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1.  Site-specific quantitative analysis of cardiac mitochondrial protein phosphorylation 
Journal of proteomics  2012;81:15-23.
We report the development of a multiple-reaction monitoring (MRM) strategy specifically tailored to the detection and quantification of mitochondrial protein phosphorylation. We recently derived 68 MRM transitions specific to protein modifications in the respiratory chain, voltage-dependent anion channel, and adenine nucleotide translocase. Here, we have now expanded the total number of MRM transitions to 176 to cover proteins from the tricarboxylic acid cycle, pyruvate dehydrogenase complex, and branched-chain alpha-keto acid dehydrogenase complex. We utilized the transition set to analyze endogenous protein phosphorylation in human heart, mouse heart, and mouse liver. The data demonstrate the potential utility of the MRM workflow for studying the functional details of mitochondrial phosphorylation signaling.
doi:10.1016/j.jprot.2012.09.015
PMCID: PMC3593810  PMID: 23022582
Multiple-reaction monitoring; mitochondria; phosphorylation; cardioprotection; quantification; cardiac biology
2.  Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs 
Experimental neurology  2008;210(2):645-655.
Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.
doi:10.1016/j.expneurol.2007.12.019
PMCID: PMC3979422  PMID: 18291370
Traumatic brain injury; TBI; rFVIIa; Cerebral contusion; Recombinant Activated Factor VII; Hemostasis; Diffuse axonal injury; Neuroprotection
3.  The Potential Dual Effects of Anesthetic Isoflurane on Aβ-Induced Apoptosis 
Current Alzheimer research  2011;8(7):741-752.
β-amyloid protein (Aβ)-induced neurotoxicity is the main component of Alzheimer’s disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Aβ-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naïve mice, and naïve mice were treated with Aβ and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Aβ-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Aβ-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Aβ-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Aβ-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Aβ-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.
PMCID: PMC3973025  PMID: 21244349
Anesthesia; Alzheimer’s disease; isoflurane; apoptosis; β-Amyloid protein; dual effects; cytosolic calcium
4.  Establishing a novel knock-in mouse line for studying neuronal cytoplasmic dynein under normal and pathologic conditions 
Cytoskeleton (Hoboken, N.J.)  2013;70(4):215-227.
Cytoplasmic dynein plays important roles in mitosis and the intracellular transport of organelles, proteins, and mRNAs. Dynein function is particularly critical for survival of neurons, as mutations in dynein are linked to neurodegenerative diseases. Dynein function is also implicated in neuronal regeneration, driving the active transport of signaling molecules following injury of peripheral neurons. To enhance our understanding of dynein function and regulation in neurons, we established a novel knock-in mouse line in which the neuron-specific cytoplasmic dynein 1 intermediate chain 1 (IC-1) is tagged with both GFP and a 3xFLAG tag at its C-terminus. The fusion gene is under the control of IC-1’s endogenous promoter and is integrated at the endogenous locus of the IC-1-encoding gene Dync1i1. The IC-1-GFP-3xFLAG fusion protein is incorporated into the endogenous dynein complex, and movements of GFP-labeled dynein expressed at endogenous levels can be observed in cultured neurons for the first time. The knock-in mouse line also allows isolation and analysis of dynein-bound proteins specifically from neurons. Using this mouse line we have found proteins, including 14-3-3 zeta, which physically interact with dynein upon injury of the brain cortex. Thus, we have created a useful tool for studying dynein function in the central nervous system under normal and pathologic conditions.
doi:10.1002/cm.21102
PMCID: PMC3670090  PMID: 23475693
5.  Ethnic disparities in the prevalence of the metabolic syndrome in American adults: data from the Examination of National Health and Nutrition Examination Survey 1999–2010 
Data from the National Health and Nutrition Examination Survey were stratified by weight, gender, and ethnicity for six survey years from 1999 to 2010 for variables that satisfy the criteria for metabolic syndrome (MS). Results showed that 34% of the US adult population had MS. No significant gender disparities in MS prevalence were found. Black men had a significantly lower prevalence of MS than Black women and White men from 1999 to 2008 (P < 0.05). Women had a 60% higher abdominal adiposity than men in the US population (P = 0.00048; pregnant females were excluded). Although there seem to be ethnic differences in the prevalence of MS, the expression of MS is not a sufficient risk to culminate in cardiovascular disease; rather, nutritional, genetic, and environmental factors are necessary to finalize its expression into overt disease.
PMCID: PMC3954654
6.  A cohort analysis of the cardiovascular risk factors in the employees of a pediatric hospital from 2009 to 2012 
A retrospective longitudinal cohort regression analysis was completed in 853 of the 3435 employees of Cook Children's Hospital who participated all 4 years (2009 to 2012) in an employer wellness program. The presence of the metabolic syndrome (MS) was used as an outcome measure for the success of the wellness program. Data were stratified by weight, gender, and ethnicity. The odds ratios and regression analysis showed a significant decline in MS over the 4 years of the study (P = 0.008), as well as a significant association between MS and obesity and overweight status (P < 0.0001), male gender (P = 0.0018), and all ethnic categories (P < 0.05) except African American ethnicity and the multiple ethnicity category. Age was strongly associated with risk for MS. Overall, the study showed that the wellness program significantly decreased the incidence of MS (P < 0.05).
PMCID: PMC3954655
7.  Inertial particle separation by differential equilibrium positions in a symmetrical serpentine micro-channel 
Scientific Reports  2014;4:4527.
This paper presents an inertial microfluidic device with a simple serpentine micro-channel to continuously separate particles with high performance. Separation of micro/nano-particles has a variety of potential applications in biomedicine and industry. Among the existing separation technologies, a label-free technique without the use of antibody affinity, filter or centrifugation is highly desired to ensure minimal damage and alteration to the cells. Inertial microfluidics utilising hydrodynamic forces to separate particles is one of the most suitable label-free technologies with a high throughput. Our separation concept relies on size-based differential equilibrium positions of the particles perpendicular to the flow. Highly efficient separation is demonstrated with particles of different sizes. The results indicate that the proposed device has an integrative advantage to the existing microfluidic separation techniques, taking accounts of purity, efficiency, parallelizability, footprint, throughput and resolution. Our device is expected to be a good alternative to conventional separation methods for sample preparation and clinical diagnosis.
doi:10.1038/srep04527
PMCID: PMC3970124  PMID: 24681628
8.  QTLs for Seed Vigor-Related Traits Identified in Maize Seeds Germinated under Artificial Aging Conditions 
PLoS ONE  2014;9(3):e92535.
High seed vigor is important for agricultural production due to the associated potential for increased growth and productivity. However, a better understanding of the underlying molecular mechanisms is required because the genetic basis for seed vigor remains unknown. We used single-nucleotide polymorphism (SNP) markers to map quantitative trait loci (QTLs) for four seed vigor traits in two connected recombinant inbred line (RIL) maize populations under four treatment conditions during seed germination. Sixty-five QTLs distributed between the two populations were identified and a meta-analysis was used to integrate genetic maps. Sixty-one initially identified QTLs were integrated into 18 meta-QTLs (mQTLs). Initial QTLs with contribution to phenotypic variation values of R2>10% were integrated into mQTLs. Twenty-three candidate genes for association with seed vigor traits coincided with 13 mQTLs. The candidate genes had functions in the glycolytic pathway and in protein metabolism. QTLs with major effects (R2>10%) were identified under at least one treatment condition for mQTL2, mQTL3-2, and mQTL3-4. Candidate genes included a calcium-dependent protein kinase gene (302810918) involved in signal transduction that mapped in the mQTL3-2 interval associated with germination energy (GE) and germination percentage (GP), and an hsp20/alpha crystallin family protein gene (At5g51440) that mapped in the mQTL3-4 interval associated with GE and GP. Two initial QTLs with a major effect under at least two treatment conditions were identified for mQTL5-2. A cucumisin-like Ser protease gene (At5g67360) mapped in the mQTL5-2 interval associated with GP. The chromosome regions for mQTL2, mQTL3-2, mQTL3-4, and mQTL5-2 may be hot spots for QTLs related to seed vigor traits. The mQTLs and candidate genes identified in this study provide valuable information for the identification of additional quantitative trait genes.
doi:10.1371/journal.pone.0092535
PMCID: PMC3961396  PMID: 24651614
9.  An Imaging-Based Approach to the Evaluation of Xerostomia 
Lasers in surgery and medicine  2012;44(6):482-489.
Background and Objective
Goal was to evaluate the potential of in vivo optical coherence tomography (OCT) imaging to determine the response of patients with xerostomia to a dry mouth toothpaste versus fluoride tooth-paste placebo.
Study Design/Materials and Methods
Ten subjects with xerostomia participated in this double-blind, crossover, placebo-controlled study. After examination and OCT imaging, subjects used the first product for 15 days, followed by a 7-day washout period, and then they used the second product for 15 days. Data were acquired at 5-day intervals, also before and after the washout.
Results
Visual examination and tongue blade adhesion test did not reflect response to the product. Two imaging-based markers were identified: (i) In OCT images, epithelial thickness increased significantly (P < 0.05) after use of the dry mouth toothpaste, but did not change significantly (P > 0.05) after the use of a fluoride toothpaste and (2) Optical backscattering data showed progressive characteristic changes from baseline with use of the active product.
Conclusions
In this pilot study using in vivo OCT imaging, it was possible to detect and measure oral epithelial response to the dry mouth product versus placebo in patients with xerostomia.
Clinical Implications
This approach may permit site-specific assessment of xerostomia, individualized treatment planning and monitoring, and sequential mucosal mapping in patients with dry mouth.
doi:10.1002/lsm.22039
PMCID: PMC3953877  PMID: 22693075
dry mouth intervention; imaging; optical coherence tomography
10.  Anti-cancer effects of grailsine-al-glycoside isolated from Rhizoma Sparganii 
Background
An embryonic toxicity of Rhizoma sparganii was observed in mice. This study was aimed to evaluate the anticancer effects of Grailsine-Al-glycoside, the bioactive component of Rhizoma sparganii, on estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) cancer cell lines.
Methods
After A549, HeLa, HepG-2 and MCF-7 cells were treated with Grailsine-Al-glycoside, cell proliferation was analyzed by MTT, cell cycle and apoptosis by flow cytometry, and morphology with an immunofluorescence microscope.
Results
Grailsine-Al-glycoside strongly suppressed cell proliferation in a dose-dependent fashion in A549, MCF-7, HepG2, and HeLa cells, though this growth inhibitory effect on HepG2 cells was not as strong and long lasting. Compared to the control, Grailsine-Al-glycoside caused a significant increase of apoptosis in A549, MCF-7 and Hela cells. A549 and MCF-7 cells were arrested at the G2/S phase whereas HepG2 cells were arrested at the G1 phase by a high concentration of Grailsine-Al-glycoside . Cell shapes were also changed by the presence of Grailsine-Al-glycoside.
Conclusions
Grailsine-Al-glycoside from Rhizoma sparganii inhibited the proliferation of ER+ and some ER- cancer cells. Grailsine-Al-glycoside may be used as a chemotherapeutic agent against ER+ and ERRα-expressing ER- cancers.
doi:10.1186/1472-6882-14-82
PMCID: PMC3943449  PMID: 24589031
Grailsine-Al-glycoside; Rhizoma sparganii; Estrogen receptor-positive; Estrogen-related receptor alpha
11.  Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention 
Introduction
Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).
Methods
At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.
Results
Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92).
Conclusions
Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
doi:10.1016/j.lungcan.2012.11.011
PMCID: PMC3566344  PMID: 23261228
lung cancer; chemoprevention; phase II clinical trial; sulindac; NSAIDs
12.  Unique genome-wide map of TCF4 and STAT3 targets using ChIP-seq reveals their association with new molecular subtypes of glioblastoma 
Neuro-Oncology  2013;15(3):279-289.
Background
Aberrant activation of beta-catenin/TCF4 and STAT3 signaling in glioblastoma multiforme (GBM) has been reported. However, the molecular mechanisms related to this process are still poorly understood.
Methods
Genome-wide screening of the binding characteristics of the transcription factors TCF4 and STAT3 in GBM cells was performed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the association of TCF4 and STAT3 coregulated genes with The Cancer Genome Atlas (TCGA) GBM subtypes (classical, mesenchymal, neural, and proneural). New molecular classification of GBM was proposed and validated in Western and Asian populations.
Results
We identified 1250 overlapping putative target genes that were coregulated by TCF4 and STAT3. Further, the coregulated genes had the potential to guide TCGA GBM subtypes. Finally, we proposed a new molecular classification of GBM into 2 subtypes (proneural-like and mesenchymal-like) and showed that the new classification could be applied to both Western and Asian populations. In addition, the GBM response to temozolomide therapy differed depending on its subtype; mesenchymal-like GBM benefited, while there was no benefit for proneural-like GBM.
Conclusions
This is the first comprehensive study to combine a ChIP-seq assay of TCF4 and STAT3 and data mining of patient cohorts to derive molecular subtypes of GBM.
doi:10.1093/neuonc/nos306
PMCID: PMC3578485  PMID: 23295773
ChIP-seq; glioblastoma; molecular subtype; STAT3; TCF4
13.  H/D Exchange Centroid Monitoring is Insufficient to Show Differences in the Behavior of Protein States 
Differential hydrogen/deuterium exchange (H/DX) coupled with mass spectrometry (H/DX-MS) offers a rapid and sensitive characterization of changes in protein following perturbations induced by changes in folding, ligand binding, oligomerization, and modification. The characterization of H/DX rates in software tools and automated data processing often relies on the centroid mass calculation, and, thereby, the deuterium distribution in the mass spectra is neglected. Here we present an example demonstrating the clear limitation of using only a centroid approach to characterize the H/DX rate, in which the change in protein is not reflected as the difference in deuterium uptake based on centroid calculation.
doi:10.1007/s13361-012-0555-z
PMCID: PMC3594389  PMID: 23397137
14.  Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats 
PLoS ONE  2014;9(2):e90069.
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
doi:10.1371/journal.pone.0090069
PMCID: PMC3938595  PMID: 24587209
15.  Chronic medication does not affect hyperactive error responses in obsessive-compulsive disorder 
Psychophysiology  2010;47(5):913-920.
Patients with obsessive-compulsive disorder (OCD) show an increased error-related negativity (ERN), yet previous studies have not controlled for medication use, which may be important given evidence linking performance monitoring to neurotransmitter systems targeted by treatment, such as serotonin. In an examination of 19 unmedicated OCD patients, 19 medicated OCD patients, 19 medicated patient controls without OCD, and 21 unmedicated healthy controls, we found greater ERNs in OCD patients than in controls, irrespective of medication use. Severity of generalized anxiety and depression was associated with ERN amplitude in controls but not patients. These data confirm previous findings of an exaggerated error response in OCD, further showing that it cannot be attributed to medication. The absence in patients of a relationship between ERN amplitude and anxiety/depression, as was found in controls, suggests that elevated error signals in OCD may be disorder-specific.
doi:10.1111/j.1469-8986.2010.00988.x
PMCID: PMC3928597  PMID: 20230510
Error-related negativity (ERN); Event-related potentials (ERPs); Anxiety; Anterior cingulate cortex (ACC)
16.  Down-Regulation of Nicotinamide N-methyltransferase Induces Apoptosis in Human Breast Cancer Cells via the Mitochondria-Mediated Pathway 
PLoS ONE  2014;9(2):e89202.
Nicotinamide N-methyltransferase (NNMT) has been found involved in cell proliferation of several malignancies. However, the functional role of NNMT in breast cancer has not been elucidated. In the present study, we showed that NNMT was selectively expressed in some breast cancer cell lines, down-regulation of NNMT expression in Bcap-37 and MDA-MB-231 cell lines by NNMT shRNA significantly inhibited cell growth in vitro, decreased tumorigenicity in mice and induced apoptosis. The silencing reciprocal effect of NNMT was confirmed by over-expressing NNMT in the MCF-7 and SK-BR-3 breast cancer cell lines which lack constitutive expression of NNMT. In addition, down-regulation of NNMT expression resulted in reducing expression of Bcl-2 and Bcl-xL, up-regulation of Bax, Puma, cleaved caspase-9, cleaved caspase-3 and cleaved PARP, increasing reactive oxygen species production and release of cytochrome c from mitochondria, and decreasing the phosphorylation of Akt and ERK1/2. These data suggest that down-regulation of NNMT induces apoptosis via the mitochondria-mediated pathway in breast cancer cells.
doi:10.1371/journal.pone.0089202
PMCID: PMC3928407  PMID: 24558488
17.  STAT3 activation in tumor cell-free lymph nodes predicts a poor prognosis for gastric cancer 
STAT3 is constitutively activated in many human cancers including gastric cancer and plays crucial roles in modulating cancer cell proliferation, survival, metastasis as well as the microenvironment of pre-metastatic niches. Accumulating evidence has implicated STAT3 as a promising target for cancer therapy and it has been well established that tumor cell metastasized to lymph node is associated with poor prognosis. However, little is known about the relation between STAT3 activation in tumor cell-free lymph nodes and patient clinical outcomes. The objective of the current study was to investigate the role of STAT3 activity in tumor cell-free lymph nodes in tumor progression and prognosis for gastric cancer patients. Immunohistochemical analyses for p-STAT3, Ki-67, CD68 and Bcl-xL were performed in tumor cell-free lymph nodes from 60 gastric cancer patients. Survival analysis was conducted by using the Kaplan-Meier method. Immunohistochemical analyses showed that hyperactivity of STAT3 in tumor cell-free lymph nodes was significantly associated with tumor recurrence, and STAT3 activation pattern coincides with expression Ki-67, CD68, Bcl-xL. Survival analysis revealed that persistent STAT3 activation in uninvolved lymph nodes was positively associated with poor overall survival (P<0.05). These findings suggest that STAT3 activation in tumor-free lymph nodes is involved in the pathogenesis and metastasis of gastric cancer and that elevated STAT3 activity in lymph nodes prior to tumor cell arrival may indicate a poorer prognosis. These clinical studies support our findings in mouse tumor models showing that STAT3 activation is crucial for pre-metastatic niche formation and metastasis.
PMCID: PMC3971319
STAT3; gastric cancer; tumor cell-free lymph node; recurrence; prognosis
18.  Sparse Representation for Tumor Classification Based on Feature Extraction Using Latent Low-Rank Representation 
BioMed Research International  2014;2014:420856.
Accurate tumor classification is crucial to the proper treatment of cancer. To now, sparse representation (SR) has shown its great performance for tumor classification. This paper conceives a new SR-based method for tumor classification by using gene expression data. In the proposed method, we firstly use latent low-rank representation for extracting salient features and removing noise from the original samples data. Then we use sparse representation classifier (SRC) to build tumor classification model. The experimental results on several real-world data sets show that our method is more efficient and more effective than the previous classification methods including SVM, SRC, and LASSO.
doi:10.1155/2014/420856
PMCID: PMC3942202  PMID: 24678505
19.  Recoverability Analysis for Modified Compressive Sensing with Partially Known Support 
PLoS ONE  2014;9(2):e87985.
The recently proposed modified-compressive sensing (modified-CS), which utilizes the partially known support as prior knowledge, significantly improves the performance of recovering sparse signals. However, modified-CS depends heavily on the reliability of the known support. An important problem, which must be studied further, is the recoverability of modified-CS when the known support contains a number of errors. In this letter, we analyze the recoverability of modified-CS in a stochastic framework. A sufficient and necessary condition is established for exact recovery of a sparse signal. Utilizing this condition, the recovery probability that reflects the recoverability of modified-CS can be computed explicitly for a sparse signal with nonzero entries. Simulation experiments have been carried out to validate our theoretical results.
doi:10.1371/journal.pone.0087985
PMCID: PMC3919832  PMID: 24520341
20.  Draft Genome Sequence of Clostridium ultunense Strain BS (DSMZ 10521), Recovered from a Mixed Culture 
Genome Announcements  2014;2(1):e01269-13.
Clostridium ultunense BS is the first isolated strain (type strain) of C. ultunense that was identified as a mesophilic syntrophic acetate-oxidizing bacterium (SAOB). Here, we report the draft genome sequence of this strain, which will help us to elucidate the mechanism of syntrophic acetate oxidization.
doi:10.1128/genomeA.01269-13
PMCID: PMC3916497  PMID: 24504003
21.  Obstetric complications among US women with asthma 
Objective
To characterize complications of pregnancy, labor and delivery associated with maternal asthma in a contemporary US cohort.
Study Design
A retrospective cohort based on electronic medical record data from 223,512 singleton deliveries from 12 clinical centers across the United States between 2002–2008.
Results
Women with asthma had higher odds of preeclampsia (adjusted odds ratio (aOR)=1.14; 95% confidence interval (95%CI)=1.06–1.22), superimposed preeclampsia (aOR=1.34; 95%CI=1.15–1.56), gestational diabetes (aOR=1.11; 95%CI=1.03–1.19), placental abruption (aOR=1.22; 95%CI=1.09–1.36), and placenta previa (aOR=1.30; 95%CI=1.08–1.56). Asthmatic women had a higher odds of preterm birth overall (aOR=1.17; 95%CI=1.12–1.23) and of medically-indicated preterm delivery (aOR=1.14; 95%CI=1.01–1.29). Asthmatics were less likely to have spontaneous labor (aOR=0.87; 95%CI=0.84–0.90) and vaginal delivery (aOR=0.84; 95%CI=0.80–0.87). Risks were higher for breech presentation (aOR=1.13; 95%CI=1.05–1.22), hemorrhage (aOR=1.09; 95%CI=1.03–1.16), pulmonary embolism (aOR=1.71; 95%CI=1.05–2.79), and maternal ICU admission (aOR=1.34; 95%CI=1.04–1.72).
Conclusion
Maternal asthma increased risk for nearly all outcomes studied in a general obstetric population.
doi:10.1016/j.ajog.2012.11.007
PMCID: PMC3557554  PMID: 23159695
asthma; cesarean delivery; pregnancy complication; preterm birth
22.  Differential expression of serum miR-126, miR-141 and miR-21 as novel biomarkers for early detection of liver metastasis in colorectal cancer 
Objective
MicroRNAs (miRNAs) have potential as diagnostic biomarkers in cancer. Evaluation of the association between miRNA expression patterns and early detection of liver metastasis in colorectal cancer (CRC) has not been reported.
Methods
We investigated the expression of metastasis-associated miRs-31, 335, 206, 141, 126, 200b, 200c, 21, Let7a, Let7b and Let7c in localized, liver-metastatic and other organ-metastatic CRC (OM-CRC). Expressions of target miRNAs in serum were evaluated in 116 consecutive localized CRC (L-CRC), 72 synchronous liver-metastatic CRC (SLM-CRC) and 36 other OM-CRC by quantitative real-time PCR.
Results
Seven of 11 tested miRNAs could be detected from serum. Four miRNAs, miR-126, Let-7a, miR-141 and miR-21 were identified as metastasis-associated miRNAs. Compared with L-CRC, significant up-regulated expression was observed for miR-141 and miR-21 in SLM-CRC and OM-CRC, down-regulated expression was observed for miR-126 in SLM-CRC and OM-CRC, and up-regulated expression of Let-7a in OM-CRC. The receiver operating characteristic (ROC) curve showed serum miR-126 had a cut-off [log10 relative quantity (log10RQ)=–0.2005] with 77.78% sensitivity and 68.97% specificity with an area under curve (AUC) of 0.7564, miR-141 had a cut-off (log10RQ=–0.2285) with 86.11% sensitivity and 76.11% specificity with an AUC of 0.8279, and miR-21 had a cut-off (log10RQ=–0.1310) with 73.61% sensitivity and 66.38% specificity with an AUC of 0.7479.
Conclusions
We identified liver metastasis-associated miRNAs, suggesting serum miR-126, miR-141 and miR-21 may be novel biomarkers for clinical diagnosis of early stage liver-metastatic CRC.
doi:10.3978/j.issn.1000-9604.2014.02.07
PMCID: PMC3937759  PMID: 24653631
MicroRNA (miRNAs); colorectal cancer (CRC); liver metastasis; diagnosis
23.  Epidemiology of Zoonotic Hepatitis E: A Community-Based Surveillance Study in a Rural Population in China 
PLoS ONE  2014;9(1):e87154.
Background
Hepatitis E is caused by two viral genotype groups: human types and zoonotic types. Current understanding of the epidemiology of the zoonotic hepatitis E disease is founded largely on hospital-based studies.
Methods
The epidemiology of hepatitis E was investigated in a community-based surveillance study conducted over one year in a rural city in eastern China with a registered population of 400,162.
Results
The seroprevalence of hepatitis E in the cohort was 38%. The incidence of hepatitis E was 2.8/10,000 person-years. Totally 93.5% of the infections were attributed to genotype 4 and the rest, to genotype 1. Hepatitis E accounted for 28.4% (102/359) of the acute hepatitis cases and 68.9% (102/148) of the acute viral hepatitis cases in this area of China. The disease occurred sporadically with a higher prevalence during the cold season and in men, with the male-to-female ratio of 3∶1. Additionally, the incidence of hepatitis E increased with age. Hepatitis B virus carriers have an increased risk of contracting hepatitis E than the general population (OR = 2.5, 95%CI 1.5–4.2). Pre-existing immunity to hepatitis E lowered the risk (relative risk  = 0.34, 95% CI 0.21–0.55) and reduced the severity of the disease.
Conclusions
Hepatitis E in the rural population of China is essentially that of a zoonosis due to the genotype 4 virus, the epidemiology of which is similar to that due to the other zoonotic genotype 3 virus.
doi:10.1371/journal.pone.0087154
PMCID: PMC3909025  PMID: 24498033
24.  The Multicenter, Phase II Prospective Study of Paclitaxel Plus Capecitabine as First-Line Chemotherapy in Advanced Gastric Carcinoma 
The Oncologist  2014;19(2):173-174.
Background.
The efficacy and toxicity of paclitaxel plus capecitabine (PX) as first-line treatment in advanced gastric cancer (AGC) was evaluated.
Methods.
Patients with previously untreated AGC were included. PX was given every 3 weeks until a maximum of six cycles or progression. Capecitabine monotherapy was continued for patients without disease progression. The primary endpoint was progression-free survival, and secondary endpoints were objective response rate, overall survival (OS), and safety.
Results.
Overall, 194 patients were treated per protocol and one patient was excluded because of allergy to paclitaxel. Response was evaluated in 175 patients, with an objective response rate of 34.8%. After a median follow-up of 33.2 months, disease progression was observed in 141 patients, 137 died, and 16 were lost to follow-up, with progression-free survival of 188 days and OS of 354 days. In multivariate Cox regression analysis, no factor remained an independent predictor of OS. Forty-five patients who received capecitabine monotherapy after PX had longer OS (531 days). Adverse events were mild (Fig. 1), and the most common grade 3–4 toxicities were leucopenia and neutropenia.
Conclusion.
PX as a first-line treatment has promising efficacy in AGC. Based on these data, a phase III study has been launched for further investigation.
doi:10.1634/theoncologist.2013-0137
PMCID: PMC3926790  PMID: 24457378
25.  A Part-Based Probabilistic Model for Object Detection with Occlusion 
PLoS ONE  2014;9(1):e84624.
The part-based method has been a fast rising framework for object detection. It is attracting more and more attention for its detection precision and partial robustness to the occlusion. However, little research has been focused on the problem of occlusion overlapping of the part regions, which can reduce the performance of the system. This paper proposes a part-based probabilistic model and the corresponding inference algorithm for the problem of the part occlusion. The model is based on the Bayesian theory integrally and aims to be robust to the large occlusion. In the stage of the model construction, all of the parts constitute the vertex set of a fully connected graph, and a binary variable is assigned to each part to indicate its occlusion status. In addition, we introduce a penalty term to regularize the argument space of the objective function. Thus, the part detection is formulated as an optimization problem, which is divided into two alternative procedures: the outer inference and the inner inference. A stochastic tentative method is employed in the outer inference to determine the occlusion status for each part. In the inner inference, the gradient descent algorithm is employed to find the optimal positions of the parts, in term of the current occlusion status. Experiments were carried out on the Caltech database. The results demonstrated that the proposed method achieves a strong robustness to the occlusion.
doi:10.1371/journal.pone.0084624
PMCID: PMC3894947  PMID: 24465420

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