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1.  Peripheral deep anterior lamellar keratoplasty using a cryopreserved donor cornea for Terrien’s marginal degeneration*  
Objective: To evaluate the clinical efficacy of peripheral deep anterior lamellar keratoplasty (DALK) using a cryopreserved donor cornea for Terrien’s marginal degeneration (TMD). Methods: Thirty-one eyes of 27 patients with TMD underwent peripheral DALK using cryopreserved donor corneas. According to the distance between the inner edge of the lesion and the limbus, a ring-shaped or D-shaped DALK was performed. All grafts were stored at −20 °C. Cryopreserved corneoscleral rims were prepared for ring-shaped grafts and cryopreserved whole eyeballs were prepared for D-shaped grafts. The general conditions, intraoperative performance, postoperative corneal reconstruction, astigmatism, best corrected visual acuity (BCVA), and various complications were analyzed. Results: Ring-shaped DALK was performed in 28 eyes and D-shaped DALK was performed in 3 eyes. Postoperative follow-up time was (28.4±24.8) months. There was evidence of inflammation before surgery in 12 eyes (38.7%) and intraoperative perforation occurred in 13 eyes (41.9%). The corneal structures of all eyes were reconstructed. Postoperative astigmatism and BCVA showed improvement (both P=0.00) except for cases that underwent D-shaped DALK. Ten eyes (32.2%) developed transient ocular hypertension and one eye (3.2%) developed secondary glaucoma. No primary disease recurrence or corneal allograft rejection was observed. Conclusions: Peripheral DALK for TMD using cryopreserved donor tissue is an effective technique that eliminates rejection and extends the use of donor eyes. Inflammatory history or intraoperative perforation has no adverse effect on graft recovery. However, D-shaped DALK did not achieve good visual outcomes.
doi:10.1631/jzus.B1400083
PMCID: PMC4265560  PMID: 25471835
Terrien’s marginal degeneration (TMD); Deep anterior lamellar keratoplasty (DALK); Cryopreservation
2.  A Microdeletion of Chromosome 9q33.3 Encompasses the Entire LMX1B Gene in a Chinese Family with Nail Patella Syndrome 
Nail patella syndrome (NPS) is an autosomal dominant disorder characterized by nail malformations, patellar apoplasia, or patellar hypoplasia. Mutations within the LMX1B gene are found in 85% of families with NPS; thus, this gene has been characterized as the causative gene of NPS. In this study, we identified a heterozygous microdeletion of the entire LMX1B gene using multiplex ligation-dependent probe amplification (MLPA) in a Chinese family with NPS. The determination of the deletion breakpoints by Illumina genome-wide DNA analysis beadchip showed that the deletion was located in chromosome 9q33.3 and spanned about 0.66 Mb in size. This heterozygous deletion provides strong evidence for haploinsufficiency as the pathogenic mechanism of NPS.
doi:10.3390/ijms151120158
PMCID: PMC4264161  PMID: 25380522
gene deletion; LMX1B; MLPA; nail patella syndrome
3.  SHIV Antigen Immunization Alters Patterns of Immune Responses to SHIV/Malaria Coinfection and Protects against Life-Threatening SHIV-Related Malaria 
The Journal of Infectious Diseases  2013;208(2):260-270.
Whether vaccination against a virus can protect against more virulent coinfection with the virus and additional pathogen(s) remains poorly characterized. Overlapping endemicity of human immunodeficiency virus (HIV) and malaria suggests that HIV/malaria coinfection frequently complicates acute and chronic HIV infection. Here we showed that vaccination of macaques with recombinant Listeria ΔactA prfA* expressing simian/human immunodeficiency virus (SHIV) gag and env elicited Gag- and Env-specific T-cell responses, and protected against life-threatening SHIV-related malaria after SHIV/Plasmodium fragile coinfection. SHIV antigen immunization reduced peak viremia, resisted SHIV/malaria-induced lymphoid destruction, and blunted coinfection-accelerated decline of CD4+ T-cell counts after SHIV/malaria coinfection. SHIV antigen immunization also weakened coinfection-driven overreactive proinflammatory interferon-γ (IFNγ) responses and led to developing T helper cell 17/22 (Th17/Th22) responses after SHIV/malaria coinfection. The findings suggest that vaccination against AIDS virus can alter patterns of immune responses to the SHIV/malaria coinfection and protect against life-threatening SHIV-related malaria.
doi:10.1093/infdis/jit151
PMCID: PMC3685226  PMID: 23568175
co-infection; HIV/AIDS; immunology; malaria; T cell; vaccination
4.  Pharmacokinetics and tissue distribution study of tanshinone IIA after oral administration of Bushen Huoxue Qubi granules to rats with blood stasis syndrome 
Pharmacognosy Magazine  2014;10(39):285-291.
Background:
Bushen Huoxue Qubi (BHQ) granules, a traditional Chinese medicine preparation, has been clinically used for the treatment of the blood stasis syndrome.
Objective:
The main objective is to investigate whether the diseased condition would alter the pharmacokinetics and tissue distribution of tanshinone IIA in BHQ, which was given orally to the acute blood stasis rats.
Materials and Methods:
The main bioactive constituent in BHQ, tanshinone IIA, was measured in the plasma and tissues of animals by the high performance liquid chromatography with ultraviolet detection. The analysis was successfully performed on an Agilent TC-C18 column (250 × 4.6 mm I.D., 5 μm) protected with a  Octadecylsilane (ODS) guard column (10 × 4.6 mm I.D., 5 μm). The mobile phase was aqueous solution (A) (containing 0.40% aqueous acetic acid) and acetonitrile (B). The conditions of the solvent gradient elution were 35-40% (B) in 0-15 min, 40-42% (B) in 15-18 min and 42-70% (B) in 18-30 min at a flow rate of 1.0 mL/min. Detection was conducted with wavelength of 270 nm at 30°C.
Results:
Good linearity relationships were found (r2> 0.9955) over the investigated concentration range for bio-samples. Blood stasis was associated with significantly higher area under the concentration-time curve (AUC), the maximum plasma concentration (Cmax) and biological half-life (t1/2), lower total body clearance (CL) and apparent volume of distribution (Vd) of tanshinone IIA in plasma and higher AUC0-t of tanshinone IIA in the analyzed tissues of rats treated with BHQ.
Conclusion:
Blood stasis could alter pharmacokinetics and tissue distribution of tanshinone IIA in BHQ.
doi:10.4103/0973-1296.137369
PMCID: PMC4159922  PMID: 25210316
Blood stasis; Bushen Huoxue Qubi granules; high performance liquid chromatography; pharmacokinetics; tanshinone IIA; tissue distribution
5.  A RG-II Type Polysaccharide Purified from Aconitum coreanum Alleviates Lipopolysaccharide-Induced Inflammation by Inhibiting the NF-κB Signal Pathway 
PLoS ONE  2014;9(6):e99697.
Korean mondshood root polysaccharides (KMPS) isolated from the root of Aconitum coreanum (Lévl.) Rapaics have shown anti-inflammatory activity, which is strongly influenced by their chemical structures and chain conformations. However, the mechanisms of the anti-inflammatory effect by these polysaccharides have yet to be elucidated. A RG-II polysaccharide (KMPS-2E, Mw 84.8 kDa) was isolated from KMPS and its chemical structure was characterized by FT-IR and NMR spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The backbone of KMPS-2E consisted of units of [→6) -β-D-Galp (1→3)-β-L-Rhap-(1→4)-β-D-GalpA-(1→3)-β-D-Galp-(1→] with the side chain →5)-β-D-Arap (1→3, 5)-β-D-Arap (1→ attached to the backbone through O-4 of (1→3,4)-L-Rhap. T-β-D-Galp is attached to the backbone through O-6 of (1→3,6)-β-D-Galp residues and T-β-D-Ara is connected to the end group of each chain. The anti-inflammatory effects of KMPS-2E and the underlying mechanisms using lipopolysaccharide (LPS) - stimulated RAW 264.7 macrophages and carrageenan-induced hind paw edema were investigated. KMPS-2E (50, 100 and 200 µg/mL) inhibits iNOS, TLR4, phospho-NF-κB–p65 expression, phosphor-IKK, phosphor-IκB-α expression as well as the degradation of IκB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS and IL-6) mediated by the NF-κB signal pathways in macrophages. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophorectic mobility shift assay (EMSA) in a dose-dependent manner and it reduced NF-κB DNA binding affinity by 62.1% at 200µg/mL. In rats, KMPS-2E (200 mg/kg) can significantly inhibit carrageenan-induced paw edema as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation.
doi:10.1371/journal.pone.0099697
PMCID: PMC4057409  PMID: 24927178
6.  SGK, renal function and Hypertension 
Journal of nephrology  2010;23(0 16):S124-S129.
The serum and glucocorticoid inducible-kinase-1 (SGK1) is expressed following cell stress and exposure to a variety of hormones including gluco- and mineralocorticoids. It is activated by insulin and growth factors via phosphatidylinositol-3-kinase and the 3-phosphoinositide dependent kinase PDK1. SGK1 enhances the activity of a variety of ion channels, such as ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and ClCKb, carriers, such as NHE3, NKCC2, NCC and SGLT1, as well as the Na+/K+-ATPase. SGK1 contributes to Na+ retention and K+ elimination of the kidney as well as mineralocorticoid stimulation of salt appetite. A certain SGK1 gene variant (combined polymorphisms in intron 6 [I6CC] and in exon 8 [E8CC/CT]) is associated with moderately enhanced blood pressure. The SGK1 gene variant has been shown to affect 3–5 % of Caucasians and some 10% of Africans. The gene variant sensitizes the carriers to the hypertensive effects of hyperinsulinemia. Moreover, the SGK1 gene variant is associated with increased body mass index, presumably a result of enhanced SGLT1 activity with accelerated intestinal glucose absorption. Obesity predisposes the carriers of the gene variant to development of type II diabetes. Moreover, SGK1 stimulates coagulation. Thus, SGK1 may participate in the pathogenesis of metabolic syndrome or syndrome X, a condition characterized by the coincidence of essential hypertension, procoagulant state, obesity, insulin resistance and hyperinsulinemia.
PMCID: PMC4026186  PMID: 21170869
blood pressure; obesity; fibrosis; inflammation; coagulation
7.  ‘Seeding’ with protease to optimize protein crystallization conditions in in situ proteolysis 
Addition of protease instead of seeds using a robot can be used to optimize the concentration of protease in in situ proteolysis experiments and has been successfully tested using two proteins.
In situ proteolysis is one of the most effective rescue strategies for protein crystallization, and optimization of the ratio between the protein and the protease is one of the key steps in the process. Seeding is a very powerful tool to optimize crystallization conditions and can be performed by most crystallization robots. Addition of protease instead of seed stock using a robot can be used to optimize the concentration of protease in in situ proteolysis experiments and has been successfully tested using two proteins.
doi:10.1107/S174430911201161X
PMCID: PMC3374523  PMID: 22691798
in situ proteolysis; optimization
8.  Poly(ADP-Ribose) Polymerase 1 Promotes Oxidative-Stress-Induced Liver Cell Death via Suppressing Farnesoid X Receptor α 
Molecular and Cellular Biology  2013;33(22):4492-4503.
Farnesoid X receptor α (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl)ate FXR. Poly(ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wild-type and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.
doi:10.1128/MCB.00160-13
PMCID: PMC3838191  PMID: 24043304
9.  Reduced interhemispheric functional connectivity of children with autism spectrum disorder: evidence from functional near infrared spectroscopy studies 
Biomedical Optics Express  2014;5(4):1262-1274.
Autism spectrum disorder (ASD) is a neuro-developmental disorder, which has been associated with atypical neural synchronization. In this study, functional near infrared spectroscopy (fNIRS) was used to study the differences in functional connectivity in bilateral inferior frontal cortices (IFC) and bilateral temporal cortices (TC) between ASD and typically developing (TD) children between 8 and 11 years of age. As the first report of fNIRS study on the resting state functional connectivity (RSFC) in children with ASD, ten children with ASD and ten TD children were recruited in this study for 8 minute resting state measurement. Compared to TD children, children with ASD showed reduced interhemispheric connectivity in TC. Children with ASD also showed significantly lower local connectivity in bilateral temporal cortices. In contrast to TD children, children with ASD did not show typical patterns of symmetry in functional connectivity in temporal cortex. These results support the feasibility of using the fNIRS method to assess atypical functional connectivity of cortical responses of ASD and its potential application in diagnosis.
doi:10.1364/BOE.5.001262
PMCID: PMC3985986  PMID: 24761305
(170.2655) Functional monitoring and imaging; (170.5380) Physiology; (170.3880) Medical and biological imaging
10.  RNA Sequencing Reveals Upregulation of RUNX1-RUNX1T1 Gene Signatures in Clear Cell Renal Cell Carcinoma 
BioMed Research International  2014;2014:450621.
In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.
doi:10.1155/2014/450621
PMCID: PMC3982423  PMID: 24783204
11.  (Z)-N-[(Z)-3-(2,5-Di­methyl­phenyl­imino)­butan-2-yl­idene]-2,5-di­methyl­aniline 
The asymmetric unit of the title compound, C20H24N2, contains one half-mol­ecule, with the single C—C bond of the 1,4-di­aza­butadiene fragment situated on a centre of symmetry. The benzene rings are inclined to the 1,4-di­aza­butadiene mean plane by 59.5 (1)°.
doi:10.1107/S1600536814001020
PMCID: PMC3998329  PMID: 24764890
12.  Identification of Poly(ADP-Ribose) Polymerase-1 as a Cell Cycle Regulator through Modulating Sp1 Mediated Transcription in Human Hepatoma Cells 
PLoS ONE  2013;8(12):e82872.
The transcription factor Sp1 is implicated in the activation of G0/G1 phase genes. Modulation of Sp1 transcription activities may affect G1-S checkpoint, resulting in changes in cell proliferation. In this study, our results demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP-1) promoted cell proliferation by inhibiting Sp1 signaling pathway. Cell proliferation and cell cycle assays demonstrated that PARP inhibitors or PARP-1 siRNA treatment significantly inhibited proliferation of hepatoma cells and induced G0/G1 cell cycle arrest in hepatoma cells, while overexpression of PARP-1 or PARP-1 activator treatment promoted cell cycle progression. Simultaneously, inhibition of PARP-1 enhanced the expression of Sp1-mediated checkpoint proteins, such as p21 and p27. In this study, we also showed that Sp1 was poly(ADP-ribosyl)ated by PARP-1 in hepatoma cells. Poly(ADP-ribosyl)ation suppressed Sp1 mediated transcription through preventing Sp1 binding to the Sp1 response element present in the promoters of target genes. Taken together, these data indicated that PARP-1 inhibition attenuated the poly(ADP-ribosyl)ation of Sp1 and significantly increased the expression of Sp1 target genes, resulting in G0/G1 cell cycle arrest and the decreased proliferative ability of the hepatoma cells.
doi:10.1371/journal.pone.0082872
PMCID: PMC3868549  PMID: 24367566
13.  HER2 Status in Gastric and Gastroesophageal Junction Cancer Assessed by Local and Central Laboratories: Chinese Results of the HER-EAGLE Study 
PLoS ONE  2013;8(11):e80290.
Trastuzumab has been approved for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction cancers (GC and GJC) in combination with chemotherapy. The aim of this HER2 early/advanced gastric epidemiology (HER-EAGLE) study was to evaluate the frequency of HER2 over-expression and to evaluate agreement on HER2 status assessment in GC and GJC patients in local laboratories versus a central laboratory in China. Tumor samples from 734 GC or GJC patients who were enrolled at 11 different hospitals in China were examined. HER2 status was assessed by immunohistochemistry (IHC), and followed by dual-color silver-enhanced in Situ hybridization (DSISH) in IHC 2+ cases. Clinicopathologic characteristics were collected from all of the patients. HER2-positive tumors were identified in 12.0% (88/734) of the GC and GJC cases. There were significantly higher rates of HER2 positivity in patients with GJC (GJC: 18.1%, GC: 9.7%, P=0.002), and intestinal-type cancers using the Lauren classification (intestinal: 23.6%, diffuse/mixed: 4.3%, P<0.0001). No significant difference in HER2 positivity was identified between resection and biopsy samples, or between early and advanced disease stages. The agreement between local laboratories and the central laboratory on HER2 status scoring was good (kappa=0.86). The main reason of HER2 status discordance between local and the central laboratories was IHC result mis-interpretation in local laboratories. These results suggest that IHC followed by DSISH testing is an accurate and cost-effective procedure in China.
doi:10.1371/journal.pone.0080290
PMCID: PMC3828190  PMID: 24244671
14.  Variations in the Levels of Mulberroside A, Oxyresveratrol, and Resveratrol in Mulberries in Different Seasons and during Growth 
The Scientific World Journal  2013;2013:380692.
This study aimed to investigate the composition of three major stilbenes (mulberroside A, oxyresveratrol, and resveratrol) in different portions of mulberries collected in different seasons and their change molds during growth by high-performance liquid chromatography. Mulberroside A levels were the highest in the bark and roots of Morus atropurpurea Roxb, Morus alba Linn, and Morus latifolia Poir. Oxyresveratrol levels were the highest in roots and stem. Both of these high levels were in September. The amount of resveratrol was very low in all samples. In the stem, Morus latifolia Poir contained more mulberroside A than the other two mulberries. Mulberroside A was not detected in the leaves of the three mulberries. In Morus atropurpurea Roxb seedlings, the root tended to contain more of the three stilbenes than leaves. The temporal peaks of resveratrol were always ahead of those for oxyresveratrol. The levels of the stilbenes varied in different portions of the varieties of mulberries collected in different season and in the seedlings of Morus atropurpurea Roxb.
doi:10.1155/2013/380692
PMCID: PMC3760103  PMID: 24023529
15.  Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates 
PLoS Pathogens  2013;9(8):e1003501.
Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis.
Author Summary
Tuberculosis(TB), caused by Mycobacterium tuberculosis(Mtb), remains a leading cause of morbidity and mortality worldwide. While CD4+/CD8+ T cells are protective, role of γδ T cells in TB and other infections remains unknown in humans. Vγ2Vδ2 T cells exist only in primates, represent a dominant circulating γδ T-cell subpopulation, and recognize phosphoantigen from Mtb and some selected pathogens. Here, we determined whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection increased resistance to TB in macaques. Phosphoantigen plus IL-2 administration induced expansion and pulmonary accumulation of Vγ2Vδ2 T cells, significantly reduced Mtb counts and attenuated TB lesions in lung tissues. Expanded Vγ2Vδ2 T cells produced anti-TB cytokines IFNγ, perforin and granulysin, and co-produced perforin and granulysin in lung tissue. Perforin/granulysin-co-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin killed Mtb bacteria, and inhibited intracellular Mtb in presence of perforin. Furthermore, expansion of Vγ2Vδ2 T effectors enhanced pulmonary responses of peptide-specific CD4+/CD8+ T cells, which correlated with the ability of Vγ2Vδ2 T effector cells to produce IL-12. These results provide first evidence implicating a protective role of Vγ2Vδ2 T effector cells in TB, supporting a rationale to explore Vγ2Vδ2 T-cell-targeted treatment of drug-resistant TB or HIV-related TB.
doi:10.1371/journal.ppat.1003501
PMCID: PMC3744401  PMID: 23966854
16.  Abnormality in face scanning by children with autism spectrum disorder is limited to the eye region: Evidence from multi-method analyses of eye tracking data 
Journal of Vision  2013;13(10):5.
There has been considerable controversy regarding whether children with autism spectrum disorder (ASD) and typically developing children (TD) show different eye movement patterns when processing faces. We investigated ASD and age- and IQ-matched TD children's scanning of faces using a novel multi-method approach. We found that ASD children spent less time looking at the whole face generally. After controlling for this difference, ASD children's fixations of the other face parts, except for the eye region, and their scanning paths between face parts were comparable either to the age-matched or IQ-matched TD groups. In contrast, in the eye region, ASD children's scanning differed significantly from that of both TD groups: (a) ASD children fixated significantly less on the right eye (from the observer's view); (b) ASD children's fixations were more biased towards the left eye region; and (c) ASD children fixated below the left eye, whereas TD children fixated on the pupil region of the eye. Thus, ASD children do not have a general abnormality in face scanning. Rather, their abnormality is limited to the eye region, likely due to their strong tendency to avoid eye contact.
doi:10.1167/13.10.5
PMCID: PMC3739407  PMID: 23929830
autism spectrum disorder; face processing; face recognition; eye movements; eye tracking
17.  Multieffector-Functional Immune Responses of HMBPP-Specific Vγ2Vδ2 T Cells in Nonhuman Primates Inoculated with Listeria monocytogenes ΔactA prfA* 
Although Listeria monocytogenes can induce systemic infection causing spontaneous abortion, septicemia, and meningitis, studies have not been performed to investigate human anti-L. monocytogenes immune responses, including those of Ag-specific Vγ2Vδ2 T cells, a dominant human γδ T cell subset. L. monocytogenes is the only pathogen known to possess both the mevalonate and non-mevalonate isoprenoid biosynthesis pathways that produce metabolic phosphates or phosphoantigens activating human Vγ2Vδ2 T cells, making it interesting to explore in vivo anti-L. monocytogenes immune responses of Vγ2Vδ2 T cells. In this study, we demonstrated that subclinical systemic L. monocytogenes infection of rhesus macaques via parenteral inoculation or vaccination with an attenuated Listeria strain induced multieffector-functional immune responses of phosphoantigen-specific Vγ2Vδ2 T cells. Subclinical systemic infection and reinfection with attenuated L. monocytogenes uncovered the ability of Vγ2Vδ2 T cells to mount expansion and adaptive or recall-like expansion. Expanded Vγ2Vδ2 T cells could traffic to and accumulate in the pulmonary compartment and intestinal mucosa. Expanded Vγ2Vδ2 T cells could evolve into effector cells producing IFN-γ, TNF-α, IL-4, IL-17, or perforin after L. monocytogenes infection, and some effector Vγ2Vδ2 T cells could coproduce IL-17 and IFN-γ, IL-4 and IFN-γ, or TNF-α and perforin. Surprisingly, in vivo-expanded Vγ2Vδ2 T effector cells in subclinical L. monocytogenes infection could directly lyse L. monocytogenes-infected target cells and inhibit intracellular L. monocytogenes bacteria. Thus, we present the first demonstration, to our knowledge, of multieffector-functional Vγ2Vδ2 T cell responses against L. monocytogenes.
doi:10.4049/jimmunol.1200641
PMCID: PMC3412419  PMID: 22745375
18.  Interleukin-8 Mediates Resistance to Antiangiogenic Agent Sunitinib in Renal Cell Carcinoma 
Cancer research  2010;70(3):1063-1071.
The broad spectrum kinase inhibitor sunitinib is a first-line therapy for advanced clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Unfortunately, most patients develop sunitinib resistance and progressive disease after about 1 year of treatment. In this study, we evaluated the mechanisms of resistance to sunitinib to identify the potential tactics to overcome it. Xenograft models were generated that mimicked clinical resistance to sunitinib. Higher microvessel density was found in sunitinib-resistant tumors, indicating that an escape from antiangiogenesis occurred. Notably, escape coincided with increased secretion of interleukin-8 (IL-8) from tumors into the plasma, and coadministration of an IL-8 neutralizing antibody resensitized tumors to sunitinib treatment. In patients who were refractory to sunitinib treatment, IL-8 expression was elevated in ccRCC tumors, supporting the concept that IL-8 levels might predict clinical response to sunitinib. Our results reveal IL-8 as an important contributor to sunitinib resistance in ccRCC and a candidate therapeutic target to reverse acquired or intrinsic resistance to sunitinib in this malignancy.
doi:10.1158/0008-5472.CAN-09-3965
PMCID: PMC3719378  PMID: 20103651
19.  The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation 
Considering the fact that iRGD (tumor-homing peptide) demonstrates tumor-targeting and tumor-penetrating activity, and that B16-F10 (murine melanoma) cells overexpress both αv integrin receptor and neuropilin-1 (NRP-1), the purpose of this study was to prepare a novel doxorubicin (DOX)-loaded, iRGD-modified, sterically-stabilized liposome (SSL) (iRGD-SSL-DOX) in order to evaluate its antitumor activity on B16-F10 melanoma cells in vitro and in vivo. The iRGD-SSL-DOX was prepared using a thin-film hydration method. The characteristics of iRGD-SSL-DOX were evaluated. The in vitro leakage of DOX from iRGD-SSL-DOX was tested. The in vitro tumor-targeting and tumor-penetrating characteristics of iRGD-modified liposomes on B16-F10 cells were investigated. The in vivo tumor-targeting and tumor-penetrating activities of iRGD-modified liposomes were performed in B16-F10 tumor-bearing nude mice. The antitumor effect of iRGD-SSL-DOX was evaluated in B16-F10 tumor-bearing C57BL/6 mice in vivo. The average particle size of the iRGD-SSL-DOX was found to be 91 nm with a polydispersity index (PDI) of 0.16. The entrapment efficiency of iRGD-SSL-DOX was 98.36%. The leakage of DOX from iRGD-SSL-DOX at the 24-hour time point was only 7.5%. The results obtained from the in vitro flow cytometry and confocal microscopy, as well as in vivo biodistribution and confocal immunofluorescence microscopy experiments, indicate that the tumor-targeting and tumor-penetrating activity of the iRGD-modified SSL was higher than that of unmodified SSL. In vivo antitumor activity results showed that the antitumor effect of iRGD-SSL-DOX against melanoma tumors was higher than that of SSL-DOX in B16-F10 tumor-bearing mice. In conclusion, the iRGD-SSL-DOX is a tumor-targeting and tumor-penetrating peptide modified liposome which has significant antitumor activity against melanoma tumors.
doi:10.2147/IJN.S46962
PMCID: PMC3716561  PMID: 23885174
tumor-targeting and tumor-penetrating; integrin receptor; NRP-1; iRGD; liposome; doxorubicin
20.  Low expression of LOC285194 is associated with poor prognosis in colorectal cancer 
Background
The long non-coding RNAs (lncRNAs) study has gradually become one of the hot topics in the field of RNA biology. One lncRNA which has attracted attention is LOC285194, a lncRNA demonstrated the potential tumor-suppressor role in osteosarcoma. The aim of this study was to examine the expression of LOC285194 in colorectal cancer (CRC) patients and to investigate the relationship between this lncRNA levels and existing clinicopathologic parameters and patient survival.
Methods
The expression of LOC285194 was detected by quantitative real-time polymerase chain reaction in pairs of tumorous and adjacent normal tissues of 81 colorectal cancer patients with a follow-up of 5 years, as well as in three colorectal cancer cell lines and normal intestinal mucous cell line. Then, we analyzed the potential relationship between this lncRNA levels in tumor tissues and existing clinicopathological features of CRC, and clinical outcome.
Results
The relative expression levels of LOC285194 was significantly lower in tumor tissues (p < 0.001) and colorectal cancer cell lines compared with adjacent normal tissues and normal intestinal mucous cell line. In addition, low expression of LOC285194 was correlated with larger tumor size (p = 0.015), higher tumor stage (p = 0.034), and more distant metastasis (p = 0.046). Kaplan-Meier analysis indicated that patients with low LOC285194 expression had a poor disease free survival (p = 0.010). Moreover, multivariate analysis showed that decreased expression of LOC285194 was an independent predictor of disease-specific survival.
Conclusion
Our data indicate that LOC285194 might be a novel prognostic indicator in colorectal cancer and may be a potential target for diagnosis and gene therapy.
doi:10.1186/1479-5876-11-122
PMCID: PMC3665590  PMID: 23680400
Colorectal cancer; Long non-coding RNAs; LOC285194; Survival
21.  An atomic-force basis for the bacteriolytic effects of granulysin 
Colloids and surfaces. B, Biointerfaces  2012;100:10.1016/j.colsurfb.2012.05.011.
While granulysin has been suggested to play an important role in adaptive immune responses against bacterial infections by killing pathogens, and molecular force for protein–protein interaction or protein–bacteria interaction may designate the specific functions of a protein, the molecular-force basis underlying the bacteriolytic effects of granulysin at single-molecule level remains unknown. Here, we produced and purified bactericidal domain of macaque granulysin (GNL). Our bacterial lysis assays suggested that GNL could efficiently kill bacteria such as Listeria monocytogenes. Furthermore, we found that the interaction force between GNL and L. monocytogenes measured by an atomic force microscopy (AFM) was about 22.5 pN. Importantly, our AFM-based single molecular analysis suggested that granulysin might lyse the bacteria not only through electrostatic interactions but also by hydrogen bonding and van der Waals interaction. Thus, this work provides a previous unknown mechanism for bacteriolytic effects of granulysin.
doi:10.1016/j.colsurfb.2012.05.011
PMCID: PMC3653176  PMID: 22766293
AFM; Granulysin; Perforin; Bacteria; Listeria monocytogenes
22.  IL-2 Simultaneously Expands Foxp3+ T Regulatory and T Effector Cells and Confers Resistance to Severe Tuberculosis (TB): Implicative Treg–T Effector Cooperation in Immunity to TB 
The possibility that simultaneous expansion of T regulatory cells (Treg) and T effector cells early postinfection can confer some immunological benefits has not been studied. In this study, we tested the hypothesis that early, simultaneous cytokine expansion of Treg and T effector cells in a tissue infection site can allow these T cell populations to act in concert to control tissue inflammation/damage while containing infection. IL-2 treatments early after Mycobacterium tuberculosis infection of macaques induced simultaneous expansion of CD4+CD25+Foxp3+ Treg, CD8+CD25+Foxp3+ T cells, and CD4+ T effector/CD8+ T effector/Vγ2Vδ2 T effector populations producing anti-M. tuberculosis cytokines IFN-γ and perforin, and conferred resistance to severe TB inflammation and lesions. IL-2–expanded Foxp3+ Treg readily accumulated in pulmonary compartment, but despite this, rapid pulmonary trafficking/accumulation of IL-2–activated T effector populations still occurred. Such simultaneous recruitments of IL-2–expanded Treg and T effector populations to pulmonary compartment during M. tuberculosis infection correlated with IL-2–induced resistance to TB lesions without causing Treg-associated increases in M. tuberculosis burdens. In vivo depletion of IL-2–expanded CD4+Foxp3+ Treg and CD4+ T effectors during IL-2 treatment of M. tuberculosis-infected macaques significantly reduced IL-2–induced resistance to TB lesions, suggesting that IL-2–expanded CD4+ T effector cells and Treg contributed to anti-TB immunity. Thus, IL-2 can simultaneously activate and expand T effector cells and Foxp3+ Treg populations and confer resistance to severe TB without enhancing M. tuberculosis infection.
doi:10.4049/jimmunol.1101291
PMCID: PMC3412415  PMID: 22474020
23.  Membrane-bound IL-22 after de novo production in tuberculosis and anti-M.tuberculosis effector function of IL-22+CD4+ T cells 
The role of IL-22-producing CD4+ T cells in intracellular pathogen infections is poorly characterized. IL-22-producing CD4+ T cells may also express other effector molecules, and therefore synergize or contribute to anti-microbial effector function. This hypothesis cannot be tested by conventional approaches manipulating a single IL-22 cytokine at genetic and protein levels, and IL-22+ T cells cannot be purified for evaluation due to secretion nature of cytokines. Here, we surprisingly found that upon activation, CD4+ T cells in M. tuberculosis-infected macaques or humans could evolve into T effector cells bearing membrane-bound IL-22 after de novo IL-22 production. Membrane-bound IL-22+ CD4+ T effector cells appeared to mature in vivo and sustain membrane distribution in highly-inflammatory environments during active M. tuberculosis infection. NSOM/QD-based nanoscale molecular imaging revealed that membrane-bound IL-22, like CD3, distributed in membrane and engaged as ~100–200 nm nanoclusters or ~300–600 nm nanodomains for potential interaction with IL-22 receptor. Importantly, purified membrane-bound IL-22+ CD4+ T cells inhibited intracellular M. tuberculosis replication in macrophages. Our findings suggest that IL-22-producing T cells can evolve to retain IL-22 on membrane for prolonged IL-22 half-lives and to exert efficient cell-cell interaction for anti-M. tuberculosis effector function.
doi:10.4049/jimmunol.1004129
PMCID: PMC3586328  PMID: 21632708
Tuberculosis; IL-22; Infection; NSOM/QD; nanoscale molecular imaging
24.  TCR Repertoire, Clonal Dominance, and Pulmonary Trafficking of Mycobacterium-Specific CD4+ and CD8+ T Effector Cells in Immunity Against Tuberculosis 
Clonal responses of Mycobacterium tuberculosis-specific CD4+ or CD8+ T effector cells producing antituberculosis cytokine IFN-γ in the context of immune protection against tuberculosis remain poorly characterized in humans. Utilizing decade-long TCR expertise, we previously developed a useful method to isolate clonotypic TCR sequences from Ag-specific IFN-γ–producing T cells and to specifically measure clonotypic TCR frequencies in the T cell pool. In this study, we investigated TCR Vβ repertoires/CDR3 usage, clonal expansion or dominance, and pulmonary trafficking or accumulation for purified protein deritative (PPD)-specific T effector cells producing IFN-γ during bacillus Calmette-Guérin (BCG) vaccination and subsequent M. tuberculosis challenge of macaques. We found that while PPD-specific CD4+ and CD8+ T effector clones employed diverse TCR Vβ repertoires, 30–33% of IFN-γ+CD4+ T cell clones from three M. tuberculosis-infected macaques expressed TCR bearing a conserved residue leucine in CDR3. Many Ag-specific IFN-γ+ CD4+ and few CD8+ T effector cells emerged as dominant clones during mycobacterial infections and underwent major recall expansion after pulmonary M. tuberculosis infection of BCG-vaccinated macaques. PPD-specific T cell clones readily trafficked to the airway or lung after BCG vaccination or M. tuberculosis infection, and some of them continuously accumulated in lungs during M. tuberculosis infection even after they became undetectable in the circulation. Importantly, remarkable recall expansion and pulmonary accumulation of T effector cells coincided with BCG-induced protection against tuberculosis. Thus, rapid clonal expansion and pulmonary accumulation of Ag-specific T effector cells appear to be one of the immune mechanisms underlying immunity against tuberculosis.
doi:10.4049/jimmunol.1001222
PMCID: PMC3586329  PMID: 20805423
25.  NSOM/QD-based fluorescence-topographic image fusion directly reveals nano-spatial peak-valley polarities of CD69 and CD71 activation molecules on cell-membrane fluctuations during T-cell activation 
Immunology letters  2011;140(1-2):44-51.
Nano-spatial distribution of cell surface molecules on cell membrane fluctuations during T-cell activation has not been reported. In this study, we innovated application of near-field scanning optical microscopy (NSOM)/quantum dots (QD)-based nanotechnology through three-dimensional image fusion algorithm to merge the simultaneously-obtained dual-color fluorescence information and three-dimensional topography. This novel imaging system made it possible to visualize nano-spatial distribution and organization of early-activation molecules CD69 and late-activation molecules CD71 on cell-membrane fluctuations during T-cell activation. Interestingly, most CD69 molecules were clustered to form 250–500 nm nano-domains polarizing predominantly in the peak of the cell-membrane fluctuations. In contrast, although CD71 molecules were also clustered as 250–500 nm nano-domains, they polarized dominantly in the valley of the cell-membrane fluctuations. The peak-valley polarities of CD69 nano-domains and CD71 nano-domains implied their different functions. CD69 nano-domains polarizing on membrane-peak fluctuations might serve as transient platforms driving TCR/CD3-induced signaling and activation, whereas CD71 nano-domains distributing in the membrane-valley fluctuations appeared to facilitate iron uptake for increased metabolisms in T-cell activation. Importantly, this NSOM/QD-based fluorescence-topographic image fusion provides a powerful tool to visualize nano-spatial distribution of cell-surface molecules on cell-membrane fluctuations and enable better understanding of distribution-function relationship.
doi:10.1016/j.imlet.2011.06.003
PMCID: PMC3563326  PMID: 21704079
Nanoimmunology; Nanobiotechnology; NSOM; T-cell activation; CD69; CD71

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