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1.  Plasmodium falciparum synthetic LbL microparticle vaccine elicits protective neutralizing antibody and parasite-specific cellular immune responses 
Vaccine  2013;31(15):1898-1904.
Epitopes of the circumsporozoite (CS) protein of Plasmodium falciparum, the most pathogenic species of the malaria parasite, have been shown to elicit protective immunity in experimental animals and human volunteers. The mechanisms of immunity include parasite-neutralizing antibodies that can inhibit parasite motility in the skin at the site of infection and in the bloodstream during transit to the hepatocyte host cell and also block interaction with host cell receptors on hepatocytes. In addition, specific CD4+ and CD8+ cellular mechanisms target the intracellular hepatic forms, thus preventing release of erythrocytic stage parasites from the infected hepatocyte and the ensuing blood stage cycle responsible for clinical disease. An innovative method for producing particle vaccines, layer-by-layer (LbL) fabrication of polypeptide films on solid CaCO3 cores, was used to produce synthetic malaria vaccines containing a tri-epitope CS peptide T1BT* comprising the antibody epitope of the CS repeat region (B) and two T-cell epitopes, the highly conserved T1 epitope and the universal epitope T*. Mice immunized with microparticles loaded with T1BT* peptide developed parasite-neutralizing antibodies and malaria-specific T-cell responses including cytotoxic effector T-cells. Protection from liver stage infection following challenge with live sporozoites from infected mosquitoes correlated with neutralizing antibody levels. Although some immunized mice with low or undetectable neutralizing antibodies were also protected, depletion of T-cells prior to challenge resulted in the majority of mice remaining resistant to challenge. In addition, mice immunized with microparticles bearing only T-cell epitopes were not protected, demonstrating that cellular immunity alone was not sufficient for protective immunity. Although the microparticles without adjuvant were immunogenic and protective, a simple modification with the lipopeptide TLR2 agonist Pam3Cys increased the potency and efficacy of the LbL vaccine candidate. This study demonstrates the potential of LbL particles as promising malaria vaccine candidates using the T1BT* epitopes from the P. falciparum CS protein.
PMCID: PMC3611586  PMID: 23481177
malaria vaccines; microparticle; peptide; sporozoite
3.  Tissue elasticity displayed by elastography and its correlation with the characteristics of collagen type I and type III in prostatic stroma 
Asian Journal of Andrology  2014;16(2):305-308.
We investigated the prostate elasticity displayed by elastography and its correlation with the content and distribution of collagen type I (Col1) and type III (Col3). A total of 62 patients underwent transrectal real-time tissue elastography (TRTE) examinations. Targeted biopsies were performed after 12-core systematic biopsy. The tissues corresponding to the elastograms were stained with picric acid-sirius red. The distribution of Col1 and type Col3 was observed, and the collagen volume fraction (CVF) of these two types of collagen fibers was calculated. The CVFs of Col1 in the stiff and soft groups were 0.05 ± 0.02 and 0.02 ± 0.01 (P = 0.002), respectively. The CVFs of Col3 in the stiff and soft groups were 0.05 ± 0.04 and 0.07 ± 0.03 (P = 0.13), respectively. The circular analysis results showed that collagen fibers were disorganized both in the soft and stiff groups. Col1 and Col3 were mainly cross-linked, and some parallelization was observed in the sections. The distributions of Col1 and Col3 were different between the stiff and soft groups (P = 0.03). In conclusion, the texture of the prostate is due to the content of Col1 and its relative correlation with Col3.
PMCID: PMC3955345  PMID: 24435054
elastography; extracellular matrix; lesion; prostate; ultrasound
4.  IGFBP-3 and TNF-α Regulate Retinal Endothelial Cell Apoptosis 
We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes.
To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α.
Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active.
Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
IGFBP-3 KO mice have the early characteristics of diabetic retinopathy noted in rodents.
PMCID: PMC3741024  PMID: 23868984
IGFBP-3; apoptosis; TNF-α
5.  Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions 
To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features.
Between July 2005 and July 2012, 4,453 ultrasound-detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features.
Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter ≤10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01).
Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm.
PMCID: PMC3895748  PMID: 24400744
Breast; Beast cancer; Core needle biopsy; Surgical excision; Ultrasound
6.  Complete Genome Sequence of Exiguobacterium sp. Strain MH3, Isolated from Rhizosphere of Lemna minor 
Genome Announcements  2013;1(6):e01059-13.
We report the complete genome sequence of Exiguobacterium sp. strain MH3, isolated from the rhizosphere of duckweed. The genome assembly is 3.16 Mb, with a G+C content of 47.24%, and it may provide useful information about plant-microbe interactions and the genetic basis for the tolerance of the strain to various environmental stresses.
PMCID: PMC3868855  PMID: 24356831
7.  DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements and chimaeric transcripts in mouse ES cells 
Cell stem cell  2011;8(6):10.1016/j.stem.2011.04.004.
DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes up-regulated following deletion of the H3K9 methyltransferase Setdb1 are distinct from those de-repressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly de-repressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of up-regulated genes are induced in association with de-repression of promoter proximal ERVs, half in the context of “chimaeric” transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs.
PMCID: PMC3857791  PMID: 21624812 CAMSID: cams3765
8.  Cell-Cycle Control of Developmentally Regulated Transcription Factors Accounts for Heterogeneity in Human Pluripotent Cells 
Stem Cell Reports  2013;1(6):532-544.
Heterogeneity within pluripotent stem cell (PSC) populations is indicative of dynamic changes that occur when cells drift between different states. Although the role of metastability in PSCs is unclear, it appears to reflect heterogeneity in cell signaling. Using the Fucci cell-cycle indicator system, we show that elevated expression of developmental regulators in G1 is a major determinant of heterogeneity in human embryonic stem cells. Although signaling pathways remain active throughout the cell cycle, their contribution to heterogeneous gene expression is restricted to G1. Surprisingly, we identify dramatic changes in the levels of global 5-hydroxymethylcytosine, an unanticipated source of epigenetic heterogeneity that is tightly linked to cell-cycle progression and the expression of developmental regulators. When we evaluated gene expression in differentiating cells, we found that cell-cycle regulation of developmental regulators was maintained during lineage specification. Cell-cycle regulation of developmentally regulated transcription factors is therefore an inherent feature of the mechanisms underpinning differentiation.
•Embryonic stem cells are lineage primed in G1•Transcription of developmentally regulated genes is cell-cycle regulated•5hmC is cell-cycle regulated•Stem cells initiate differentiation from G1
Pluripotent stem cell heterogeneity has been attributed to stochastic variations in signaling pathways across the population. Using Fucci cell-cycle reporters, Dalton and colleagues show that stem cell “lineage priming” in G1 is associated with cell-cycle-dependent changes in the transcription of developmentally regulated genes. Moreover, these changes are paralleled by levels of the epigenetic mark 5-hydroxymethylcytosine. These findings identify the cell cycle as major source of heterogeneity in human pluripotent stem cells.
PMCID: PMC3871385  PMID: 24371808
9.  Upregulation of SOX9 in osteosarcoma and its association with tumor progression and patients’ prognosis 
Diagnostic Pathology  2013;8:183.
SOX9 plays an important role in bone formation and tumorigenesis. However, its involvement in osteosarcoma is still unclear. The aim of this study was to investigate the expression pattern and the clinical significance of SOX9 in human osteosarcoma.
SOX9 mRNA and protein expression levels were detected by RT-PCR and Western blot assays, respectively, using 30 pairs of osteosarcoma and noncancerous bone tissues. Then, immunohistochemistry was performed to analyze the association of SOX9 expression in 166 osteosarcoma tissues with clinicopathological factors or survival of patients.
SOX9 expression at mRNA and protein levels were both significantly higher in osteosarcoma tissues than those in corresponding noncancerous bone tissues (both P < 0.001). Immunohistochemical staining indicated that SOX9 localized to the nucleus and high SOX9 expression was observed in 120 of 166 (72.3%) osteosarcoma specimens. In addition, high SOX9 expression was more frequently occurred in osteosarcoma tissues with advanced clinical stage (P = 0.02), positive distant metastasis (P = 0.008) and poor response to chemotherapy (P = 0.02). Osteosarcoma patients with high SOX9 expression had shorter overall survival and disease-free survival (both P < 0.001). Furthermore, the multivariate analysis confirmed that upregulation of SOX9 was an independent and significant prognostic factor to predict poor overall survival and disease-free survival (both P = 0.006).
Our data show for the first time that SOX9 is upregulated in aggressive osteosarcoma tissues indicating that SOX9 may participate in the osteosarcoma progression. More importantly, SOX9 status is a useful prognostic factor for predicting the prognosis of osteosarcoma, suggesting that SOX9 may contribute to the optimization of clinical treatments for osteosarcoma patients.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3829210  PMID: 24188461
Osteosarcoma; SOX9; Prognosis; Overall survival; Disease-free survival
10.  Association of Aggression and Non-Suicidal Self Injury: A School-Based Sample of Adolescents 
PLoS ONE  2013;8(10):e78149.
Non-suicidal self-injury (NSSI) in adolescent has drawn increasing attention because it is associated with subsequent depression, drug abuse, anxiety disorders, and suicide. In the present study, we aimed to estimate the prevalence of non-suicidal self-injury (NSSI) in a school-based sample of Chinese adolescents and to explore the association between aggression and NSSI.
This study was part of a nationwide study on aggression among adolescents in urban areas of China. A sample of 2907 school students including 1436 boys and 1471 girls were randomly selected in Guangdong Province, with their age ranging from 10 to 18 years old. NSSI, aggression, emotional management and other factors were measured by self-administrated questionnaire. Multinomial logistic regression was used to estimate the association between aggression and NSSI, after adjustment for participants’ emotional management, and other potential confounding variables.
The one year self-reported prevalence of NSSI was 33.6%. Of them, 21.7% engaged in ‘minor NSSI’, 11.9% in ‘moderate/severe NSSI’. 96.9% of self-injuries engaged in one to five different types of NSSI in the past year. Hostility, verbal and indirect aggression was significantly associated with self-reported NSSI after adjusting for other potential factors both in ‘minor NSSI’ and ‘moderate/severe NSSI’. Hostility, verbal and indirect aggression was significantly associated with greater risk of ‘minor NSSI’ and ‘moderate/severe NSSI’ in those who had poor emotional management ability.
These findings highlight a high prevalence of NSSI and indicate the importance of hostility, verbal and indirect aggression as potentially risk factor for NSSI among Chinese adolescents.
PMCID: PMC3813494  PMID: 24205132
11.  Antagonism of CD11b with Neutrophil Inhibitory Factor (NIF) Inhibits Vascular Lesions in Diabetic Retinopathy 
PLoS ONE  2013;8(10):e78405.
Leukocytes and proteins that govern leukocyte adhesion to endothelial cells play a causal role in retinal abnormalities characteristic of the early stages of diabetic retinopathy, including diabetes-induced degeneration of retinal capillaries. Leukocyte integrin αmβ2 (CD11b/CD18, MAC1), a protein mediating adhesion, has been shown to mediate damage to endothelial cells by activated leukocytes in vitro. We hypothesized that Neutrophil Inhibitory Factor (NIF), a selective antagonist of integrin αmβ2, would inhibit the diabetes-induced degeneration of retinal capillaries by inhibiting the excessive interaction between leukocytes and retinal endothelial cells in diabetes. Wild type animals and transgenic animals expressing NIF were made diabetic with streptozotocin and assessed for diabetes-induced retinal vascular abnormalities and leukocyte activation. To assess if the leukocyte blocking therapy compromised the immune system, animals were challenged with bacteria. Retinal superoxide production, leukostasis and leukocyte superoxide production were increased in wild type mice diabetic for 10 weeks, as was the ability of leukocytes isolated from diabetic animals to kill retinal endothelial cells in vitro. Retinal capillary degeneration was significantly increased in wild type mice diabetic 40 weeks. In contrast, mice expressing NIF did not develop any of these abnormalities, with the exception that non-diabetic and diabetic mice expressing NIF generated greater amounts of superoxide than did similar mice not expressing NIF. Importantly, NIF did not significantly impair the ability of mice to clear an opportunistic bacterial challenge, suggesting that NIF did not compromise immune surveillance. We conclude that antagonism of CD11b (integrin αmβ2) by NIF is sufficient to inhibit early stages of diabetic retinopathy, while not compromising the basic immune response.
PMCID: PMC3804483  PMID: 24205223
12.  Antisense oligonucleotide suppression of human IGF-1R inhibits the growth and survival of in vitro cultured epithelial ovarian cancer cells 
Preclinical evaluation of the anti-neoplastic activity of antisense oligonucleotide (AS) suppression of human insulin-like growth factor I receptor (IGF-IR) in human epithelial ovarian cancer (EOC).
Ovarian cancer cells from 36 patients with EOC were investigated under serum-free tissue culture conditions. IGF-I production was evaluated by standard ELISA. IGF-IR and phosphorylated IRS-1, AKT, and MAP kinase expression and protein levels were evaluated by immunohistochemistry and Western blotting. Cancer cell growth and proliferation assays were performed in triplicates using MTT assay. Apoptosis was evaluated by TUNNEL assay.
All ovarian cancer tissue samples tested produced IGF-I and expressed IGF-IR, supporting the existence of an autocrine loop. Treatment of primary ovarian cancer cell lines with an IGF-1R AS inhibited growth and proliferation and decreased clonogenicity in soft agar assay. AS treatment was demonstrated to inhibit the expression of IGF-1R and decrease the concentration of phosphorylated IRS-1, AKT, and MAP kinase signaling protein downstream of the IGF-IR. We also observed that the IGF-1R AS sensitized cancer cell lines to cisplatin in vitro through the PI3K pathway.
IGF-IR enhances the proliferation and tumorigenicity of human ovarian cancer cells and inhibition of IGF-IR by AS oligonucleotide treatment potentiates the activity of cisplatin in vitro. Therefore, IGF-1R is a potential molecular target in ovarian cancer.
PMCID: PMC3851551  PMID: 24103397
Antisense; IGF-1R; Epithelial ovarian cancer
13.  Valproic acid-associated low fibrinogen and delayed intracranial hemorrhage: case report and mini literature review 
A 41-year-old male had suffered from gradual hearing loss in his right ear for 2 years. Head computed tomography and magnetic resonance imaging scans showed a neoplasm in the cerebellopontine angle region, which was confirmed by the diagnosis of acoustic neurilemmoma by pathological findings after surgery. Following surgery, he routinely received valproic acid (VPA) to prevent seizures. However, the patient presented with hypofibrinogenemia and cerebral hemorrhage after taking VPA for 12 days. The hypofibrinogenemia recurred when VPA was re-administered. After withdrawal of VPA, his fibrinogen concentration rose to normal within several days. As far as we are aware, this is the first case of cerebral hemorrhage due to VPA to have been reported. Herein, as well as reporting on this case, a mini review of the relevant literature is also presented.
PMCID: PMC3746782  PMID: 23976844
side effect; hypofibrinogenemia; cerebral hemorrhage; cerebellopontine angle; neoplasm
14.  β2-Adrenergic Receptor Knockout Mice Exhibit A Diabetic Retinopathy Phenotype 
PLoS ONE  2013;8(7):e70555.
There is considerable evidence from our lab and others for a functional link between β-adrenergic receptor and insulin receptor signaling pathways in retina. Furthermore, we hypothesize that this link may contribute to lesions similar to diabetic retinopathy in that the loss of adrenergic input observed in diabetic retinopathy may disrupt normal anti-apoptotic insulin signaling, leading to retinal cell death. Our studies included assessment of neural retina function (ERG), vascular degeneration, and Müller glial cells (which express only β1 and β2-adrenergic receptor subtypes). In the current study, we produced β2-adrenergic receptor knockout mice to examine this deletion on retinal neurons and vasculature, and to identify specific pathways through which β2-adrenergic receptor modulates insulin signaling. As predicted from our hypothesis, β2-adrenergic receptor knockout mice display certain features similar to diabetic retinopathy. In addition, loss of β2-adrenergic input resulted in an increase in TNFα, a key inhibitor of insulin receptor signaling. Increased TNFα may be associated with insulin-dependent production of the anti-apoptotic factor, Akt. Since the effects occurred in vivo under normal glucose conditions, we postulate that aspects of the diabetic retinopathy phenotype might be triggered by loss of β2-adrenergic receptor signaling.
PMCID: PMC3722144  PMID: 23894672
15.  MyD88-Dependent Pathways in Leukocytes Affect the Retina in Diabetes 
PLoS ONE  2013;8(7):e68871.
Previous studies by us and other have provided evidence that leukocytes play a critical role in the development of diabetic retinopathy, suggesting a possible role of the innate immune system in development of the retinopathy. Since MyD88 is a convergence point for signaling pathways of the innate immune system (including Toll-Like Receptors (TLRs) and interleukin-1ß (IL-1ß)), the purpose of this study was to assess the role of MyD88 and its dependent pathways on abnormalities that develop in retina and white blood cells related to diabetic retinopathy.
C57BL/6J mice were made diabetic with streptozotocin. Chimeric mice were generated in which MyD88-dependent pathways were deleted from bone marrow-derived only. Mice were sacrificed at 2 mos of diabetes for assessment of, leukostasis, albumin accumulation in neural retina, leukocyte-mediated killing of retinal endothelial cells, and cytokine/chemokine generation by retinas of diabetic mice in response to TLR agonists,
IL-6 and CXCL1 were generated in retinas from diabetic (but not nondiabetic mice) following incubation with Pam3CysK/TLR2, but incubation with other TLR ligands or IL-1ß did not induce cytokine production in retinas from nondiabetic or diabetic mice. Diabetes-induced abnormalities (leukostasis, ICAM-1 expression on the luminal surface of the vascular endothelium, retinal superoxide generation) were significantly inhibited by removing either MyD88 or the signaling pathways regulated by it (TLRs 2 and 4, and IL-1ß) from bone marrow-derived cells only. Leukocyte-mediated killing of endothelial cells tended to be decreased in the marrow-derived cells lacking TLR2/4, but the killing was significantly exacerbated if the marrow cells lacked MyD88 or the receptor for IL-1ß (IL-1ßr).
MyD88-dependent pathways play an important role in the development of diabetes-induced inflammation in the retina, and inhibition of MyD88 might be a novel target to inhibit early abnormalities of diabetic retinopathy and other complications of diabetes.
PMCID: PMC3708907  PMID: 23874797
16.  MicroRNA-145 downregulation associates with advanced tumor progression and poor prognosis in patients suffering osteosarcoma 
OncoTargets and therapy  2013;6:833-838.
Microribonucleic acid (miRNA)-145 (miR-145) has been identified as a tumor suppressor in several types of human cancers. Especially, miR-145 expression has been found to be significantly decreased in osteosarcoma tissues, and enforced expression of this miRNA could inhibit invasion and angiopoiesis of osteosarcoma cells. However, its clinical significance in osteosarcoma is still unclear. Therefore, the aim of this study was to analyze the association of miR-145 expression with clinicopathologic features and prognosis in patients suffering osteosarcoma.
miR-145 expression was detected by quantitative real-time reverse transcriptase polymerase chain reaction analysis using 166 pairs of osteosarcoma and noncancerous bone tissues. Then, the associations of miR-145 expression with clinicopathological factors or survival of patients suffering osteosarcoma were determined.
The expression levels of miR-145 in osteosarcoma tissues were significantly lower than those in corresponding noncancerous bone tissues (P < 0.0001). In addition, miR-145 downregulation more frequently occurred in osteosarcoma specimens with advanced clinical stage (P = 0.003) and positive distant metastasis (P = 0.008). Moreover, the univariate analysis demonstrated that osteosarcoma patients with low miR-145 expression had poorer overall (P = 0.003) and disease-free survival (P < 0.001). Furthermore, the multivariate analysis identified low miR-145 expression as an independent prognostic factor for both overall (P = 0.01) and disease-free survival (P = 0.008).
For the first time, the current data offer convincing evidence that the down-regulation of miR-145 may be associated with tumor aggressiveness and tumor metastasis of osteosarcoma, and that this miRNA may be an independent prognostic marker for osteosarcoma patients.
PMCID: PMC3712084  PMID: 23874105
osteosarcoma; miR-145; prognosis; overall survival; disease-free survival
17.  Abdominal CT With Model-Based Iterative Reconstruction (MBIR): Initial Results of a Prospective Trial Comparing Ultralow-Dose With Standard-Dose Imaging 
AJR. American journal of roentgenology  2012;199(6):1266-1274.
The purpose of this study was to report preliminary results of an ongoing prospective trial of ultralow-dose abdominal MDCT.
Imaging with standard-dose contrast-enhanced (n = 21) and unenhanced (n = 24) clinical abdominal MDCT protocols was immediately followed by ultralow-dose imaging of a matched series of 45 consecutively registered adults (mean age, 57.9 years; mean body mass index, 28.5). The ultralow-dose images were reconstructed with filtered back projection (FBP), adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR). Standard-dose series were reconstructed with FBP (reference standard). Image noise was measured at multiple predefined sites. Two blinded abdominal radiologists interpreted randomly presented ultralow-dose images for multilevel subjective image quality (5-point scale) and depiction of organ-based focal lesions.
Mean dose reduction relative to the standard series was 74% (median, 78%; range, 57–88%; mean effective dose, 1.90 mSv). Mean multiorgan image noise for low-dose MBIR was 14.7 ± 2.6 HU, significantly lower than standard-dose FBP (28.9 ± 9.9 HU), low-dose FBP (59.2 ± 23.3 HU), and ASIR (45.6 ± 14.1 HU) (p < 0.001). The mean subjective image quality score for low-dose MBIR (3.0 ± 0.5) was significantly higher than for low-dose FBP (1.6 ± 0.7) and ASIR (1.8 ± 0.7) (p < 0.001). Readers identified 213 focal noncalcific lesions with standard-dose FBP. Pooled lesion detection was higher for low-dose MBIR (79.3% [169/213]) compared with low-dose FBP (66.2% [141/213]) and ASIR (62.0% [132/213]) (p < 0.05).
MBIR shows great potential for substantially reducing radiation doses at routine abdominal CT. Both FBP and ASIR are limited in this regard owing to reduced image quality and diagnostic capability. Further investigation is needed to determine the optimal dose level for MBIR that maintains adequate diagnostic performance. In general, objective and subjective image quality measurements do not necessarily correlate with diagnostic performance at ultralow-dose CT.
PMCID: PMC3689212  PMID: 23169718
adaptive statistical iterative reconstruction (ASIR); CT; dose reduction; low-dose CT radiation; model-based iterative reconstruction (MBIR)
18.  Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate 
PLoS ONE  2013;8(6):e62489.
This study investigated the effects of pregnane X receptor (PXR/NR1I2) and CYP2B6 genetic variants on sodium ferulate (SF)-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered with and without SF pretreatment for 14 days in 33 healthy subjects. The area under the time-concentration curve (AUC) ratio of AUC_hyd (AUC(0-∞) of hydroxybupropion)/AUC_bup (AUC(0-∞) of bupropion) represents the CYP2B6 hydroxylation activity, which was significantly lower in CYP2B6*6 carriers (NR1I2 TGT noncarriers or carriers) than in noncarriers in both the basal and SF-induced states (p-value<0.05). AUC ratio and AUC_hyd of NR1I2 -24113AA variant were markedly lower than GA and GG genotypes (7.5±2.1 versus 14.5±3.3 and 20.6±1.1, and 8873±1431 versus 14,504±2218 and 17,586±1046) in the induced states. However, -24020(-)/(-) variant didn't show significant difference in the induction of CYP2B6 hydroxylation activity by SF compared with other -24020[GAGAAG]/(-) genotypes. NR1I2 TGT haplotype (-25385T+g.7635G+g.8055T) carriers exhibited a significantly decreased AUC ratio, compared with TGT noncarriers, in the basal states (7.6±1.0 versus 9.7±1.0), while this result wasn't observed in CYP2B6*6 noncarriers. Moreover, individuals with complete mutation-type [CYP2B6*6/*6+NR1I2 TGT+ -24113AA+ -24020 (-)/(-)] showed even lower percent difference of AUC ratio (8.7±1.2 versus 39.5±8.2) than those with complete wild-type. In conclusion, it is suggested that NR1I2 variants decrease the bupropion hydroxylation induced by SF treatment, particularly in CYP2B6*6 carriers.
Trial Registration ChiCTR-TRC-11001285
PMCID: PMC3686783  PMID: 23840296
19.  Surgical resection of large and giant petroclival meningiomas via a modified anterior transpetrous approach 
Neurosurgical Review  2013;36:587-594.
The authors describe a modified anterior transpetrous approach (ATPA) for the surgical resection of 21 cases of petroclival meningiomas (PCMs). Briefly, a curved periauricular skin incision was used. The cerebellar tentorium and the dura on the petrous apex were coagulated and incised to expose the petrous apex bone fully. The drilling of the petrous apex bone was performed subdurally and began internally from the trigeminal impression, not exceeding 1.5 cm laterally, not exceeding 6 mm from the posterior edge of the petrous ridge, and not exceeding 8 mm in depth from the surface of the petrous bone. The tumors were removed totally in 12 (57.1 %) cases, subtotally in 8 (38.1 %) cases, and partially in 1 (4.8 %) case. The transient neurological deficit includes mild oculomotor nerve palsy in three cases, abducens nerve palsy in six cases, language disorder in three cases, and mild hemiplegia in two cases. Facial numbness became worse postoperatively in six patients, and only two patients improved at 6 months after surgery. No death occurred in this series. The modified ATPA is an efficient treatment alterative for large or giant PCMs located at the medial and superior internal acoustic meatus with relatively low risk of complications.
PMCID: PMC3771372  PMID: 23775013
Petroclival; Meningioma; Surgical treatment; Anterior transpetrous approach
20.  Understanding the Complexity of Temperature Dynamics in Xinjiang, China, from Multitemporal Scale and Spatial Perspectives 
The Scientific World Journal  2013;2013:259248.
Based on the observed data from 51 meteorological stations during the period from 1958 to 2012 in Xinjiang, China, we investigated the complexity of temperature dynamics from the temporal and spatial perspectives by using a comprehensive approach including the correlation dimension (CD), classical statistics, and geostatistics. The main conclusions are as follows (1) The integer CD values indicate that the temperature dynamics are a complex and chaotic system, which is sensitive to the initial conditions. (2) The complexity of temperature dynamics decreases along with the increase of temporal scale. To describe the temperature dynamics, at least 3 independent variables are needed at daily scale, whereas at least 2 independent variables are needed at monthly, seasonal, and annual scales. (3) The spatial patterns of CD values at different temporal scales indicate that the complex temperature dynamics are derived from the complex landform.
PMCID: PMC3697761  PMID: 23843732
21.  Accessing of recombinant human monoclonal antibodies from patient libraries by eukaryotic ribosome display 
Human antibodies  2012;21(0):1-11.
What are effective antibodies and when do they arise to prevent or delay disease onset during a natural infection or in the course of vaccination? To address these questions at a molecular level requires longitudinal studies, capturing and analyzing the antibody repertoire at regular intervals following exposure or sero-conversion. Such studies require a method that allows the rapid generation and evaluation of monoclonal antibodies from relatively small volumes of blood. Here we describe an approach for rapidly generating human monoclonal antibodies in vitro by directly screening single-chain antibody repertories derived from donor peripheral blood mononuclear cells using ribosome display. Two single-chain antibody libraries were constructed using RNA extracted from peripheral blood mononuclear cells of two HIV-1 long-term non-progressor donors (K530 and M325). Both libraries were subjected to a single round of in vitro ribosome display for enrichment of human monoclonal antibodies against recombinant gp120K530, derived from virus isolated from donor K530. This study has validated a novel, in vitro method for the rapid generation of human monoclonal antibodies. An antibody library could be constructed from as little as 3 μg of total RNA, the equivalent of 3–5 mL of human blood.
PMCID: PMC3677101  PMID: 22885956
HIV-1; antibody library; ribosome display; enzyme linked immunosorbent assay (ELISA)
22.  4-HNE Increases Intracellular ADMA Levels in Cultured HUVECs: Evidence for miR-21-Dependent Mechanisms 
PLoS ONE  2013;8(5):e64148.
To investigate whether 4-hydroxynonenal (4-HNE) regulates asymmetric dimethylarginine (ADMA) metabolism through pathway independent of direct adduct formation with ADMA metabolizing enzyme and the involvement of microRNA (miRNA) miR-21 in human umbilical venous endothelial cells (HUVECs).
Cultured HUVECs were treated with 4-HNE (at concentrations of 1, 5, and 10 µM, respectively) or 1‰ DMSO (vehicle control) for 24 h. MiR-21 inhibitor (final concentration of 100 nM) was transfected at 1 h before 4-HNE treatment. HUVECs were also transfected with miR-21 (at concentrations of 50 nM and 100 nM) and cultured for 12, 24, and 48 h, respectively. DDAH mRNA and miR-21 expression in the HUVECs were determined by semi-quantitative real time PCR. DDAH1 and DDAH2 protein expression were analyzed by Western blot. ADMA in the cell medium and cell lysates were analyzed by ELISA. ADMA metabolizing activity of the cell lysates was also determined.
MiR-21 decreased DDAH1 and DDAH2 expression and ADMA metabolic activity significantly, while increased intracellular ADMA accumulation significantly in HUVECs. 10 µM 4-HNE treatment for 24 h increased the expression of miR-21 and intracellular ADMA concentration, decreased the expression of DDAH1/2 mRNA and protein, decreased ADMA metabolizing activity of the cell lysates significantly. MiR-21 inhibitor reversed the inhibitory effects of 4-HNE on DDAH1 expression completely, and partially reversed the changes in ADMA metabolizing activity and intracellular ADMA accumulation challenged by 10 µM 4-HNE.
4-HNE down-regulates DDAH1 expression and increases intracellular ADMA accumulation in HUVECs through a miR-21-dependent mechanism.
PMCID: PMC3661487  PMID: 23717555
23.  The rs1142345 in TPMT Affects the Therapeutic Effect of Traditional Hypoglycemic Herbs in Prediabetes 
Therapeutic interventions in prediabetes are important in the primary prevention of type 2 diabetes (T2D) and its chronic complications. However, little is known about the pharmacogenetic effect of traditional herbs on prediabetes treatment. A total of 194 impaired glucose tolerance (IGT) subjects were treated with traditional hypoglycemic herbs (Tianqi Jiangtang) for 12 months in this study. DNA samples were genotyped for 184 mutations in 34 genes involved in drug metabolism or transportation. Multinomial logistic regression analysis indicated that rs1142345 (A > G) in the thiopurine S-methyltransferase (TPMT) gene was significantly associated with the hypoglycemic effect of the drug (P = 0.001, FDR P = 0.043). The “G” allele frequencies of rs1142345 in the healthy (subjects reverted from IGT to normal glucose tolerance), maintenance (subjects still had IGT), and deterioration (subjects progressed from IGT to T2D) groups were 0.094, 0.214, and 0.542, respectively. Binary logistic regression analysis indicated that rs1142345 was also significantly associated with the hypoglycemic effect of the drug between the healthy and maintenance groups (P = 0.027, OR = 4.828) and between the healthy and deterioration groups (P = 0.001, OR = 7.811). Therefore, rs1142345 was associated with the clinical effect of traditional hypoglycemic herbs. Results also suggested that TPMT was probably involved in the pharmacological mechanisms of T2D.
PMCID: PMC3657408  PMID: 23737827
24.  Deletion of Aldose Reductase from Mice Inhibits Diabetes-Induced Retinal Capillary Degeneration and Superoxide Generation 
PLoS ONE  2013;8(4):e62081.
Pharmacologic inhibition of aldose reductase (AR) previously has been studied with respect to diabetic retinopathy with mixed results. Since drugs can have off-target effects, we studied the effects of AR deletion on the development and molecular abnormalities that contribute to diabetic retinopathy. Since recent data suggests an important role for leukocytes in the development of the retinopathy, we determined also if AR in leukocytes contributes to leukocyte-mediated death of retinal endothelial cells in diabetes.
Wild-type (WT; C57BL/6J) and AR deficient (AR−/−) mice were made diabetic with streptozotocin. Mice were sacrificed at 2 and 10 months of diabetes to evaluate retinal vascular histopathology, to quantify retinal superoxide production and biochemical and physiological abnormalities in the retina, and to assess the number of retinal endothelial cells killed by blood leukocytes in a co-culture system.
Diabetes in WT mice developed the expected degeneration of retinal capillaries, and increased generation of superoxide by the retina. Leukocytes from diabetic WT mice also killed more retinal endothelial cells than did leukocytes from nondiabetic animals (p<0.0001). Deletion of AR largely (P<0.05) inhibited the diabetes-induced degeneration of retinal capillaries, as well as the increase in superoxide production by retina. AR-deficiency significantly inhibited the diabetes-induced increase in expression of inducible nitric oxide synthase (iNOS) in retina, but had no significant effect on expression of intercellular adhesion molecule-1 (ICAM-1), phosphorylated p38 MAPK, or killing of retinal endothelial cells by leukocytes.
AR contributes to the degeneration of retinal capillaries in diabetic mice. Deletion of the enzyme inhibits the diabetes-induced increase in expression of iNOS and of superoxide production, but does not correct a variety of other pro-inflammatory abnormalities associated with the development of diabetic retinopathy.
PMCID: PMC3628579  PMID: 23614016
25.  Carpal tunnel expansion by palmarly directed forces to the transverse carpal ligament 
This study investigated the expansion of the carpal tunnel resulting from the application of palmarly directed forces to the transverse carpal ligament (TCL) from inside the carpal tunnel. Ten fresh-frozen cadaveric hands were dissected to evacuate the carpal tunnel and thus to expose the TCL. A custom lever device was built to apply forces, ranging from 10 to 200 N, to the TCL. Without force application, the carpal tunnel area was 148.4 ± 36.8 mm2. The force application caused the TCL to form arches with an increase in cross-sectional areas of 33.3 ± 5.6 mm2 at 10 N and 48.7 ± 11.4 mm2 at 200 N, representing respective increases of 22.4% and 32.8% relative to the initial carpal tunnel area. The TCL length remained constant under the applied forces. It was found that the TCL arch formation was due to the narrowing of the arch width, which resulted from the migration of the bony insertion sites of the TCL. A geometrical model of the carpal tunnel was then developed to elucidate the relationships among the arch width, TCL length, arch height, and arch area. The model illustrated the effectiveness of carpal tunnel expansion by TCL elongation or arch width narrowing.
PMCID: PMC3612018  PMID: 19604023
Transverse carpal ligament; Carpal tunnel; Force; Deformation

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