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1.  Single-Walled Carbon Nanotubes Alleviate Autophagic/Lysosomal Defects in Primary Glia from a Mouse Model of Alzheimer’s Disease 
Nano Letters  2014;14(9):5110-5117.
Defective autophagy in Alzheimer’s disease (AD) promotes disease progression in diverse ways. Here, we demonstrate impaired autophagy flux in primary glial cells derived from CRND8 mice that overexpress mutant amyloid precursor protein (APP). Functionalized single-walled carbon nanotubes (SWNT) restored normal autophagy by reversing abnormal activation of mTOR signaling and deficits in lysosomal proteolysis, thereby facilitating elimination of autophagic substrates. These findings suggest SWNT as a novel neuroprotective approach to AD therapy.
PMCID: PMC4160261  PMID: 25115676
Single-walled carbon nanotubes; primary glia; autophagy; Alzheimer’s disease
2.  Role of Procalcitonin and Interleukin-6 in Predicting Cancer, and Its Progression Independent of Infection 
PLoS ONE  2015;10(7):e0130999.
Procalcitonin (PCT) and Interleukin-6 (IL-6) have emerged as biomarkers for different inflammatory conditions. The purpose of the study was to evaluate the role of PCT and IL-6 as biomarkers of cancer and its progression in a large cohort of patients. This cross-sectional study included residual plasma samples collected from cancer patients, and control subjects without cancer. Levels of PCT and IL-6 were determined by Kryptor compact bioanalyzer. We identified 575 febrile cancer patients, 410 non-febrile cancer patients, and 79 non-cancer individuals. The median PCT level was lower in control subjects (0.029 ng/ml) compared to cancer patients with stage I-III disease (0.127 ng/ml) (p<0.0001) and stage IV disease (0.190 ng/ml) (p<0.0001). It was also higher in febrile cancer patients (0.310 ng/ml) compared to non-febrile cancer patients (0.1 ng/ml) (p<0.0001). Median IL-6 level was significantly lower in the control group (0 pg/ml) than in non-febrile cancer patients with stages I-III (7.376 pg/ml) or stage IV (9.635 pg/ml) (p<0.0001). Our results suggest a potential role for PCT and IL-6 in predicting cancer in non-febrile patients. In addition, PCT is useful in detecting progression of cancer and predicting bacteremia or sepsis in febrile cancer patients.
PMCID: PMC4492776  PMID: 26148092
3.  Aged-Related Changes in Body Composition and Association between Body Composition with Bone Mass Density by Body Mass Index in Chinese Han Men over 50-year-old 
PLoS ONE  2015;10(6):e0130400.
Aging, body composition, and body mass index (BMI) are important factors in bone mineral density (BMD). Although several studies have investigated the various parameters and factors that differentially influence BMD, the results have been inconsistent. Thus, the primary goal of the present study was to further characterize the relationships of aging, body composition parameters, and BMI with BMD in Chinese Han males older than 50 years.
The present study was a retrospective analysis of the body composition, BMI, and BMD of 358 Chinese male outpatients between 50 and 89 years of age that were recruited from our hospital between 2009 and 2011. Qualified subjects were stratified according to age and BMI as follows: 50–59 (n = 35), 60–69 (n = 123), 70–79 (n = 93), and 80–89 (n = 107) years of age and low weight (BMI: < 20 kg/m2; n = 21), medium weight (20 ≤ BMI < 24 kg/m2; n = 118), overweight (24 ≤ BMI < 28 kg/m2; n = 178), and obese (BMI ≥ 28 kg/m2; n = 41). Dual-energy X-ray absorptiometry (DEXA) was used to assess bone mineral content (BMC), lean mass (LM), fat mass (FM), fat-free mass (FFM), lumbar spine (L1-L4) BMD, femoral neck BMD, and total hip BMD. Additionally, the FM index (FMI; FM/height2), LM index (LMI; LM/height2), FFM index (FFMI; [BMC+LM]/height2), percentage of BMC (%BMC; BMC/[BMC+FM+LM] × 100%), percentage of FM (%FM; FM/[BMC+FM+LM] × 100%), and percentage of LM (%LM; LM/(BMC+FM+LM) × 100%) were calculated. Osteopenia or osteoporosis was identified using the criteria and T-score of the World Health Organization.
Although there were no significant differences in BMI among the age groups, there was a significant decline in height and weight according to age (p < 0.0001 and p = 0.0002, respectively). The LMI and FFMI also declined with age (both p < 0.0001) whereas the FMI exhibited a significant increase that peaked in the 80-89-years group (p = 0.0145). Although the absolute values of BMC and LM declined with age (p = 0.0031 and p < 0.0001, respectively), there was no significant difference in FM. In terms of body composition, there were no significant differences in %BMC but there was an increase in %FM (p < 0.0001) and a decrease in %LM (p < 0.0001) with age. The femoral neck and total hip BMD significantly declined with age (p < 0.0001 and p = 0.0027, respectively) but there were no differences in L1-L4. BMD increased at all sites (all p < 0.01) as BMI increased but there were declines in the detection rates of osteoporosis and osteopenia (both p < 0.001). A logistic regression revealed that when the medium weight group was given a BMI value of 1, a decline in BMI was an independent risk factor of osteoporosis or osteopenia, while an increase in BMI was a protective factor for BMD. At the same time, BMD in L1-L4 exhibited a significant positive association with FMI (p = 0.0003) and the femoral neck and total hip BMDs had significant positive associations with FFMI and LMI, respectively (both p < 0.0001).
These data indicate that LMI and FFMI exhibited significant negative associations with aging in Chinese Han males older than 50 years, whereas FMI had a positive association. BMD in the femoral neck and total hip declined with age but an increased BMI was protective for BMD. LMI and FFMI were protective for BMD in the femoral neck and total hip.
PMCID: PMC4475062  PMID: 26090818
4.  Ginsenoside Rb1 Treatment Attenuates Pulmonary Inflammatory Cytokine Release and Tissue Injury following Intestinal Ischemia Reperfusion Injury in Mice 
Objective. Intestinal ischemia reperfusion (II/R) injury plays a critical role in remote organ dysfunction, such as lung injury, which is associated with nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In the present study, we tested whether ginsenoside Rb1 attenuated II/R induced lung injury by Nrf2/HO-1 pathway. Methods. II/R injury was induced in male C57BL/6J mice by 45 min of superior mesenteric artery (SMA) occlusion followed by 2 hours of reperfusion. Ginsenoside Rb1 was administrated prior to reperfusion with or without ATRA (all-transretinoic acid, the inhibitor of Nrf2/ARE signaling pathway) administration before II/R. Results. II/R induced lung histological injury, which is accompanied with increased levels of malondialdehyde (MDA), interleukin- (IL-) 6, and tumor necrosis factor- (TNF-) α but decreased levels of superoxide dismutase (SOD) and IL-10 in the lung tissues. Ginsenoside Rb1 reduced lung histological injury and the levels of TNF-α and MDA, as well as wet/dry weight ratio. Interestingly, the increased Nrf2 and HO-1 expression induced by II/R in the lung tissues was promoted by ginsenoside Rb1 treatment. All these changes could be inhibited or prevented by ATRA. Conclusion. Ginsenoside Rb1 is capable of ameliorating II/R induced lung injuries by activating Nrf2/HO-1 pathway.
PMCID: PMC4487341  PMID: 26161243
5.  VSIG4 is highly expressed and correlated with poor prognosis of high-grade glioma patients 
The high-grade glioma (HGG) remains as the greatest challenge for cancer management worldwide. Identification of novel therapeutics and diagnostic method is in urgent need. The V-set and immunoglobulin domain-containing protein 4 (VSIG4) is a complement receptor for C3b/iC3b and inhibits cytotoxic T lymphocytes activation, which may play important roles in glioma oncogenesis. In this study, we performed immunohistochemistry in tissue microarray to determine the expression of VSIG4 in malignant glioma and normal brain. We then applied univariate and multivariate analyses to evaluate the expression of VSIG4 and correlated with prognosis of glioma patients. We have shown that VSIG4 was significantly elevated in high-grade glioma compared with those of normal brain tissues (P<0.001). We have also found that high VSIG4 expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in high-grade glioma patients [hazard ratio (HR) =1.786, P=0.011 and HR=2.199, P=0.001, respectively]. Patients with low VSIG4 expression had a significantly longer median OS and PFS than those with high VSIG4 expression. Subgroup analysis stratifying HGG patients by both VSIG4 expression and tumor grade further confirmed the independent prognostic role of VSIG4 in HGG patients, while no adjuvant radiotherapy, small extent of resection and higher tumor grade were other three independent risk factors for HGG poor prognosis. Similar findings were also obtained using data from Cancer Genome Atlas (TCGA). Together, our results support that VISG4 can be used as a prognostic factor and potentially an immunotherapeutic target for glioma.
PMCID: PMC4532749  PMID: 26279760
VSIG4; proliferation; human glioma; prognosis
6.  Cellular imaging of endosome entrapped small gold nanoparticles 
MethodsX  2015;2:306-315.
Graphical abstract
Small gold nanoparticles (sAuNPs, <10 nm in a core diameter) have been used for drug delivery and cancer therapy due to their high payload to carrier ratio. Information about the amount and location of sAuNPs in cells and tissues is critical to many applications. However, the current detection method (i.e., transmission electron microscopy) for such sAuNPs is limited due to the extensive sample preparation and the limited field of view. Here we use confocal laser scanning microscopy to provide endosome-entrapped sAuNP distributions and to quantify particle uptake into cells. The quantitative capabilities of the system were confirmed by inductively coupled plasma-mass spectrometry, with an observed linear relation between scattering intensity and the initial cellular uptake of sAuNPs using 4 nm and 6 nm core particles.
The summary of the method is:
•This non-invasive imaging strategy provides a tool for label-free real-time tracking and quantification of sAuNPs using a commercially available confocal laser scanning microscope.•Scattering intensity depends on particle size.•The linear relation established between scattering intensity and uptaken gold amount enables simultaneous quantitative assessment through simple image analysis.
PMCID: PMC4487928  PMID: 26151001
Confocal measurement of cellular uptake of gold nanoparticles; Gold nanoparticles; Confocal laser scanning microscopy; Nanoparticle quantification; ICP-MS; Reflectance imaging
7.  Effects of hypoxia inducible factor-1α on apoptotic inhibition and glucocorticoid receptor downregulation by dexamethasone in AtT-20 cells 
Hypoxia inducible factor-1α (HIF-1α) is the central transcriptional regulator of hypoxic responses during the progression of pituitary adenomas. Although previous immunohistochemical studies revealed that HIF-1α is expressed in adreno-cortico-tropic-hormone (ACTH) pituitary adenomas, the role of HIF-1α remains unclear.
AtT-20 cells were incubated under hypoxic conditions (1 % O2) for 12 h. HIF-1α mRNA and protein expression levels were measured by real-time PCR and western blotting, respectively. BrdU was used to determine the effects of hypoxia on cell viability. AtT-20 cells were transfected with siRNA targeting HIF-1α, followed by hypoxia (1 % O2) for 12 h. Apoptosis was determined by annexin V-FITC flow cytometry and Tdt-mediated dUTP nick end-labelling (TUNEL) assay. In addition, we examined interactions between HIF-1α, glucocorticoid receptor (GR), and dexamethasone under both normoxic and hypoxic conditions.
Hypoxia triggered the time-dependent proliferation of AtT-20 cells in association with increased HIF-1α mRNA and protein levels. However, the viability of AtT-20 cells decreased greatly when they were first transfected with HIF-1α-siRNA and then exposed to hypoxia. According to flow cytometry (annexin V-FITC and PI staining) and TUNEL analyses, a greater percentage of cells were apoptotic when transfected with HIF-1α siRNA and subsequently cultured under hypoxic conditions compared to those in the normoxia and mock groups. After AtT-20 cells were cultured in 1 % O2 and then treated with dexamethasone, HIF-1α levels significantly increased or decreased in normoxic or hypoxic conditions, respectively. Dexamethasone suppressed GR expression to a higher degree in hypoxic than normoxic conditions. Downregulation of GR by dexamethasone was greatly prevented in cells that were transfected with HIF-1α siRNA.
These findings strongly suggest that HIF-1α exerts an antiapoptotic role and participates in the downregulation of GR by dexamethasone in hypoxic AtT-20 cells.
PMCID: PMC4464719  PMID: 26002039
Hypoxia inducible factor–1α; Glucocorticoid receptor; Apoptosis; Dexamethasone; ACTH pituitary adenomas
8.  Let-7 Sensitizes KRAS Mutant Tumor Cells to Chemotherapy 
PLoS ONE  2015;10(5):e0126653.
KRAS is the most commonly mutated oncogene in human cancers and is associated with poor prognosis and drug resistance. Let-7 is a family of tumor suppressor microRNAs that are frequently suppressed in solid tumors, where KRAS mutations are highly prevalent. In this study, we investigated the potential use of let-7 as a chemosensitizer. We found that let-7b repletion selectively sensitized KRAS mutant tumor cells to the cytotoxicity of paclitaxel and gemcitabine. Transfection of let-7b mimic downregulated the expression of mutant but not wild-type KRAS. Combination of let-7b mimic with paclitaxel or gemcitabine diminished MEK/ERK and PI3K/AKT signaling concurrently, triggered the onset of apoptosis, and reverted the epithelial-mesenchymal transition in KRAS mutant tumor cells. In addition, let-7b repletion downregulated the expression of β-tubulin III and ribonucleotide reductase subunit M2, two proteins known to mediate tumor resistance to paclitaxel and gemcitabine, respectively. Let-7 may represent a new class of chemosensitizer for the treatment of KRAS mutant tumors.
PMCID: PMC4422443  PMID: 25946136
9.  Effect of 24 Weeks of Statin Therapy on Systemic and Vascular Inflammation in HIV-Infected Subjects Receiving Antiretroviral Therapy 
The Journal of Infectious Diseases  2014;209(8):1156-1164.
Background. Human immunodeficiency virus (HIV)–infected individuals are at increased risk of cardiovascular disease (CVD) due in part to inflammation. Statins decrease inflammation in the general population, but their effect during HIV infection is largely unknown.
Methods. This is an ongoing randomized, double-blinded, placebo-controlled trial to evaluate the effect of statin therapy on inflammatory markers during HIV infection. Subjects received rosuvastatin 10 mg daily or placebo for 24 weeks. Subjects were receiving stable (>12 weeks) antiretroviral therapy and had a low-density lipoprotein (LDL) cholesterol level of ≤130 mg/dL and evidence of heightened immune activation or inflammation. This was a prespecified interim analysis.
Results. A total of 147 subjects were enrolled (78% were male, 70% were black, and the median age was 47 years). By 24 weeks, LDL cholesterol levels had decreased in the statin group, compared with an increase in the placebo group (−28% vs +3.8%; P < .01). A 10% reduction in the lipoprotein-associated phospholipase A2 (Lp-PLA2) level was seen in the statin group, compared with a 2% reduction in the placebo group (P < .01). In multivariable regression, receipt of statin treatment and having a nadir CD4+ T-cell count of ≤100 cell/µL were the only statistically significant predictors of a decrease in Lp-PLA2 level. Markers of systemic inflammation did not change significantly between groups.
Conclusions. Twenty-four weeks of rosuvastatin therapy significantly decreased the level of Lp-PLA2, a vascular-specific, inflammatory enzyme that predicts cardiovascular events in the general population. Statins may hold promise as a means of attenuating CVD risk in HIV-infected individuals by decreasing Lp-PLA2 levels.
PMCID: PMC3969551  PMID: 24415784
HIV; statin; cardiovascular disease; inflammation; lipoprotein-associated phospholipase A2; coagulation
10.  Effects of Interactions of Auxin-Producing Bacteria and Bacterial-Feeding Nematodes on Regulation of Peanut Growths 
PLoS ONE  2015;10(4):e0124361.
The influences of an IAA (indole-3-acetic acid)-producing bacterium (Bacillus megaterium) and two bacterial-feeding nematodes (Cephalobus sp. or Mesorhabditis sp.) on the growth of peanut (Arachis hypogaea L. cv. Haihua 1) after various durations of time were investigated in natural soils. The addition of bacteria and nematodes and incubation time all significantly affected plant growth, plant root growth, plant nutrient concentrations, soil nutrient concentrations, soil microorganisms and soil auxin concentration. The addition of nematodes caused greater increases in these indices than those of bacteria, while the addition of the combination of bacteria and nematodes caused further increases. After 42-day growth, the increases in soil respiration differed between the additions of two kinds of nematodes because of differences in their life strategies. The effects of the bacteria and nematodes on the nutrient and hormone concentrations were responsible for the increases in plant growth. These results indicate the potential for promoting plant growth via the addition of nematodes and bacteria to soil.
PMCID: PMC4395078  PMID: 25867954
11.  Giant retroperitoneal bronchogenic cyst mimicking a cystic teratoma: A case report 
Oncology Letters  2015;9(6):2701-2705.
Retroperitoneal bronchogenic cysts (RBCs) are regarded as a rare type of congenital dysplasia disease that stems from the primitive foregut. Thus far, the exact pathogenesis of RBCs remains unknown. Due to an atypical clinical manifestation, RBCs are often incidentally detected and diagnosed by imaging modalities, such as computed tomography and magnetic resonance imaging. However, they are easily misdiagnosed due to their non-specific imaging features. Additionally, the most appropriate treatment strategy for an RBC is considered to be surgical resection. The present study reports the rare case of a 36-year-old female with a large RBC containing fatty fluid that was previously misdiagnosed as liposarcoma or cystic teratoma. Following a complex surgical resection, pathological findings confirmed a diagnosis of RBC. The follow-up examination showed that the patient was in good health at 16 months post-surgery, with no evidence of recurrence. Although rare, bronchogenic cysts must be considered in the differential diagnosis of retroperitoneal teratoma, and surgical resection should be pursued for symptom resolution and to establish a definitive histology.
PMCID: PMC4473486  PMID: 26137131
retroperitoneal bronchogenic cyst; diagnostic imaging; therapeutics
12.  The Challenges and the Promise of Molecular Targeted Therapy in Malignant Gliomas1 
Neoplasia (New York, N.Y.)  2015;17(3):239-255.
Malignant gliomas are the most common malignant primary brain tumors and one of the most challenging forms of cancers to treat. Despite advances in conventional treatment, the outcome for patients remains almost universally fatal. This poor prognosis is due to therapeutic resistance and tumor recurrence after surgical removal. However, over the past decade, molecular targeted therapy has held the promise of transforming the care of malignant glioma patients. Significant progress in understanding the molecular pathology of gliomagenesis and maintenance of the malignant phenotypes will open opportunities to rationally develop new molecular targeted therapy options. Recently, therapeutic strategies have focused on targeting pro-growth signaling mediated by receptor tyrosine kinase/RAS/phosphatidylinositol 3-kinase pathway, proangiogenic pathways, and several other vital intracellular signaling networks, such as proteasome and histone deacetylase. However, several factors such as cross-talk between the altered pathways, intratumoral molecular heterogeneity, and therapeutic resistance of glioma stem cells (GSCs) have limited the activity of single agents. Efforts are ongoing to study in depth the complex molecular biology of glioma, develop novel regimens targeting GSCs, and identify biomarkers to stratify patients with the individualized molecular targeted therapy. Here, we review the molecular alterations relevant to the pathology of malignant glioma, review current advances in clinical targeted trials, and discuss the challenges, controversies, and future directions of molecular targeted therapy.
PMCID: PMC4372648  PMID: 25810009
BBB, blood-brain barrier; CDK4, cyclin-dependent kinase 4; CDKN2A, cyclin-dependent kinase inhibitor 2A; c-KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; EGFR, epidermal growth factor receptor; FT, farnesyl transferase; FTI, FT inhibitor; GBMs, glioblastomas; GSCs, glioma stem cells; HDAC, histone deacetylase; IDH, isocitrate dehydrogenase; MAPK, mitogen-activated protein kinase; MGMT, O6-methylguanine DNA methyltransferase; miRNAs, microRNAs; mTOR, mammalian target of rapamycin; OS, overall survival; PDGFR, PDGF receptor; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma susceptibility protein 1; RTK, receptor tyrosine kinase; SHH, sonic hedgehog; TCGA, The Cancer Genome Atlas; TKIs, receptor tyrosine kinase inhibitors; TMZ, temozolomide; VEGF, vascular endothelial growth factor
13.  Prevention of Transmission of Multidrug-Resistant Organisms during Catheter Exchange using Antimicrobial Catheters 
Exchanging a central venous catheter (CVC) over a guide wire for a fresh uncoated CVC in the presence of bacteremia can result in cross-infection of the newly exchanged CVC. A recent retrospective clinical study showed that exchanging a catheter over a guide wire in the presence of bacteremia using an antimicrobial minocycline-rifampin (M/R) catheter may improve outcomes. To expand on this, we developed an in vitro cross-contamination model of exchange to evaluate the efficacy of different antimicrobial CVCs in preventing cross-contamination of multidrug-resistant organisms during exchange. Uncoated CVCs were allowed to form biofilm by methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans. After 24 h, the biofilm-colonized CVCs were placed in a glass tube containing bovine calf serum plus Mueller-Hinton broth, and each catheter was exchanged over a guide wire for a fresh uncoated or an M/R-, chlorhexidine-silver sulfadiazine (CHX/SS)-, or chlorhexidine-M/R (CHX-M/R)-coated CVC. Cross-contamination of exchanged catheters was enumerated by sonication and quantitative plating methods. The exchange of M/R CVCs completely prevented cross-contamination by MRSA biofilms compared to control exchanged CVCs (P < 0.0001). Exchange with CHX/SS CVCs reduced but did not completely prevent cross-contamination by MRSA (P = 0.005). Exchange with CHX-M/R CVCs completely prevented cross-contamination by MRSA, P. aeruginosa, and C. albicans biofilms (P < 0.0001). Furthermore, CHX-M/R CVCs were superior to M/R CVCs against P. aeruginosa and C. albicans (P = 0.003) and were superior to CHX/SS CVCs against MRSA and P. aeruginosa (P = 0.01). In conclusion, exchange with the novel CHX-M/R CVC was the only exchange effective in completely and concurrently preventing cross-contamination from bacteria and Candida.
PMCID: PMC4135861  PMID: 24957841
14.  Polymorphisms in TP53 are associated with risk and survival of osteosarcoma in a Chinese population 
Osteosarcoma (OS) is the most frequent histological form of primary bone cancer in adolescence. TP53 is a tumor suppressor gene which is essential for regulating cell division and preventing tumor formation. The purpose of this study is to examine whether genetic mutations in the TP53 gene are associated with OS risk and survival in a Chinese population. Five polymorphisms in the TP53 gene were selected in a case-control study, including 210 OS patients and 420 cancer-free controls. We found that subjects carrying rs12951053 CC genotype and rs1042522 GG genotype were significantly associated with risk of OS [odds ratio (OR) = 1.68, 95% confidence intervals (CI): 1.05-2.68; OR = 1.89, 95% CI: 1.16-3.07] compared with subjects carrying the common genotypes. Results of haplotype analysis also showed that A-G-G-A-C haplotype (rs12951053, rs1042522, rs8064946, rs9895829 and rs12602273) conferred significant decreased risk of OS (OR = 0.37, 95% CI: 0.19-0.72) compared with A-C-G-A-C haplotype. Besides, rs1042522 was an independent prognostic factor for OS with hazard radio (HR) = 1.94 (95% CI: 1.03-3.65) in GG genotype than in CC genotype. Our data suggest that genetic mutations in the TP53 gene are associated with risk and survival of OS in Chinese population.
PMCID: PMC4440149  PMID: 26045840
Osteosarcoma; TP53; polymorphism; haplotype; susceptibility; survival
15.  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
16.  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
17.  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
18.  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
19.  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  PMID: 25678854
MCAO; Gadd45b; BDNF; Apoptosis
20.  Filamin C, a dysregulated protein in cancer revealed by label-free quantitative proteomic analyses of human gastric cancer cells 
Oncotarget  2014;6(2):1171-1189.
Gastric cancer (GC) is the fourth and fifth most common cancer in men and women, respectively. We identified 2,750 proteins at false discovery rates of 1.3% (protein) and 0.03% (spectrum) by comparing the proteomic profiles of three GC and a normal gastric cell lines. Nine proteins were significantly dysregulated in all three GC cell lines, including filamin C, a muscle-specific filamin and a large actin-cross-linking protein. Downregulation of filamin C in GC cell lines and tissues were verified using quantitative PCR and immunohistochemistry. Data-mining using public microarray datasets shown that filamin C was significantly reduced in many human primary and metastasis cancers. Transient expression or silencing of filamin C affected the proliferation and colony formation of cancer cells. Silencing of endogenous filamin C enhanced cancer cell migration and invasion, whereas ectopic expression of filamin C had opposing effects. Silencing of filamin C increased the expression of matrix metallopeptidase 2 and improved the metastasis of prostate cancer in a zebrafish model. High filamin C associated with better prognosis of prostate cancer, leukemia and breast cancer patients. These findings establish a functional role of filamin C in human cancers and these data will be valuable for further study of its mechanisms.
PMCID: PMC4359225  PMID: 25577646
Gastric cancer; Proteomics; Filamin C; Metastasis; Tumor suppressor
21.  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
22.  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
23.  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
24.  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
25.  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

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