysfunction. Additionally, the miRNAs implicated in vascular diseases such as atherosclerosis and abdominal aortic aneurysms are discussed along with the translational potential and challenges of using miRNAs and its analogs as therapeutic agents. Future Directions: Although at its infancy, research on oxidative stress-responsive miRNAs and their regulation of SIRT1 may provide new insights in understanding vascular disorders. Moreover, systematic approaches integrating in silico, in vitro, and in vivo observations can be useful tools in revealing the pathways modulating endothelial biology. Antioxid. Redox Signal. 19, 1522–1538.
PMCID: PMC3797452  PMID: 23477488
13.  Correlation of EGFR mutation and histological subtype according to the IASLC/ATS/ERS classification of lung adenocarcinoma 
Objective: To evaluate the correlation of EGFR mutation and histological subtypes of lung adenocarcinoma based on the IASLC/ATS/ERS classification. Methods: EGFR exons 18-21 of 206 resected lung adenocarcinoma specimens were analyzed with pyrosequecing, then the differences between histological subtypes and EGFR mutation were compared. Results: EGFR mutation was detected in 123 specmens, most of which were papillary and acinar predominant adenocarcinoma. EGFR mutation rate of the specimens with papillary, acinar or lepidic component was higher than without these components (P < 0.05), and with solid or mucinous component was lower than that without the component (P < 0.05). EGFR mutation in solid predominant mixed other subtypes was more commonly found than that of pure solid component (P=0.018). Conclusions: The presence of well-differentiated components in lung adenocarcinoma, such as lepidic, papillary and acinar, indicates a higher EGFR mutation rate, while the solid and mucinous component indicate a lower EGFR mutation rate. There is heterogeneity of EGFR mutation in lung adenocarcinoma.
PMCID: PMC4270542  PMID: 25550848
Lung neoplasms; adenocarcinoma; receptor; epidermal growth factor
14.  Endoglin is necessary for angiogenesis in human ovarian carcinoma-derived primary endothelial cells 
Cancer Biology & Therapy  2013;14(10):937-948.
Endoglin (CD105, END) is upregulated in proliferating endothelial cells, suggesting potential therapeutic properties. However, it is not clear whether endoglin mediates an enhanced proliferative rate or may be upregulated as part of a negative feedback loop. To gain insights into context-dependent and cell type-dependent regulatory effects of endoglin, we studied its role properties in human ovarian carcinoma-derived endothelial cells (ODMECs). We isolated and cultured primary ODMECs from epithelial ovarian carcinoma tissue. ODMECs had higher expression of endoglin and VEGFR-2, and also exhibited enhanced spontaneous formation of vessel-like structures in vitro. Transfection of siRNA targeting endoglin in ODMECs cells resulted in the reduction of the proliferation and tube formation. These results indicate that a subset of ODMECs display abnormal angiogenic properties and this phenotype was blocked by decreasing endoglin levels, suggesting endoglin is essential for stimulating angiogenesis, and targeting it may be an attractive approach to anti-angiogenesis therapy for ovarian carcinoma.
PMCID: PMC3926891  PMID: 23917399
ovarian carcinoma; endothelial cells; endoglin; siRNA; ODMEC
15.  Evaluation of the effectiveness of semen storage and sperm purification methods for spermatozoa transcript profiling 
Different semen storage and sperm purification methods may affect the integrity of isolated spermatozoal RNA. RNA-Seq was applied to determine whether semen storage methods (pelleted vs. liquefied) and somatic cell lysis buffer (SCLB) vs. PureSperm (PS) purification methods affect the quantity and quality of sperm RNA. The results indicate that the method of semen storage does not markedly impact RNA profiling whereas the choice of purification can yield significant differences. RNA-Seq showed that the majority of mitochondrial and mid-piece associated transcripts were lost after SCLB purification, which indicated that the mid-piece of spermatozoa may have been compromised. In addition, the number of stable transcript pairs from SCLB-samples was less than that from the PS samples. This study supports the view that PS purification better maintains the integrity of spermatozoal RNAs.
PMCID: PMC3927401  PMID: 23869956
mitochondrial RNA; preferentially isolated transcripts; stable transcript pairs
16.  Assessment of Risk Factors for Delayed Colonic Post-Polypectomy Hemorrhage: A Study of 15553 Polypectomies from 2005 to 2013 
PLoS ONE  2014;9(10):e108290.
Background and Aim
Delayed colonic postpolypectomy bleeding is the commonest serious complication after polypectomy. This study aimed to utilize massive sampling data of polypectomy to analyze risk factors for delayed postpolypectomy bleeding.
Patients and Methods
The endoscopic data of 5600 patients with 15553 polyps removed (2005 to 2013) were analyzed retrospectively through univariate analysis and multiple logistic regression analysis to evaluate the risk factors for delayed bleeding.
Delayed postpolypectomy bleeding occurred in 99 polyps (0.6%). The rates of bleeding for different polypectomy methods including hot biopsy forcep, biopsy forcep, Argon Plasma Coagulation (APC), Endoscopy piecemeal mucosal resection (EPMR), Endoscopic Mucosal Resection (EMR), and snare polypectomy were 0.1%, 0.0%, 0.0%, 6.9%, 0.9% and 1.0%, respectively. The risk factors for delayed bleeding were the size of polyps over 10 mm (odds ratio [OR] = 4.6, 95% CI, 2.9–7.2), pathology of colonic polyps (inflammatory/hyperplastic, OR = 1; adenomatous, OR = 1.4, 95% CI, 0.7–2.6; serrated, OR = 1.5, 95% CI, 0.2–11.9; juvenile, OR = 4.3, 95% CI, 1.8–11.0; Peutz-Jegher, OR = 3.3, 95% CI, 1.0–10.7), and immediate postpolypectomy bleeding (OR = 2.9, 95% CI, 1.4–5.9). In addition, although polypectomy method was not a risk factor, compared with hot biopsy forcep, snare polypectomy, EMR, and EPMR had increased risks of delayed bleeding, with ORs of 3.2 (0.4–23.3), 2.8 (0.4–21.7) and 5.1 (0.5–47.7), respectively.
Polyp size over 10 mm, pathology of colonic polyps (especially juvenile, Peutz-Jegher), and immediate postpolypectomy bleeding were significant risk factors for delayed postpolypectomy bleeding.
PMCID: PMC4182718  PMID: 25271734
17.  Competitive growth mechanisms of AlN on Si (111) by MOVPE 
Scientific Reports  2014;4:6416.
To improve the growth rate and crystal quality of AlN, the competitive growth mechanisms of AlN under different parameters were studied. The mass transport limited mechanism was competed with the gas-phase parasitic reaction and became dominated at low reactor pressure. The mechanism of strain relaxation at the AlN/Si interface was studied by transmission electron microscopy (TEM). Improved deposition rate in the mass-transport-limit region and increased adatom mobility were realized under extremely low reactor pressure.
PMCID: PMC4166946  PMID: 25231628
18.  A crossed random effects modeling approach for estimating diagnostic accuracy from ordinal ratings without a gold standard 
Statistics in medicine  2013;32(20):3472-3485.
In diagnostic studies without a gold standard, the assumption on the dependence structure of the multiple tests or raters plays an important role in model performance. In case of binary disease status, both conditional independence and crossed random effects structure have been proposed and their performance investigated. Less attention has been paid to the situation where the true disease status is ordinal, with the exception of Wang et al [1] who assumed conditionally independent multiple tests when studying traditional Chinese medicine and Wang and Zhou [2] who assumed a normal subject random effect but a fixed rater effect. In this paper, we propose crossed subject- and rater-specific random effects to account for the dependence structure and assess the robustness of the proposed model to misspecification in the random effects distributions. The models are applied to data from the Physician Reliability Study which focuses on assessing the diagnostic accuracy in a population of raters for the staging of endometriosis, a gynecological disorder in women. Using this new methodology, we estimate the probability of a correct classification and show that regional experts can more easily classify the intermediate stage than resident physicians.
PMCID: PMC3740052  PMID: 23529923
Random effects models; Endometriosis; MCEM algorithm
19.  Mechanosensitive microRNAs - Role in Endothelial Responses to Shear Stress and Redox State 
Endothelial functions are highly regulated by imposed shear stress in vivo. The characteristics of shear stress determine mechanotransduction events that regulate phenotypic outcomes including redox and inflammatory states. Recent data indicates that microRNAs (miRs) in vascular endothelial cells (ECs) play an essential role in shear stress-regulated endothelial responses. More specifically, athero-protective pulsatile flow (PS) induces miRs that inhibit mediators of oxidative stress and inflammation while promoting those involved in maintaining vascular homeostasis. Conversely, oscillatory flow (OS) elicits the opposing networks. This is exemplified by the PS-responsive transcription factor, krueppel-like factor 2 (KLF2), which regulates miR expression but is also regulated by OS-sensitive miRs to ultimately regulate the oxidative and inflammatory state of the endothelium. In this review, we outline important findings demonstrating the multifaceted roles of shear stress-regulated miRs in endothelial redox and inflammatory balance. Furthermore, we discuss the use of algorithms in deciphering signaling networks differentially regulated by PS and OS.
PMCID: PMC3762952  PMID: 23727269
Endothelium; Shear Stress; miR; KLF2; Oxidative Stress; Inflammation
20.  Induction of B7-H1 expression by human cytomegalovirus in extravillous cytotrophoblast cells and role of MAPK pathway 
Pakistan Journal of Medical Sciences  2014;30(5):1039-1043.
Objective: This paper is aimed at to evaluate B7-H1 expression as induced by human cytomegalovirus (HCMV) in extravillous cytotrophoblast cell line HPT-8 and possible underlying mechanism.
Method: Real time PCR and flow cytometry were used to determine B7-H1 mRNA and protein before and after HCMV infection in HPT-8 cells. Western blot analysis was used to determine the level of MAPK phosphorylation in HPT-8 cell lines infected with HCMV.
Results: 100TCID50 was found to be the most effective dose, capable of stimulating B7-H1 mRNA and protein expression in HPT-8 cells. When empty control group was considered to have a B7-H1 mRNA value of 1, B7-H1 mRNA was 4.32 in 100TCID50 group. In flow cytometry study, mean fluorescence intensity (MFI) of 100TCID50 group was 16.14, while empty control group was 1.34. Both mRNA and protein expression were found to be significantly increased (P<0.05) in 100TCID50 group compared to empty control group. The result of Western blot analysis showed increase in B7-H1 expression caused by the extracellular signaling that was related to ERK activation and the ERK inhibitor U0126 was found to reverse this increase.
Conclusion: HCMV upregulates B7-H1 expression in human extravillous cytotrophoblast cell line HPT-8, which is related to MAPK activation. Our result would be helpful in finding better therapies against intrauterine HCMV infection.
PMCID: PMC4163228  PMID: 25225522
Cytomegalovirus; Cytotrophoblast; B7-H1; MAPK
21.  Effectiveness and Complications of Ultrasound Guided Fine Needle Aspiration for Primary Liver Cancer in a Chinese Population with Serum α-Fetoprotein Levels ≤200 ng/ml - A Study Based on 4,312 Patients 
PLoS ONE  2014;9(8):e101536.
Hepatocellular carcinoma (HCC) can be diagnosed by noninvasive approaches with serum α-fetoprotein (AFP) levels >200 ng/ml and/or a radiological imaging study of tumor mass >2 cm in patients with chronic liver disease. Percutaneous fine needle aspiration (FNA) under ultrasound (US) guidance has a diagnostic specificity of 95% and is superior to radiological imaging studies.
The aim of this study is to elucidate the effectiveness and complications of fine needle aspiration in a Chinese population with primary liver cancer and AFP levels ≤200 ng/ml.
Materials and Methods
A retrospective study was conducted over a period of 28 years. This selection period included patients with a suspected diagnosis of primary liver cancer whose AFP levels were ≤200 ng/ml and who underwent US-FNA. This data was then analyzed with cytomorphological features correlating with medical history, radiological imaging, AFP, and follow-up information.
Of the 1,929 cases with AFP ≤200 mg/ml, 1,756 underwent FNA. Of these, 1,590 cases were determined malignant and the remaining 166 were determined benign. Further, 1,478 malignant cases were diagnosed by FNA alone, and of these, 1,138 were diagnosed as PLC. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of the diagnoses were 92.96%, 100%, 100%, 59.71%, and 93.62% respectively. There was no significant difference in the sensitivity, specificity, PPV and NPV between the subgroups with tumor size<2 cm and ≥2 cm. Major complications included implantation metastasis and hemorrhage.
Patients with PLC, especially those who present with an AFP ≤200 ng/ml, should undergo FNA. If negative results are obtained by FNA, it still could be HCC and repeated FNA procedure may be needed if highly suspicious of HCC on imaging study. The superiority of FNA in overall accuracy may outweigh its potential complications, such like hemorrhage and implantation metastasis.
PMCID: PMC4149350  PMID: 25170868
22.  SREBP2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility 
Circulation  2013;128(6):632-642.
The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells (ECs) via sterol regulatory element binding protein 2 (SREBP2).
Methods and Results
Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in ECs. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 (NOX2) and NLRP3. Consistently, SREBP2, NOX2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, EC-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.
Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographic distribution of atherosclerotic lesions.
PMCID: PMC3798034  PMID: 23838163
shear stress; endothelial cell; atherosclerosis; inflammasome; SREBP
23.  Immunotoxicity Assessment of Rice-Derived Recombinant Human Serum Albumin Using Human Peripheral Blood Mononuclear Cells 
PLoS ONE  2014;9(8):e104426.
Human serum albumin (HSA) is extensively used in clinics to treat a variety of diseases, such as hypoproteinemia, hemorrhagic shock, serious burn injuries, cirrhotic ascites and fetal erythroblastosis. To address supply shortages and high safety risks from limited human donors, we recently developed recombinant technology to produce HSA from rice endosperm. To assess the risk potential of HSA derived from Oryza sativa (OsrHSA) before a First-in-human (FIH) trial, we compared OsrHSA and plasma-derived HSA (pHSA), evaluating the potential for an immune reaction and toxicity using human peripheral blood mononuclear cells (PBMCs). The results indicated that neither OsrHSA nor pHSA stimulated T cell proliferation at 1x and 5x dosages. We also found no significant differences in the profiles of the CD4+ and CD8+ T cell subsets between OsrHSA- and pHSA-treated cells. Furthermore, the results showed that there were no significant differences between OsrHSA and pHSA in the production of cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10 and IL-4. Our results demonstrated that OsrHSA has equivalent immunotoxicity to pHSA when using the PBMC model. Moreover, this ex vivo system could provide an alternative approach to predict potential risks in novel biopharmaceutical development.
PMCID: PMC4123919  PMID: 25099245
24.  Perfluorochemicals and Endometriosis The ENDO Study 
Epidemiology (Cambridge, Mass.)  2012;23(6):799-805.
Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues.
We formulated two samples. The first was an operative sample comprising 495 women aged 18–44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007–2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity.
Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17–3.06]) and perfluorononanoic acid (2.20 [1.02–4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99–2.66] and 1.99 [0.91–4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05–3.30]) and PFOA (2.58 [1.18–5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively).
Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.
PMCID: PMC4122261  PMID: 22992575
25.  Deregulation of Feedback Inhibition of Phosphoenolpyruvate Carboxylase for Improved Lysine Production in Corynebacterium glutamicum 
Allosteric regulation of phosphoenolpyruvate carboxylase (PEPC) controls the metabolic flux distribution of anaplerotic pathways. In this study, the feedback inhibition of Corynebacterium glutamicum PEPC was rationally deregulated, and its effect on metabolic flux redistribution was evaluated. Based on rational protein design, six PEPC mutants were designed, and all of them showed significantly reduced sensitivity toward aspartate and malate inhibition. Introducing one of the point mutations (N917G) into the ppc gene, encoding PEPC of the lysine-producing strain C. glutamicum LC298, resulted in ∼37% improved lysine production. In vitro enzyme assays and 13C-based metabolic flux analysis showed ca. 20 and 30% increases in the PEPC activity and corresponding flux, respectively, in the mutant strain. Higher demand for NADPH in the mutant strain increased the flux toward pentose phosphate pathway, which increased the supply of NADPH for enhanced lysine production. The present study highlights the importance of allosteric regulation on the flux control of central metabolism. The strategy described here can also be implemented to improve other oxaloacetate-derived products.
PMCID: PMC3911046  PMID: 24334667

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