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1.  Busulfan, Melphalan, and Bortezomib versus High-Dose Melphalan as a Conditioning Regimen for Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma 
High-dose melphalan 200 mg/m2 (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m2 (MEL 140) and VEL 1.6 mg/m2 were administered i.v. on days −2 and −1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P =.89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.
PMCID: PMC5075527  PMID: 27164062
Stem cell transplantation; Multiple myeloma; Conditioning regimen; Busulfan; Melphalan; Bortezomib
2.  Rotavirus Strain Trends During the Postlicensure Vaccine Era: United States, 2008–2013 
The Journal of infectious diseases  2016;214(5):732-738.
Group A rotaviruses (RVA) are a significant cause of pediatric gastroenteritis worldwide. The New Vaccine Surveillance Network (NVSN) has conducted active surveillance for RVA at pediatric hospitals and emergency departments at 3–7 geographically diverse sites in the United States since 2006.
Over 6 consecutive years, from 2008 to 2013, 1523 samples from NVSN sites that were tested positive by a Rotaclone enzyme immunoassay were submitted to the Centers for Disease Control and Prevention for genotyping.
In the 2009, 2010, and 2011 seasons, genotype G3P[8] was the predominant genotype throughout the network, with a 46%–84% prevalence. In the 2012 season, G12P[8] replaced G3P[8] as the most common genotype, with a 70% prevalence, and this trend persisted in 2013 (68.0% prevalence). Vaccine (RotaTeq; Rotarix) strains were detected in 0.6%–3.4% of genotyped samples each season. Uncommon and unusual strains (eg, G8P[4], G3P[24], G2P[8], G3P[4], G3P[6], G24P[14], G4P[6], and G9P[4]) were detected sporadically over the study period. Year, study site, and race were found to be significant predictors of genotype.
Continued active surveillance is needed to monitor RVA genotypes in the United States and to detect potential changes since vaccine licensure.
PMCID: PMC5075963  PMID: 27302190
rotavirus; genotype; prevalence; surveillance; vaccine
3.  Sensitive and specific nested PCR assay for detection of rotavirus A in samples with a low viral load☆ 
Techniques such as the real-time reverse transcription-polymerase chain reaction (qRT-PCR) can detect RNA in samples with a low viral load. However, these amplicons typically are either too short or at insufficient concentrations for use in subsequent sequencing reactions for genotyping and detection confirmation. The assay developed in this study detects rotavirus G genotypes and P genotypes with viral loads as low as 6.2 and 8.2 copies per reaction, respectively. The assay was validated using a panel of 91 stool samples, 32 reference rotavirus strains, and 6 non-target enteric virus samples.
PMCID: PMC5075964  PMID: 27421626
Rotavirus; Nested; RT-PCR; Sensitivity; Specificity
4.  Endometrial Cancer Insulin-Like Growth Factor 1 Receptor (IGF1R) Expression Increases with Body Mass Index and Is Associated with Pathologic Extent and Prognosis 
Obesity is a main risk factor for endometrial carcinoma (EC). Insulin-like growth factor 1 receptor (IGF1R) expression may influence this association.
IGF1R IHC was performed on a tissue microarray with 894 EC and scored according to the percentage and intensity of staining to create immunoreactivity scores, which were dichotomized into low and high IGF1R expression groups. Logistic regression modeling assessed associations with body mass index (BMI), age, histology, pathologic extent of disease (pT), and lymph node metastasis (pN). Overall survival (OS) and disease-free survival (DFS) were compared between IGF1R expression groups using Kaplan–Meier curves and log-rank tests.
The proportion of patients with high IGF1R expression increased as BMI (<30, 30–39, and 40+ kg/m2) increased (P = 0.002). The adjusted odds of having high IGF1R expression was 1.49 [95% confidence interval (CI), 1.05–2.10, P = 0.024] for patients with BMI 30 to 39 kg/m2 compared with <30 kg/m2 and 1.62 (95% CI, 1.13–2.33, P = 0.009) for patients with BMI 40+ kg/m2 compared with <30 kg/m2. High IGF1R expression was associated with pT and pN univariately and with pT after adjusting for BMI, pN, age, and histologic subtype. DFS and OS were better with high IGF1R expression, P = 0.020 and P = 0.002, respectively, but DFS was not significant after adjusting for pT, pN, and histologic subtype of the tumor.
There is an association between BMI and EC IGF1R expression. Higher IGF1R expression is associated with lower pT and better DFS and OS.
These findings suggest a link between IGF1R EC expression and obesity, as well as IGF1R expression and survival.
PMCID: PMC5075967  PMID: 26682991
5.  Future Therapeutic Approaches for Inflammatory Bowel Diseases 
Gastroenterology  2011;140(6):1838-1846.
In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy.
PMCID: PMC5076881  PMID: 21530750
IBD Therapy; Biomarkers; IBD Immunology
6.  An atypical SCF-like ubiquitin ligase complex promotes Wallerian degeneration through regulation of axonal Nmnat2 
Cell reports  2016;17(3):774-782.
Axon degeneration is a tightly regulated self-destructive program that is a critical feature of many neurodegenerative diseases, but the molecular mechanisms regulating this program remain poorly understood. Here we identify Skp1a, a core component of an SCF-type E3 ubiquitin ligase complex, as a critical regulator of axon degeneration after injury in mammalian neurons. Depletion of Skp1a prolongs survival of injured axons in vitro and in the optic nerve in vivo. We demonstrate that Skp1a regulates the protein level of the NAD+ synthesizing enzyme Nmnat2 in axons. Loss of axonal Nmnat2 contributes to a local ATP deficit that triggers axon degeneration. Knockdown of Skp1a elevates basal levels of axonal Nmnat2, thereby delaying axon degeneration through prolonged maintenance of axonal ATP. Consistent with Skp1a functioning through regulation of Nmnat2, Skp1a knockdown fails to protect axons from Nmnat2 knockdown. These results illuminate the molecular mechanism underlying Skp1a-dependent axonal destruction.
Graphical Abstract
PMCID: PMC5075525  PMID: 27732853
neurodegeneration; Wallerian degeneration; E3 ubiquitin ligase; Nicotinamide/nicotinic acid mononucleotide adenylyltransferase
7.  Scientometric study of academic publications on antioxidative herbal medicines in type 2 diabetes mellitus 
Scientometric analysis is increasingly used for research assessment. We aimed to perform a scientometric analysis of research productivity in field of antioxidative hypoglycemic herbal medicine and diabetes.
Some of search terms were “type 2 diabetes”, “antioxidant”, “herb”, “phytotherapy”, “ethnopharmacology”, “Chinese medicine”, “traditional medicine”, in Scopus web databases until January 2015, and limited to human. The collected data were used to generate the specific features such as publication year, main journal in the field, citation, subject area, and co-authorship network of authors and institutes. Data was analyzed using analysis tools provided by Scopus database, SPSS version 11 and VOSviewer software.
Overall, 468 studies were related to this topic in human. The number of publications in the field showed an increasing trend. Majority of the published papers were original articles (71 %) and the most productive year was 2013. Top subject areas were medicine followed by drug. The first productive country was the US. The documents were cited totally 10724 times with average citation/article 22.91, and h-index 55. The highest cited article was a systematic review study, and top source was “Journal of Ethnopharmacology”. The highest international collaboration was with the US. Top authors and institutes in the co-authorship network assessment were from Iran.
A promising scientific productivity is shown in the studied field world wide. This study provided practical information to researchers who look for studies with potentially highly citation, and also would be helpful for researchers to conduct better researches that eventually could lead to more publications in this field.
PMCID: PMC5073927  PMID: 27785446
Herbal medicine; Antioxidative; Diabetes mellitus; Scientometric analysis
8.  High-pitch spiral CT with 3D reformation: an alternative choice for imaging vascular anomalies with affluent blood flow in the head and neck of infants and children 
The British Journal of Radiology  2015;88(1052):20150005.
To evaluate the feasibility of high-pitch spiral CT in imaging vascular anomalies (VAs) with affluent blood flow in the head and neck of infants and children.
For patients with suspected VAs and affluent blood flow pre-detected by ultrasound, CT was performed with high-pitch mode, individualized low-dose scan protocol and three-dimensional (3D) reformation. A five-point scale was used for image quality evaluation. Diagnostic accuracy was calculated with clinical diagnosis with/without pathological results as the reference standard. Radiation exposure and single-phase scan time were recorded. Treatment strategies were formulated based on CT images and results and were monitored through follow-up results.
20 lesions were identified in 15 patients (median age of 11 months). The mean score of image quality was 4.13 ± 0.74. 7 patients (7/15, 46.67%) were diagnosed with haemangiomas, 6 patients (6/15, 40%) were diagnosed with venous malformations and 2 patients (2/15, 13.33%) were diagnosed with arteriovenous malformations. The average effective radiation doses of a single phase and of the total procedure were 0.27 ± 0.08 and 0.86 ± 0.21 mSv. The average scanning time of a single phase was 0.46 ± 0.09 s. After treatment, 13 patients (13/15, 86.67%) achieved excellent results, and 2 patients (2/15, 13.33%) showed good results in follow-up visits.
High-pitch spiral CT with an individualized low-dose scan protocol and 3D reformation is an effective modality for imaging VAs with affluent blood flow in the head and neck of infants and children when vascular details are needed and ultrasound and MRI could not provide the complete information.
Advances in knowledge:
This study proposes an alternative modality for imaging VAs with affluent blood flow.
PMCID: PMC4651378  PMID: 26055504
9.  Impact of adjustable cryogel properties on the performance of prostate cancer cells in 3D 
SpringerPlus  2016;5(1):902.
Biochemical and physical characteristics of extracellular environment play a key role in assisting cell behavior over different molecular pathways. In this study, we investigated how the presence of chemical binding sites, the pore network and the stiffness of designed scaffolds affected prostate cancer cells.
A blend of poly hydroxyethyl methacrylate–alginate–gelatin scaffold was synthesized by cryogelation process using polyethyleneglycol diacrylate (PEGda) and glutaraldehyde as cross linkers. The chemical and mechanical scaffold properties were varied by concentration of gelatin and PEGda, respectively. The pore network was modified by applying different ‘freezing time’. Growth, spheroid formation and localization of androgen receptor (AR) were measured to evaluate cell response within various cryogel types.
Insufficient porosity in combination with a brittle nature affects cell growth negatively. Spheroid size was reduced by porosity, elasticity as well as by the absence of the cell adhesive motif composed of arginine, glycine und aspartic acid (RGD). Localization of AR indicates its activity and should be under normal culture conditions in the nucleus. But in this study, we could investigate for the first time that AR remains in the cytoplasm when AR positive prostate cancer cells are cultured in scaffolds without RGD as well as in case of an insufficient pore network (total porosity under 10 %) and a too less stiffness of around 10 kPa.
The results indicate that for getting a reliable preclinical drug screening a three-dimensional prostate model system with appropriate biochemical and physical surrounding is needed.
PMCID: PMC4923005  PMID: 27386348
Cryogel; Stiffness; Porosity; 3D cell culture; Prostate cancer; Androgen receptor (AR) localization
10.  The income-based disparities in preeclampsia and postpartum hemorrhage: a study of the Korean National Health Insurance cohort data from 2002 to 2013 
SpringerPlus  2016;5(1):895.
There is limited evidence on the effects of relatively low socioeconomic status on maternal health. Additionally, the global economic recession that began in 2008 could have worsened disparities in maternal complications. To explore disparities in maternal health, we analyzed the occurrence of preeclampsia and postpartum hemorrhage according to level of household income. A population-based cohort data set from the Korean National Health Insurance was used to calculate the age-adjusted incidence, slope index of inequality, and Kunst and Mackenbach relative index of inequality (RIIKM) for preeclampsia and postpartum hemorrhage from 2002 to 2013. In the aggregated data of 65,479 live births, women with lower household income showed a higher risk of developing preeclampsia and postpartum hemorrhage than those with higherhigher incomes after adjusting for conventional risk factors. The absolute and relative inequalities for both complications showed no significant change over the period from 2002 to 2013. Considering the difference in the trends and risks of major obstetric complications according to level of household income, policies to monitor and reduce disparities in maternal health across different economic levels need to be implemented.
PMCID: PMC4923012  PMID: 27386343
Disparity; Preeclampsia; Korean National Health Insurance
11.  A quantum chemical study of the mechanisms of olefin addition to group 9 transition metal dioxo compounds 
SpringerPlus  2016;5(1):867.
The mechanistic aspects of ethylene addition to MO2(CH2)(CH3) (M=Co, Rh, Ir) have been investigated with a Hartree–Fock/DFT hybrid functional at the MO6/LACVP* and B3LYP/LACVP* levels of theory to elucidate the reaction pathways on the singlet, doublet and triplet potential energy surfaces (PES). In the reaction of the IrO2CH2CH3 complex with ethylene, [3 + 2]C,O addition is the most plausible pathway on the singlet PES, the [3 + 2]O,O addition is the most favoured pathway on the doublet surface whiles the stepwise [1 + 1] addition involving the oxygen atom of the complex in the first step and the carbon atom of the complex in the second step is the most plausible pathway on the triplet PES. For the reaction of the RhO2(CH2)(CH3) complex, the [2 + 2]Rh,O addition pathway is the most favoured on the singlet surface, the [2 + 2]Rh,C is the most plausible pathway on the triplet PES and [3 + 2]C,O is the most plausible on the doublet surface. For the reactions of the CoO2(CH2)(CH3) complex, the [1 + 2]O addition is the most plausible on the singlet PES, [3 + 2]C=Co=O cycloaddition to form the five–membered intermediate is the most preferred pathway on the doublet PES, whiles on the triplet PES the preferred pathway is the [3 + 2] addition across the O=Co=O bond of the metal complex. The reactions of olefins with the Co dioxo complex have lower activation barriers for the preferred [3 + 2] and [2 + 2] addition pathways as well as fewer side reactions than those of the rhodium and iridium systems. This could imply that the cobalt dioxo complexes can efficiently and selectively catalyze specific reactions in oxidation of olefins than Rh and Ir oxo complexes will do and therefore Co oxo complexes may be better catalysts for specific oxidation reactions of olefins than Rh and Ir complexes are. The activation barriers for the formation of the four—or five-membered metallacycle intermediates through [2 + 2] or [3 + 2] cyclo-addition are lower on the triplet PES than on the singlet PES for the formation of similar analogues. There are fewer competitive reaction pathways on the triplet surface than on the singlet PES. Also, cycloadditions that seem impossible on the singlet PES seem possible on the doublet and or triplet PESs, this is the case typically for the Rh and Co complexes, illustrating the importance of multiple spin states in organometallic reactions.Graphical AbstractTable of Contents Synopsis: A study of the mechanism of ethylene addition to MO2(CH2)(CH3)(M=Co,Rh,Ir) shows the reactions of the Co complex have lower activation barriers for the preferred [3+2] and [2+2] addition pathways and fewer side reactions than those of Rh and Ir. Reactions are more feasible and selective on the triplet PES than on the singlet PES. These illustrate the importance of multiple spin states in organometallic reactions and shows catalyst activity and selectivity decreases down the group.
PMCID: PMC4920779  PMID: 27386316
Olefin oxidation; Epoxidation; Transition metal; Computational; Mechanism
12.  Nonparametric Bayes Modeling for Case Control Studies with Many Predictors 
Biometrics  2015;72(1):184-192.
It is common in biomedical research to run case-control studies involving high-dimensional predictors, with the main goal being detection of the sparse subset of predictors having a significant association with disease. Usual analyses rely on independent screening, considering each predictor one at a time, or in some cases on logistic regression assuming no interactions. We propose a fundamentally different approach based on a nonparametric Bayesian low rank tensor factorization model for the retrospective likelihood. Our model allows a very flexible structure in characterizing the distribution of multivariate variables as unknown and without any linear assumptions as in logistic regression. Predictors are excluded only if they have no impact on disease risk, either directly or through interactions with other predictors. Hence, we obtain an omnibus approach for screening for important predictors. Computation relies on an efficient Gibbs sampler. The methods are shown to have high power and low false discovery rates in simulation studies, and we consider an application to an epidemiology study of birth defects.
PMCID: PMC4803642  PMID: 26394204
Bayesian nonparametrics; Big data; Epidemiology; Retrospective likelihood; Sparse parallel factor analysis model; Tensor factorization
13.  Association analysis for detecting significant single nucleotide polymorphisms for phosphorus-deficiency tolerance at the seedling stage in soybean [Glycine max (L) Merr.] 
Breeding Science  2016;66(2):191-203.
Tolerance to low-phosphorus soil is a desirable trait in soybean cultivars. Previous quantitative trait locus (QTL) studies for phosphorus-deficiency tolerance were mainly derived from bi-parental segregating populations and few reports from natural population. The objective of this study was to detect QTLs that regulate phosphorus-deficiency tolerance in soybean using association mapping approach. Phosphorus-deficiency tolerance was evaluated according to five traits (plant shoot height, shoot dry weight, phosphorus concentration, phosphorus acquisition efficiency and use efficiency) comprising a conditional phenotype at the seedling stage. Association mapping of the conditional phenotype detected 19 SNPs including 13 SNPs that were significantly associated with the five traits across two years. A novel cluster of SNPs, including three SNPs that consistently showed significant effects over two years, that associated with more than one trait was detected on chromosome 3. All favorable alleles, which were determined based on the mean of conditional phenotypic values of each trait over the two years, could be pyramided into one cultivar through parental cross combination. The best three cross combinations were predicted with the aim of simultaneously improving phosphorus acquisition efficiency and use efficiency. These results will provide a thorough understanding of the genetic basis of phosphorus deficiency tolerance in soybean.
PMCID: PMC4784997  PMID: 27162491
association mapping; phosphorus-deficiency tolerance; seedling stage; soybean [Glycine max (L) Merr.]
14.  Polyhydramnios in Lrp4 knockout mice with bilateral kidney agenesis: Defects in the pathways of amniotic fluid clearance 
Scientific Reports  2016;6:20241.
Amniotic fluid volume during mid-to-late gestation depends mainly on the urine excretion from the foetal kidneys and partly on the fluid secretion from the foetal lungs during foetal breathing-like movements. Urine is necessary for foetal breathing-like movements, which is critical for foetal lung development. Bilateral renal agenesis and/or obstruction of the urinary tract lead to oligohydramnios, which causes infant death within a short period after birth due to pulmonary hypoplasia. Lrp4, which functions as an agrin receptor, is essential for the formation of neuromuscular junctions. Herein, we report novel phenotypes of Lrp4 knockout (Lrp4−/−) mice. Most Lrp4−/− foetuses showed unilateral or bilateral kidney agenesis, and Lrp4 knockout resulted in polyhydramnios. The loss of Lrp4 compromised foetal swallowing and breathing-like movements and downregulated the expression of aquaporin-9 in the foetal membrane and aquaporin-1 in the placenta, which possibly affected the amniotic fluid clearance. These results suggest that amniotic fluid removal was compromised in Lrp4−/− foetuses, resulting in polyhydramnios despite the impairment of urine production. Our findings indicate that amniotic fluid removal plays an essential role in regulating the amniotic fluid volume.
PMCID: PMC4742865  PMID: 26847765
15.  Use of metabolomics for the chemotaxonomy of legume-associated Ascochyta and allied genera 
Scientific Reports  2016;6:20192.
Chemotaxonomy and the comparative analysis of metabolic features of fungi have the potential to provide valuable information relating to ecology and evolution, but have not been fully explored in fungal biology. Here, we investigated the chemical diversity of legume-associated Ascochyta and Phoma species and the possible use of a metabolomics approach using liquid chromatography-mass spectrometry for their classification. The metabolic features of 45 strains including 11 known species isolated from various legumes were extracted, and the datasets were analyzed using chemometrics methods such as principal component and hierarchical clustering analyses. We found a high degree of intra-species consistency in metabolic profiles, but inter-species diversity was high. Molecular phylogenies of the legume-associated Ascochyta/Phoma species were estimated using sequence data from three protein-coding genes and the five major chemical groups that were detected in the hierarchical clustering analysis were mapped to the phylogeny. Clusters based on similarity of metabolic features were largely congruent with the species phylogeny. These results indicated that evolutionarily distinct fungal lineages have diversified their metabolic capacities as they have evolved independently. This whole metabolomics approach may be an effective tool for chemotaxonomy of fungal taxa lacking information on their metabolic content.
PMCID: PMC4742866  PMID: 26847260
16.  New Flexible Channels for Room Temperature Tunneling Field Effect Transistors 
Scientific Reports  2016;6:20293.
Tunneling field effect transistors (TFETs) have been proposed to overcome the fundamental issues of Si based transistors, such as short channel effect, finite leakage current, and high contact resistance. Unfortunately, most if not all TFETs are operational only at cryogenic temperatures. Here we report that iron (Fe) quantum dots functionalized boron nitride nanotubes (QDs-BNNTs) can be used as the flexible tunneling channels of TFETs at room temperatures. The electrical insulating BNNTs are used as the one-dimensional (1D) substrates to confine the uniform formation of Fe QDs on their surface as the flexible tunneling channel. Consistent semiconductor-like transport behaviors under various bending conditions are detected by scanning tunneling spectroscopy in a transmission electron microscopy system (in-situ STM-TEM). As suggested by computer simulation, the uniform distribution of Fe QDs enable an averaging effect on the possible electron tunneling pathways, which is responsible for the consistent transport properties that are not sensitive to bending.
PMCID: PMC4742867  PMID: 26846587
17.  Skyrmion motion driven by oscillating magnetic field 
Scientific Reports  2016;6:20360.
The one-dimensional magnetic skyrmion motion induced by an electric current has attracted much interest because of its application potential in next-generation magnetic memory devices. Recently, the unidirectional motion of large (20 μm in diameter) magnetic bubbles with two-dimensional skyrmion topology, driven by an oscillating magnetic field, has also been demonstrated. For application in high-density memory devices, it is preferable to reduce the size of skyrmion. Here we show by numerical simulation that a skyrmion of a few tens of nanometres can also be driven by high-frequency field oscillations, but with a different direction of motion from the in-plane component of the tilted oscillating field. We found that a high-frequency field for small skyrmions can excite skyrmion resonant modes and that a combination of different modes results in a final skyrmion motion with a helical trajectory. Because this helical motion depends on the frequency of the field, we can control both the speed and the direction of the skyrmion motion, which is a distinguishable characteristic compared with other methods.
PMCID: PMC4742868  PMID: 26847334
18.  Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1 
Scientific Reports  2016;6:20600.
To improve the pharmacokinetics and to study the anti-cervical cancer and anti-stem cells (CSCs) mechanism of Quinacrine (QC), a spherical nano particle of QC (i.e. NQC) was prepared and characterized. QC and NQC showed higher cytotoxicity in multiple cancer cells than the normal epithelial cells. NQC exhibited more toxicity in cervical cancer cells and its CSCs than QC. A dose-dependent decreased expression of Hedgehog-GLI (HH-GLI) components were noted in NQC treated HeLa cells and its CSCs. NQC increased the expressions of negatively regulated HH-GLI components (GSK3β, PTEN) and caused apoptosis in CSCs. Reduction of GLI1 at mRNA and promoter level were noted after NQC exposure. The expressions of HH-GLI components, GLI1 promoter activity and apoptosis were unaltered in NQC treated GLI1-knockdown cells. In silico, cell based and in vitro reconstitution assay revealed that NQC inhibit HH-GLI cascade by binding to the consensus sequence (5′GACCACCCA3′) of GLI1 in GLI-DNA complex through destabilizing DNA-GLI1 complex. NQC reduced the tumors size and proliferation marker Ki-67 in an in vivo xenograft mice model. Thus, NQC induced apoptosis in cancers through inhibition of HH-GLI cascade by GLI1. Detail interaction of QC-DNA-GLI complex can pave path for anticancer drug design.
PMCID: PMC4742869  PMID: 26846872
19.  Microbiologically Influenced Corrosion of 2707 Hyper-Duplex Stainless Steel by Marine Pseudomonas aeruginosa Biofilm 
Scientific Reports  2016;6:20190.
Microbiologically Influenced Corrosion (MIC) is a serious problem in many industries because it causes huge economic losses. Due to its excellent resistance to chemical corrosion, 2707 hyper duplex stainless steel (2707 HDSS) has been used in the marine environment. However, its resistance to MIC was not experimentally proven. In this study, the MIC behavior of 2707 HDSS caused by the marine aerobe Pseudomonas aeruginosa was investigated. Electrochemical analyses demonstrated a positive shift in the corrosion potential and an increase in the corrosion current density in the presence of the P. aeruginosa biofilm in the 2216E medium. X-ray photoelectron spectroscopy (XPS) analysis results showed a decrease in Cr content on the coupon surface beneath the biofilm. The pit imaging analysis showed that the P. aeruginosa biofilm caused a largest pit depth of 0.69 μm in 14 days of incubation. Although this was quite small, it indicated that 2707 HDSS was not completely immune to MIC by the P. aeruginosa biofilm.
PMCID: PMC4742871  PMID: 26846970
20.  Dirac fermions at high-index surfaces of bismuth chalcogenide topological insulator nanostructures 
Scientific Reports  2016;6:20220.
Binary bismuth chalcogenides Bi2Se3, Bi2Te3, and related materials are currently being extensively investigated as the reference topological insulators (TIs) due to their simple surface-state band dispersion (single Dirac cone) and relatively large bulk band gaps. Nanostructures of TIs are of particular interest as an increased surface-to-volume ratio enhances the contribution of surfaces states, meaning they are promising candidates for potential device applications. So far, the vast majority of research efforts have focused on the low-energy (0001) surfaces, which correspond to natural cleavage planes in these layered materials. However, the surfaces of low-dimensional nanostructures (nanoplatelets, nanowires, nanoribbons) inevitably involve higher-index facets. We perform a systematic ab initio investigation of the surfaces of bismuth chalcogenide TI nanostructures characterized by different crystallographic orientations, atomic structures and stoichiometric compositions. We find several stable terminations of high-index surfaces, which can be realized at different values of the chemical potential of one of the constituent elements. For the uniquely defined stoichiometric termination, the topological Dirac fermion states are shown to be strongly anisotropic with a clear dependence of Fermi velocities and spin polarization on the surface orientation. Self-doping effects and the presence of topologically trivial mid-gap states are found to characterize the non-stoichiometric surfaces. The results of our study pave the way towards experimental control of topologically protected surface states in bismuth chalcogenide nanostructures.
PMCID: PMC4742872  PMID: 26847409
21.  Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment 
Scientific Reports  2016;6:20605.
Rapidly growing tumours in vivo often outgrow their surrounding available blood supply, subjecting themselves to a severely hypoxic microenvironment. Understanding how tumour cells adapt themselves to survive hypoxia may help to develop new treatments of the tumours. Given the limited blood perfusion to the enlarging tumour, whatever factor(s) that allows the tumour cells to survive likely comes from the tumour cells themselves or its associated stromal cells. In this report, we show that HIF-1α-overexpressing breast cancer cells, MDA-MB-231, secrete heat shock protein-90alpha (Hsp90α) and use it to survive under hypoxia. Depletion of Hsp90α secretion from the tumour cells was permissive to cytotoxicity by hypoxia, whereas supplementation of Hsp90α-knockout tumour cells with recombinant Hsp90α, but not Hsp90β, protein prevented hypoxia-induced cell death via an autocrine mechanism through the LDL receptor-related protein-1 (LRP1) receptor. Finally, direct inhibition of the secreted Hsp90α with monoclonal antibody, 1G6-D7, enhanced tumour cell death under hypoxia. Therefore, secreted Hsp90α is a novel survival factor for certain tumours under hypoxia.
PMCID: PMC4742873  PMID: 26846992
22.  The Spermatophore in Glossina morsitans morsitans: Insights into Male Contributions to Reproduction 
Scientific Reports  2016;6:20334.
Male Seminal Fluid Proteins (SFPs) transferred during copulation modulate female reproductive physiology and behavior, impacting sperm storage/use, ovulation, oviposition, and remating receptivity. These capabilities make them ideal targets for developing novel methods of insect disease vector control. Little is known about the nature of SFPs in the viviparous tsetse flies (Diptera: Glossinidae), vectors of Human and Animal African trypanosomiasis. In tsetse, male ejaculate is assembled into a capsule-like spermatophore structure visible post-copulation in the female uterus. We applied high-throughput approaches to uncover the composition of the spermatophore in Glossina morsitans morsitans. We found that both male accessory glands and testes contribute to its formation. The male accessory glands produce a small number of abundant novel proteins with yet unknown functions, in addition to enzyme inhibitors and peptidase regulators. The testes contribute sperm in addition to a diverse array of less abundant proteins associated with binding, oxidoreductase/transferase activities, cytoskeletal and lipid/carbohydrate transporter functions. Proteins encoded by female-biased genes are also found in the spermatophore. About half of the proteins display sequence conservation relative to other Diptera, and low similarity to SFPs from other studied species, possibly reflecting both their fast evolutionary pace and the divergent nature of tsetse’s viviparous biology.
PMCID: PMC4742874  PMID: 26847001
23.  Zinc Finger 259 Gene Polymorphism rs964184 is Associated with Serum Triglyceride Levels and Metabolic Syndrome 
Metabolic syndrome (MetS) is characterized by a cluster of cardiovascular risk factors that include: abdominal obesity, dyslipidaemia, hypertension, insulin resistance and impaired glucose tolerance. Recent genome wide association studies have identified several susceptibility regions involved in lipid metabolism that are also associated with MetS. We have explored the association of 9 genetic polymorphisms involved in lipid metabolism and hypertension, including: MTHFR C677T, SELE L554F, FGB - 455G>A, GNB3 C825T, ZNF259 C>G, PSRC-1 A>G, CETP I405V, LPL S447X and LPA C>T in 97 subjects with MetS and 96 individuals without MetS who were recruited randomly from Mashhad stroke and heart atherosclerotic disorder (MASHAD) study using a stratified cluster random sampling technique. Anthropometric parameters and biochemical measurements were determined in all the subjects. Genotyping was carried out followed by univariate and multivariate analyses. The subjects with MetS had a higher triglyceride and lower HDL- C. CG+ GG genotypes of ZNF259 polymorphism (rs964184 C>G) and TT+CT genotypes of MTHFR C677T (rs1801133) were associated with MetS, and individuals carrying the G allele for ZNF259 or the T allele for MTHFR polymorphisms were associated with MetS (e.g, odds ratio (OR) for CG+GG genotypes vs. CC wild type: 2.52, CI=1.33-4.77; P=0.005). However, after multiple comparison adjustment, this relationship remained significant only for CG+ GG genotypes of ZNF259 polymorphism. Moreover, the ZNF259 CG+ GG genotypes were associated with increased serum concentrations of triglycerides and LDL-C, compared to the wild type. These data support the necessity for further studies in larger multicenter settings.
PMCID: PMC4916779  PMID: 27386434
Metabolic syndrome; gene polymorphisms; lipid pathway
24.  Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients 
To evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases.
Fifty-nine adults were included in this cross-sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography.
Abnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p-value < 0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value = 0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p-value = 0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p-value = 0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography.
A significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases.
PMCID: PMC4786771  PMID: 26969771
Sickle cell disease; Respiratory function tests; Computed tomography; Echocardiography
25.  Determination of an unrelated donor pool size for human leukocyte antigen-matched platelets in Brazil 
Successful transfusion of platelet refractory patients is a challenge. Many potential donors are needed to sustain human leukocyte antigen matched-platelet transfusion programs because of the different types of antigens and the constant needs of these patients. For a highly mixed population such as the Brazilian population, the pool size required to provide adequate platelet support is unknown.
A mathematical model was created to estimate the appropriate size of an unrelated donor pool to provide human leukocyte antigen-compatible platelet support for a Brazilian population. A group of 154 hematologic human leukocyte antigen-typed patients was used as the potential patient population and a database of 65,500 human leukocyte antigen-typed bone marrow registered donors was used as the donor population. Platelet compatibility was based on the grading system of Duquesnoy.
Using the mathematical model, a pool containing 31,940, 1710 and 321 donors would be necessary to match more than 80% of the patients with at least five completely compatible (no cross-reactive group), partial compatible (one cross-reactive group) or less compatible (two cross-reactive group) donors, respectively.
The phenotypic diversity of the Brazilian population has probably made it more difficulty to find completely compatible donors. However, this heterogeneity seems to have facilitated finding donors when cross-reactive groups are accepted as proposed by the grading system of Duquesnoy. The results of this study may help to establish unrelated human leukocyte antigen-compatible platelet transfusions, a procedure not routinely performed in most Brazilian transfusion services.
PMCID: PMC4786768  PMID: 26969768
Platelet transfusion; HLA; Refractoriness; Donors

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