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1.  Rosuvastatin Treatment Reduces Markers of Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy 
Soluble CD14, a marker of monocyte activation and independent predictor of mortality in HIV disease, is reduced by rosuvastatin treatment. Monocyte tissue factor expression in HIV-infected subjects is reduced by rosuvastatin treatment, potentially reducing thrombotic risk.
Background. Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist.
Methods. The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)–infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8+CD38+HLA-DR+ ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1).
Results. After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (−13.4% vs 1.2%, P = .002) and in proportions of tissue factor–positive patrolling (CD14DimCD16+) monocytes (−38.8% vs −11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation.
Conclusions. Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy.
Clinical Trials Registration NCT01218802.
PMCID: PMC3905756  PMID: 24253250
HIV-1; monocytes; tissue factor; rosuvastatin
2.  Improved Early Outcomes Using a T Cell Replete Graft Compared with T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation 
Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.
PMCID: PMC4320643  PMID: 22796535
Haploidentical stem cell transplantation; T cell depletion; T cell replete haploidentical graft; GVHD prevention; High-dose posttransplantation cyclophosphamide
3.  PPARγ Upregulation Induced by Vagus Nerve Stimulation Exerts Anti-Inflammatory Effect in Cerebral Ischemia/Reperfusion Rats 
It is well known that peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, plays a protective role in anti-inflammatory responses in both acute and chronic central nerve system (CNS) insults. Emerging evidence in rats suggests that vagus nerve stimulation (VNS), while restraining inflammatory cytokine production in the peripheral nervous system, also exerts a significant CNS neuroprotective function against ischemic stroke injury. The aim of this study was to explore the role of PPARγ in VNS-mediated anti-inflammatory protection against ischemic stroke damage.
Adult male Sprague-Dawley rats (total n=160) preconditioned through transfection with either PPARγ small interfering RNA (siRNA) or lentiviral vector without siRNA and surgically subjected to middle cerebral artery occlusion and reperfusion subsequently received VNS treatment at 30 min post-occlusion. The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining. Subsequently, the neurological deficits scores, the infarct volume, and the brain histopathology were all evaluated. Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.
We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05). However, rats with PPARγ silencing failed to manifest significant neuroprotection and anti-inflammatory effect induced by VNS treatment (p>0.05).
PPARγ may participate in the process by which VNS modulates the neuro-inflammatory response following ischemia/reperfusion in rats.
PMCID: PMC4310716  PMID: 25619160
Cholinergic Fibers; Hypoxia-Ischemia, Brain; Peroxisome Proliferator-Activated Receptors; Vagus Nerve Stimulation
4.  Lower esophageal microbiota species are affected by the eradication of Helicobacter pylori infection using antibiotics 
The aim of this study was to investigate the effect of Helicobacter pylori (H. pylori) infection on the lower esophageal microbiota and the eradication of H. pylori through the use of antibiotics. Forty-five BALB/C mice were randomly divided into negative control, infection and treatment groups. The mice were sacrificed and DNA was extracted from the lower esophageal microbiota. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) was performed to determine the composition of the microbiota. Quantity One® 1-D Analysis Software was used for the analysis of the DGGE profiles. The different bands from the groups were amplified with 16S rDNA V6 region primers. DNA sequencing and Basic Local Alignment Search Tool analysis were performed for the identification of the bands. H. pylori colonization led to severe ulcers in the stomachs of the mice, and these ulcers were alleviated by antibiotic treatment. The infection group had an increased number of bacterial species in the stomach compared with the control and treatment groups. DGGE fingerprinting of the lower esophagus showed that there were significant differences in the number of bands (P<0.05), diversity index and abundance among the groups (P<0.05); however, no significant differences in homogeneity were observed (P>0.05). Although the composition of flora species in the lower espohagus varied, the dominant species, and their relative contents, were similar in the control, infection and treatment groups. The present study provided a microecological basis for the understanding of the pathogenesis of lower esophageal diseases, following the eradication of H. pylori infection with antibiotics.
PMCID: PMC4316990  PMID: 25667614
lower esophagus; microbiota; Helicobacter pylori; infection; antibiotics; polymerase chain reaction-denaturing gradient gel electrophoresis
5.  Gadd45b is a Novel Mediator of Neuronal Apoptosis in Ischemic Stroke 
Apoptosis plays an essential role in ischemic stroke pathogenesis. Research on the process of neuronal apoptosis in models of ischemic brain injury seems promising. The role of growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) in brain ischemia has not been fully examined to date. This study aims to investigate the function of Gadd45b in ischemia-induced apoptosis. Adult male Sprague-Dawley rats were subjected to brain ischemia by middle cerebral artery occlusion (MCAO). RNA interference (RNAi) system, which is mediated by a lentiviral vector (LV), was stereotaxically injected into the ipsilateral lateral ventricle to knockdown Gadd45b expression. Neurologic scores and infarct volumes were assessed 24 h after reperfusion. Apoptosis-related molecules were studied using immunohistochemistry and Western blot analysis. We found that Gadd45b-RNAi significantly increased infarct volumes and worsened the outcome of transient focal cerebral ischemia. Gadd45b-RNAi also significantly increased neuronal apoptosis as indicated by increased levels of Bax and active caspase-3, and decreased levels of Bcl-2. These results indicate that Gadd45b is a beneficial mediator of neuronal apoptosis.
PMCID: PMC4323375
MCAO; Gadd45b; BDNF; Apoptosis
6.  Lymphocyte Recovery Predicts Outcomes in Cord Blood and T Cell–Depleted Haploidentical Stem Cell Transplantation 
Alternative donor stem cell transplantation from cord blood or haploidentical peripheral blood donors is increasingly being used for patients who lack a matched related or unrelated donor. A higher nonrelapse mortality (NRM) rate has been noted with these 2 types of transplants, primarily because of infectious complications. Here, we hypothesized that the time to lymphocyte recovery (absolute lymphocyte count [ALC] of ≥ 1000/μL for the first 3 consecutive days) after transplant correlates with outcomes. We retrospectively analyzed 65 consecutive patients treated at our institution with cord blood (n = 37) and haploidentical (n = 28) transplantation with myeloablative fludarabine, melphalan, and thiotepa conditioning. Patients with lymphocyte recovery at day 60 posttransplant were more likely to survive long term than those without lymphocyte recovery. In multivariate analysis, ALC recovery was the only independent prognostic factor associated with mortality; patients without ALC recovery were 10.5 times (95% confidence interval [CI]: 4.3–25.4) more likely to die than those with ALC recovery (P < .0001). This difference appeared to be related to NRM (hazard ratio [HR] =0.1, 95% CI: 0.02–0.6, P = .008), whereas ALC recovery did not influence the rate of disease relapse. These results suggest that ALC recovery is an important prognostic indicator for patients treated with cord blood and T cell–depleted peripheral haploidentical transplants.
PMCID: PMC4231815  PMID: 21126598
Lymphocyte recovery; Nonrelapse mortality; Cord blood transplantation; T cell–depleted haploidentical stem cell transplantation
7.  Effectiveness of Primary Anti-Aspergillus Prophylaxis during Remission Induction Chemotherapy of Acute Myeloid Leukemia 
Although antifungal prophylaxis is frequently administered to patients with acute myeloid leukemia (AML) during remission-induction chemotherapy (RIC), its impact on reducing invasive fungal infections (IFIs) outside clinical trials is rarely reported. We performed a retrospective observational study to identify risk factors for development of IFIs (definite or probable, using revised European Organization for Research and Treatment of Cancer [EORTC] criteria) and all-cause mortality in a cohort of 152 AML patients receiving RIC (2009 to 2011). We also compared rates of IFI and mortality in patients who received echinocandin versus anti-Aspergillus azole (voriconazole or posaconazole) prophylaxis during the first 120 days of RIC. In multivariate analysis, clofarabine-based RIC (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.5 to 8.3; P = 0.004) and echinocandin prophylaxis (HR, 4.6; 95% CI, 1.8 to 11.9; P = 0.002) were independently associated with higher rates of IFI rates during RIC. Subsequent analysis failed to identify any malignancy- or chemotherapy-related covariates linked to echinocandin prophylaxis that accounted for the higher rates of breakthrough IFI. Although the possibility of other confounding variables cannot be excluded, our findings suggest that echinocandin-based prophylaxis during RIC for AML may be associated with a higher risk of breakthrough IFI.
PMCID: PMC3993271  PMID: 24590477
8.  Asbestos: use, bans and disease burden in Europe 
To analyse national data on asbestos use and related diseases in the European Region of the World Health Organization (WHO).
For each of the 53 countries, per capita asbestos use (kg/capita/year) and age-adjusted mortality rates (deaths/million persons/year) due to mesothelioma and asbestosis were calculated using the databases of the United States Geological Survey and WHO, respectively. Countries were further categorized by ban status: early-ban (ban adopted by 2000, n = 17), late-ban (ban adopted 2001–2013, n = 17), and no-ban (n = 19).
Between 1920–2012, the highest per capita asbestos use was found in the no-ban group. After 2000, early-ban and late-ban groups reduced their asbestos use levels to less than or equal to 0.1 kg/capita/year, respectively, while the no-ban group maintained a very high use at 2.2 kg/capita/year. Between 1994 and 2010, the European Region registered 106 180 deaths from mesothelioma and asbestosis, accounting for 60% of such deaths worldwide. In the early-ban and late-ban groups, 16/17 and 15/17 countries, respectively, reported mesothelioma data to WHO, while only 6/19 countries in the no-ban group reported such data. The age-adjusted mortality rates for mesothelioma for the early-ban, late-ban and no-ban groups were 9.4, 3.7 and 3.2 deaths/million persons/year, respectively. Asbestosis rates for the groups were 0.8, 0.9 and 1.5 deaths/million persons/year, respectively.
Within the European Region, the early-ban countries reported most of the current asbestos-related deaths. However, this might shift to the no-ban countries, since the disease burden will likely increase in these countries due the heavy use of asbestos.
PMCID: PMC4221761  PMID: 25378740
9.  Synthesis of titanium nitride for self-aligned gate AlGaN/GaN heterostructure field-effect transistors 
Nanoscale Research Letters  2014;9(1):590.
In this study, titanium nitride (TiN) is synthesized using reactive sputtering for a self-aligned gate process. The Schottky barrier height of the TiN on n-GaN is around 0.5 to 0.6 eV and remains virtually constant with varying nitrogen ratios. As compared with the conventional Ni electrode, the TiN electrode presents a lower turn-on voltage, while its reverse leakage current is comparable with that of Ni. The results of annealing evaluation at different temperatures and duration times show that the TiN/W/Au gate stack can withstand the ohmic annealing process at 800°C for 1 or 3 min. Finally, the self-aligned TiN-gated AlGaN/GaN heterostructure field-effect transistors are obtained with good pinch-off characteristics.
PMCID: PMC4214824  PMID: 25364317
Titanium nitride; Self-aligned gate; AlGaN/GaN heterostructure field-effect transistors; 73.40.Kp; 77.84.Bw; 73.40.Qv
10.  Hydrothermal Synthesis of Monodisperse Single-Crystalline Alpha-Quartz Nanospheres 
Uniformly-sized, single-crystal alpha-quartz nanospheres have been synthesized at 200°C and 15atm under continuous stirring starting from uniform, amorphous Stöber silica colloids and using NaCl and alkali hydroxide as mineralizers. Quartz nanosphere size is controlled by the colloid particle size via direct devitrification. Uniform, high-purity nanocrystalline quartz is important for understanding nanoparticle toxicology and for advanced polishing and nanocomposite fabrication.
PMCID: PMC4201858  PMID: 21629887
11.  Perivascular Fat, Inflammation, and Cardiovascular Risk in HIV-infected Patients on Antiretroviral Therapy 
International journal of cardiology  2013;168(4):4039-4045.
HIV-infection is characterized by chronic immune activation that persists despite effective antiretroviral therapy (ART) and is associated with elevated cardiovascular risk. Whether specific perivascular fat depots are associated with inflammation in HIV is unknown.
In a cross-sectional study, epicardial (EAT) and thoracic periaortic (TAT) adipose tissue volume were measured by computed tomography in 100 HIV-infected adults, on stable ART, with LDL-cholesterol ≤130mg/dL and evidence of heightened T-cell activation (CD8+CD38+HLA−DR+ ≥19%) or increased inflammation (high sensitivity C-reactive protein ≥2mg/L).
Overall, 77% were male and 70% African American. Mean (standard deviation) age and body mass index were 47 (10) years and 28 (6.4) kg/m2, respectively. All subjects had HIV-1 RNA <1,000 copies/mL with mean (standard deviation) CD4+ T cell count of 665 (280) cells/μL; 50% were on a protease inhibitor. EAT and TAT were correlated with each other (r=0.766, p<0.0001). Both were associated with metabolic syndrome, atherogenic lipid profile, insulin resistance, total and central body fat, serum biomarkers of inflammation, and soluble CD163, but not with cellular immune activation markers. In multivariable models that adjusted for age, sex, and other measures of adiposity, both perivascular fat depots were independently associated with the presence of coronary calcium.
Perivascular fat is associated with soluble CD163, biomarkers of inflammation, insulin resistance, and subclinical atherosclerosis in this population of virologically suppressed HIV-infected patients on ART. The association of perivascular fat with coronary artery calcification appears to be independent of other measures of adiposity.
PMCID: PMC3805774  PMID: 23886531
Adipose tissue; Atherosclerosis; HIV; Inflammation; Macrophages
12.  Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization 
Molecular cell  2013;52(3):340-352.
Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylationmimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.
PMCID: PMC4183148  PMID: 24120661
13.  The use of minocycline-rifampin coated central venous catheters for exchange of catheters in the setting of staphylococcus aureus central line associated bloodstream infections 
BMC Infectious Diseases  2014;14(1):518.
Central venous catheters (CVC) removal and reinsertion of a new CVC in the setting of central line associated bloodstream infections (CLABSI) is not always possible in septic patients. The purpose of this study was to evaluate the outcome of patients with Staphylococcus aureus-CLABSI (SA-CLABSI) who had their CVCs exchanged over guidewire for minocycline/rifampin-coated (M/R)-CVC within seven days of bacteremia.
Each case was matched with two control patients who had SA-CLABSI and had their CVC removed within seven days and two control patients who had their CVC retained beyond seven days. In addition, an in vitro model was developed for exchange of catheters.
We identified 40 patients with SA-CLABSI. Eight patients had their CVC exchanged over guidewire with M/R-CVC and were compared to 16 patients who had their CVC removed and 16 other patients who had their CVC retained. Patients who had their CVC exchanged over guidewire had a similar clinical response and relapse rates compared to patients whose CVC was removed or retained. However the rate of overall mortality was higher in patients who retained their CVC compared to those whose CVC was exchanged or removed (p = 0.034). The in vitro catheter exchange model showed that catheter exchange over guidewire using M/R-CVC completely prevented biofilm colonization compared to exchange using uncoated CVC (p < 0.0001).
In the setting of SA-CLABSI, exchanging the CVC over guidewire with M/R-CVC could be an alternative to removing the CVC and reinserting another CVC at a different site and may be associated with a lower rate of overall mortality. Further large prospective randomized clinical trials are warranted.
PMCID: PMC4261544  PMID: 25253042
Central venous catheters; Staphylococcus aureus; Central line associated bloodstream infections
14.  Intraductal tubular adenomas (pyloric gland-type) of the pancreas: clinicopathologic features are similar to gastric-type intraductal papillary mucinous neoplasms and different from intraductal tubulopapillary neoplasms 
Diagnostic Pathology  2014;9(1):172.
Intraductal tubular adenoma of the pancreas, pyloric gland type (ITA), is an infrequent intraductal benign lesion located in the main duct and large branch duct of the pancreas. The purpose of this report is to introduce seven new cases and to compare their clinicopathologic features and KRAS mutations to gastric-type intraductal papillary mucinous neoplasms (IPMNs) and intraductal tubulopapillary neoplasms (ITPNs).
Clinical findings, morphologic features, immunophenotypes and KRAS alterations were investigated in 7 patients with intraductal tubular adenomas, 16 patients with gastric-type intraductal papillary mucinous neoplasms and 6 patients with intraductal tubulopapillary neoplasms.
There were more female patients in the ITA and gastric-type IPMN groups, whereas the opposite pattern was observed in the ITPN group. ITAs and gastric-type IPMNs were lined by columnar cells, similar to pyloric glands, with large extracellular deposits of mucin. ITPNs were polypoid and papillary mass located in the pancreatic ducts, which did not show large deposits of mucin. All ITAs and gastric-type IPMNs expressed MUC5AC strongly and diffusely, and 3/6 ITPNs expressed MUC5AC focally and weakly. KRAS mutations were identified in 4 ITAs (4/7, 57%), 9 IPMNs (9/16, 56%) and 2 ITPNs (2/6, 33%).
The intraductal tubular adenoma should not be considered a precursor lesion of intraductal tubulopapillary neoplasms. No adequate data established ITA should separate as a specific entity from IPMNs.
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PMCID: PMC4180592  PMID: 25245835
Pancreas; Intraductal tubular adenoma; Pyloric gland adenoma; Intraductal papillary mucinous neoplasm; Intraductal tubulopapillary neoplasm
15.  Proteomic Analysis on the Alteration of Protein Expression in the Early-Stage Placental Villous Tissue of Electromagnetic Fields Associated With Cell Phone Exposure 
Reproductive Sciences  2013;20(9):1055-1061.
To explore the possible adverse effects and search for cell phone electromagnetic field (EMF)-responsive proteins in human early reproduction, a proteomics approach was employed to investigate the changes in protein expression profile induced by cell phone EMF in human chorionic tissues of early pregnancy in vivo.
Volunteer women about 50 days pregnant were exposed to EMF at the average absorption rate of 1.6 to 8.8 W/kg for 1 hour with the irradiation device placed 10 cm away from the umbilicus at the midline of the abdomen. The changes in protein profile were examined using 2-dimensional electrophoresis (2-DE).
Up to 15 spots have yielded significant change at least 2- to 2.5-folds up or down compared to sham-exposed group. Twelve proteins were identified— procollagen–proline, eukaryotic translation elongation factor 1 delta, chain D crystal structure of human vitamin D-binding protein, thioredoxin-like 3, capping protein, isocitrate dehydrogenase 3 alpha, calumenin, Catechol-O-methyltransferase protein, proteinase inhibitor 6 (PI-6; SerpinB6) protein, 3,2-trans-enoyl-CoA isomerase protein, chain B human erythrocyte 2,3-bisphosphoglycerate mutase, and nucleoprotein.
Cell phone EMF might alter the protein profile of chorionic tissue of early pregnancy, during the most sensitive stage of the embryos. The exposure to EMF may cause adverse effects on cell proliferation and development of nervous system in early embryos. Furthermore, 2-DE coupled with mass spectrometry is a promising approach to elucidate the effects and search for new biomarkers for environmental toxic effects.
PMCID: PMC3745709  PMID: 23420827
placental villous; proteomics; cell phone EMF; radiofrequency; early development
16.  Multiplexed Imaging of Nanoparticles in Tissues using Laser Desorption/Ionization Mass Spectrometry 
Journal of the American Chemical Society  2013;135(34):12564-12567.
Imaging of nanomaterials in biological tissues provides vital information for the development of nanotherapeutics and diagnostics. Multiplexed imaging of different nanoparticles (NPs) greatly reduces costs, the need to use multiple animals, and increases the biodistribution information that can enhance diagnostic applications and accelerate the screening of potential therapeutics. Various approaches have been developed for imaging NPs; however, the readout of existing imaging techniques relies on specific properties of the core material or surface ligands, and these techniques are limited because of the relatively small number of NPs that can be simultaneously measured in a single experiment. Here, we demonstrate the use of laser desorption/ionization mass spectrometry (LDI-MS) in an imaging format to investigate surface chemistry dictated intra-organ distribution of NPs. This new LDI-MS imaging method enables multiplexed imaging of NPs with potentially unlimited readouts and without additional labeling of the NPs. It provides the capability to detect and image attomole levels of NPs with almost no interferences from biomolecules. Using this new imaging approach we find that the intra-organ distributions of same-sized NPs are directly linked to their surface chemistry.
PMCID: PMC3801209  PMID: 23931011
17.  Adipokines and vascular health in treated HIV infection: an obesity paradox? 
AIDS (London, England)  2013;27(8):1353-1356.
We examined the relationship between plasma adipokine concentrations and ultrasound measures of vascular health in 100 HIV-infected adults on antiretroviral therapy. Leptin was positively correlated with flow-mediated dilation of the brachial artery and negatively with carotid intima–media thickness. These relationships were independent of traditional risk factors and trunk fat in women but not men. Neither adiponectin nor resistin was associated with either measure of vascular health.
PMCID: PMC4140858  PMID: 23462216
18.  Effects of cisplatin on the contractile function of thoracic aorta of Sprague-Dawley rats 
Biomedical Reports  2014;2(6):893-897.
DNA-damaging agents have been reported to be associated with cardiovascular complications, however, the underlying mechanisms remain to be clarified. In the present study, the possible vascular effects of cisplatin was assessed by measuring its effects on the contractile function of thoracic aortic rings dissected from Sprague-Dawley (SD) rats. Contraction of the aortic ring was induced by 60 mM KCl or 10−6 M phenylephrine (PE) in an ex vivo perfusion system. Cisplatin (200 μM) counteracted KCl- and PE-induced contraction by 57.6 and 91.8%, respectively, in endothelium-intact aortic rings. Similar results were obtained in endothelium-denuded aortas. Electromicroscopy analysis revealed severe damage to blood vessel walls in vivo by cisplatin. In addition, cisplatin significantly inhibited adenosine triphosphate (ATP)-induced intracellular Ca2+ concentration ([Ca2+]i) increases in human umbilical vein endothelial cells (HUVECs). These results suggested that the DNA-damaging agent cisplatin can affect the contractile function of thoracic aortas. In addition, in accordance with its DNA-damaging properties, the cardiovascular toxicity of cisplatin may be the result of its direct cytotoxicity.
PMCID: PMC4179771  PMID: 25279165
DNA damage; cisplatin; cardiovascular toxicity; vascular contraction
19.  Uncoupling Protein 2 Regulates Palmitic Acid-Induced Hepatoma Cell Autophagy 
BioMed Research International  2014;2014:810401.
Mitochondrial uncoupling protein 2 (UCP2) is suggested to have a role in the development of nonalcoholic steatohepatitis (NASH). However, the mechanism remains unclear. Autophagy is an important mediator of many pathological responses. This study aims to investigate the relationship between UCP2 and hepatoma cells autophagy in palmitic acid- (PA-) induced lipotoxicity. H4IIE cells were treated with palmitic acid (PA), and cell autophagy and apoptosis were examined. UCP2 expression, in association with LC3-II and caspase-3, which are indicators of cell autophagy and apoptosis, respectively,was measured. Results demonstrated that UCP2 was associated with autophagy during PA-induced hepatic carcinoma cells injury. Tests on reactive oxygen species (ROS) showed that UCP2 overexpression strongly decreases PA-induced ROS production and apoptosis. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing enhances PA-induced ROS production and apoptosis. Autophagy partially participates in this progress. Moreover, UCP2 was associated with ATP synthesis during PA-induced autophagy. In conclusion, increasing UCP2 expression in hepatoma cells may contribute to cell autophagy and antiapoptotic as result of fatty acid injury. Our results may bring new insights for potential NASH therapies.
PMCID: PMC4143590  PMID: 25512910
20.  Nucleotide Diversity of Maize ZmBT1 Gene and Association with Starch Physicochemical Properties 
PLoS ONE  2014;9(8):e103627.
Cereal Brittle1 protein has been demonstrated to be involved in the ADP-Glc transport into endosperm plastids, and plays vital roles in the biosynthesis of starch. In this study, the genomic sequences of the ZmBT1 gene in 80 elite maize inbred lines were obtained, and the nucleotide polymorphisms and haplotype diversity were detected. A total of 30 variants, including 22 SNPs and 8 indels, were detected from the full sequences of this gene. Among these polymorphic sites, 9 SNPs and 2 indels were found to be located in the coding region. The polymorphisms of CDS sequences classified the maize ZmBT1 gene into 6 haplotypes, which encode 6 different ZmBT1 proteins. Neutrality tests revealed a decrease in population size and/or balancing selection on the maize ZmBT1 locus. To detect the association between sequence variations of this gene and the starch physicochemical properties, 7 pasting and 4 gelatinization traits of starch were measured for the tested inbred lines using rapid visco analyzer (RVA) and differential scanning calorimeter (DSC), respectively. The result of association analysis revealed that an indel in the coding region was significantly associated with the phenotypic variation of starch gelatinization enthalpy.
PMCID: PMC4118901  PMID: 25084007
21.  Vagus Nerve Stimulation Attenuates Cerebral Ischemia and Reperfusion Injury via Endogenous Cholinergic Pathway in Rat 
PLoS ONE  2014;9(7):e102342.
Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS) following focal cerebral ischemia and reperfusion (I/R) may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti-inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD) rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA), and immunofluorescence staining for the endogenous “cholinergic anti-inflammatory pathway” was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR), phosphorylated Akt (p-Akt), and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS) had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL) positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways.
PMCID: PMC4103831  PMID: 25036185
22.  Hepatic inflammation scores correlate with common carotid intima-media thickness in rats with NAFLD induced by a high-fat diet 
BMC Veterinary Research  2014;10:162.
Non-alcoholic fatty liver disease (NAFLD), an emerging public health problem, may be a highly atherogenic condition. But the relationship between fatty liver diseases and carotid atherosclerosis in small-animal is incompletely understood. The purpose of the present study was to evaluate carotid intima-media thickness (IMT) in NAFLD rats using high-frequency ultrasonic diagnostic equipment, and to ascertain if the degree of hepatic pathological changes was associated with carotid IMT.
Liver injury was induced by a high-fat diet for 8, 12 and 16 weeks, separately, in fifty four SD rats (27 treated, 27 controls). Liver echogenicity and IMT of the carotid and aorta were evaluated and compared to histological findings of them. In comparison with the rats in the control group, fatty liver disease in rats was characterized by homogeneous and diffusely increased echogenicity (bright liver), an increased anteroposterior diameter of the liver and serum biochemical changes. Hepatic histological analyses demonstrated indications of simple steatosis in rats induced by an 8-week high-fat diet, and a high-fat diet for 12 weeks and 16 weeks could induce steatohepatitis (NASH) in rats. The 12- and 16-week groups had a significantly higher inflammation scores than those of the control groups. IMT values for the carotid and aorta were remarkably increased in the NASH groups compared with the control groups (P < 0.05). The end-diastolic velocity and systolic peak velocity of the carotid and aorta in the NASH groups were significantly smaller than those in the control group. A significant correlation between the IMT of the carotid with hepatic inflammation score (r2 = 0.598, P = 0.001) and the systolic peak velocity of the carotid (r2 = −0.342, P = 0.041) were shown in NAFLD rats.
We demonstrated that ultrasound imaging in the diagnosis of fatty liver disease and early atherosclerosis in rats is feasible and efficient, and that carotid IMT increased significantly in NASH rats but not in simple steatotic rats. A significant correlation between the IMT of the carotid artery with hepatic inflammation score were shown in NAFLD rats. This method for non-invasive diagnosis is especially relevant in the research of the pathogenesis and therapy of NAFLD and atherosclerosis using rodent models.
PMCID: PMC4223401  PMID: 25030203
Non-alcoholic fatty liver disease; Atherosclerosis; Ultrasound; Intima-media thickness; Rat
23.  Th2 cytokines from malignant cells suppress Th1 responses and enforce a global Th2 bias in leukemic cutaneous T cell lymphoma 
In leukemic CTCL (L-CTCL) malignant T cells accumulate in the blood and give rise to widespread skin inflammation. Patients have intense pruritus, increased IgE, decreased Th1 responses and most die from infection. Depleting malignant T cells while preserving normal immunity is a clinical challenge. L-CTCL has been variably described as a malignancy of regulatory, Th2 and Th17 cells.
Experimental design
We analyzed phenotype and cytokine production in malignant and benign L-CTCL T cells, characterized the effects of malignant T cells on healthy T cells and studied the immunomodulatory effects of treatment modalities in L-CTCL patients.
12/12 L-CTCL patients overproduced Th2 cytokines. Remaining benign T cells were also strongly Th2 biased, suggesting a global Th2 skewing of the T cell repertoire. Culture of benign T cells away from the malignant clone reduced Th2 and enhanced Th1 responses but separate culture had no effect on malignant T cells. Co-culture of healthy T cells with L-CTCL T cells reduced IFNγ production and neutralizing antibodies to IL-4 and IL-13 restored Th1 responses. In patients, enhanced Th1 responses were observed following a variety of treatment modalities that reduced malignant T cell burden.
A global Th2 bias exists in both benign and malignant T cells in L-CTCL and may underlie the infectious susceptibility of patients. Th2 cytokines from malignant cells strongly inhibited Th1 responses. Our results suggest therapies that inhibit Th2 cytokine activity, by virtue of their ability to improve Th1 responses, may have the potential to enhance both anti-cancer and anti-pathogen responses.
PMCID: PMC3715586  PMID: 23785046
24.  Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection 
AIDS (London, England)  2014;28(7):969-977.
To use multimodality imaging to explore the relationship of biomarkers of inflammation, T-cell activation and monocyte activation with coronary calcification and subclinical vascular disease in a population of HIV-infected patients on antiretroviral therapy (ART).
A panel of soluble and cellular biomarkers of inflammation and immune activation was measured in 147 HIV-infected adults on ART with HIV RNA less than 1000 copies/ml and low-density lipoprotein cholesterol (LDL-C) 130 mg/dl or less. We examined the relationship of biomarkers to coronary calcium (CAC) score and multiple ultrasound measures of subclinical vascular disease.
Overall, median (interquartile range, IQR) age was 46 (40–53) years; three-quarters of participants were male and two-thirds African-American. Median 10-year Framingham risk score was 6%. Participants with CAC more than 0 were older, less likely to be African-American and had higher current and lower nadir CD4+ T-cell counts. Most biomarkers were similar between those with and without CAC; however, soluble CD14 was independently associated with CAC after adjustment for traditional risk factors. Among those with a CAC score of zero, T-cell activation and systemic inflammation correlated with carotid intima–media thickness and brachial hyperemic velocity, respectively. Compared with normal participants and those with CAC only, participants with increasing degrees of subclinical vascular disease had higher levels of sCD14, hs-CRP and fibrinogen (all P<0.05).
Soluble CD14 is independently associated with coronary artery calcification, and, among those with detectable calcium, predicts the extent of subclinical disease in other vascular beds. Future studies should investigate the utility of multimodality imaging to characterize vascular disease phenotypes in this population.
PMCID: PMC4097603  PMID: 24691204
carotid intima–media thickness; coronary artery calcium; endothelial function; HIV; inflammation; microbial translocation; soluble CD14
25.  Differentiation of cancer cell type and phenotype using quantum dot-gold nanoparticle sensor arrays 
Cancer letters  2012;334(2):196-201.
We demonstrate rapid and efficient sensing of mammalian cell types and states using nanoparticle-based sensor arrays. These arrays are comprised of cationic quantum dots (QDs) and gold nanoparticles (AuNPs) that interact with cell surfaces to generate distinguishable fluorescence responses based on cell surface signatures. The use of QDs as the recognition elements as well as the signal transducers presents the potential for direct visualization of selective cell surface interactions. Notably, this sensor is unbiased, precluding the requirement of pre-knowledge of cell state biomarkers and thus providing a general approach for phenotypic profiling of cell states, with additional potential for imaging applications.
PMCID: PMC3669636  PMID: 23022266
Quantum dots; Gold nanoparticles; Cell surface differentiation; Sensor array

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